Archive for October, 2019

An unexpected early morning phone call from the hospital is never good news. When Joy Johnson answered, her first thought was that Sharon Birzer, her partner of 15 years, was dead. Her fears were amplified by the voice on the other end refusing to confirm or deny it. Just come in and talk to one of the doctors, she remembers the voice saying.

Johnson knew this was a real possibility. A few weeks earlier, she and Birzer sat in the exam room of a lymphoma specialist at Stanford University. Birzers cancer had grown, and fast first during one type of chemotherapy, then through a second. Out of standard options, Birzers local oncologist had referred her for a novel treatment called chimeric antigen receptor T-cell therapy or CAR-T. Birzer and Johnson knew the treatment was risky. They were warned there was a chance of death. There was also a chance of serious complications such as multi-organ failure and neurological impairment. But it was like warning a drowning person that her lifeboat could have problems. Without treatment, the chance of Birzers death was all but certain. She signed the consent form.

Johnson hung up the phone that early morning and sped to the hospital. She met with a doctor and two chaplains in a windowless room in the cancer ward, where happy photos of cancer alumni smiled down from the walls. This is getting worse and worse, Johnson thought. As she remembers it, the doctor went through the timeline of what happened for 10 minutes, explaining how Birzer became sicker and sicker, before Johnson interrupted with the thought splitting her world in two: I need you to tell me whether shes alive or dead.

Birzer wasnt dead. But she was far from okay. The ordeal began with Birzer speaking gibberish. Then came seizures so severe there was concern she wouldnt be able to breathe on her own. When it took a few different medications to stop Birzer from seizing, her doctors sedated her, put a breathing tube down her throat, and connected her to a ventilator. Now, she was unconscious and in the intensive care unit (ICU).

Birzer was one of the early patients to receive CAR-T, a radical new therapy to treat cancer. It involved removing Birzers own blood, filtering for immune cells called T-cells, and genetically engineering those cells to recognize and attack her lymphoma. CAR-T made history in 2017 as the first FDA-approved gene therapy to treat any disease. After three to six months of follow-up, the trials that led to approval showed response rates of 80 percent and above in aggressive leukemias and lymphomas that had resisted chemotherapy. Patients on the brink of death were coming back to life.

This is something I often dream of seeing but rarely do. As a doctor who treats cancer, I think a lot about how to frame new treatments to my patients. I never want to give false hope. But the uncertainty inherent to my field also cautions me against closing the door on optimism prematurely. We take it as a point of pride that no field of medicine evolves as rapidly as cancer the FDA approves dozens of new treatments a year. One of my biggest challenges is staying up to date on every development and teasing apart what should and shouldnt change my practice. I am often a mediator for my patients, tempering theoretical promises with everyday realism. To accept a research finding into medical practice, I prefer slow steps showing me proof of concept, safety, and efficacy.

CAR-T, nearly three decades in the making, systemically cleared these hurdles. Not only did the product work, its approach was also unique among cancer treatments. Unlike our usual advances, this wasnt a matter of prescribing an old drug for a new disease or remixing known medications. CAR-T isnt even a drug. This is a one-time infusion giving a person a better version of her own immune system. When the FDA approved its use, it wasnt a question of whether my hospital would be involved, but how we could stay ahead. We werent alone.

Today, two FDA-approved CAR-T products called Kymriah and Yescarta are available in more than 100 hospitals collectively across the U.S. Hundreds of clinical trials are tinkering with dosages, patient populations, and types of cancer. Some medical centers are manufacturing the cells on-site.

The FDA approved CAR-T with a drug safety program called a Risk Evaluation and Mitigation Strategy (REMS). As I cared for these patients, I quickly realized the FDAs concerns. Of the 10 or so patients Ive treated, more than half developed strange neurologic side effects ranging from headaches to difficulty speaking to seizures to falling unconscious. We scrambled to learn how to manage the side effects in real time.

Johnson and Birzer, who I didnt treat personally but spoke to at length for this essay, understood this better than most. Both had worked in quality control for a blood bank and were medically savvier than the average patient. They accepted a medical system with a learning curve. They were fine with hearing I dont know. Signing up for a trailblazing treatment meant going along for the ride. Twists and bumps were par for the course.

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Cancer, by definition, means something has gone very wrong within a cell has malfunctioned and multiplied. The philosophy for fighting cancer has been, for the most part, creating and bringing in treatments from outside the body. Thats how we got to the most common modern approaches: Chemotherapy (administering drugs to kill cancer), radiation (using high energy beams to kill cancer), and surgery (cutting cancer out with a scalpel and other tools). Next came the genetics revolution, with a focus on creating drugs that target a precise genetic mutation separating a cancer cell from a normal one. But cancers are genetically complex, with legions of mutations and the talent to develop new ones. Its rare to have that one magic bullet.

Over the last decade or so, our approach shifted. Instead of fighting cancer from the outside, we are increasingly turning in. The human body is already marvelously equipped to recognize and attack invaders, from the common cold to food poisoning, even if the invaders are ones the body has never seen before. Cancer doesnt belong either. But since cancer cells come from normal ones, theyve developed clever camouflages to trick and evade the immune system. The 2018 Nobel Prize in Physiology or Medicine was jointly awarded to two researchers for their work in immunotherapy, a class of medications devoted to wiping out the camouflages and restoring the immune systems upper hand. As I once watched a fellow oncologist describe it to a patient: Im not treating you. You are treating you.

What if we could go one step further? What if we could genetically engineer a patients own immune cells to spot and fight cancer, as a sort of best hits of genetic therapy and immunotherapy?

Enter CAR-T. The technology uses T-cells, which are like the bouncers of the immune system. T-cells survey the body and make sure everything belongs. CAR-T involves removing a persons T-cells from her blood and using a disarmed virus to deliver new genetic material to the cells. The new genes given to the T-cells help them make two types of proteins. The first giving the technology its name is a CAR, which sits on the T-cells surface and binds to a protein on the tumor cells surface, like a lock and key. The second serves as the T-cells caffeine jolt, rousing it to activate. Once the genetic engineering part is done, the T-cells are prodded to multiply by being placed on a rocking device that feeds them nutrients while filtering their wastes. When the cells reach a high enough number a typical dose ranges from hundreds of thousands to hundreds of millions they are formidable enough to go back into the patient. Once inside, the cancer provokes the new cells to replicate even more. After one week, a typical expansion means multiplying by about another 1,000-fold.

Practically, it looks like this: A person comes in for an appointment. She has a catheter placed in a vein, perhaps in her arm or her chest, that connects to a large, whirring machine which pulls in her blood and separates it into its components. The medical team set the T-cells aside to freeze while the rest of the blood circulates back into the patient in a closed loop. Then, the hospital ships the cells frozen to the relevant pharmaceutical companys headquarters or transports them to a lab on-site, where thawing and manufacturing takes from a few days to a few weeks. When the cells are ready, the patient undergoes about three days of chemotherapy to kill both cancer and normal cells, making room for the millions of new cells and eradicating normal immune players that could jeopardize their existence. She then gets a day or two to rest. When the new cells are infused back into her blood, we call that Day 0.

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I remember the first time I watched a patient get his Day 0 infusion. It felt anti-climactic. The entire process took about 15 minutes. The CAR-T cells are invisible to the naked eye, housed in a small plastic bag containing clear liquid.

Thats it? my patient asked when the nurse said it was over. The infusion part is easy. The hard part is everything that comes next.

Once the cells are in, they cant turn off. That this may cause collateral damage was evident from the start. In 2009 working in parallel with other researchers at Memorial Sloan Kettering Cancer Center in New York and the National Cancer Institute in Maryland oncologists at the University of Pennsylvania opened a clinical trial for CAR-T in human leukemia patients. (Carl June, who led the CAR-T development, did not respond to Undarks interview request.) Of the first three patients who got CAR-T infusions, two achieved complete remission but nearly died in the process. The first was a retired corrections officer named Bill Ludwig, who developed extremely high fevers and went into multi-organ failure requiring time in the ICU. At the time, the medical teams had no idea why it was happening or how to stop it. But time passed. Ludwig got better. Then came the truly incredible part: His cancer was gone.

With only philanthropic support, the trial ran out of funding. Of the eligible patients they intended to treat, the Penn doctors only treated three. So they published the results of one patient in the New England Journal of Medicine and presented the outcomes of all three patients, including Ludwig, at a cancer conference anyway. From there, the money poured in. Based on the results, the Swiss pharmaceutical company Novartis licensed the rights of the therapy.

The next year, six-year-old Emily Whitehead was on the brink of death when she became the first child to receive CAR-T. She also became extremely ill in the ICU, and her cancer was also eventually cured. Her media savvy parents helped bring her story public, making her the poster child for CAR-T. In 2014, the FDA granted CAR-T a breakthrough therapy designation to expedite the development of extremely promising therapies. By 2017, a larger trial gave the treatment to 75 children and young adults with a type of leukemia B-cell acute lymphoblastic leukemia that failed to respond to chemotherapy. Eighty-one percent had no sign of cancer after three months.

In August 2017, the FDA approved a CAR-T treatment as the first gene therapy in the U.S. The decision was unanimous. The Oncologic Drugs Advisory Committee, a branch of the FDA that reviews new cancer products, voted 10 to zero in favor of Kymriah. Committee members called the responses remarkable and potentially paradigm changing. When the announcement broke, a crowd formed in the medical education center of Penn Medicine, made up of ecstatic faculty and staff. There were banners and T-shirts. A remarkable thing happened was the tagline, above a cartoon image of a heroic T-cell. Two months later, in October 2017, the FDA approved a second CAR-T formulation called Yescarta from Kite Pharma, a subsidiary of Gilead Sciences, to treat an aggressive blood cancer in adults called diffuse large B-cell lymphoma, the trial of which had shown a 54 percent complete response rate, meaning all signs of cancer had disappeared. In May 2018, Kymriah was approved to treat adults with non-Hodgkin lymphoma.

That year, the American Society of Clinical Oncology named CAR-T the Advance of the Year, beating out immunotherapy, which had won two years in a row. When I attended the last American Society of Hematology meeting in December 2018, CAR-T stole the show. Trying to get into CAR-T talks felt like trying to get a photo with a celebrity. Running five minutes late to one session meant facing closed doors. Others were standing room only. With every slide, it became difficult to see over a sea of smartphones snapping photos. At one session I found a seat next to the oncologist from my hospital who treated Birzer. Look, she nudged me. Do you see all these non-member badges? I turned. Members were doctors like us who treated blood cancers. I couldnt imagine who else would want to be here. Who are they? I asked. Investors, she said. It felt obvious the moment she said it.

For patients, the dreaded c word is cancer. For oncologists, its cure. When patients ask, Ive noticed how we gently steer the conversation toward safer lingo. We talk about keeping the cancer in check. Cure is a dangerous word, used only when so much time has passed from her cancer diagnosis we can be reasonably certain its gone. But that line is arbitrary. We celebrate therapies that add weeks or months because the diseases are pugnacious, the biology diverse, and the threat of relapse looming. Oncologists are a tempered group, or so Ive learned, finding inspiration in slow, incremental change.

This was completely different. These were patients who would have otherwise died, and the trials were boasting that 54 to 81 percent were cancer-free upon initial follow-up. PET scans showed tumors that had speckled an entire body melt away. Bone marrow biopsies were clear, with even the most sensitive testing unable to detect disease.

The dreaded word was being tossed around could this be the cure weve always wanted?

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When a new drug gets FDA approval, it makes its way into clinical practice, swiftly and often with little fanfare. Under the drug safety program REMS, hospitals offering CAR-T were obligated to undergo special training to monitor and manage side effects. As hospitals worked to create CAR-T programs, oncologists like me made the all too familiar transition from first-time user to expert.

It was May 2018 when I rotated through my hospitals unit and cared for my first patients on CAR-T. As I covered 24-hour shifts, I quickly learned that whether I would sleep that night depended on how many CAR-T patients I was covering. With each treatment, it felt like we were pouring gasoline on the fire of patients immune systems. Some developed high fevers and their blood pressures plummeted, mimicking a serious infection. But there was no infection to be found. When resuscitating with fluids couldnt maintain my patients blood pressures, I sent them to the ICU where they required intensive support to supply blood to their critical organs.

We now have a name for this effect cytokine release syndrome that occurs in more than half of patients who receive CAR-T, starting with Ludwig and Whitehead. The syndrome is the collateral damage of an immune system on the highest possible alert. This was first seen with other types of immunotherapy, but CAR-T took its severity to a new level. Usually starting the week after CAR-T, cytokine release syndrome can range from simple fevers to multi-organ failure affecting the liver, kidneys, heart, and more. The activated T-cells make and recruit other immune players called cytokines to join in the fight. Cytokines then recruit more immune cells. Unlike in the early trials at Penn, we now have two medicines to dampen the effect. Steroids calm the immune system in general, while a medication called tocilizumab, used to treat autoimmune disorders such as rheumatoid arthritis, blocks cytokines specifically.

Fortuity was behind the idea of tocilizumab: When Emily Whitehead, the first child to receive CAR-T, developed cytokine release syndrome, her medical team noted that her blood contained high levels of a cytokine called interleukin 6. Carl June thought of his own daughter, who had juvenile rheumatoid arthritis and was on a new FDA-approved medication that suppressed the same cytokine. The team tried the drug, tocilizumab, in Whitehead. It worked.

Still, we were cautious in our early treatments. The symptoms of cytokine release syndrome mimic the symptoms of severe infection. If this were infection, medicines that dampen a patients immune system would be the opposite of what youd want to give. There was another concern: Would these medications dampen the anti-cancer activity too? We didnt know. Whenever a CAR-T patient spiked a fever, I struggled with the question is it cytokine release syndrome, or is it infection? I often played it safe and covered all bases, starting antibiotics and steroids at the same time. It was counterintuitive, like pressing both heat and ice on a strain, or treating a patient simultaneously with fluids and diuretics.

The second side effect was even scarier: Patients stopped talking. Some, like Sharon Birzer, spoke gibberish or had violent seizures. Some couldnt interact at all, unable to follow simple commands like squeeze my fingers. How? Why? At hospitals across the nation, perfectly cognitively intact people who had signed up to treat their cancer were unable to ask what was happening.

Our nurses learned to ask a standardized list of questions to catch the effect, which we called neurotoxicity: Where are we? Who is the president? What is 100 minus 10? When the patients scored too low on these quizzes, they called me to the bedside.

In turn, I relied heavily on a laminated booklet, made by other doctors who were using CAR-T, which we tacked to a bulletin board in our doctors workroom. It contained a short chart noting how to score severity and what to do next. I flipped through the brightly color-coded pages telling me when to order a head CT-scan to look for brain swelling and when to place scalp electrodes looking for seizures. Meanwhile, we formed new channels of communication. As I routinely called a handful of CAR-T specialists at my hospital in the middle of the night, national consortiums formed where specialists around the country shared their experiences. As we tweaked the instructions, we scribbled updates to the booklet in pen.

I wanted to know whether my experience was representative. I came across an abstract and conference talk that explored what happened to 277 patients who received CAR-T in the real world, so I emailed the lead author, Loretta Nastoupil, director of the Department of Lymphoma and Myeloma at the University of Texas MD Anderson Cancer Center in Houston. Fortuitously, she was planning a trip to my university to give a talk that month. We met at a caf and I asked what her research found. Compared to the earlier trials, the patients were much sicker, she said. Of the 277 patients, more than 40 percent wouldnt have been eligible for the very trials that got CAR-T approved. Was her team calling other centers for advice? They were calling us, she said.

Patients included in clinical trials are carefully selected. They tend not to have other major medical problems, as we want them to survive whatever rigorous new therapy we put them through. Nastoupil admits some of it is arbitrary. Many criteria in the CAR-T trials were based on criteria that had been used in chemotherapy trials. These become standard languages that apply to all studies, she said, listing benchmarks like a patients age, kidney function, and platelet count. But we have no idea whether criteria for chemotherapy would apply to cellular therapy.

Now, with a blanket FDA approval comes clinical judgment. Patients want a chance. Oncologists want to give their patients a chance. Young, old, prior cancer, heart disease, or liver disease without strict trial criteria, anyone is fair game.

When I was making rounds at my hospital, I never wandered too far from these patients rooms, medically prepared for them to crash at any moment. At the same time, early side effects made me optimistic. A bizarre truism in cancer is that side effects may bode well. They could mean the treatment is working. Cancer is usually a waiting game, requiring months to learn an answer. Patients and doctors alike seek clues, but the only real way to know is waiting: Will the next PET scan show anything? What are the biopsy results?

CAR-T was fundamentally different from other cancer treatments in that it worked fast. Birzers first clue came just a few hours after her infusion. She developed pain in her lower back. She described it as feeling like she had menstrual cramps. A heavy burden of lymphoma lay in her uterus. Could the pain mean that the CAR-T cells had migrated to the right spot and started to work? Her medical team didnt know, but the lead doctors instinct was that it was a good sign.

Two days later, her temperature shot up to 102. Her blood pressure dropped. The medical team diagnosed cytokine release syndrome, as though right on schedule, and gave her tocilizumab.

Every day, the nurses would ask her questions and have her write simple sentences on a slip of paper to monitor for neurotoxicity. By the fifth day, her answers changed. She started saying things that were crazy, Johnson explained.

One of Birzer's sentences was guinea pigs eat greens like hay and pizza. Birzer and Johnson owned two guinea pigs, so their diet would be something Birzer normally knew well. So Johnson tried to reason with her: They dont eat pizza. And Birzer replied, They do eat pizza, but only gluten-free.

Johnson remembers being struck by the certainty in her partners delirium. Not only was Birzer confused, she was confident she was not. She was doubling down on everything, Johnson described. She was absolutely sure she was right.

Johnson vividly remembers the evening before the frightening early-morning phone call that brought her rushing back to the hospital. Birzer had said there was no point in Johnson staying overnight; she would only watch her be in pain. So Johnson went home. After she did, the doctor came by multiple times to evaluate Birzer. She was deteriorating and fast. Her speech became more and more garbled. Soon she couldnt name simple objects and didnt know where she was. At 3 a.m., the doctor ordered a head CT to make sure Birzer wasnt bleeding into her brain.

Fortunately, she wasnt. But by 7 a.m. Birzer stopped speaking altogether. Then she seized. Birzers nurse was about to step out of the room when she noticed Birzers arms and legs shaking. Her eyes stared vacantly and she wet the bed. The nurse called a code blue, and a team of more doctors and nurses ran over. Birzer was loaded with high-dose anti-seizure medications through her IV. But she continued to seize. As nurses infused more medications into her IV, a doctor placed a breathing tube down her throat.

Birzers saga poses the big question: Why does CAR-T cause seizures and other neurologic problems? No one seemed to know. My search of the published scientific literature was thin, but one name kept cropping up. So I called her. Juliane Gust, a pediatric neurologist and scientist at Seattle Childrens Hospital, told me her investigations of how CAR-T affects the brain were motivated by her own experiences. When the early CAR-T trials opened at her hospital in 2014, she and her colleagues began getting calls from oncologists about brain toxicities they knew nothing about. Where are the papers? she remembered thinking. There was nothing.

Typically, the brain is protected by a collection of cells aptly named the blood-brain-barrier. But with severe CAR-T neurotoxicity, research suggests, this defense breaks down. Gust explained that spinal taps on these patients show high levels of cytokines floating in the fluid surrounding the spine and brain. Some CAR-T cells circulate in the fluid too, she said, but these numbers do not correlate with sicker patients. CAR-T cells are even seen in the spinal fluid of patients without any symptoms.

What does this mean? Gust interprets it as a patients symptoms having more to do with cytokines than the CAR-T cells. Cytokine release syndrome is the number one risk factor for developing neurotoxicity over the next few days, she said. The mainstay for neurotoxicity is starting steroids as soon as possible. In the beginning we didnt manage as aggressively. We were worried about impairing the function of the CAR-T, she added. Now we give steroids right away.

But the steroids dont always work. Several doses of steroids didnt prevent Birzer from seizing. The morning after Johnsons alarming phone call, after the meeting at the hospital when she learned what had happened, a chaplain walked her from the conference room to the ICU. The first day, Johnson sat by her partners bedside while Birzer remained unconscious. By the next evening, she woke up enough to breathe on her own. The doctors removed her breathing tube, and Birzer looked around. She had no idea who she was or where she was.

Birzer was like a newborn baby, confused and sometimes frightened by her surroundings. She frequently looked like she was about to say something, but she couldnt find the words despite the nurses and Johnsons encouragement. One day she spoke a few words. Eventually she learned her name. A few days later she recognized Johnson. Her life was coming back to her, though she was still suspicious of her reality. She accused the nurses of tricking her, for instance, when they told her Donald Trump was president.

She took cues from the adults around her on whether her actions were appropriate. The best example of this was her I love you phase. One day, she said it to Johnson in the hospital. A few nurses overheard it and commented on how sweet it was. Birzer was pleased with the reaction. So she turned to the nurse: I love you! And the person emptying the trash: I love you! Months later, she was having lunch with a friend who asked, Do you remember when you told me you loved me? Birzer said, Well, I stand by that one.

When she got home, she needed a walker to help with her shakiness on her feet. When recounting her everyday interactions, she would swap in the wrong people, substituting a friend for someone else. She saw bugs that didnt exist. She couldnt hold a spoon or a cup steady. Johnson would try to slow her down, but Birzer was adamant she could eat and drink without help. Then peas would fly in my face, Johnson said.

Patients who experience neurotoxicity fall into one of three categories. The majority are impaired but then return to normal without long-term damage. A devastating handful, less than 1 percent, develop severe brain swelling and die. The rest fall into a minority that have lingering problems even months out. These are usually struggles to think up the right word, trouble concentrating, and weakness, often requiring long courses of rehabilitation and extra help at home.

As Birzer told me about her months of rehab, I thought how she did seem to fall somewhere in the middle among the patients Ive treated. On one end of the spectrum was the rancher who remained profoundly weak a year after his infusion. Before CAR-T, he walked across his ranch without issue; six months later, he needed a walker. Even with it, he fell on a near weekly basis. On the other end was the retired teacher who couldnt speak for a week she would look around her ICU room and move her mouth as though trying her hardest and then woke up as though nothing happened. She left the hospital and instantly resumed her life, which included a recent trip across the country. In hindsight, I remember how we worried more about giving the therapy to the teacher than the rancher, as she seemed frailer. Outcomes like theirs leave me with a familiar humility I keep learning in new ways as a doctor: We often cant predict how a patient will do. Our instincts can be just plain wrong.

I asked Gust if we have data to predict who will land in which group. While we can point to some risk factors higher burdens of cancer, baseline cognitive problems before therapy the individual patient tells you nothing, she confirmed.

So we wait.

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Doctors like me who specialize in cancer regularly field heart-wrenching questions from patients. They have read about CAR-T in the news, and now they want to know: What about me? What about my cancer?

So, who gets CAR-T? That leads to the tougher question who doesnt? That depends on the type of cancer and whether their insurance can pay.

CAR-T is approved to treat certain leukemias and lymphomas that come from the blood and bone marrow. Since the initial approval, researchers have also set up new CAR-T trials for all sorts of solid tumors from lung cancer to kidney cancer to sarcoma. But progress has been slow. While some promising findings are coming from the lab and in small numbers of patients on early phase trials, nothing is yet approved in humans. The remarkable responses occurring in blood cancers just werent happening in solid tumors.

Cancer is one word, but its not one disease. Its easier to prove why something works when it works than show why it doesnt work when it doesnt work, said Saar Gill, a hematologist and scientist at the University of Pennsylvania who co-founded a company called Carisma Therapeutics using CAR-T technology against solid tumors. That was his short answer, at least. The longer answer to why CAR-T hasnt worked in solid cancers involves what Gill believes are two main barriers. First, its a trafficking problem. Leukemia cells tend to be easier targets; they bob through the bloodstream like buoys in an ocean. Solid tumors are more like trash islands. The cancer cells stick together and grow an assortment of supporting structures to hold the mound together. The first problem for CAR-T is that the T-cells may not be able to penetrate the islands. Then, even if the T-cells make it in, theyre faced with a hostile environment and will likely die before they can work.

At Carisma, Gill and his colleagues look to get around these obstacles though a different immune cell called the macrophage. T-cells are not the only players of the immune system, after all. Macrophages are gluttonous cells that recognize invaders and engulf them for destruction. But studies have shown they cluster in solid tumors in a way T-cells dont. Gill hopes genetically engineered macrophages can be the stowaways that sneak into solid tumor and attack from the inside out.

Another big challenge, even for leukemias and lymphomas, is resistance, where the cancers learn to survive the CAR-T infusion. While many patients in the trials achieved remission after a month, we now have two years worth of data and the outlook isnt as rosy. For lymphoma, that number is closer to 40 percent. Patients celebrating cures initially are relapsing later. Why?

The CAR-T cells we use target a specific protein on cancer cells. But if the cancer no longer expresses that protein, that can be a big problem, and were finding thats exactly whats happening. Through blood testing, we see that many patients who relapse lose the target.

Researchers are trying to regain the upper hand by designing CAR-Ts to target more than one receptor. Its an old idea in a new frame: An arms race between our medicines and the illnesses that can evolve to evade them. Too much medical precision in these cases is actually not what we want, as it makes it easier for cancer to pinpoint whats after it and develop an escape route. So, the reasoning goes, target multiple pieces at once. Confuse the cancer.

Then theres the other dreaded c word: Cost. Novartis Kymriah runs up to $475,000 while Kite Pharmas Yescarta is $373,000. That covers manufacturing and infusion. Not included is the minimum one-week hospital stay or any complications.

They are daunting numbers. Some limitations on health care we accept maybe the patients are too sick; maybe they have the wrong disease. The wrong cost is not one we as a society look kindly upon. And drug companies shy away from that kind of attention.

Cost origins in medicine are notoriously murky. Novartis, confident in its technology, made an offer to offset the scrutiny in CAR-T. If the treatment didnt work after one month, the company said it wouldnt send a bill.

Not everyone agrees that cost is an issue. Gill, for example, believes the concern is over-hyped. Its not a major issue, he told me over the phone. Look, of course [with] health care in this country, if you dont have insurance, then youre screwed. That is no different when it comes to CAR-T as it is for anything else, he said. The cost conversation must also put CAR-T in context. Gill went on to list what these patients would be doing otherwise months of chemotherapy, bone marrow transplants, hospital stays for cancer-associated complications and the associated loss of income as patients and caregivers miss work. These could add up to far more than a one-time CAR-T infusion. A bone marrow transplant, for example, can cost from $100,000 to more than $300,000. The cancer-fighting drug blinatumomab, also used to treat relapsed leukemia, costs $178,000 a year. Any discussion of cost is completely irresponsible without weighing the other side of the equation, Gill said.

How the system will get on board is another question. Logistics will be an issue, Gill conceded. The first national Medicare policy for covering CAR-T was announced in August 2019, two years after the first product was approved. The Centers for Medicare and Medicaid Services has offered to reimburse a set rate for CAR T-cell infusion, and while this figure was recently raised, it remains less than the total cost. Despite the expansion of medical uses, at some centers referrals for CAR-T are dropping as hospitals worry its a net loss. And while most commercial insurers are covering CAR-T therapies, companies less accustomed to handling complex therapies can postpone approval. Ironically, the patients considering CAR-T are the ones for whom the window for treatment is narrowest. A delay of even a few weeks can mean the difference between a cure and hospice.

This, of course, poses a big problem. A breakthrough technology is only as good as its access. A major selling point of CAR-T besides the efficacy is its ease. Its a one-and-done treatment. Engineered T-cells are intended to live indefinitely, constantly on the alert if cancer tries to come back. Compare that to chemotherapy or immunotherapy, which is months of infusions or a pill taken indefinitely. CAR-T is more akin to surgery: Cut it out, pay the entire cost upfront, and youre done.

Birzer was lucky in this respect. I asked her and Johnson if cost had factored into their decision to try CAR-T. They looked at each other. It wasnt an issue, said Johnson. They remembered getting a statement in the mail for a large sum when they got home. But Birzer had good insurance. She didnt pay a cent.

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One year after Birzers infusion, I met her and Johnson at a coffee shop near their home in San Francisco. They had saved a table. Johnson had a newspaper open. Birzer already had her coffee, and I noticed her hand trembling as she brought it to her mouth. She described how she still struggles to find exactly the right words. She sometimes flings peas. But shes mostly back to normal, living her everyday life. She has even returned to her passion, performing stand-up comedy, though she admitted that at least for general audiences: My jokes about cancer didnt kill.

People handed a devastating diagnosis dont spend most of their time dying. They are living, but with a heightened awareness for a timeline the rest of us take for granted. They sip coffee, enjoy their hobbies, and read the news while also getting their affairs in order and staying on the lookout, constantly, for the next treatment that could save them.

Hoping for a miracle while preparing to die are mutually compatible ideas. Many of my patients have become accustomed to living somewhere in that limbo. It is humbling to witness. They hold out hope for a plan A, however unlikely it may be, while also adjusting to the reality of a plan B. They live their lives; and they live in uncertainty.

I see patients in various stages of this limbo. In clinic, I met a man with multiple myeloma six months after a CAR-T trial that supposedly cured him. He came in with a big smile but then quietly began praying when it was time to view PET results. He asked how the other patients on the trial were doing, and I shared the stats. While percentages dont say anything about an individual experience, theyre also all patients have to go on. When someone on the same treatment dies, its shattering for everyone. Was one person the exception, or a harbinger of anothers fate? Who is the outlier?

I look at these patients and think a sober truth: Before CAR-T, all would likely die within six months. Now, imagine taking 40 percent and curing them. Sure, a naysayer might point out, its only 40 percent. Whats the hype if most still succumb to their cancer? But there was nothing close to that before CAR-T. I agree with how Gill described it: I think CAR-T cells are like chemotherapy in the 1950s. Theyre not better than chemotherapy theyre just different. For an adversary as tough as cancer, well take any tool we can get.

There remain many questions. Can we use CAR-T earlier in a cancers course? Lessen the side effects? Overcome resistance? Streamline manufacturing and reimbursement? Will it work in other cancers? Patients will sign up to answer.

For now, Birzer seems to be in the lucky 40 percent. Her one-year PET scan showed no cancer. I thought of our last coffee meeting, where I had asked if she ever worried she wouldnt return to normal. She didnt even pause. If youre not dead, she said, youre winning.

* * *

Ilana Yurkiewicz, M.D., is a physician at Stanford University and a medical journalist. She is a former Scientific American Blog Network columnist and AAAS Mass Media Fellow. Her writing has also appeared in Aeon Magazine, Health Affairs, and STAT News, and has been featured in "The Best American Science and Nature Writing."

This article was originally published on Undark. Read the original article.

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The Possibilities and Risks of Genetically Altering Immune Cells to Fight Cancer - Smithsonian.com

MENLO PARK, Calif., Oct. 24, 2019 (GLOBE NEWSWIRE) -- Adverum Biotechnologies, Inc.,(Nasdaq: ADVM), a clinical-stage gene therapy company targeting unmet medical needs in ocular and rare diseases, today announced that the first patient was dosed in the third cohort (n=9) of the ongoing OPTIC phase 1 clinical trial for ADVM-022 for the treatment of neovascular or wet age-related macular degeneration (wet AMD). Patients in this cohort are receiving a single intravitreal injection of gene therapy candidate ADVM-022 at a dose of 2 x 10 ^11 vg/eye.

We are excited to report dosing the first patient in the third cohort of OPTIC. This expansion of OPTIC will generate important clinical data to support the further development of ADVM-022, said Aaron Osborne, MBBS, chief medical officer of Adverum. Based on the recently presented data from the first cohort of OPTIC, which demonstrated a sustained response to a single injection of ADVM-022 out to a median of 34 weeks, with no patient in the first cohort requiring anti-VEGF rescue therapy, we believe that ADVM-022 has the potential to be a transformative treatment option for patients with wet AMD.

Dante Pieramici, M.D., co-director of the California Retina Research Foundation, Managing Partner of The California Retina Consultants and investigator in the OPTIC trial, said, An intravitreal gene therapy that can significantly reduce the number of injections required to maintain vision would be welcomed by patients with wet AMD as well as their caregivers and physicians. Im encouraged by the recently presented clinical data from the first cohort of the OPTIC trial showing that the therapy was safe and well tolerated with no rescue injections required in patients who previously required frequent anti-VEGF injections to control their wet AMD.

About the OPTIC Phase 1 Trial of ADVM-022 in Wet AMDThe multi-center, open-label, phase 1 trial is designed to assess the safety and tolerability of a single intravitreal (IVT) administration of ADVM-022 in patients with wet AMD who are responsive to anti-vascular endothelial growth factor (VEGF) treatment. In the first cohort, patients (n=6) received ADVM-022 at a dose of 6 x 10^11 vg/eye and in the second cohort (n=6) patients received ADVM-022 at a dose of 2 x 10^11 vg/eye. In the third cohort (n=9), patients are receiving ADVM-022 at a dose of 2 x 10^11 vg/eye and in the fourth cohort (n=9), patients will receive ADVM-022 at a dose of 6 x 10^11 vg/eye. Patients in the first and second cohorts received prophylactic oral steroids, while patients in the third and fourth cohorts will receive prophylactic steroid eye drops. The primary endpoint of the trial is the safety and tolerability of ADVM-022 after a single IVT administration. Secondary endpoints include change in best-corrected visual acuity (BCVA), change in central subfield thickness (CST) and macular volume, as well as mean number of anti-VEGF rescue injections and percentage of patients needing anti-VEGF rescue injections. Each patient enrolled in the study will be followed for a total of two years.

Eight leading retinal centers acrossthe United Statesare participating in the OPTIC phase 1 trial for ADVM-022. For more information on the OPTIC phase 1 clinical trial of ADVM-022 in wet AMD, please visithttps://clinicaltrials.gov/ct2/show/NCT03748784.

About ADVM-022 Gene TherapyADVM-022 utilizes a propriety vector capsid, AAV.7m8, carrying an aflibercept coding sequence under the control of a proprietary expression cassette. ADVM-022 is administered as a one-time intravitreal injection, designed to deliver long-term efficacy, reduce the burden of frequent anti-VEGF injections, optimize patient compliance, and to improve vision outcomes for wet AMD and diabetic retinopathy patients.

In recognition of the need for new treatment options for wet AMD, the U.S. Food and Drug Administration granted Fast Track designation for ADVM-022 for the treatment of this disease.

Adverum is currently evaluating ADVM-022 in the OPTIC study, a phase 1 clinical trial in patients 50 years and older with wet AMD. Additionally, Adverum plans to submit an Investigational New Drug Application for ADVM-022 for the treatment of diabetic retinopathy to the U.S. Food and Drug Administration in the first half of 2020.

About Adverum Biotechnologies, Inc.Adverum Biotechnologies (Nasdaq: ADVM) is a clinical-stage gene therapy company targeting unmet medical needs for serious ocular and rare diseases. Adverum is evaluating its novel gene therapy candidate, ADVM-022, as a one-time, intravitreal injection for the treatment of its lead indication, wet age-related macular degeneration. For more information, please visit http://www.adverum.com

Forward-looking StatementsStatements contained in this press release regarding events or results that may occur in the future are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements include, but are not limited to statements regarding: Adverums plans for advancing ADVM-022; the potential benefits of ADVM-022: the expected timing of submitting an IND for diabetic retinopathy, all of which are based on certain assumptions made by Adverum on current conditions, expected future developments and other factors Adverum believes are appropriate in the circumstances. Adverum may not achieve any of these in a timely manner, or at all, or otherwise carry out the intentions or meet the expectations disclosed in its forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include risks inherent to, without limitation: Adverums novel technology, which makes it difficult to predict the time and cost of product candidate development and obtaining regulatory approval; the results of early clinical trials not always being predictive of future results; the potential for future complications or side effects in connection with use of ADVM-022; obtaining regulatory approval for gene therapy product candidates; enrolling patients in clinical trials; reliance on third parties for conducting the OPTIC trial and vector production; and ability to fund operations through completion of the OPTIC trial and thereafter. Risks and uncertainties facing Adverum are described more fully in Adverums Form 10-Q filed with the SEC on August 8, 2019 under the heading Risk Factors. All forward-looking statements contained in this press release speak only as of the date on which they were made. Adverum undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

Investor and Media Inquiries:

Investors:Myesha LacyAdverum BiotechnologiesVice President, Investor Relations and Corporate Communicationsmlacy@adverum.com1-650-304-3892

Media:Cherilyn Cecchini, M.D.Account Supervisorccecchini@lifescipublicrelations.com1-646-876-5196

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Adverum Biotechnologies Doses First Patient in Third Cohort of OPTIC Phase 1 Clinical Trial of ADVM-022 Intravitreal Gene Therapy for Wet AMDPatients...

NIH launches new collaboration to develop gene-based cures for sickle cell disease and HIV on global scale

The National Institutes of Health plans to invest at least $100 million over the next four years toward an audacious goal: develop affordable, gene-based cures for sickle cell disease (SCD) and HIV. The Bill & Melinda Gates Foundation will also invest $100 million toward this goal. The intention is for these cures to be made globally available, including in low-resource settings.

This initiative follows a bold announcement made earlier this year by President Donald J. Trump during the State of the Union Address to end the HIV epidemic in the United States in the next 10 years.Ending the HIV Epidemic: A Plan for Americaaims to leverage the powerful data and tools now available to reduce new HIV diagnoses in the United States by 75% in five years and by 90% by 2030.The Trump Administration has also elevated the attention paid to sickle cell disease, identifying it as an intractable health challenge with the potential for dramatic advances in the coming years.

Dramatic advances in genetics over the last decade have made effective gene-based treatments a reality, including new treatments for blindness and certain types of leukemia. Yet these breakthroughs are largely inaccessible to most of the world by virtue of the complexity and cost of treatment requirements, which currently limit their administration to hospitals in wealthy countries. To make these treatments effective and available for SCD and HIV, which disproportionately affect populations living in Africa or of African descent, new investment is needed to focus research on the development of curative therapies that can be delivered safely, effectively and affordably in low-resource settings.

The collaboration between the NIH and the Gates Foundation sets out a bold goal of advancing safe, effective and durable gene-based cures to clinical trials in the United States and relevant countries in sub-Saharan Africa within the next seven to 10 years. The ultimate goal is to scale and implement these treatments globally in areas hardest hit by these diseases.

This unprecedented collaboration focuses from the get-go on access, scalability and affordability of advanced gene-based strategies for sickle cell disease and HIV to make sure everybody, everywhere has the opportunity to be cured, not just those in high-income countries, said NIH Director Francis S. Collins, M.D., Ph.D.We aim to go big or go home.

The collaboration will align aggressive, high-reward research efforts to accelerate progress on shared gene-based strategies to cure SCD and HIV. Both organizations also will continue to invest in other parallel research efforts on cures for SCD and HIV outside of this collaboration.

In recent years, gene-based treatments have been groundbreaking for rare genetic disorders and infectious diseases, said Trevor Mundel, M.D., Ph.D., President, Global Health Program, Bill & Melinda Gates Foundation. While these treatments are exciting, people in low- and middle-income countries do not have access to these breakthroughs. By working with the NIH and scientists across Africa, we aim to ensure these approaches will improve the lives of those most in need and bring the incredible promise of gene-based treatments to the world of public health.

SCD and HIV are major burdens on health in low-resource communities around the world. Approximately 95% of the 38 million people living with HIV globally are in the developing world, with 67% in sub-Saharan Africa, half of whom are living untreated. Fifteen million babies will be born with SCD globally over the next 30 years, with about 75% of those births occurring in sub-Saharan Africa. An estimated 50-90% of infants born with SCD in low-income countries will die before their 5th birthday and SCD is identified as the underlying cause of about 1 in 12 newborn deaths in sub-Saharan Africa.

Collaboration Details

The collaboration will focus on two areas of coordination:

Though SCD, a genetically inherited disease, and HIV, an acquired infectious disease, present significantly different scientific challenges, gene-based treatments hold promise for both, and many of the technical challenges for gene-based cures are expected to be common to both diseases.

To achieve the goals of the collaboration, both projects will require new delivery systems that can get prospective therapies to the right places in the body and optimize treatments to target the cells involved in the respective diseases efficiently and specifically. For SCD, that would mean repairing or compensating for the mutations in hemoglobin that cause SCD in hematopoietic stem cells. For HIV, that would mean targeting the reservoir of proviral DNA that continues to lurk inside a small number of cells, even after many years of effective antiviral treatment.

Such treatments that happen entirely within the body, known asin vivotreatments, would be a major step forward from current treatments, which apply genetic therapies to cells taken outside the body (ex vivo) and then reinfused.

We are losing too much of Africas future to sickle cell disease and HIV, said Matshidiso Rebecca Moeti, M.B.B.S., Regional Director for Africa, World Health Organization. Beating these diseases will take new thinking and long-term commitment. Im very pleased to see the innovative collaboration announced today, which has a chance to help tackle two of Africas greatest public health challenges.

The collaborations goal for SCD is to develop an easy-to-administer, gene-based intervention to either correct the SCD gene mutations or promote fetal hemoglobin gene expression to achieve normal hemoglobin function. The path to a cure will rely in part on the development of gene-based delivery systems capable of selectively targetinghematopoietic stem cells. This will result in the precise correction of gene mutations or addition of a gene to promote sufficient levels of normal hemoglobin expression and function.

Our excitement around this partnership rests not only in its ability to leverage the expertise in two organizations to reduce childhood mortality rates in low-resource countries, but to bring curative therapies for sickle cell disease and HIV to communities that have been severely burdened by these diseases for generations, said Gary H. Gibbons, M.D., Director, National Heart, Lung, and Blood Institute (NHLBI), part of the NIH.A persons health should not be limited by their geographic location, whether rural America or sub-Saharan Africa; harnessing the power of science is needed to transcend borders to improve health for all.

In addition, more needs to be done to understand the burden of SCD in sub-Saharan Africa and to screen newborns for SCD in high-risk geographic areas. NHLBI has already begun to establish a clinical research infrastructure in sub-Saharan Africa. However, additional clinical research and capacity-building efforts are needed to deliver point-of-care screening, such as at the time of infant vaccinations, and to initiate a standard of care. These activities will be undertaken by NIH and Gates Foundation outside of the collaboration, but will support collaboration efforts.

Nearly 38 million people worldwide are living with HIV, with 770,000 deaths due to AIDS in 2018 alone. Like SCD, people in sub-Saharan Africa face a disproportionate risk of HIV. Antiretroviral therapy is highly effective and has made it possible for people with HIV to live long, healthy lives without transmitting the disease to sexual partners. However, treatment must be maintained for a lifetime. A low-cost, safe, effective and durable cure that also prevents reinfection upon sexual exposure has long been a goal to curb the HIV global pandemic.

A number of approaches will be considered to meet the goal of a scalable HIV cure. Both the Gates Foundation and National Institute of Allergy and Infectious Diseases (NIAID), part of NIH, are already funding cure research, exploring gene-based treatments in concert with long-acting therapeutics, monoclonal antibodies and other immune-based targets. This collaboration will allow the partners to intensify and better coordinate ongoing research efforts on these strategies, accelerating studies into early phase clinical trials to safely test promising tools and interventions.A particularly appealing approach is to identify the location of the reservoir of infected cells that still harbor integrated HIV genomes after treatment and target those DNA sequences with gene editing technology.

This collaboration is an ambitious step forward, harnessing the most cutting-edge scientific tools and NIHs sizable global HIV research infrastructure to one day deliver a cure and end the global HIV pandemic, said NIAID Director Anthony S. Fauci, M.D. We are taking into account those with the greatest need at the foundation of this effort, to ensure that, if realized, this exceptional public health achievement will be made accessible to all.

Originally posted here:
NIH, Gates Foundation partner for gene-based cures - BSA bureau

LONDON--(BUSINESS WIRE)--The report, global age-related macular degeneration (AMD) therapeutics market has been added to Technavios catalog. It provides a comprehensive analysis of the market, including its global and regional market share as well as market segmentation based on type and geography for the forecast period 2019-2023.

To learn more about the global trends impacting the future of market research: Download Free Sample Report

This report on the age-related macular degeneration (AMD) therapeutics market includes:

Age-related macular degeneration (AMD) therapeutics market analysis and forecast 2019-2023: Features

Age-Related Macular Degeneration (AMD) Therapeutics Market 2019-2023: Competitive Landscape

Age-Related Macular Degeneration (AMD) Therapeutics Market 2019-2023: Geographic Landscape

Age-Related Macular Degeneration (AMD) Therapeutics Market 2019-2023: Type Landscape

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High prevalence of AMD will drive the age-related macular degeneration (AMD) therapeutics market

The prevalence of AMD is increasing significantly, owing to the presence of high-risk factors such as aging, smoking, high cholesterol, and high blood pressure. Moreover, despite the high prevalence of AMD, no approved therapies are available in the market for the treatment of the condition. Thus, the high prevalence coupled with the huge unmet medical need of dry AMD are expected to drive market growth during the forecast period.

Development of gene therapy for AMD An emerging trend in the osteoporosis market

At present, only a few drugs are approved for the treatment of AMD. However, the side effects associated with them are very severe, and the majority of them act against VEGF only. Hence, there is a huge unmet need for safe and novel drugs to treat AMD. The currently available anti-VEGF therapies require repetitive and inconvenient intraocular injections. Hence, several companies are working on novel drugs to combat AMD, among which gene therapy is expected to cure the disease effectively. Hence, the development of gene therapy is expected to be a positive trend for the global AMD therapeutics market.

Other Key Topics Covered in the Report are:

MARKET LANDSCAPE

MARKET SIZING

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Growth of Age-Related Macular Degeneration (AMD) Therapeutics Market to be Impacted by the Development of Gene Therapy for AMD | Technavio - Business...

NOVATO Oct 24, 2019 (Thomson StreetEvents) -- Edited Transcript of Biomarin Pharmaceutical Inc earnings conference call or presentation Wednesday, October 23, 2019 at 8:30:00pm GMT

* Daniel K. Spiegelman

BioMarin Pharmaceutical Inc. - Executive VP & CFO

* Henry J. Fuchs

BioMarin Pharmaceutical Inc. - President of Worldwide Research & Development

BioMarin Pharmaceutical Inc. - Chairman & CEO

BioMarin Pharmaceutical Inc. - Executive VP & Chief Commercial Officer

BioMarin Pharmaceutical Inc. - VP of IR

SVB Leerink LLC, Research Division - MD of Rare Diseases & Senior Research Analyst

* Philip M. Nadeau

William Blair & Company L.L.C., Research Division - Co-Group Head of Biopharma Equity Research

Welcome to the BioMarin's Third Quarter 2019 Financial Results Conference Call. Hosting the conference call today from BioMarin is Traci McCarty, Vice President, Investor relations. Please go ahead, Traci.

Traci McCarty, BioMarin Pharmaceutical Inc. - VP of IR [2]

Thank you, Grace. Thank you, everyone, for joining us today. To remind you, this nonconfidential presentation contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc., including expectations regarding BioMarin's financial performance, commercial products and potential future products in different areas of therapeutic research and development. Results may differ materially depending on the progress of BioMarin's product programs, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market and developments by competitors, and those factors are detailed in BioMarin's filings with the Securities and Exchange Commission such as 10-Q, 10-K and 8-K reports.

On the call today from BioMarin's management team are J.J. Bienaim, Chairman and Chief Executive Officer; Henry Fuchs, President of Worldwide Research and Development; Dan Spiegelman, Executive Vice President and Chief Financial Officer; Robert Baffi, President of Global Manufacturing and Technical Operations; and Jeff Ajer, Executive Vice President and Chief Commercial Officer. Consistent with the last 2 quarterly calls, we intend to keep this call to 1 hour in length. If we do not get to your question, please send me an e-mail or give me a call and we'll get right back to. Thank you for your understanding. Now I'd like to turn the call over to our Chairman and CEO, J.J. Bienaim.

Jean-Jacques Bienaim, BioMarin Pharmaceutical Inc. - Chairman & CEO [3]

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Thank you, Traci. Good afternoon, and thank you for joining us on today's call. We are proud to share our highest quarterly revenue results to date at BioMarin, a record $461 million in revenues in the third quarter, which represents an 18% growth over the third quarter of last year and demonstrates the increasing strength of our base business. And while we are excited about our next-generation products valrox and vosoritide, we never lose sight of the importance of our existing products to both the people who rely on them to improve their health and to the financial health of our business. In these unpredictable times, this is reassuring that between our strong balance sheet and excellent commercial business, we are not reliant on the financial markets.

As we round out 2019, confidence in our base business combined with R&D expense management, we've also been tightening our both GAAP and non-GAAP guidance to the top of the range for the full year. Our continued commitment to grow our profitability was demonstrated by cash generated in the third quarter, which was just over [$30] million. In addition to our strong base business, the potential returns from our investments in valrox and vosoritide are on the horizon. Approximately 3 years ago, we laid out a 5-year plan for financial success of the business, and we remain on track. We said that R&D expenses as a percentage of revenues would peak and then come down. Over the last 3 years, it has come down from 60% to 43% of revenues and on its way to our long-term goal of 25%, all while preserving a high level of productivity from our R&D engine. Our top line has grown 15% or more year-over-year with a $2 billion revenue target for 2020. And valrox and vosoritide should see growth well beyond that after 2020.

And of course, we have been focusing on the bottom line as well. In 2016, we said that we would be non-GAAP positive starting in 2017. We were non-GAAP positive in 2017, and we have continued to grow each year. Our next target is GAAP profitability, and from here, with the success we anticipate from valrox and vosoritide profit and significantly profitable growth is on the horizon. We are all aware of recent market volatility and the negative impacts it has had on our shareholders in the short term.

However, with a potential business payoff of our strategies in full view, we remain steadfast in our focus to get valrox and vosoritide approved and launched. And with over $1 billion in cash and investments, our 2 potential blockbusters on the horizon and a third already on the market which is Palynziq, we are poised to leverage the R&D, commercial and manufacturing expertise and capabilities established over the last several years.

At the heart of our business and what creates our growth opportunities is our R&D engine. And with that in mind, we look forward to hosting you at our Annual R&D day in New York on November 14, where we will provide updates on our late-stage programs as well as shine a light on the next potential growth drivers beyond valrox and vosoritide. We will also have an interesting lineup of preclinical candidates to share with you. As we can see, the lease programs will be added next to our development pipeline. Please email the IR team for further details, and we hope you will be able to join us. Now I would like to turn the call over to Jeff who will provide more details on the commercial business in the quarter and our expectations for the remainder of the year. Jeff?

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Jeffrey Robert Ajer, BioMarin Pharmaceutical Inc. - Executive VP & Chief Commercial Officer [4]

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Thank you, J.J. As J.J. mentioned, the third quarter was record-breaking in terms of revenue for BioMarin driven by a strong revenue quarter for Vimizim and $30 million in revenue growth from our newest brands, Palynziq and Brineura. Globally, BioMarin's commercial brands contributed $428 million, a 19% increase quarter-over-quarter and $1.2 billion year-to-date or 14% year-over-year growth. I will detail the breakdown of individual product contributions, but we'll start with a positive development in Brazil, a major market for our MPS brands. In the third quarter, we recognized the first installment of a 12-month supply agreement with the Brazilian Ministry of Health for both Vimizim and Naglazyme, which combined for a total contribution of $45 million. This new 1-year supply agreement should result in more revenue predictability through Q2 of 2020, although there will still be uneven order patterns quarter-to-quarter. Importantly, under this new arrangement with the Brazilian Ministry of Health, we would expect the majority of the roughly $90 million contract to be applied in 2019.

And now a little more detail on Vimizim globally. Quarterly revenue of $164 million represented the year-over-year increase of 33%. While a large Brazil order was a major factor in the quarter, patient growth of 11% globally also contributed to the increased and will support long-term additional revenue growth. For the full year, we are tightening our guidance to between $540 million and $570 million. For Naglazyme, the revenues driven from Brazil were offset by decreases due to ordering patterns in the EUMEA region, and thus, Q3 revenue totaling $94 million was down 4% versus Q2. Despite the neutralizing effect of both the favorable and unfavorable ordering in this quarter, overall patient growth remained steady, and we expect consistent annual revenue growth will continue. For the full year, we see revenues tightening to between $360 million and $380 million tightening the range.

Turning now to the PKU brands and starting with Palynziq. In the U.S., July marked the 1-year milestone of drug availability post FDA approval and the trajectory of patient referrals and correlating revenues are meeting expectations across all metrics. Q3 revenues of $24 million, essentially all of which came from U.S. sales, were driven by a combination of the growing number of patients, who have now achieved once-daily dosing and new patients initiating therapy. A reminder that it takes, on average, 5 months for a patient referral to get to commercial therapy and then to daily dosing, at which point, that patient is a material revenue driver.

At the end of Q3 in the United States, there were 670 patients on Palynziq commercial therapy, 142 of those patients from clinical studies and 528 patients formally naive to Palynziq. There were an additional 153 enrolled naive patients who have not yet received their first commercial dispense. A total of 823 adult PKU patients therefore either already being treated with commercial Palynziq or well on their way to their first shipment.

Turning our attention now to the EU launch. In May 2019, we announced approval for Palynziq by the EMA, and since that time, have engaged in very active education efforts, preparation of reimbursement dossiers and promotional activities in first-priority markets. I'm happy to share that physicians are treating patients now in Germany, the first EU country to market. Without the benefit of patients transitioning from clinical trial, in combination with the timing required to achieve reimbursement approvals, we expect that it will take time to realize material revenue contributions from Europe. We're very happy with the progress that we've made to date, and we've reaffirmed revenue guidance for Palynziq tightening range.

Shifting now to Kuvan. Global revenues in the third quarter totaled $121 million, representing a 6% increase year-over-year. The majority of this was due to patient growth in the United States and achieved in parallel through changing patient demographics as more adult PKU patients now have the option to treat with Palynziq. We are adjusting up our full year guidance for Kuvan.

Finally, an update on Brineura. Net product revenues were $20 million in Q3 driven by patient uptake in diverse global market across all 4 regions. Our teams continue to focus their efforts on driving early diagnosis and identifying new patients who will benefit from therapy, coupled with unlocking reimbursement in countries around the world. As a result of these efforts, Brineura has exhibited steady growth over time and now is reaching the level of material revenue contributions on a quarterly basis. We expect continued growth going forward and reaffirm our guidance for Brineura.

In conclusion, I'm very pleased with the commercial team's execution and performance in the third quarter of 2019 in all 4 regions and excited to track and report the progress of the launch of Palynziq in EU. For the remainder of the year, with our established commercial base business, we are confident in our ability to achieve full year revenue guidance of approximately $1.7 billion. So thank you. And now I'd like to turn the call over to Hank.

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Henry J. Fuchs, BioMarin Pharmaceutical Inc. - President of Worldwide Research & Development [5]

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Thanks, Jeff, and congratulations to you and your team. Starting with valrox for adults with severe hemophilia A, an exciting new regulatory development has been announced today. We are pleased to share that the European Medicines Agency has recently granted our request for accelerated assessment of valrox. In their assessment report, the European Medicines Agency acknowledged valrox's potential to address the existing unmet need by providing patients with a treatment option that only requires a single intravenous administration and then subsequently is expected to provide steady levels of endogenously produced coagulation factor VIII for a substantial amount of time. This decision is particularly important because it shows that based on the data the EMA has already received, EMA recognizes valrox's potential as a product of major interest for public health and therapeutic innovation. This decision is also important as the accelerated assessment procedure reduces the timeframe for the European Medicine Agency commitment -- Committee for Medicinal Products for Human Use (CHMP) to review our planned marketing authorization application for valrox on track for later this year. Needless to say, we are gratified to accept this recognition of valrox given the impact it could have for patients with severe hemophilia A.

Another positive development we want to share is the news that our Shanbally facility has been successfully inspected by the Irish HPRA for testing and release of gene therapy products. These newly constructed laboratories are part of our overall strategy for meeting worldwide regulatory requirements for product distribution. This added capability prepares us to meet in-country testing requirements for the release of commercial product in the EU region.

We continue to expect to submit marketing applications in both the United States and Europe in this quarter based on recent meetings with the FDA and EMA as we announced earlier in this quarter. These submissions were based on the recently completed Phase III interim analysis and the updated 3-year Phase I/II data of patients treated with valoctocogene roxaparvovec. Enrollment in the generate I Phase III open-label study is expected to complete mid-November, with the 52-week results anticipated in that study at the end of 2020. As we have said previously, although the trial is open-label, we have a data access plan in place, which is designed to significantly mirror a blinded trial. This precludes anyone not directly monitoring the trial to access any emerging data from this study, and we are not updating any of our prior analyses. As for the ongoing Phase II study, we intend to share a 4-year update with a 6e13 dose as well as a 3-year update on a 4e13 dose at the middle of next year at an appropriate medical conference.

Turning to our next late-stage program, vosoritide for children with achondroplasia is finished -- nearing the finish line. Our global multipronged program has been designed to achieve maximum clinical benefit for infants and children with achondroplasia from newborns through growth plate closure. Beginning with the Phase III program, results from the large global study that includes children from ages 5 to 18 are -- the data are expected by the end of the year. Needless to say, we look forward to sharing all these top line results with you at that time. Another key component of our global program in achondroplasia is the Phase II, 0-5 year old study. Given our conviction and the opinion stated at the achon AdCom meeting that the FDA held earlier in the year and last year, treatment with vosoritide started as early as possible may translate into the best results for children with achondroplasia. We're thrilled with the progress of this ongoing study. We have completed enrollment in the first cohort of the study, which includes children from 2 to 5 years of age. The second cohort, which includes children from 6 months of age through 2 years of age, is expected to complete by the year end and the last cohort of the study, which includes newborns through 6 months of age, began earlier enrolling this month. Needless to say, the level of interest from families seeking treatment for their very young children is very consistent with our belief in starting treatment as early as possible. We hope to provide more insight and detail in this program at R&D day.

Turning to BMN 307, our investigational gene therapy for PKU, we are pleased to have received orphan designation for BMN 307 this past Monday from the FDA. As you likely saw in our recent press release, we submitted a clinical trial application, or CTA, with the Medicines and Healthcare Product Regulatory Agency in the United Kingdom, or the HPRA -- sorry, the MHRA for BMN 307. We expect to start enrolling patients with material manufactured with a commercial-ready process to derisk the program to facilitate rapid clinical development in the Phase I/II trial in early 2020, and we are actively preparing regulatory submissions for other countries. We are excited about the prospect of BMN 307 as it represents a potential third PKU treatment option in our PKU franchise and a second gene-therapy development program, leveraging our learnings and capabilities from valrox.

And finally, on pipeline changes. We announced today that we have entered into a licensing agreement with Allievex for Tralesinidase Alfa, formally BMN 250, an investigational enzyme-replacement therapy for the treatment of Sanfilippo Syndrome Type B. As we've stated previously, our focus is shifting to larger indications where we can have an impact with our highly integrated products so we are thrilled to have Allievex now shepherding the continued development of Tralesinidase Alfa. We couldn't be happier for patients and their families as we expect they will benefit tremendously from Allievex's focus on treatments for rare neurogenerative diseases. We look forward to hosting you at our upcoming R&D day on November 14 in New York, where we will showcase our next potential commercial products, namely valrox and vosoritide including some baseline data never shared before. Another highlight will include an updated look at the natural history information, including trends of vosoritide treatment through 54 months as well as evaluation of untreated patients with achondroplasia. With our earlier-stage pipeline, we look forward to sharing a preview of the next potential INDs we are considering for development. We hope you will attend, so please reach out to our IR department should you need more information. Thank you for continued support, and I'll now call -- turn the call over to Dan to review the financial quarters. Dan?

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Daniel K. Spiegelman, BioMarin Pharmaceutical Inc. - Executive VP & CFO [6]

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Thank you Hank. Please refer to today's press release summarizing our financial results for full details on the third quarter. First, with respect to revenues, we reported total revenues in the quarter of $461 million and are on track for full year 2019 revenues of approximately $1.7 billion, being in the expected range of $1.69 billion to $1.72 billion. In addition to tracking towards the middle of the range for full year total product revenues, as J.J. mentioned, we expect both GAAP and non-GAAP results to be at the top end of the ranges due to continued R&D expense management as we continue to improve overall margins. An important item of note for the quarter is the impact of foreign exchange on our financial results. Over the past year, the dollar has strengthened materially against the Euro and the British pound and even more significantly against several of the Latin American currencies. Overall, net of our hedging, full year revenue is projected to be negatively affected by approximately $20 million to $25 million such that our full year revenue would have been at the high end of our guidance instead of the midrange without these negative FX impacts. Thanks to our hedging contracts, which offset more than half of the potential revenue impact from the strengthening dollar and natural expense hedge offsets, full year bottom line forecasted results are not materially impacted this year by exchange rates.

One specific revenue item that Jeff did not discuss was Aldurazyme revenue in the quarter. It increased by $17 million versus 2Q due to delays in that quarter with Sinofi's QA release that has since been resolved. Year-to-date, Aldurazyme is down $44 million due to a onetime (inaudible) of revenue in Q1 2018 though patients on therapy, as reported by Genzyme, continue to grow in 2019 versus 2018.

Moving to operating expenses. Both R&D and SG&A expenses in the third quarter roughly track to previously provided full year guidance. SG&A is expected to come in at the upper end of the range between $670 million and $690 million. SG&A expenses in the third quarter were impacted by the expansion of sales and marketing capabilities as we launched Palynziq in Europe and continue to prepare for valrox and vosoritide approvals and launch.

In the third quarter, R&D expenses reflect the continued enrollment of additional patients in the global Phase III Generate I study, the manufacturing of BMN 307, our PKU gene therapy product, ahead of clinical trials early next year and the children in the 0 to 5-year-old study with vosoritide.

However, despite the progress of these later-stage development programs, with the decision not to pursue development of both BMN 270 for Frie -- 290, I'm sorry, for Friedreich's ataxia and BMN 250, we now expect R&D expense for the full year to be lower than previously guided. For the full year, we now expect R&D expenses of between $710 million and $740 million.

Turning to BioMarin results. GAAP net income in the third quarter was $55 million as compared to a GAAP net loss of $12.6 million in the third quarter of 2018. GAAP net income in the third quarter increased primarily due to a net profit from operations and a benefit from income taxes of approximately $45 million. For the full year, we expect GAAP loss to come in at the low end of our initial guidance range and now expect the loss of between $65 million and $45 million.

As you know, we also measure our performance on a non-GAAP basis, which is based on EBITDA and also excludes stock compensation, contingent consideration and certain other specified items. Our non-GAAP income in the third quarter was $78 million compared to non-GAAP income of $61 million in the third quarter of 2018. We are now narrowing the range of full year non-GAAP income to be between $150 million and $170 million. The use of cash, cash equivalents and investments as of September 30, 2019, we have $1.15 billion as compared to $1.1 billion on June 30, 2019.

And finally, a note on our cash flows for the third quarter. Year-to-date cash used for operational activities totaled just about $9 million, whereas cash generated by operating activities for the third quarter were just over $70 million. GAAP profitability and continued cash flow growth are expected as our revenues increase. Our P&L structure is expected to be similar to our larger biotech peers we aspire to follow.

In closing, BioMarin's current commercial business remains on track to deliver roughly $1.7 billion in revenues this year and close to $2 billion next year, with increasing GAAP and non-GAAP bottom line profitability. Over the next 18 months, we also expect to accelerate into the next phase of higher revenue and growth through potential approvals of valrox and vosoritide, which could lead to approvals and revenue contributions starting before the end of 2020.

Thanks for your support, and I will now open it to your questions. Operator?

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Questions and Answers

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Operator [1]

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(Operator Instructions) Your first question comes from the line of Salveen Richter from Goldman Sachs.

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Salveen Jaswal Richter, Goldman Sachs Group Inc., Research Division - VP [2]

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So for vosoritide, how should we think about the clinical meaningfulness of the Phase III data? So while you showed about a 2-centimeter a year benefit at the same dose in the Phase II, clearly, there is a range for various stratification measures that adds up here or gets you on a normal growth curve. So if you can give us any clarity there, and I have a follow-up.

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Henry J. Fuchs, BioMarin Pharmaceutical Inc. - President of Worldwide Research & Development [3]

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Salveen, the clinical meaningfulness of just the Phase III study I don't think can be considered in isolation because the Phase III study is a relatively short duration of 1 year, in that, it's placebo-controlled, and that was what we and our investigators agreed was feasible to study and generate high-quality data. I think the way to think about clinical meaningfulness of vosoritide is in terms of cumulative effect over chronic therapy. And to remind you, we reported last year the accumulated benefit of vosoritide through 42 months of chronic therapy in our Phase I/II cohort of 10 patients. This year, we'll be giving you another update on that, which will now carry patients through 54 months of therapy. And as I mentioned in my talking points, we are now in a position to start addressing what the height gain over untreated patients can be expected to be given that we're now coming online with our own contemporaneous natural history study. So all that taken together says the value of the Phase III trial is to prove that vosoritide is effective compared to placebo. But the magnitude of the benefit should be weighed in the context of longer-term therapy.

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Salveen Jaswal Richter, Goldman Sachs Group Inc., Research Division - VP [4]

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That was helpful. And then can you discuss the forward trajectory and dynamics for Kuvan? Do you expect the majority of patients here to transition over to Palynziq prior to IP expiration?

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Jeffrey Robert Ajer, BioMarin Pharmaceutical Inc. - Executive VP & Chief Commercial Officer [5]

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Salveen, it is certainly our goal to transition as many adult Kuvan patients to Palynziq as possible before loss of exclusivity in a year, and we are making a lot of progress. 38% of our Palynziq referrals, our naive Palynziq patient referrals, are Kuvan transitions, so making a lot of progress there. It is also true that though there remain a smaller now number of new adult patients that are being referred in for Kuvan treatment, and it is also true, particularly in the United States, that our pediatric population is growing on Kuvan. So the trajectory, I would think, would be similar to what we are reporting year-to-date with patient growth of about 6% tied to continued revenue growth. Our focus, both in Europe and the United States, is overwhelmingly now on adult patients gaining access to, and benefiting from, Palynziq therapy.

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Jean-Jacques Bienaim, BioMarin Pharmaceutical Inc. - Chairman & CEO [6]

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Salveen, I'm sorry, just want to remind you on the line that the loss of exclusivity in Q4 of next year is only in the U.S. In Europe, in ex U.S. we have protection until 2024. I'd also give you one point that maybe it's no different from your traditional generic modeling is that when you've a small molecule, you lose protection of market exclusivity. When you lose a patient to a generic they very rarely come back to the brand, if ever. In our case, what in the case we do starting in Q4 2020, October, November 2020. If we do lose a Kuvan patient to a generic, they are not lost forever to our business in the sense that they can always go to Palynziq down the road, so they are not lost forever.

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Operator [7]

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Your next question comes from the line of Phil Nadeau from Cowen and Company.

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Philip M. Nadeau, Cowen and Company, LLC, Research Division - MD & Senior Research Analyst [8]

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One on vosoritide for me also. In the Phase II data, we saw at month 12, just below a 50% increase in annualized growth velocity. Hank, is there any reason why we shouldn't expect that in the Phase III? Are there any notable differences in the patient populations who are enrolled that could change the expected results?

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Henry J. Fuchs, BioMarin Pharmaceutical Inc. - President of Worldwide Research & Development [9]

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Not really, no. We purposely kept the eligibility criteria fairly consistent and also the outcome measures, between the outcome measure and the dose and regimen are the same so we should expect a fairly similar result. Now the one thing that we've pointed out is that we've been doing those calculations compared to the baseline run in. But as you -- as people have pointed out and as you noticed from (inaudible) achondroplasia growth studies, there is a gentle negative slope so at 1 year, there could be some negative placebo effects, such that we underestimated that 1 year the magnitude in treatment benefit of vosoritide. And I think that's going to get to be more and more important as you go out farther and farther in time because those declines will start to add up. And I was suggesting that at the R&D day, we'll have an opportunity to look at those, both of those phenomena, the chemo derived benefit from product treatment as well as contrast that to similar populations of patients who have not been treated with vosoritide.

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Philip M. Nadeau, Cowen and Company, LLC, Research Division - MD & Senior Research Analyst [10]

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Got it. Okay. And even though the age 5 to 14 is exactly the same between Phase II and Phase III, do you know whether the people who are actually enrolled have a similar age characteristic? So was the Phase II weighted towards younger patients and Phase III is getting older patients or as far as you know, the ages in the trial are also identical?

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Henry J. Fuchs, BioMarin Pharmaceutical Inc. - President of Worldwide Research & Development [11]

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Edited Transcript of BMRN earnings conference call or presentation 23-Oct-19 8:30pm GMT - Yahoo Finance

Regeneron will lose out on hundreds of millions of dollars if a rival to its top-selling drug performs the way Wall Street expects. Even more would be at risk if recently proposed changes to government insurance become a reality.

In these situations, when a drugmaker's biggest product is under fire, acquisitions can look like an attractive way to put out the flames. AbbVie's $63 billion bid to acquire Allergan stems almost entirely from the buyer trying to find new revenue streams before generics start eating away at its mega-blockbuster drug, Humira.

But Regeneron isn't like other drugmakers. In the 30 years since its founding, it has never acquired another company. Though Regeneron isn't completely shut off to the idea of doing M&A, there's little to indicate the biotech is actively trying to change its deal track record.

Regeneron maintains that it doesn't need to buy drugs because of its R&D skills. Under the direction of CEO Len Schleifer and Chief Scientific Officer George Yancopoulos, the biotech has brought seven new medicines to market, including five from a long-standing partnership with Sanofi.

"When I look at Gilead, for example, or even Biogen [there is] a lot of investor pressure to buy something," Evan Seigerman, a Credit Suisse analyst, told BioPharma Dive. "Regeneron is still good at telling the narrative that 'we can develop our own assets and we have the best capabilities, so we're not going to buy anything.'"

The biggest of those assets is Eylea, a drug for multiple eye diseases that hit $6.75 billion in global sales last year.

For 2019, the average Wall Street estimate has Eylea reaching $7.43 billion in sales. For 2020 and beyond, however, analysts are torn about how it will fare in light of a new competitor.

*Selection of four investment bank forecasts for global Eylea sales

Earlier this month, Novartis began selling in the U.S. a drug for wet AMD, an age-related vision loss disease for which Eylea is also approved. Novartis on its third quarter earnings call touted how the drug, Beovu, is off to a strong launch, though the company didn't provide sales numbers.

While some analysts initially viewed Beovu's label as weaker than expected Christopher Raymond of Piper Jaffray called the drug "little more than an also-ran" it is still poised to steal market share from Eylea. Just how much share is the big question facing Regeneron.

RBC Capital Markets' research team said it recently spoke with an eye specialist who plans on switching one-third of her Eylea-treated wet AMD patients to Beovu. On a broader scale, the American Society of Retina Specialists found in a recent survey of 1,009 people from ophthalmology organizations that 50% plan on prescribing Beovu for wet AMD patients who don't adequately respond to drugs like Eylea or Roche's Lucentis.

Beovu may not be the only challenge to Eylea, either. President Donald Trump and Democrats in the House of Representatives have pitched different plans that would affect how Medicare pays for certain drugs. Medicare Part B spends more on Eylea than any other drug, leaving it particularly exposed if changes to government insurance take shape.

Amid these uncertainties, Regeneron's share price has fallen 16% since the beginning of the year. By contrast, the Nasdaq Biotechnology Index, which includes Regeneron, rose 13% over the period.

"They really do have quite a successful R&D engine," Kennen MacKay of RBC said. "But with the stock trading where it is, maybe there's a feeling that's no longer enough."

Jacob Bell / BioPharma Dive, market data

Regeneron's success is tied to its prowess in developing monoclonal antibodies a type of drug that, while a novelty in the past, is now a mainstay of many drugmakers' pipelines.

Some on Wall Street fret that Regeneron's competitive edge may have weakened as more companies entered this space. Last month, Geoffrey Porges of SVB Leerink went so far as to pose the provocative question: "Is Regeneron becoming the TiVo of biopharma?"

Whether or not those worries are valid, analysts can't envision Regeneron buying anything because that would be so out of character.

"These companies really do have a certain genetic makeup of what they're about, especially Regeneron," Cowen & Co.'s Yaron Werber told BioPharma Dive. "Doing M&A is not something that's in their DNA."

The threats to Eylea are therefore unlikely big enough or realized enough to push Regeneron toward acquisitions. According to consensus figures provided by Credit Suisse, analysts envision sales of the eye drug growing over the next year in spite of Beovu, as it takes greater market share in areas like diabetic macular edema.

Investors also have other bright spots to keep their attention off M&A. Dupixent, a treatment for eczema and asthma, achieved triple-digit growth over the last year and could help offset future hits to Eylea.

Regeneron's pipeline drugs, meanwhile, face significant competition.Roche and Amgen are working on rival cancer agents, while Merck & Co., Bristol-Myers Squibb and Alexion Pharmaceuticals already market blockbuster drugs for diseases that Regeneron is targeting.

"There's a deep pipeline, but it's lacking that one disruptive product that investors always want to see," Werber said. "It's a pipeline that still is getting defined."

Regeneron could find that disruptive product through bets on newer technologies. The company entered a gene editing deal with Intellia Therapeutics in 2016, a cell therapy deal with Bluebird bio in 2018, and an RNA-focused deal with Alnylam Pharmaceuticals this April.

"There's nothing inherently good about doing M&A."

Nouhad Husseini

Head of Business Development, Regeneron

While Regeneron has favored partnerships to acquisitions, it could do the latter if it wanted. By the end of June, the company held just over $1 billion in cash and cash equivalents and another $4.5 billion in marketable securities.

"The deal we did with Alnylam, or Intellia, or any of our partners where we're accessing external innovation, we could have just as easily decided to acquire one of those companies," Nouhad Husseini, Regeneron's head of business development, said in an interview.

Husseini holds reservations about outright acquisitions, though he said he could see Regeneron buying something in the short- or medium-term. Collaborations have worked out well, he notes, because both sides can stay focused on the science without getting distracted by the upheaval that often comes from M&A.

"The way I look at it is: M&A and doing a partnering deal, it's shades of gray and there are pros and cons. It's a way of structuring the deal, nothing more than that," Husseini said. "We really value these companies who have this independent entrepreneurial spirit, and I've seen firsthand what happens when big companies come in and acquire these little companies."

Scientific independence is a value shared by other biotech dealmakers as well.

Gilead and Galapagos structured their $5.1 billion research deal so the smaller company would remain a motivated partner, according to Gilead CEO Daniel O'Day. Gilead also announced in May that it will keep separate its cell therapy subsidiary, Kite Pharma, which O'Day reasoned would improve efficiency.

Jeffrey Leiden, the CEO of Boston-based Vertex, told BioPharma Dive earlier this year that he planned on letting Semma Therapeutics, which Vertex had just acquired for $1 billion, operate with more autonomy because of the target company's leadership team and expertise in stem cell-derived therapies.

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Pharmacquired: Eylea could be in trouble, but that doesn't make Regeneron a buyer - BioPharma Dive

The Gene Therapy Market report presents and displays a vigorous vision of the global scenario in terms of market size, market potentials, and competitive environment. A new professional intelligence report published by stats and reports has the ability to help the decision-makers in the most important market in the world that has played a significantly important role in making a progressive impact on the global economy. The study is derived from primary and secondary statistical data and consists of qualitative and quantitative analysis of the industry and key players.

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Global Gene Therapy Market New Innovation| Size, Share, Application, Revenue, And Sales Till 2022 - Sino News Daily

New York City, NY: October 25, 2019 Published via (Wired Release) Excellent growth of Cryonics Technology Market|Comprehensive study by Global Innovations, New Business Developments,SWOT Analysis with key players, Capital Investment, Technological Innovation and Emerging Trends of Outlook To 2029

Global Cryonics Technology Market 2020 report contains wide-extending measurable details of Cryonics Technology Market, which enables the customer to separate the future maneuver and anticipate right execution.Cryonics Technology market reveals dynamics in many geographic segments for this business landscape and future state of affairs over the forecast amount.cryonics technology market research report 2020 is a comprehensive, professional report delivering market research data that is suitable for new market participants or established players. The Research report presents a full evaluation of the Market and has current growth factors, future trends, facts, attentive views, and market data approved by the industry.

The research report gives an in-depth explanation of the trends and consumer behavior patterns that are likely to govern the evolution of the global cryonics technology market. The research covers a crucial market segmentation analysis that is a rich source of all essential segments including Cryonics Technology types, applications, technologies, end-users, and regions. The study provides an idea of what condition the market will face, what will be the growth rate and which type of failure will occur. The comprehensive valuation of the market is presented in the report entailing facts, existing growth factors, attentive outlooks, coming trends, and industry-confirmed market data forecast until 2029.

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Market Segmentation:

Some of the Major Cryonics Technology Market Players Are:

PraxairCellulisCryologicsCryothermKrioRusVWRThermo Fisher ScientificCustom Biogenic SystemsOregon CryonicsAlcor Life Extension FoundationOsiris CryonicsSigma-AldrichSouthern Cryonics

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Latest Research report on Cryonics Technology Market Size predicts favorable growth and forecast - TheLoop21

In a first for the sector, industry bodies Subsea UK and the Umbilical Manufacturers Federation (UMF) have joined forces to deliver a conference focussing on the new developments and opportunities which exist in the subsea umbilicals industry.

The global subsea umbilicals, risers and flowline market is forecast to be worth more than 5 billion by 2021 and the half-day conference, which will take place on Thursday, 21 November at the Chester Hotel in Aberdeen, will focus on the opportunities which exist in the growing sector. Ahead of the conference, a networking reception will take place at the hotel the Wednesday night before.A number of experts, including representatives from oil and gas super-majors and service companies will explore a range of topics relating to subsea umbilicals including project achievements to date, life extension and safety. Shell, Equinor, Subsea 7, Aker Solutions, Oceaneering, JDR Cable Systems, Fibron, Nexans, MAATS Tech and Trelleborg will all deliver presentations at the event.Neil Gordon, chief executive at Subsea UK, said: The subsea umbilical market has seen a massive growth in recent years, and it is predicted to expand and be part of a multi-billion-pound market. We have developed this conference in direct response to the number of opportunities which exist in subsea umbilicals and created a programme which showcases the latest technical advances and knowledge which exists in the sector.

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Conference to focus on the subsea umbilical industry - Engineer Live

1. Sinclair Cares: Genetic testing can help you check your risk of getting breast cancer  News3LV
2. Sinclair Cares: Breast cancer genetic testing  NBC 15 WPMI
3. Expert Discusses the Selection of Individuals for Germline Testing Based on Breast Cancer...  Targeted Oncology
4. Testing for Honesty  Curetoday.com
5. Using genetic testing to possibly prevent breast cancer  KATC Lafayette News
6. View full coverage on Google News

See the rest here:
Sinclair Cares: Genetic testing can help you check your risk of getting breast cancer - News3LV

ALISO VIEJO, Calif., Oct. 23, 2019 /PRNewswire/ --Ambry Genetics(Ambry), a leading clinical genetics company, announced today the publication in JAMA Network Open of a study on retrospective RNA genetic testing for hereditary cancer risk. The study reveals that adding RNA testing could provide more accurate results for one out of every 43 patients undergoing DNA testing and could improve medical care. Now, through +RNAinsight,Ambry is the first and only lab to offer a commercially available clinical test to conduct RNA and DNA genetic testing for hereditary cancer risk at the same time.

DNA testing is a powerful tool used to tailor medical care based on an individual's cancer risk. However, standard DNA testing can produce inconclusive results, find a change in our DNA to be a variant of unknown significance (VUS), and fail to determine whether it increases cancer risk. When this happens, healthcare providers might not have the information needed to recommend appropriate preventive and early detection steps, or certain therapeutic treatments, and relatives may not be referred for genetic testing for their own care. Adding RNA to DNA testing can overcome this limitation, providing more evidence that can determine whether a variant increases cancer risk.

In this study, investigators fromAmbry and collaborating institutions (Dana-Farber Cancer Institute, Cedars-Sinai Medical Center, Rutgers Cancer Institute, and University of Kansas Cancer Center) evaluated the ability of RNA genetic testing to help determine whether certain VUSs actually increased cancer risks and whether patient care changed after those determinations.

For a substantial percentage of the VUS tested, the study found that adding RNA to DNA testing determined whether they actually increased cancer risk. Specifically, RNA genetic testing clarified 88 percent of 56 selected VUS, determining that 47 percent were actually disease-causing and 41 percent were benign. In addition, all of the patients whom Ambry previously tested and who had these same VUS, received updated reports. As a result, an additional 88 patients had their inconclusive results clarified as positive (i.e., increased risk for cancer) and 322 had their inconclusive results clarified as negative.

"Adding RNA genetic testing to standard DNA testing for hereditary cancer risk needs to be the standard of care," said Rachid Karam, MD, PhD, Director of the Translational Genomics Lab at Ambry Genetics. "Our data shows +RNAinsight will let thousands of more patients know if they have genetic variations that increase their risks for cancer and take action."

The study also found that determining whether a VUS in fact increases a patient's cancer risk can substantially impact that patient's care. Of the clinicians who received clarified results and responded to a study survey, 44 percent changed their care for patients and 78 percent changed their care for patient relatives. For example, for those patients whose results for the BRCA1 gene were changed from VUS to disease-causing, new recommendations included risk-reducing surgeries and increased cancer surveillance.

When assessing the types of variants identified in a cohort of 307,812 patients who had undergone standard DNA testing at Ambry Genetics for hereditary cancer risk, the study determined that 7,265 or one in 43 patients could benefit from the addition of RNA genetic testing. Given that 700,000 people in the United States are expected to receive genetic testing for hereditary cancer risk in 2019, more than 16,000 individual results could change and be clarified with RNA genetic testing annually.

The study further showed that only 10 percent of patients invited to receive RNA genetic testing after having undergone DNA testing actually sent in samples. Given the substantial loss-to-follow-up from retrospective RNA testing and the proportion of patients estimated to benefit, Ambry has decided to make RNA genetic testing available to all patients at the same time as DNA testing through +RNAinsight, which is now available through doctors and genetic counselors around the country. For more information, please go to RNAinsight.com.

About Ambry Genetics

Ambry Genetics, as part of Konica Minolta Precision Medicine, excels at translating scientific research into clinicallyactionabletest results based upon a deep understanding of the human genome and the biology behind genetic disease. Our unparalleled track record of discoveries over 20 years, and growing database that continues to expand in collaboration with academic, corporate and pharmaceutical partners, means we are first to market with innovative products and comprehensive analysis that enable clinicians to confidently inform patient health decisions. We care about what happens to real people, their families, and the people they love, and remain dedicated to providing them and their clinicians with deeper knowledge and fresh insights, so together they can make informed, potentially life-altering healthcare decisions.For more information, please visit ambrygen.com.

For more information on risk factors for hereditary cancer, please visit cancer.gov's fact sheet on hereditary cancer and genetic testing.

Press Contact:Liz Squirepress@ambrygen.com202-617-4662

SOURCE Ambry Genetics

http://www.ambrygen.com

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Ambry Genetics Published Data that Finds Adding RNA Genetic Testing Provides More Accurate, Actionable Results for Patients who Receive DNA Testing...

As more people dig into their family roots, seemingly, many are equally inclined to satiate their curiosity about their hereditary risks for conditions such as cancers, heart disease and diabetes.

This consumer interest in ones healthcare is aligning with health systems desire to lower costs through better population health management. New Orleans based Ochsner Health System announced last week that it is launching a digital population health screening program where people can learn about their family history of disease by identifying increased risk for diseases like those. Ochsner has selected Burlingame, California-based Color to perform the gene testing and analyze results.

The program, formulated byOchsners innovation lab, innovationOchsner (iO) will identify patients particularly vulnerable tohereditary cancers and heart disease and recommend them for testing in this pilot program. Specifically, the program will test:

A testing kit will be sent to the homes of selected patients, who will, in turn, send a DNA sample. Once the results are in,Colors services and tools allow for a deep dive into health discussions and help ease family sharing, explained Richard Milani, chief clinical transformation officer, Ochsner Health System and Medical Director, iO, in a phone interview.

Ochsner clinical teams can talk further about care plans with patients and help them deal with the proceeding steps within the healthcare system, Milani continued. The results will be integrated into Ochsners EHR system.

This isnt so much a research study as it is actionable; something that can go into the clinical record appropriately, securely and safely, so that our primary care physicians and specialists are involved and we can take appropriate actions for patients at high risk for (those conditions), he noted.

Almost two million individuals in the U.S. are at heightened risk for less than ideal health outcomes traced to the fact that they have genetic mutations with one of the three conditions. Milani noted that, potentially, with a higher degree of surveillance or earlier intervention, these health issues could have been circumvented.

Ochsner is not the only health system interested in genomics. Geisinger, the health system in Pennsylvania, announced in 2018 a wide-scaleDNA-sequencing programfree for patients.

There are several gene testing players in the market including 23andMe and Helix. Milani noted that Ochsner selected Color because the company met all the lab criteria, including certification by Clinical Laboratory Improvement Amendments (CLIA). Whats more, Milani remarked, unlike some of its competitors, Color conducts secondary confirmation of abnormal results and offers genetic counselors who review results with and spend time with patients.

They were very thorough in their methodology and confirmation, very robust in genetic counseling, he noted.

Color uses clinical-grade genetic testing technology while also providing support to individuals and providers with genetic counseling services, which direct to consumer genetic testing doesnt, said Caroline Savello, Colors vice president of Commercial and lead on the partnership, in a phone interview

Color, for its part, wants to make genetic testing aseasy as possible for patients to access.

(The way its been, a patient) has to come in, see multiple people, get a referral for genomics clinic, wait four to six weeks tor appointment, said Caroline Savello, Colors vice president of Commercial and lead on the partnership, in a phone interview. Today, however, samples can be collected at home, and people can educate themselves on what theyll be able to learn from a test, pose questions to trained specialists by phone and learn those results in a way that really reduces the exceptionalism of the technology of genomics.

Earlier this year, the National Institutes of Health awarded Color a $4.6 million grant to serve as the nationwide genetic counseling service for their All of Us Research Program.

She added that once genetic testing becomes more accessible, you see much higher compliance rates, greater engagement and much higher completion rates of even simple things like health history.

There is some work that providers need to do to make genetic information understood and actionable.

I dont think that, in general, health industries are well prepared to consume this information and manage it appropriately. We need to be able to educate our workforce to house data appropriately and use it to change for health maintenance.

Photo: iLexx, Getty Images

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Inside Ochsner Health System's partnership with Color to offer certain patients gene testing - MedCity News

Asia Pacific Prenatal and Newborn Genetic Testing Market to 2027 Regional Analysis and Forecasts by Type, Disease Indication, Technology, and End User. The Asia Pacific prenatal and newborn genetic testing market is expected to reach US$ 2,570.

New York, Oct. 24, 2019 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Asia Pacific Prenatal and Newborn Genetic Testing Market to 2027 - Regional Analysis and Forecasts by Type, Disease Indication, Technology, End User and Country" - https://www.reportlinker.com/p05815381/?utm_source=GNW 37 Mn in 2027 from US$ 878.28 in 2018. The market is estimated to grow with a CAGR of 12.8% from 2019-2027.The key factors responsible for the growth of the market in Asia Pacific are rising burden of genetic diseases among infants, increasing fertility rates and developing healthcare scenario with rising awareness among populace regarding the benefits of prenatal testing.On the other hand, use of digital microfluidics in newborn testing is likely to be a prevalent trend in the future years.

Soaring birth rates among developing economies are responsible for fueling global baby boom.However, the rising birth rate also contributes to rising birth defects and infants suffering from several genetic diseases.

According to a report published by Bill and Melinda Gates Foundation in 2018, there are almost 250 babies born every minute around the globe. Moreover, according to the Centers for Disease Control and Prevention, the fertility rates for Hispanic women was highest in 2017 among Hispanic women with 67.1 births per 1,000 women.Asian countries such as India and China also have high fertility rates due to factors such as effects of religion, inadequate supply of family welfare services, poverty, and others. According to the World Bank in 2016, the fertility rates in India were reported to be 2.23 births per women as compared to 1.80 in the United States and 1.62 in China. Moreover, neighboring countries in India, such as Pakistan also has alarming rates of fertility. In 2016, the birth rate in Pakistan was reported to be 3.48 births per woman as per the World Bank data. However, the birthrate in India have successfully reduced its high fertility rate, but still is high as compared to other developed nations. According to the United Nations (UN) report published on June 2019, the fertility rate has reduced to 2.1. Therefore, by 2050 additional 273 million people will be added to Indias population. The increasing number of parturient women across the world are thus likely to create increasing demand for prenatal and newborn genetic tests across the globe leading to the growth of the market.The Asia Pacific prenatal and newborn genetic testing market, based on the disease indication was segmented into cystic fibrosis, sickle cell anemia, downs syndrome, phenylketonuria, recurrent pregnancy loss, and Antiphospholipid syndrome, and other diseases.In 2018, Down syndrome segment held the largest share of the market, by disease indication.

The highest share of Down syndrome attributes to the high prevalence of this genetic abnormality among fetuses and availability of multiple tests for its screening and diagnostics. However, the cystic fibrosis segment is expected to grow at the fastest rate during the coming year.Some of the major primary and secondary sources for prenatal and newborn genetic testing included in the report are Food & Drug Administration (FDA), Indian Institutes of Technology (IITs), International Trade Administration (ITA), Japan Society of Obstetrics and Gynecology (JSOG), Council of Scientific and Industrial Research (cSIR), Pakistan Down Syndrome Association (PDSA) and others.Read the full report: https://www.reportlinker.com/p05815381/?utm_source=GNW

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The Asia Pacific prenatal and newborn genetic testing market is expected to reach US$ 2,570.37 Mn in 2027 from US$ 878.28 in 2018. The market is...

In April 2018, California authorities revealed that theyd used a novel investigative technique to arrest a man they called the Golden State Killer, a serial murderer whod escaped capture for decades.

For the first time, police had submitted DNA from a crime scene into a consumer DNA database, where information about distant relatives helped them identify a suspect.

The announcement kindled a revolution in forensics that has since helped solve more than 50 rapes and homicides in 29 states.

But earlier this year, that online database changed its privacy policy to restrict law enforcement searches, and since then, these cold cases have become much harder to crack. The change is allowing some criminals who could be identified and caught to remain undetected and unpunished, authorities say.

There are cases that wont get solved or will take longer to solve, Lori Napolitano, the chief of forensic services at the Florida Department of Law Enforcement, said.

The switch was imposed by GEDmatch, a free website where people share their DNA profiles in hopes of finding relatives. The company had faced criticism for allowing police to search profiles without users permission, and decided that it would rather make sure members understood explicitly how investigators were using the site. So, it altered its terms of service to automatically exclude all members from law enforcement searches and left it to them to opt in.

Overnight, the number of profiles available to law enforcement dropped from more than 1 million to zero. While the pool has grown slowly since then, as more people click a police-shield icon on GEDmatch allowing authorities to see their profile, cases remain more difficult to solve, investigators say.

CeCe Moore, a leading specialist in using DNA evidence and family trees to identify criminal suspects a method known as investigative genetic genealogy depends on GEDmatch for her work. After entering a suspects DNA profile into the site, she reviews the results and assesses the likelihood of law enforcement being able to determine the suspects identity. She then scores each case from 1 to 5, 1 being a sure thing and 5 a long shot.

Im giving a lot more fives than I used to, said Moore, who helped solve several cases using GEDmatch before the site changed its terms of service, including the 1987 killing of a young Canadian couple, the 1988 murder of an 8-year-old Indiana girl and the 1992 rape and strangulation of a Pennsylvania schoolteacher.

This sharp drop in the usefulness of a promising technology has sparked an effort by law enforcement authorities and researchers like Moore to convince the public to take action. These groups hope to persuade more Americans to obtain their DNA profiles from direct-to-consumer genetic testing companies most of which have large databases but dont allow law enforcement searches and share them publicly, including with law enforcement, on databases like GEDmatch. One direct-to-consumer company, FamilyTreeDNA, allows law enforcement to search its database, but charges for it and limits results.

Some people are reluctant, worried that their DNA profiles will be hacked or used against their wishes, whether in the pursuit of a criminal or in the sale of data to health care companies. There are also concerns that DNA sharing will lead to the end of anonymity.

But law enforcement authorities and genetic sleuths who work with them argue that there is greater public good in helping to keep killers and rapists off the streets.

In the interest of public safety, dont you want to make it easy for people to be caught? said Colleen Fitzpatrick, a genetic genealogist who co-founded the DNA Doe Project, which identifies unknown bodies, and runs IdentiFinders, which helps find suspects in old crimes. Police really want to do their job. Theyre not after you. They just want to make you safe.

To illustrate those points, investigators tell the story of Angie Dodge.

Dodge, 18, was raped and murdered in 1996 in her Idaho Falls, Idaho, apartment. A year later, a man confessed to the crime, and although he later recanted and his DNA didnt match that of semen left on Dodges body, he was convicted of participating in the killing and sentenced to life in prison.

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Dodges mother grew convinced that the prisoner, Christopher Tapp, was not her daughters killer. She pressed authorities to reopen the case. In 2017, Tapp was freed in a deal with prosecutors in which his conviction of aiding and abetting the murder remained.

So did the question of who left their DNA at the crime scene.

Almost a year later, California authorities said theyd used genetic genealogy to catch the Golden State Killer.

The announcement generated a surge of interest in the technique, as genetic genealogists teamed up with private companies to sell their services to law enforcement. (Public crime labs are not equipped to do the kind of DNA analysis required, and police generally arent fluent in methods used to build family trees.) Parabon NanoLabs was the first, hiring Moore to run its genetic genealogy services. Idaho Falls police asked the company to try it.

Parabon submitted the Dodge suspects DNA profile into GEDmatch in May 2018, but the DNA was so degraded that, even with more than 1 million profiles to compare against, the connections were sparse. Moore decided that genetic genealogy wouldnt work and declined to take up the case.

But Dodges mother, Carol, begged Moore to keep trying. Moore relented and examined the connections more closely. With help from her team of genetic genealogists, she explored a series of leads that didnt pan out. They kept at it for months, eventually discovering a new branch of the suspects family tree and a potential suspect.

Police followed that man, collecting a cigarette butt he discarded and using it to obtain his DNA. It matched the crime scene profile, and in May 2019 Brian Leigh Dripps confessed, police said. A few weeks later, Tapp was exonerated. Dripps is awaiting trial.

Moore chronicled that search at a recent gathering of genetic researchers, investigators, prosecutors and lab technicians in Palm Springs, California. If she had been working on the Dodge case after GEDmatch limited access to its database, she told attendees of the International Symposium on Human Identification, this case would not have been able to be solved by genetic genealogy.

She said she understood why GEDmatchs owners made the decision, but the result was allowing some violent criminals to remain free for longer than they would have been with the full power of genetic genealogy. She pleaded with her audience to take DNA tests and upload their profiles into GEDmatch.

We dont want this very valuable tool to slip out of our hands, Moore said.

Curtis Rogers didnt ask for this.

Rogers, 81, works in Florida as a court-appointed guardian for the elderly. He founded GEDmatch as a free public service in 2010 after being inspired by his own experience connecting with people who shared his last name. He partnered with a computer programmer who wrote software that made it easy for people to find relatives through certain shared pieces of genetic material. The site became popular among professional and amateur genealogists, and as direct-to-consumer genetic testing services grew, GEDmatch enabled people to compare their DNA profiles in a single place.

Rogers knew little of law enforcements interest in his website until the Golden State Killer announcement. The news upset Rogers and some members. But he eventually accepted the sites role in solving violent crimes where other forensic techniques including searches for matches in criminal DNA databases had failed.

I am not totally comfortable with GEDmatch being used to catch violent criminals but I doubt it would be possible to prevent it, Rogers told NBC News last year. I feel it is important to make sure all our users are educated to the possible uses of GEDmatch so they can make up their own minds.

As law enforcement searches of his site surged, Rogers imposed a few restrictions. He allowed investigators to pursue leads on homicides and rapes, but not less serious crimes like assaults.

Then, late last year, police in Utah asked Rogers to use the site to investigate an attack on an elderly church organist, who was seriously hurt but survived. Rogers agreed, and police used GEDmatch to identify a 17-year-old suspect, who was arrested in April.

But that bending of Rogers own rules on how police could use GEDmatch triggered a backlash that led him to change the sites terms of service. On May 18, all GEDmatch members were removed from law enforcement searches and offered a chance to opt in if they wanted to be included.

Ethicists said the decision ensured that users would be properly informed about how their profiles would be used.

People using genetic genealogy databases for their own purposes never anticipated this kind of access to their genetic information or that information being used to identify people theyre related to, said Amy McGuire, director of the Center for Medical Ethics and Health Policy at the Baylor College of Medicine.

There is a genuine tension between wanting to protect consumers and be respectful of their wishes and recognizing that working with law enforcement provides a social benefit, she said.

A Baylor College of Medicine survey last year found 91 percent of respondents favored law enforcement using consumer DNA databases to solve violent crimes, and 46 percent for nonviolent crimes.

But with fewer links from GEDmatch to examine, investigators now have to spend more time seeking connections that could lead them to a killer. That means chasing down more leads, or asking innocent distant relatives to submit their DNA for genetic testing in hopes that their profile will help fill out the family tree. That kind of target testing raises its own set of privacy concerns.

You only need to look at the pace of press releases since the time of the Golden State Killer and see that there was virtually one every week, if not more, and the pace of those cases being solved has reduced itself, said Anne Marie Schubert, the district attorney in Sacramento County, California, where she oversaw the Golden State Killer investigation.

The limited GEDmatch access ultimately means higher costs for law enforcement who turn for help to Parabon, which dominates the private market for such work, or FamilyTreeDNA, one of the earliest direct-to-consumer genetic testing companies.

It also means that more cases might remain unsolved.

If I had a larger team, we would certainly try more cases, Moore said. But because agencies are paying Parabon, we dont want them to waste valuable resources or give false hopes.

Rogers says he has done the right thing for his members, and for the field he loves.

We are here for genealogists, not for law enforcement, he said. On the other hand, law enforcement is here to stay. I feel a big obligation to make sure its used properly. I dont want some half-cocked law enforcement person to do something that creates a story and ruins everything for everyone.

Rogers has sent emails to members urging them to allow law enforcement to search their profiles, linking to a video message from a relative of one of the Golden State Killers victims.

Many of these families have suffered for decades. They need your support, he wrote in an email to members. We hope you will encourage others who have been genealogically DNA tested to also add their information. We believe it is the caring thing to do.

So far, Rogers said, 181,000 members have opted in. Thats far from the critical mass of 1 million that some researchers say is needed to solve cold cases with regularity. It could be many months, and perhaps years, before GEDmatchs law enforcement-accessible database reaches that size.

Im sorry we had to do this. However, I feel very strongly that when we bit the bullet and did what we did, we set the whole future on a much stronger base, Rogers said of genealogy. Two or three years from now, this whole thing will be forgotten.

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Police were cracking cold cases with a DNA website. Then the fine print changed. - NBC News

Clinical exome sequencing has revolutionized genetic testing for children with inherited disorders, and Baylor College of Medicine researchers have led efforts to apply these DNA methods in the clinic. Nevertheless, in more than two-thirds of cases, the underlying genetic changes in children who undergo sequencing are unknown. Researchers everywhere are looking to new methods to analyze exome sequencing data to look for new associations between specific genes and those rare genetic diseases called Mendelian disorders. Investigators at theHuman Genome Sequencing Centerhave developed new approaches for large-scale analysis of Mendelian disorders, published today in theAmerican Journal of Human Genetics.

The investigators used an Apache Hadoop data lake, a data management platform, to aggregate the exome sequencing data from approximately 19,000 individuals from different sources. Using information from previously solved disease cases, they established methods to rapidly select candidates for Mendelian disease. They found 154 candidate disease-associating genes, which previously had no known association between mutation and rare genetic disease, according toAdam Hansen, lead author of the study and graduate student inmolecular and human geneticsat Baylor.

We found at least five people for each of these 154 genes that have very rare genetic mutations that we suspect might be causing disease, Hansen said. This shows the power of big data approaches toward accelerating the rate of discovery of associations between genes and rare diseases.

These computational methods solve the dual problems of large-scale data management and careful management of data access permission. saidDr. Richard Gibbs, study author and professor of molecular and human genetics and director of the Human Genome Sequencing Center at Baylor. They are perfect for outward display of data from the Baylor College of Medicine programs.

Exome sequencing currently only diagnoses 30 to 40% of patients, Hansen said. He hopes that diagnosis rate will increase with the discovery of new associations between mutations in certain genes and rare diseases.

The genetics community can now focus on genetic mutations in these genes when they see undiagnosed patients, Hansen said. Since our initial analysis, 19 of these genes have already been confirmed as disease-associating by independent researchers. The collective effort of the genetics community will advance our understanding of these genes and provide further evidence for their potential role in disease.

Other researchers at the Human Genome Sequencing Center who were involved in the study included Mullai Muragan, Donna Muzny, Fritz Sedlazeck, Aniko Sabo, Shalini Jhangiani, Kim Andrews, Michael Khayat, and Liwen Wang.

This work was supported in part by grants UM1 HG008898 from the National Human Genome Research Institute (NHBLI) to the Baylor College of Medicine Center for Common Disease Genetics; UM1 HG006542 from the NHGRI/National Heart, Lung, and Blood Institute (NHLBI) to the Baylor Hopkins Center for Mendelian Genomics; R01 NS058529 and R35 NS105078 (J.R.L.) from the National Institute of Neurological Disorders and Stroke (NINDS); and P50 DK096415 (N.K.) from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

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Connecting gene mutations, rare genetic diseases - Baylor College of Medicine News

PENCOED, Wales, Oct. 23, 2019 /PRNewswire/ --ReNeuron Group plc (AIM: RENE), a UK-based global leader in the development of cell-based therapeutics, is pleased to announce that new data relating to its CTX stem cell platform will be presented today at the 27th Annual Congress of the European Society of Gene and Cell Therapy(ESGCT), a leading scientific conference taking place this week in Barcelona, Spain.

Dr. Steve Pells, Principal Investigator at ReNeuron, will present new data showing the phenotypic stability and scalability of a mesenchymal stem cell line derived from the Company's proprietary, conditionally immortalized, human neural stem cell line (CTX) following re-programming to a pluripotent state.

The Company has previously presented data demonstrating that its CTX stem cell line, currently undergoing clinical evaluation for the treatment of stroke disability, can be successfully and rapidly re-programmed to an embryonic stem cell-like state enabling differentiation into any cell type. In essence, this means that the Company is able to take its neural stem cells back to being stem cells that can be made to develop into any other type of stem cell including bone, nerve, muscle and skin.

The new data being presented today show for the first time that these CTX-iPSCs (induced pluripotent stem cells) can indeed be differentiated along different cell lineages to generate, for example, mesenchymal stem cell lines. Further, the mesenchymal stem cell lines generated can be grown at scale by virtue of the Company's conditional immortalization technology, enabling the efficient production of clinical-grade cell therapy candidates.

These results are particularly encouraging as they demonstrate that CTX, a well-characterized, clinical-grade neural stem cell line, could be used to produce new conditionally immortalized allogeneic (i.e. non-donor-specific) cell lines from any of the three primary germ cell layers which form during embryonic development. ReNeuron is currently exploring the potential to develop further new allogeneic cell lines as potential therapeutic agents in diseases of unmet medical need for subsequent licensing to third parties.

Further information about the conference may be found at:

https://www.esgct.eu/congress/barcelona-2019.aspx

"The data we are presenting at the ESGCT Annual Congress represent a significant advance in the use of cell re-programming to generate new allogeneic cell lines as potential therapeutic candidates," commented Dr. Randolph Corteling, Head of Research at ReNeuron. "Importantly, the maintenance of the immortalization technology within these new cell lines may allow for the scaled production of 'off the shelf' allogeneic stem cells, such as haematopoietic stem cells as a potential alternative approach to those cancer immunotherapies currently in development that rely on the use of the patient's own T-cells."

About ReNeuronReNeuron is a global leader in cell-based therapeutics, harnessing its unique stem cell technologies to develop 'off the shelf' stem cell treatments, without the need for immunosuppressive drugs. The Company's lead clinical-stage candidates are in development for the blindness-causing disease, retinitis pigmentosa, and for disability as a result of stroke. ReNeuron is also advancing its proprietary exosome technology platform as a potential delivery system for drugs that would otherwise be unable to reach their site of action. ReNeuron's shares are traded on the London AIM market under the symbol RENE.L. For further information visit http://www.reneuron.com.

ENQUIRIES:

ReNeuron

+44 (0)20 3819 8400

Olav Helleb, Chief Executive Officer

Michael Hunt, Chief Financial Officer

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+44 (0) 20 7466 5000

Mark Court, Tilly Abraham

Argot Partners (US)

Stephanie Marks, Claudia Styslinger

Stifel Nicolaus Europe Limited

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Jonathan Senior, Stewart Wallace, Ben Maddison (NOMAD and Joint Broker)

N+1 Singer

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ReNeuron Presents Positive Data at the 27th Annual Congress of the European Society of Gene and Cell Therapy on Lead Cell Line - PRNewswire

Stem Cell Therapy Market: Snapshot

Of late, there has been an increasing awareness regarding the therapeutic potential of stem cells for management of diseases which is boosting the growth of the stem cell therapy market. The development of advanced genome based cell analysis techniques, identification of new stem cell lines, increasing investments in research and development as well as infrastructure development for the processing and banking of stem cell are encouraging the growth of the global stem cell therapy market.

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One of the key factors boosting the growth of this market is the limitations of traditional organ transplantation such as the risk of infection, rejection, and immunosuppression risk. Another drawback of conventional organ transplantation is that doctors have to depend on organ donors completely. All these issues can be eliminated, by the application of stem cell therapy. Another factor which is helping the growth in this market is the growing pipeline and development of drugs for emerging applications. Increased research studies aiming to widen the scope of stem cell will also fuel the growth of the market. Scientists are constantly engaged in trying to find out novel methods for creating human stem cells in response to the growing demand for stem cell production to be used for disease management.

It is estimated that the dermatology application will contribute significantly the growth of the global stem cell therapy market. This is because stem cell therapy can help decrease the after effects of general treatments for burns such as infections, scars, and adhesion. The increasing number of patients suffering from diabetes and growing cases of trauma surgery will fuel the adoption of stem cell therapy in the dermatology segment.

Global Stem Cell Therapy Market: Overview

Also called regenerative medicine, stem cell therapy encourages the reparative response of damaged, diseased, or dysfunctional tissue via the use of stem cells and their derivatives. Replacing the practice of organ transplantations, stem cell therapies have eliminated the dependence on availability of donors. Bone marrow transplant is perhaps the most commonly employed stem cell therapy.

Osteoarthritis, cerebral palsy, heart failure, multiple sclerosis and even hearing loss could be treated using stem cell therapies. Doctors have successfully performed stem cell transplants that significantly aid patients fight cancers such as leukemia and other blood-related diseases.

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Global Stem Cell Therapy Market: Key Trends

The key factors influencing the growth of the global stem cell therapy market are increasing funds in the development of new stem lines, the advent of advanced genomic procedures used in stem cell analysis, and greater emphasis on human embryonic stem cells. As the traditional organ transplantations are associated with limitations such as infection, rejection, and immunosuppression along with high reliance on organ donors, the demand for stem cell therapy is likely to soar. The growing deployment of stem cells in the treatment of wounds and damaged skin, scarring, and grafts is another prominent catalyst of the market.

On the contrary, inadequate infrastructural facilities coupled with ethical issues related to embryonic stem cells might impede the growth of the market. However, the ongoing research for the manipulation of stem cells from cord blood cells, bone marrow, and skin for the treatment of ailments including cardiovascular and diabetes will open up new doors for the advancement of the market.

Global Stem Cell Therapy Market: Market Potential

A number of new studies, research projects, and development of novel therapies have come forth in the global market for stem cell therapy. Several of these treatments are in the pipeline, while many others have received approvals by regulatory bodies.

In March 2017, Belgian biotech company TiGenix announced that its cardiac stem cell therapy, AlloCSC-01 has successfully reached its phase I/II with positive results. Subsequently, it has been approved by the U.S. FDA. If this therapy is well- received by the market, nearly 1.9 million AMI patients could be treated through this stem cell therapy.

Another significant development is the granting of a patent to Israel-based Kadimastem Ltd. for its novel stem-cell based technology to be used in the treatment of multiple sclerosis (MS) and other similar conditions of the nervous system. The companys technology used for producing supporting cells in the central nervous system, taken from human stem cells such as myelin-producing cells is also covered in the patent.

Global Stem Cell Therapy Market: Regional Outlook

The global market for stem cell therapy can be segmented into Asia Pacific, North America, Latin America, Europe, and the Middle East and Africa. North America emerged as the leading regional market, triggered by the rising incidence of chronic health conditions and government support. Europe also displays significant growth potential, as the benefits of this therapy are increasingly acknowledged.

Asia Pacific is slated for maximum growth, thanks to the massive patient pool, bulk of investments in stem cell therapy projects, and the increasing recognition of growth opportunities in countries such as China, Japan, and India by the leading market players.

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Global Stem Cell Therapy Market: Competitive Analysis

Several firms are adopting strategies such as mergers and acquisitions, collaborations, and partnerships, apart from product development with a view to attain a strong foothold in the global market for stem cell therapy.

Some of the major companies operating in the global market for stem cell therapy are RTI Surgical, Inc., MEDIPOST Co., Ltd., Osiris Therapeutics, Inc., NuVasive, Inc., Pharmicell Co., Ltd., Anterogen Co., Ltd., JCR Pharmaceuticals Co., Ltd., and Holostem Terapie Avanzate S.r.l.

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Stem Cell Therapy Market Latest Report with Forecast to 2025 - Health News Office

Most U.S. Dairy Cows Are Descended from Just 2 Bulls. Thats Not Good, reads an NPR article. As I perused the article, it only took me a moment to make a connection to the young earth creationist teachings I was raised on.

A few years ago, Dechow and some of his colleagues at Penn State made a discovery that shocked a lot of people. All the Holstein bulls that farmers were using could trace their lineage back to one of just two male ancestors. Everything goes back to two bulls born in the 1950s and 1960s, he says. Their names were Round Oak Rag Apple Elevation and Pawnee Farm Arlinda Chief.

Or, to put it another way:

When researchers at the Pennsylvania State University looked closely at the male lines a few years ago,they discoveredmore than 99 percent of them can be traced back to one of two bulls, both born in the 1960s. That means among all the male Holsteins in the country, there are just two Y chromosomes.

There are just two Y chromosomes found among all Holstein dairy cows. Ponder that for a moment. And then consider this:According to young earth creationist doctrine, all humans after the flood could trace their lineage back to just one male ancestorNoah.

Think back to what you learned about genetics in high school. Most humans have either two X chromosomes or one X and one Y chromosome. Noah would have had one Y chromosome. His three sons would each have had the same Y chromosome. His grandchildren born after the Flood would also have had the same Y chromosome.Of course, there would have been only one Y chromosome to begin with anyway, hundreds of years before thisAdams.

Young earth creationists play fast and loose with genetics. Genetics does not work this way, and that its why researchers are worried about the U.S. dairy population.

What weve done is really narrowed down the genetic pool, saysChad Dechow, one of the researchers.

The females havent fared much better. In fact, Dechowan associate professor of dairy cattle geneticsand others say there is so much genetic similarity among them, the effective population size is less than 50. If Holsteins were wild animals, that would put them in the category of critically endangered species.

After the Flood, in young earth creationists telling, there was a human population size of 8. At creation, the human population size was 2. The level of inbreeding that would have to take place to end up with a population of millions (and, today, billions) starting with population sizes of 2 or 8 is mind numbing.

Theres a reason there are high rates of certain genetic defects among the Amish population.

Currently, more than 50,000 Lancaster County Amish can trace their lineage to just 80 ancestors

Fewer ancestors mean more sharing of genetic material and any genetic defects the same linked to potentially fatal hereditary diseases like SCID contained therein.

Meanwhile, genetic defects not found in the settler population remain locally non-existent.

This isthe founder effect, and evidence of it has been found in Amish and Mennonite populations from Pennsylvania and Ohio to Ontario, Canada.

The founder effect, population bottlenecksthese are real things that affect real, actual genetics. Again, you probably learned about these things in high school.

The thing about the founder effect and population bottlenecks is thatthey result in the loss of genetic information.That is simply how it works.

Any elementary science student knows that genetic homogeneity isnt good in the long term. It increases the risk of inherited disorders while also reducing the ability of a population to evolve in the face of a changing environment. Dairy farmers struggling to pay bills today arent necessarily focusing on the evolutionary prospects of their animals, but Dechow and his colleagues were concerned enough that they wanted to look more closely at what traits had been lost.

Young earth creationists typically respond to concerns about population bottlenecks in one of two ways. The either argue that the original couples genes contained far more genetic diversity than our genes today, effectively canceling the bottleneck entirely, or they argue that the genetic diversity we see today is the result of random mutations in DNA over time.

Lets take the first argument first. Genes simply do not work like that. A population can have more genetic diversity, but an individual person cant. A population of fifty adults living in Bozeman, Montana, for example, is going to have less genetic diversity than a group of fifty adults chosen at random from every country in the western hemisphere. But an individual adult in Bozeman is not going to have more genetic diversity than an individual adult in Brazil, Honduras, or Haiti. Genetics does not work like that.

Now, the second argumentthat the genetic diversity we see today is the result of mutations. Most scientists believe that all Y chromosomes that exist today can be traced back to one Y chromosome that existed around 150,000 years ago. In other words, all men living today have a common ancestor, sometimes termed Y-chromosomal Adam. Young earth creationists argue the same thing, but they put this ancestor only 4,000 years ago. And that matters!

Imagine the rate of mutation required to get all the Y chromosomes we have today, in only 4,000 years!Ive said it before and Im sure Ill say it again: young earth creationists are far stronger believers in evolution than any evolutionary scientist Ive ever met.

Ill leave you with one last thing, from an Answers in Genesis article titled The genetic effects of the population bottleneck associated with the Genesis Flood:

There is one other consideration to make before we conclude the discussion of created diversity, however: the introduction of mutations to the population prior to Babel. Mutational load in children increases with the age of the father (due to the fact that older men pass on gametes that have gone through many more generations/genome copying events than younger men). Thus, any child born to an ancient person could theoretically carry many genetic differences from other people. Extrapolating from the data of Crow, a man 500 years of age would donate approximately 10,000 mutations to a child (the current average is two orders of magnitude less than that). Konget al.concluded that every extra year of paternity adds an average of about 2 additional mutations. This would mean Noah would only contribute slightly more than 1,000 mutations (40 baseline mutations + 500 years x 2) after age 500. But they also discuss models with an exponential mutational increase over time and only studied men under age 50. Either way, it could be said that Noah, by far the oldest to have fathered children recorded in biblical history, was genetic poison to the future world population, as he would be expected to have contributed many new mutations to each of his three sons (and possibly his daughters-in-law, if they were daughters).

Yes. Yes, they really went there.Its ok that all humans are descended from one coupleNoah and his wifebecause Noah fathered his three sons when he was 500 years old, so they would have had lots and lots of mutations. Yep.

What was that I said about young earth creationists being stronger believers in evolution than any evolutionary scientist out there?

I guess that gives us a solution for the Holstein dairy cows, anywayresearchers should just breed them when theyre super old and their genetic diversity will come back. Because Im sure thats exactly what will happen. (It does not work like that.)

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What Do Dairy Cows' Y Chromosomes Have to Do with Young Earth Creationism? Plenty. - Patheos

Studies have shown that there is a link between cardiovascular health and brain health, but it is unclear whether genetic or environmental factors are most important in determining them both. A new study in twins suggests that nurture, rather than nature, may be decisive.

Evidence from different studies has suggested that there is a strong link between cardiovascular health and brain health.

Researchers have explained that poor cardiovascular health can, with age, contribute to dementia mechanisms, affecting cognitive function.

But what predisposes a person to poorer or better cardiovascular and brain health? So far, scientists have been unable to answer this question with any degree of certainty.

Generally speaking, there are two types of factors that could influence aspects of heart and brain health in the long term. These are genetic (nonmodifiable) factors and environmental (modifiable) factors, a conjuncture that people sometimes refer to as the "nature vs. nurture" conundrum.

To try to determine whether genes or environmental factors play a more important role in long term health outcomes for the heart and brain, researchers from Emory University in Atlanta, GA, decided to study a cohort able to provide more solid answers: pairs of twins.

Identical (monozygotic) twins have the same genetic profile, while fraternal (dizygotic) twins share about 50% of their genes. As a result, pairs of twins can allow researchers to compare the effects of nature with those of nurture more effectively than other populations.

In the current study the findings of which appear in the Journal of Alzheimer's Disease the researchers analyzed the data of 272 male pairs of monozygotic and dizygotic twins, which they were able to access via the Vietnam Era Twin Registry. All of the participants were free of both cardiovascular disease and dementia at baseline.

More specifically, the investigators looked at the relationship between cardiovascular health which they determined by scoring blood sugar and cholesterol, blood pressure, body mass index (BMI), physical activity, diet, and cigarette smoking and cognitive performance.

"Our study across the entire sample of twins confirmed that better [cardiovascular health] is associated with better cognitive health in several domains," notes senior author Dr. Viola Vaccarino, Ph.D.

"The analyses further suggested that familial factors shared by the twins explain a large part of the association and thus could be important for both cardiovascular and brain health," she adds.

According to the findings of the study, the association between heart and brain health was similar among all pairs of twins, regardless of whether they were identical or fraternal.

The researchers believe that some of the modifiable factors that contribute to a predisposition toward certain heart and brain health outcomes include factors relating to early family life, as well as socioeconomic status and education.

"Improving population-level [cardiovascular health] scores, which are extremely low in the United States, has the potential to reduce the burden of dementia along with heart disease," notes co-author Dr. Ambar Kulshreshtha, Ph.D.

"Because [cardiovascular health] factors are modifiable, prevention of cardiovascular risk factors and promotion of a healthy lifestyle beginning early in life should achieve the best results for promoting not only cardiovascular health but also cognitive health."

Dr. Ambar Kulshreshtha, Ph.D.

The findings, the investigators add, are relevant in the context of the American Heart Association's 2020 Strategic Impact Goal. This goal is a 20% improvement in cardiovascular health and a 20% reduction in deaths from cardiovascular diseases and stroke in the U.S., both by next year.

Read this article:
Heart and brain health are connected, but what influences both? - Medical News Today

Dr. Peter Schlegel, M.D., urologist-in-chief at New York-Presbyterian/Weill Cornell Medical Center and president of the American Society for Reproductive Medicine, Jan. 6, 2019

Barbara Collura, president of RESOLVE: The National Infertility Association, Jan. 10, 2019

Dr. Gloria Bachmann, M.D., director of the Women's Health Institute at Rutgers Robert Wood Johnson Medical School in New Jersey, May 22, 2019

Dr. Marc Goldstein, M.D., director of the Center for Male Reproductive Medicine and Microsurgery at the NewYork-Presbyterian Hospital/Weill Cornell Medical Center, Jan. 4, 2019

Alice Domar, Ph.D., an associate professor of obstetrics, gynecology and reproductive biology at Harvard Medical School and director of Integrative Care at Boston I.V.F., Jan. 11, 2019

Paul Flynn, 46, a social worker in Sacramento, Calif., Jan. 17, 2019

Denny Ceizyk, 52, author of Almost a Father: A Memoir of Male Infertility, Jan. 19, 2019

Diagnostic Evaluation of the Infertile Male: A Committee Opinion, Fertility & Sterility, March 2015

Treatment of Male Infertility (Beyond the Basics), UpToDate, September 2019

Temporal trends in sperm count: a systematic review and meta-regression analysis, Human Reproduction Update, November 2017

Maternal, infant and childhood risks associated with advanced paternal age: The need for comprehensive counseling for men, Maturitas, July 2019

The Negative Impact of Higher Body Mass Index on Sperm Quality and Erectile Function: A Cross-Sectional Study Among Chinese Males of Infertile Couples, The American Journal of Mens Health, Jan. Feb. 2019

Tobacco smoking and semen quality in infertile males: a systematic review and meta-analysis, BMC Public Health, January 2019

Habitual alcohol consumption associated with reduced semen quality and changes in reproductive hormones; a cross-sectional study among 1221 young Danish men, BMJ Open, September 2014

Type of underwear worn and markers of testicular function among men attending a fertility center, Human Reproduction, September 2018

Diet and men's fertility: does diet affect sperm quality? Fertility & Sterility, September 2018

Report on varicocele and infertility: a committee opinion, Fertility & Sterility, December 2014

Mens Experience of Infertility: Findings from a Qualitative Questionnaire Study, Fertility Network U.K., November 2017

Originally posted here:
Male Infertility: What to Know and How to Cope - NYT Parenting

While Gunnison Sage-grouse population numbers have declined over the last four years, federal agents are penciling out what recovery looks like for the species listed as threatened under the Endangered Species Act (ESA).

The U.S. Fish and Wildlife Service (FWS) soon will release its draft Recovery Plan for the bird, whose greatest population lies in the Gunnison Basin.

After the bird was determined to be threatened in 2015, local conservation efforts have been underway in an attempt to preserve the species and avoid a potential endangered listing, which carries much more stringent restrictions. The draft Recovery Plan is the next step in fulfilling requirements under the threatened listing and sets both population and habitat goals which must be achieved for the bird to be delisted.

Things can change over time its not set in stone forever, said FWS Regional Director Noreen Walsh.

FWS representatives met with stakeholders in Gunnison last week to explain the three-step process for Recovery Planning and Implementation under the ESA. While the draft Recovery Plan has yet to be released, FWS officials outlined its contents during the meeting.

The first step in the planning process a Species Status Assessment (SSA) was completed last April. It includes details about each of the eight populations of grouse, said FWS biologist Allison Vendramel.

The SSA informs the second step the Recovery Plan which outlines criteria, actions, time and cost involved in achieving target population and habitat goals. Once released, the public will have 60 days to offer input on the Recovery Plan.

Finally, a Recovery Implementation Strategy will be created to fulfill delisting criteria. Vendramel noted that each step can be revised and expanded as more information is learned in the process.

The road to recovery

The current draft Recovery Plan, Vendramel said, calls for resiliency, redundancy and representation for the species, and that objective and measurable thresholds would signify when recovery likely has been met.

Resiliency, she said, is dependent upon population numbers and the birds ability to adapt to annual climate fluctuations, while redundancy is reliant upon the number of grouse and their distribution. Finally, representation is indicated by the birds ability to adapt to change, its genetic make-up, behavior and ecological conditions. All three qualities must be demonstrated for the bird to be delisted.

The plan sets population and habitat goals as well. Five of the eight grouse populations will be subject to high-male count targets and habitation requirements. For the high-male count target, a running three-year average was determined over the course of at least seven consecutive years.

During the time period used for the calculation, the birds population numbers were highest. From the high-male count, population estimates are generated.

Populations which must achieve high-male count and habitat targets are located in the Gunnison and San Miguel basins, Pion Mesa, Crawford and Monticello. The Gunnison Basin, Vendramel said, demonstrates the greatest resiliency.

Two of the Gunnison Sagegrouse populations Dove Creek and the Cerro Summit-Cimarron-Sims Mesa (CSCSM) will only be required to have the amount of habitat which could potentially support a high-male count target, without actually requiring the number of males.

High-male count for Dove Creek is set at 30 while the same target for CSCSM is only seven.

Efforts to improve some populations

Colorado Parks and Wildlife (CPW) Grouse Conservation Coordinator Kathy Griffin estimates the Gunnison Basins population at 2,862 and the birds population throughout its entire range at 3,299. Those numbers have declined from high estimates in 2016 of 4,440 and 5,141, respectively.

She speculated that the decline was due to two years of drought followed by a harsh winter with late and heavy snows.

Griffin said grouse numbers for both the Gunnison and greater sage-grouse are down across their range in virtually every state, indicating it may be due to normal population fluctuations.

In Gunnison County, efforts have focused on improving habitat and minimizing future impacts to the grouse. In 2006, the county adopted regulations that seek to minimize development conflicts through its landuse review process.

By way of comparison, San Miguel County has taken a different approach than Gunnison County to preserve habitat and protect the bird by focusing on conservation easements. However, like other satellite populations, county leaders have only seen a declining trend in the annual counts, said San Miguel County Commissioner Hilary Cooper.

The San Miguel Basin population, she said, continues to be threatened by oil and gas activity, powerlines, habitat fragmentation and weather changes, and her county is learning from Gunnison Countys example.

Much of our Gunison Sagegrouse habitat is on BLM land and we are actively engaged in protests and litigation against Bureau of Land Management actions that directly impact occupied habitat and threaten the bird, specifically with oil and gas activity, Cooper told the Times. The county is currently developing a GIS analysis in order to guide the most effective actions based on the latest science and lessons learned from the more successful efforts in the Gunnison Basin population.

Steps toward delisting

Recovery actions offered in the draft Recovery Plan include site-specific interventions. Areas prioritized to minimize stressors such as noise and development would be within the four-mile radius of an active lek, according to the plan.

The draft recommends improving public awareness, offering incentives and resources to conserve and improve habitat quality and quantity and better data collection. Recovery actions include relocating Gunnison Basin birds to other populations which have enough habitat to sustain them, and conserving existing habitats by improving management plans.

Finally, delisting the bird was defined during last weeks meeting. Once a species is delisted, Vendramel said a community must decide if it wants to maintain measures which have resulted in recovery.

Delisting is the Fish and Wildlife using a biological rationale to say, This species does not need the protection of the ESA, said Vendramel, noting that when targets are achieved the federal agency exits the picture.

Still, she questioned whether communities would have the will to keep a species such as the grouse from being relisted.

Weve reached a threshold, she said of the situation that exists when targets are met. Does a community want to stay above that threshold?

Recovery Implementation Strategy workshops are scheduled throughout the birds population area in January. The final draft of the Recovery Plan is slated for approval in October 2020.

(Chris Rourke can be contacted at 970.641.1414 or at chris.rourke@gunnisontimes.com .)

See the original post here:
Steps outlined for grouse recovery - Gunnison Country Times

Cheetah Conservation Station keepers at the Smithsonians National Zoo are celebrating the arrival of a male lesser kudu calf, who was born Oct. 14 to 5-year-old mother Rogue and 9-year-old father Garrett. During their routine animal health assessments, keepers found that Rogue had given birth and observed the calf nursing, moving well and exploring his environment. A neonatal veterinary exam the following day, Oct. 15, found the calf to be healthy and strong. He is steadily gaining weight, growing from about 13 pounds at the time of his exam to about 19 pounds at 9 days old.

Animal care staff are allowing the calf to bond with mom in a quiet enclosure behind the scenes. His 10-month-old brother, Kushukuru, was present for the birth and continues to spend evenings with the calf and their mother. The younger kudu will make his public debut later this fall, weather permitting.

Keepers describe the calf as bold and alert, and they are looking forward to watching the young brothers explore the habitat, chase one another and spar with each other and their father. The Zoo will provide details about the calfs debut on its Facebook, Instagram and Twitter accounts as the date approaches. Meantime, visitors can view Garrett and Kushukuru at the Cheetah Conservation Station, along with two Abyssinian ground hornbills named Karl and Karoline that share their habitat.

Rogue arrived at the Zoo in October 2016 from the St. Louis Zoo in Missouri, per a recommendation to breed with Garrett. Most of the Zoos animals participate in the Association of Zoos and Aquariums Species Survival Plan (SSP). The SSP scientists determine which animals to breed by considering their genetic makeup, nutritional and social needs, temperament and overall health. This is the second calf for both Rogue and Garrett.

Native to arid and semi-arid areas of northeastern Africa, including parts of Ethiopia, Somalia, Kenya, Sudan, Uganda and Tanzania, lesser kudu are listed as near threatened by the International Union for Conservation of Nature. Lesser kudu number about 100,000 in the wild, but the population is decreasing due to habitat loss from human and livestock expansion, hunting and disease.

# # #

Caption: Lesser kudu female Rogue with her newborn male calf behind the scenes at the Zoos Cheetah Conservation Station.

Continued here:
Lesser Kudu Born at Smithsonian's National Zoo - Smithsonian's National Zoo and Conservation Biology Institute

In a recent article for Current Affairs, Nathan Robinson describes Harvard psychologist Steven Pinker as the most annoying man in the world because Pinker is the type of person who constantly insists hes Just Being Reasonable while he is actually being extremely goddamn unreasonable. Although Robinsons article was a bit harsh in tone, it gestures at something very real: were in the midst of an epidemic of intellectuals, almost entirely white men, who claim to embody Reason and Rationality while flagrantly and habitually succumbing to the same tribalistic tendencies that they identify as the Ultimate Enemy.

My own experience with Pinker and his ilk exemplifies the problem. Last January, I published an article here at Salon that summarized some extremely detailed criticisms that I wrote of Pinker's book "Enlightenment Now!" More specifically, I examined a few pages in the books Existential Threats chapter, one line or passage at a time, since my own research focuses on existential threats (that is, threats to civilization and humanity) and thus I have some knowledge of the topic.

Although Pinker is widely known, or at least was at one point, as a clear-headed, objective intellectual of the highest caliber, his chapter on existential threats was overflowing with quotes taken out of context, misrepresented ideas, false dichotomies, blatantly inaccurate claims, poor reasoning, dubious citations, condescending straw-man attacks and cockamamie ad hominems. If the chapter had been a first-year undergraduate term paper, and if the professor were an exceptionally easy grader who habitually dished out As for poorly researched papers, Pinkers chapter might have received a C.

(The popularity of poor scholarship seems to be on the rise, incidentally. Just consider the egregious mistakes made by Jared Diamond in his most recent book, "Upheaval.")

What was most telling, though, was the response to my article. For example, the founding editor of Skeptic magazine, Michael Shermer, tweeted this in response to my critique:

Where @RichardDawkins had his fleas (The Dawkins Delusion etc.), @sapinker has his cockroaches (the oleaginous Phil Torres desperate for attention), artfully squashed here:

Shermer then linked to a blog post by Jerry Coyne, which contained a response from Pinker. Before getting to that, though, Shermers tweet is notable for a couple of reasons. First, not only does it contain a personal attack, but the personal attack is overtly uncivil. Thats a bit humorous given that Shermer, as well as Pinker, are famous for accusing progressives, especially those who care about women and people of color, of incivility. For example, in May of this year, Pinker tweeted:

Are you concerned about the growing illiberalism, incivility, intellectual conformity, and repression of debate in today's universities? Join us at the meeting of the society set up to encourage viewpoint diversity and constructive debate on campuses. Ill be giving the keynote.

But Pinker did nothing to call out Shermer for his patently crude, puerile behavior, which has also included calling people he disagrees with (seriously) namby-pamby bedwetters and (seriously) losers. This is perhaps unsurprising when one realizes the Pinker has unwaveringly supported Shermer despite multiple women accusing Shermer of sexual harassment, assault and even rape. To my knowledge, Pinker has made no effort to contact any of Shermers purported victims. And why would he? What does truth have to do with standing by your comrades? Instead, Pinker has repeatedly de-emphasized the issue of rape in society and college campuses by tendentiously pointing to opinions that support his preferred views rather than by honestly examining the totality of evidence, which gives a quite different perspective. All of this is very worrisome, tribalistic behavior. But it gets worse.

Back to the blog that Shermer references. The particular post was published by Jerry Coyne, a biologist at the University of Chicago who has become something of Pinkers bulldog, defending him against any and all criticisms no matter what, with (almost) no questions asked. One of the most recent examples is Coyne coming to Pinkers defense after a picture emerged of Pinker with Jeffrey Epstein, the child sex-trafficker who recently killed himself in a New York jail cell.

Coyne quickly dismissed criticisms of Pinker hanging out with Epstein as mere slander and character assassination, writing that suggestions that Pinker should have known better disturbed me so much since Pinker is a friend whose character I respect. The problem is that Pinker appears in the photo with Epstein and he tweeted out an affidavit defending Epstein after Epstein was convicted of sex crimes, which happened in 2008. That is inexcusable and gross but not to Coyne, whose allegiance is rooted not in evidence but loyalty.

So it should be no surprise that Coyne tore into my critique of the existential threats chapter, inaccurately calling it a hit piece. Indeed, by any reasonable account, the article was a substantive critique of shoddy scholarship. In fact, I was in touch with four scholars or writers whose work Pinker misrepresents within just a few pages of the chapter. All of them were unhappy with the quality of Pinkers work, so its not like this was just me being a grump.

For example, the political economist Eric Zency, whom Pinker incorrectly describes as an engineer, was livid that Pinker had used a line from one of his papers to mean the exact opposite of what Zency had intended. In an email to me about Pinkers misuse of his quote, Zency remarked, How this guy managed to become a public intellectual in fields so far removed from his expertise is something to wonder at. I agree.

Pinker also wrote a response to my critique, but it only further justifies the view that Pinker is or has become, sadly an ideologue who cant acknowledge when hes wrong. Just consider that the second sentence of his response makes an ad hominem claim that Im trying to make a career out of warning people about the existential threat that AI [i.e., artificial intelligence] poses to humanity. Since ['Enlightenment Now'] evaluates and dismisses that threat, it poses an existential threat to Phil Torress career.

This is obvious nonsense. First of all, the same thing could be said about Pinker: Since his career these days is based on claiming that things have been going quite well for humanity, convincing people that AI poses an existential threat itself could be seen as an existential threat to Pinkers reputation. How Pinker and Coyne both missed this obvious flaw suggests that they werent wearing their critical-thinking hats. The aim of Pinkers comment was to discredit a critique without having to engage with its substance.

Once again, I contacted four scholars or writers who affirmed errors in a small handful of pages in Pinkers chapter. I have no doubt that if someone were to find the same problems in a chapter written by, say, Reza Aslan or Linda Sarsour, both of whom are loathed by the Pinker-Coyne crew, theyd be hailing the critique as proof that Aslan and Sarsour are intellectual frauds.

Pinker then defended one of his most flagrant mistakes: classifying a computer scientist at UC Berkeley, Stuart Russell, as someone who isnt worried about AI. The exact opposite is true! Pinker then doubled down, insisting that his description of Russell was accurate, even though Russell himself told me in an email, which I quote in my article, that hed seen this [mention in Pinker's book] and I agree its an incorrect characterization. So, you have Pinker on one side refusing to acknowledge that he incorrectly characterized a person who says he has been incorrectly characterized. This led Julia Galef, a notable effective altruist who hosts the Rationally Speaking podcast and has knowledge of the relevant issues, to tweet:

Im frustrated Steven Pinker wont admit an error in Enlightenment Now.Summary:- Pinker names Stuart Russell as an expert whos skeptical of AI risk- Someone points out that's exactly backwards; Russell is one of the main experts warning about AI risk- Pinker doubles down

She concludes that the point is its bad that Pinker got this fact wrong and wont admit it. This encapsulates the central problem: Pinker and his ilk dont acknowledge errors when they make them; they are ideologues rather than truth-seekers, willing to bend the facts, launch personal attacks and censor critics to win debates. At exactly the moment in history when we need true intellectual leadership, people who exemplify intellectual honesty and integrity, the most, we get stubborn tribespeople.

But the problem is hardly confined to those mentioned above: Shermer, Coyne and Pinker. Consider another Intellectual Dark Web (IDW) luminary, Sam Harris, one of the most famous atheists in the world because of his book "The End of Faith." Previously, I never had any reason to believe that Harris was racist but I do now. He has spent a massive amount of time and energy defending Charles Murray, author of "The Bell Curve," which argues that black people are inherently inferior to white people.

Over and over again, ad nauseam, Harris has used his large platform to suggest that Murray isnt a junk scientist peddling cowardly racist memes, but someone whos been victimized by those anti-truth progressives. Even more, Harris apparently believes Murrays claim that blacks are genetically dumber than whites. In a podcast with Josh Zepps, Harris opines the following with a wholly unjustified degree of epistemic confidence:

As bad luck would have it, but as youd absolutely predict on the basis of just sheer biology, different populations of people, different racial groups, different ethnicities, different groups of people who have been historically isolated from one another geographically, test differently in terms of their average on this measure of cognitive function. So if youre gonna give the Japanese and the Ashkenazi Jews, and African Americans, and Hawaiians youre gonna take populations who differ genetically and we know they differed genetically, thats not debatable and you give them IQ tests, it would be a miracle if every single population had the same mean IQ. And African Americans come out about a standard deviation lower than white Americans. A standard deviation for IQ is about 15 points. So, if its normed to the general population, predominantly white population for an average of 100, the average in the African American community has been around 85.

In other words: black people are dumber than white people. Why? Because of genetic evolution, meaning that IQ is in the genes and the genes of white people are, well, just plain better. What a bold stance, especially amid the ongoing rise of white nationalism in the U.S. and Europe!

In all seriousness, the irresponsibility of being a public intellectual with a large following and spouting unsupported claims with the sort of certainty you might expect from someone reciting the second law of thermodynamics is shocking. If Pinker is annoying, as Robinson claims, then Harris is intolerably obnoxious, constantly demeaning people for not being Rational and Reasonable while simultaneously making anintellectual fool of himself with claims like those above.

Other examples could be adduced, but I dont have an extra 20,000 words to spare. The point is that the entire IDW movement is annoying. Its really, really annoying its champions misrepresent positions without their (mostly white male) audience knowing, and then proceed to embarrass the opposition. They embrace unsupported claims when it suits their narrative. They facilely dismiss good critiques as hit jobs and level ad hominem attacks to undercut criticism. And they refuse they will always refuse, its what overconfident white men do to admit making mistakes when theyre obviously wrong. I am annoyed, like Robinson, mostly because I expected so much better from the most popular intellectuals of our time.

Go here to see the original:
Steven Pinker, Sam Harris and the epidemic of annoying white male intellectuals - Salon

Women wait with their malaria-struck babies for treatment in Angola. Will opponents of gene ... [+] engineering deny prevention to families like these?

Mosquitoes are not just obnoxious summer pests they are a serious health threat to most of the world. In fact, the WHO calls mosquitoes one of the deadliest animals in the world.

Why? Mosquitoes carry and spread diseases to humans that cause millions of deaths every year. The biggest threat is malaria: a half a million lives are lost annually, and Africa alone loses $12 billion in health care, productivity, investment, and tourism to the disease. Then theres Zika, dengue, chikungunya, and yellow fever each carried by mosquitoes, and each extracting their toll in human lives and livelihood.

But now, there is hope that biotechnology can help solve this crisis. The solution lies in genetically modifying a small population of mosquitoes and releasing them into malaria-prone areas. These mosquitoes carry a lethal gene that kills larvae before they reach adulthood and carry malaria to others, just stunting human illness.

Oxitec is a British biotechnology company doing just this. Over the last fifteen years or so the company has introduced Friendly Technology. Oxitecs latest results back up historic successes in Brazil, which saw dengue cases in one area reduced by 91% in a small trial. Their latest study showed a 96% reduction in mosquito numbers, this time using a more effective strategy of targeting the biting, egg-laying females - albeit leaving non-biting males to survive and reproduce. A great success, on the face of it.

The anti-GM backlash

However, Oxitec and others are taking a lot of flak from the anti-GM lobby, which according to the Genetic Literacy Project spent $850 million in the last five years alone opposing everything from the way we label genetically engineered food to fabric thats fermented from sugar.

The backlash was triggered by a paper that, ironically, seems likely to be retracted (or at least highly modified) due to exaggerated predictions of more robust mosquitoes, among others. Though reports of genetic mixing between surviving introduced mosquitoes and local mosquitoes were valid, the lethal gene was not actually present - which was the most likely outcome considering the lethality of the gene in question. A lethal gene will naturally diminish in frequency among a population.

But another consideration is to ask: does it even matter, all things considered, when eradication of disease should be the goal?

The risk of inaction

Mosquitoes are utterly deadly, and even when theyre not they provide among the largest disease burden on the planet. Tuberculosis may kill more people (around 1.3 million per year, compared with around 450,000 for malaria). But malaria infects 20 times that number of people.

Those 219 million annual malaria cases cost low income countries a significant chunk of their GDP up to 1.3% in the worst affected while just a 10% reduction in malaria was associated with a 0.3% growth in a much cited study on the economic burden of malaria. For Uganda, the economic gain from eradicating malaria would total around $50 million USD.

This doesnt take into account emerging diseases such as dengue and Zika virus, among others. In Brazil, the focus of Oxitecs recent trials aiming to reduce numbers of Aedes aegypti, 1.2 million people were infected with dengue in the first six months of 2019 six times more than in 2018 with an associated 388 deaths. Zika virus, carried by the same mosquito, exploded onto the scene in 2015 and has been associated with a range of effects on babies born to infected mothers in 10% of cases.

Yes, there are likely some knock-on ecosystem effects of releasing Oxitec mosquitoes. There might well be reduced prey for fish that eat the larvae, or less food for some of the birds that eat the flying insects. However, mosquitoes are not irreplaceable as far as the wider ecosystem is concerned, especially pests such as Aedes aegypti. There are another 3000 species of mosquito other than the three which primarily cause disease in people.

The World Health Organization (WHO) brands Aedes aegypti mosquitoes as being exquisitely adapted to city life, and that they prefer to breed in artificial containers. Given this information, it makes it even less important that lethal genes might persist among the wider population of these costly pests, less so that they might be eradicated - an opinion seemingly shared by researchers who have looked into the potential environmental costs associated with getting rid of the worst species of disease-bearing mosquitoes.

It all boils down to a cost/benefit analysis. Is the risk of some genetically modified mosquitoes passing on transgenes to wild populations worse than the risk of millions of people being infected with haemorrhagic fever and malaria, or babies being born with abnormally small heads (microcephaly)?

In any case, we will always have to take measures to reduce the burden of disease. What about the alternative forms of pest control and their relatively indiscriminate, off-target effects?

What is natural?

Oxitec, the company responsible for releasing genetically modified mosquitoes, have always known and stated - explicitly so - that some mosquitoes would survive to breed and pass on their genes. They have also taken measures to ensure that populations containing the lethal gene eventually go their predestined way.

In fact, their latest mosquitoes are meant to pass on genes to wild populations, this time to reverse the naturally occurring genetic mechanisms that render mosquitoes resistant to pesticides such as DEET. (Incidentally, multi drug resistance in the malaria parasite itself is also increasing).

To put our collective minds at ease, its worth pointing out that nature is weirder than what Oxitec is doing. mosquitoes perform their own version of enforced sterilisation, whereby male tiger mosquitoes (of the species Aedes albopictus) can mate with, and sterilize, female Aedes aegypti mosquitoes.

The fact that diseases such as Zika and dengue are present in Brazil in the first place is evidence that we are about as far removed from whatever natural used to mean as we can possibly be. Zika was introduced by a traveller from French Polynesia. The only way it got to Brazil was by aeroplane.

Its not just Zika traversing the globe in such a manner. There are emergent diseases popping up left, right and center, and it is not an easy task to keep them in check. The WHO warned us over ten years ago that infectious diseases are emerging at a rate not seen before. (One example is West Nile Virus, a mosquito-borne disease first described in 1937 in Uganda but discovered in New York in the summer of 1999. It is becoming more prevalent in California and will soon reach Silicon Valley and the San Francisco biotech region.)

It is no wonder. We live in a globally connected world with a rapidly expanding population that is a hotbed for disease-causing agents to emerge, mix, and spread (from viruses and bacteria to malaria parasites), which means that we need highly innovative, modern solutions to control them. Its an evolutionary arms race, and we need all the tools we can muster. If one of them happens to include lethal genes that successfully wipe out local populations of disease-causing mosquitoes, so be it.

Mosquito-borne diseases already threaten half of the global population.And as the climate warms and favors the mosquito, these diseases could spread to a billion more people.

Clearly, our current methods of control havent quite been enough to stop 219 million people becoming afflicted with malaria each year, or an increasing number suffering and dying from dengue and other diseases. Its not genes escaping that is the problem, but the sheer difficulty in eradicating mosquitoes and their diseases at all.

We must proceed carefully with new genetic engineering technologies, but we must also weigh the risks of inaction: each year hundreds of millions of people mostly children needlessly die, get sick, or suffer genetic defects. GMO mosquitoes are something we can do about it.

So what would you rather have: GMO mosquitoes or dying babies?

Acknowledgement: Thank you to Peter Bickerton for additional research and reporting in this post.

Please note: I am the founder ofSynBioBeta, and some of the companies that I write about are sponsors of theSynBioBeta conference(click herefor a full list of sponsors).

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British Biotech Company Sees Hope In Reducing Mosquito-Borne Diseases And Deaths With GMOs - Forbes

COLUMBUS, Ohio The first overmatched victim ofOhio State defensive end Chase Youngflashes on a projector screen in the Buckeyes football facility. Defensive coordinator Jeff Hafley hits pause to single out an offensive tackle from Florida Atlantic, frozen in game-film infamy amid an autopsy of Youngs sacks.

Hafley see-saws the film until it stops in the precise place that shows Young vaulting a half-step toward the quarterback an instant after the snap. Theres a tone of pity in Hafleys voice, as the Florida Atlantic linemen are still lined up perfectly still like a row of folding chairs.

A half-step advantage for a defensive lineman is like a 10-yard cushion for a wide receiver, and Young appears poised to bull-rush past the line with the ease of fans flowing through a turnstile.

Not one of the offensive linemen is moving, Hafley said, shaking his head. Its. Over. Doesnt it look like hes running out of the blocks in a track meet?

When the film resumes, Young proceeds to barrel around the edge virtually unimpeded for one of his 9.5 sacks, a total thats tied for No. 1 in college football. The frozen moments of singular dominance have come in flourishes through seven games, as the image of Youngs blond dreadlocks splayed out behind him as he mauls helpless quarterbacks has seemingly played on a loop this season.

Young is a 6-foot-6, 270-pound freak who appears to be darting toward greatness like, well, a sprinter coming out of the blocks. Former BuckeyeNick Bosacompares Youngs skill set to elite NFL rush endsKhalil MackandVon Miller, two generational pass-rush talents. That type of get-off, Bosa told Yahoo Sports recently. He has that speed first, power second.

Youngs potential invokes the hyperbole of an athlete that can change the paradigm of the position. Along with consistently mangling quarterbacks, he can also fluidly drop back into coverage, block kicks and has an imposing physique that one NFL scout likens toLeBron James.

The natural comparison for Young in Columbus remains the Bosa brothers, former Buckeyes who went No. 2 in the 2019 draft (Nick) and No. 3 overall in 2016 (Joey). Both Bosas have performed at a level that justify those lofty picks, but former OSU coach Urban Meyer says that Young may be the most talented of the three.

The guy looks like the Predator, said FAU coach Lane Kiffin,mimicking Youngs popular nickname. Theres only 10 guys like him in the world.

NFL scouts see him the same way, as hes widely considered the most talented prospect in all college football. His draft position will be reflective of the quarterback desperation among the NFLs most despondent franchises. Hes what you want from a guy who is going to be the No. 1 pick, said a veteran NFL scout. Hes a super athlete, hes massive and hes been productive.

Youngs emergence is a combination of fortunate genetics, conscientious parenting and a flurry of bold-faced mentors. They begin with Carla and Greg Young, his exacting mother and father who shepherded his journey through do-your-own-laundry discipline and strict regiments of pushups and tough love. Young also learned along the way from No. 1 NBA draft pick Markelle Fultz and No. 2 NFL pick Nick Bosa, and lapped up all the lessons of Larry Johnson, the Buckeyes defensive line Yoda.

As Ohio State (7-0) pursues its first College Football Playoff bid since 2016, Young is simultaneously sprinting toward meeting Fultz, his old DeMatha Catholic High School hoops teammate, in the rarest of airs. I used to tell him when I was younger that I was going to be the No. 1 pick in basketball, Fultz said. And he was going to try and meet me up top and be the No. 1 pick in football.

How didChase Younggrow into the most feared player in all of college football? It all starts with how he grew up.

The stories of Chase Youngs accelerated trajectory begin at age 3, at his familys home in Cheltenham, Maryland. When Young first jumped off the diving board at the familys housing development, he debuted with a front flip. From there, Young kept somersaulting ahead of his peers.

The evolution of Chase Young into a generational prospect starts with his parents, who provided both outsized genetics and a diverse plan for success. Greg Young is 6-foot-10, a lunar eclipse of a human who played college basketball at Bowie State and still holds the burly build of a 1980s NBA power forward. Carla Young is 6-foot, and while she didnt play sports, she helped set the tone of work ethic and competitiveness in the family.

Greg is retired from Arlington County Sheriffs Office after years of working the 7 p.m. to 7 a.m. shift. Carla has worked the last 32 years for the Department of Transportation and 34 overall years for the federal government. Greg Young worked 15 days a month, a schedule that allowed him to train his kids. (Chases sister, Weslie, played college basketball at North Carolina Wesleyan). The Youngs believed in both physical and mental development, with specialization frowned upon and weights and trainers not necessary.

The training began soon after their kids could walk. Greg and Carla insisted their kids play outside, with skateboards, sandboxes and trampolines luring their kids out of the house. They didnt do video games, Carla said, proudly.

Ohio State star Chase Young has been building up to this moment his whole life. (Yahoo Sports illustration/Photos courtesy of Young family)

Chase Young played soccer until eighth grade, played basketball until his junior year of high school and ran track into high school, developing the footwork, speed and dexterity inherent to those sports. Chase even played the piano, saxophone and violin. In high school, he sang in the choir at St. Vincent Pallotti (Maryland) before transferring to DeMatha Catholic.

Chase may be the most physically blessed player in college football, but he didnt begin seriously lifting weights until late in high school. He built a strong core with 100 pushups and 200 sit-ups a day, as Greg believed in Herschel Walkers philosophy that physique could be built on the weight of the body.

Greg insisted on toughness, including enrolling Chase to play football with older kids. Chase played quarterback for the Patuxent Rhinos, a team of 9-year-olds, easily memorizing and executing the full assortment of plays. There was just one issue. Every time he got hit, he would get up crying, Greg said. They were like, Why's he always crying? I said, He's 6!

Chase didnt get a cell phone until high school, never had a television in his bedroom and wasnt allowed to grow out his dreadlocks until 10th grade. Attendance at Sunday church was mandatory, as was family dinner with Carla cooking up meatloaf, mac-and-cheese and greens, piled high for growing kids. Privileges came with accomplishment, as Chase was allowed to get tattoos only after he got to Ohio State. Carla relented after a memorable text: Are you still gonna love me if I get a tattoo? Chase asked. Carla lets out her hearty trademark laugh. Of course!

Chase began washing and ironing his own clothes at age 7, with the unappealing alternative of having to wear dirty clothes. He began mowing the lawn at age 10 and he and his sister both were in charge of packing their own lunch.

A lot of parents can learn from them, said Randy Ransom, one of Chases youth coaches and a family friend. I wouldnt say they sheltered him, but they told him the rules and he abided by them.

As Chase navigates the final stretch of college until his vast potential will collide with professional riches, he looks back with appreciation. What my parents did, he says, it's the reason why I am who I am today.

Nick Bosa laughed on the other end of the phone. He knew the question was coming and chuckled upon its arrival. Hed grown up in the five-star shadow of his brother, Joey, so hes had years of refining his dodging technique. Chase can be as good as he wants, Nick Bosa said. I dont want to compare.

The making of Chase Young into a prospect that can inhabit the same rare conversational sphere as the Bosas continued upon his arrival at Ohio State in 2017. At that time, Joey Bosa was a burgeoning star on a defensive line where every starter Jalyn Holmes, Tyquan Lewis, Sam Hubbard and Nick Bosa ended up getting drafted.

Nick Bosa most appreciated how Youngs desire to learn and grow into a star matched his physical promise, as he jokes Young showed up at 270 pounds with a six pack. After a lifetime as Joeys little brother, Nick enjoyed the role reversal in mentoring Young.

He saw me as a role model, I guess, which was cool, Nick Bosa said. I was always looking up to people. To have someone younger than me looking up to me was cool.

The education of Chase Young came at the feet of Bosa, the loaded defensive line room and its wise leader, Johnson, the 68-year old position coach who has tutored a daunting eight first-round defensive linemen. The best evidence of Johnsons wizardry could be seen on a recent Monday in the Ohio State football facility, as his players sat outside his office, eager to seek his counsel and grandfatherly advice.

Johnson saw a unique inquisitiveness in Young during his recruitment, as Young would constantly text him during recruiting to ask question normal recruits wouldnt ask. What was it like recruiting this guy? Where do you see my weight? Where do you see me playing?

Hes probably the most intriguing guy Ive ever recruited, Johnson said.

Chase Young (2) chases down the ball carrier during the Ohio State Buckeyes' win over the Florida Atlantic Owls. (Getty)

It has become a perfect marriage of teacher and student, as Hafley calls Johnson one of the best pass-rush coaches hes ever been around. Young has evolved from a raw athlete to a nuanced pass rusher, mastering techniques like Johnsons trademark side-scissoring the offensive linemans hands away to be able to turn his hips and flip to the quarterback. Thats why some guys make $30 million and some guys dont, said Meyer, now a Fox analyst, of Youngs hips. Chase has the speed, size and flexibility.

Strength coach Mickey Marotti saw the final stages of Youngs evolution come this winter. He began paying forward the advice Nick Bosa passed onto him, motivating and teaching young linemen like former five-star Zach Harrison and redshirt freshman Javontae Jean-Baptiste. In the circle of life in the Buckeye defensive line room that Johnson calls moving the yardstick, Bosa still sends clips of good rushes to Young on Snapchat. Young passes on the message to the next generation.

Ohio State coach Ryan Day noticed Youngs off-field development a few days into summer camp, when the Buckeyes came out with low energy during pre-practice stretching. Without any prodding from coaches, Young got in front of the team and barked at them to follow his juice and energy.

Hes prompted other guys to take the lead, and you see guys coming out of their shells, Day said. In this day and age, with this generation, thats not easy to do.

When asked about Youngs physical dominance, Marotti keeps steering the conversation back to his personal attributes. Marotti teases Young that he needs a hair net for his blond locks. Young shoots back by poking fun at Marottis size-12 feet, abnormally large for a man of modest height. Marotti jokingly calls Young a newscaster politician, as their conversations veer to topics like the secrets of Marottis marriage. Its really fun, Marotti says. Hes very inquisitive, its like hes a grown-up.

Young isnt nave to the NFL riches that potentially await him in the upcoming months. He went on YouTube before the season to learn to meditate to help with focus. What hes doing right now, hes leaving a legacy, Day said. In a day and age when people get caught up in whats next, he really wants to leave a legacy here. That makes him special.

Greg Young beams when relaying the genesis of one of his sons best pass-rushing attributes, a first-step toward that Marotti calls ginormous. Greg declares: The first step came from basketball.

Young transferred to DeMatha, the erudite school outside Washington D.C., midway through his sophomore year in 2014. The move came primarily because of his football potential, but he also played one season of JV hoops and one on varsity. That coincided with Fultzs senior season of 2015-16, around the time hed emerged as a favorite to become the No. 1 pick in the 2017 NBA draft.

Youngs time playing basketball for veteran coach Mike Jones wont invoke memories of DeMatha legends like Danny Ferry, Victor Oladipo or Adrian Dantley. But Young says he entered high school at 5-foot-6 and still was growing into his body. I definitely had to struggle, Young said. I wasnt always this big, this fast in high school.

Young backed up Josh Carlton, a 6-foot-11 forward who has gone on to become a starter at UConn. Jones insists that Young earned more playing time than he was given, but Jones said he wanted to showcase the players who specialized in basketball to help their futures. Even then, Chases football future was clear.

Chase was a luxury, Jones said. I dont say that negatively at all. If we needed someone to go into the game and knock the snot out of someone, wed put him in. But he was a much better player than that. His role for us was definitely not consistent with what his ability was.

Markelle Fultz and Chase Young look on before a DeMatha Catholic High School basketball game. (Photo credit: Mike Jones)

That role meshed philosophically with how Greg taught Chase to play, as he wanted his son to test opponents by fouling them as hard as possible early in the game. Theyre either going to want to fight you, Greg reasoned, or theyre going to cry.

Jones recalls Young accepting his role, admiring how both he and his family never complained about playing time. Jones remembers Young just as fondly in the classroom, as Jones teaches public speaking at DeMatha. He complimented Youngs engagement in the class Young would be the first to offer concise feedback or say, Yo pay attention, before a classmates presentation. When he said it, Jones said with a laugh, everyone straightened up and fixed their ties.

Fultz and Young, who were friends prior to DeMatha, still stay in close touch. They trade texts, including mutual support, as they share a unique bond. I always tell him, Young said, its a matter of time before he gets healthy and its a wrap for the whole NBA.

Fultz has gone through what Young is facing, and hes told him to keep his circle tight.

[I want to make sure he] doesnt let all the hype and stuff get to him, which I dont think will happen, Fultz said. Hes a humble young man who works extremely hard. I tell him to be himself and watch the people around you.

That giant first step for Chase Young is leading to his scintillating final steps, as collegiate glory and professional riches all loom within reach. As he aims to meet his old teammate atop a different draft, Chase Young is secure in acknowledging who guided him there one pushup and laundry load at a time.

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Why freaky OSU DE Chase Young is the best player in college football: Theres only 10 guys like him in the world - Yahoo Sports