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Bone Marrow Transplantation: Autologous and Allogeneic …

Hematopoietic stem cell transplantation (HSCT) is the new name for bone marrow transplantation.

The bone marrow is home to hematopoietic stem cells (HSCs), also called pluripotent stem cells because they can give rise to any cell your body requires at any given moment. These specialized cells play an essential role in replenishing our blood supply on a daily basis to maintain blood counts in a healthy host. These cells can be collected either by performing repeated bone marrow aspirations or by mobilizing HSCs into the circulation using special medications called cytokines (like GCSF, also called neupogen), and filtering them out of your blood using a highly specialized process called apheresis. After they are collected from your body, these stem cells can be preserved by storing them in a chemical called DMSO, and placing them in a freezer. Stem cell transplantation refers to a process whereby the patients HSCs are replaced by new cells (either from yourself [autologous] or someone else [allogeneic] that grow into a healthy hematopoietic system.

There are many types of HSCTs depending on the source of stem cells as described below:

Autologous Stem Cell Transplantation:

Autologous stem cell transplants are predicated on a simple concept: if a little chemotherapy has the potential to cure, than a lot could be even better. For lymphoma that has come back after conventional chemotherapy, this disease is not usually sensitive to lower doses of chemotherapy, so there is a need to consider higher doses. The challenge of course, is that higher doses of chemotherapy, while effective at treating the lymphoma, can also destroy all your bodys normal blood cells. Hence, after receiving high dose chemotherapy, there is a need to re-infuse your own normal stem cells, collected before you get the high dose therapy.

The use of your own stem cells, collected and frozen prior to the high dose therapy, is referred to as an autologous stem cell transplant. The most common indications for this kind of stem cell transplant are recurrent non-Hodgkin lymphoma and Hodgkin lymphoma. Typically, the patient undergoes chemotherapy to put their cancer into remission. At some point during their treatment they are assessed for HSCT that includes evaluation of the marrow to ensure healthy stem cells as well as adequate heart, lung and liver function. If they qualify then the stem cells are collected usually by apheresis.

In this process, stem cells that have been stimulated to divide and mobilized by medications (ex: GCSF or Neupogen) are filtered out of the circulation through an IV and stored for future use. Once the stem cells are collected, the patient undergoes further conditioning chemotherapy to destroy all cancer cells in their body. This kind of treatment can be toxic to stem cells and may result in long term inability to produce blood. The previously collected stem cells are infused back into the patient and after 7 to 10 days the blood counts recover and the patient can go home. Since these are the patients own cells there is no danger of graft rejection or graft versus host disease. The immune system may take up to a year to fully recover.

Allogeneic Stem Cell Transplantation:

Unlike autologous stem cell transplants, allogeneic stem cell transplants are predicated on the idea that if your immune system could not detect and destroy your lymphoma before it became obvious, then maybe an immune system from someone else (a sibling or an unrelated but matched person), can identify your lymphoma as foreign, and mount an immune response against it. The problem of course is that while the donor immune system, now transplanted and growing in a new host (that is the patient), can recognize the lymphoma as foreign (graft versus lymphoma effect, or GVL), it can also recognize the normal organs of the host as foreign, and mount a graft versus host (GVHD) response against your skin, lung, liver, and gastrointestinal tract. Drugs to suppress the immune system, called immunosuppressants, are often used to help control GVHD, but can obviously compromise some of the GVL effect as well. It is a double edge sword you want GVL without the GVHD, but unfortunately the two go and-in-hand. Indications for allogeneic stem cell transplant typically include acute myeloid leukemia, aggressive lymphomas, and stem cell disorders. A donor for a patient is defined by HLA typing of blood and tissues.

HLA stands for Human Leukocyte Antigen, and describes a series of proteins that exist on the surface of all cells in your body, and which is defined genetically. The degree of relatedness between individuals can be described by the similarities or differences in these genes that code for the HLA proteins, and are used to determine who might be a suitable donor for any given patient. The more closely related the individuals (say identical twins), the lower the risk of GVHD, but the lower the risk of GVL. The greater the difference in the HLA, the greater the risk of GVHD, but consequently, the greater the GVL benefit. Of course, if the toxicity of the GVHD is so great, producing increased mortality, then the GVL benefit becomes inconsequential. Thus, allogeneic transplanters walk a very fine line in assessing each patients individual risk and benefit with this type of transplant.

An HLA matched donor is needed for the host to allow the donor blood cells to engraft in the marrow, otherwise they will be rejected by the bodys immune system. The best donor, usually meaning the least degree of graft versus host disease (GVHD), is usually a sibling. Each person has about a 25% chance of having an HLA matched sibling donor. HLA matching is different from blood typing and can be done by a simple blood test or obtaining a swab from the inside of a persons mouth. Should no siblings be identified as a match, than a search is initiated to find an unrelated HLA match through the National Marrow Donor Program (NMDP). Once a match is identified, the patient is admitted to the hospital to receive conditioning chemotherapy and / or radiation therapy. At the end of this treatment, stem cells from the donor are infused into the patient and allowed to engraft. Even with an HLA matched donor there is a considerable risk of GVHD where the new grafted donor cells will attack the patients organs.

After the transplant, the patient is given immunosuppressive medications to prevent this condition, and is required to be on these for a considerable period of time.

Cord blood transplants:

Umbilical cord blood is an excellent source of stem cells and can be used as a source of stem cells in cases where an unrelated donor cannot be found. This has saved the lives of many patients. HSCT is a complicated process that requires a commitment from the patient and their families for the best outcome .You will be referred to a specialized center for HSCT where you will receive further details and education about the process.

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Bone Marrow Transplantation: Autologous and Allogeneic ...

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Bone Marrow Stem Cell Transplant HSCT : National …

In January 2019, an international team of researchers led by Richard K. Burt, MD (Northwestern University, Chicago, IL) published results of the first randomized, control trial of bone marrow stem cell transplant (HSCT) in people with aggressive relapsing-remitting MS. They enrolled 110 people whose MS was not controlled by available disease-modifying therapies. Half received immunosuppressant therapy followed by hematopoietic (blood cell-producing) stem transplant. The other half were switched to a different disease-modifying therapy. Significantly fewer people experienced MS progression in the group that underwent HSCT, compared with the group who were switched to a different MS disease-modifying therapy. There were no deaths or life-threatening adverse events in either group. The investigators consider this study to be preliminary and recommend that further research is needed to confirm these findings and to determine longer-term outcomes and safety. Read the summary or read the abstract in JAMA.

In December 2018, Drs. John Moore, David Ma (St. Vincents Hospital, Darlinghurst, NSW, Australia) and colleagues reported results of a small clinical trial of HSCT conducted at a single medical center in Australia. This trial enrolled 35 people with relapsing-remitting MS or secondary progressive MS whose disease had not responded well to disease-modifying medications. There was no control group or blinding; all participants underwent the HSCT procedure. The team reported on results after following participants from 12 to 66 months after transplantation. After 12 months, 82% remained free of relapses, MRI-detected new or enlarging lesions, and progression (called Event-Free Survival or EFS). At two years after transplant, 65% of the group had EFS, and at three years 60%. EFS was better in those who had relapsing MS. Of 8 who experienced MS progression after transplantation, 2 had relapsing-remitting MS and 6 had secondary progressive MS. Twelve of thirteen whose disability scores improved after transplantation had relapsing-remitting MS.At this center, which has a long experience with bone marrow transplants, there were no transplant-related deaths. Many experienced complications expected from the chemotherapy cocktail (called BEAMS) used to deplete their bone marrow cells in preparation for the transplant. Read a summary or read the abstract in the JNNP.

In April 2017, researchers in Italy combined and analyzed results from 15 previously published studies of HSCT (Hematopoietic Stem Cell Transplantation) involving 764 people with various forms of MS. They found that overall, the procedure showed a significant benefit against disease activity and progression. Two years after transplantation, about 83% of all participants had not progressed; overall, studies involving more people with relapsing-remitting MS had lower progression rates. The pooled results showed an overall transplant-related mortality rate of 2.1%.There were fewer deaths in later studies as researchers gained more experience with the procedure. Read a summary of more details here or the abstract in Neurology

In February 2017, results of an international study were published. The study evaluated long-term outcomes from HSCT in 261 people with different forms of MS. The transplants took place between 1995 and 2006, with a follow-up period of up to 16 years. Several different transplant protocols were followed. After 5 years, 46% still had not experienced any progression or worsening of symptoms, including 73% of those with relapsing MS and 33% of those with secondary progressive MS. Eight deaths (2.8%) occurred within 100 days of the transplant. Most of these occurred during the early development of the procedure; improvements in patient selection and transplant techniques have significantly reduced the mortality. Those with the best outcomes tended to be younger, had relapsing MS, lower accumulation of disability and had used fewer MS therapies prior to the transplant procedure. Additional research is needed to better understand who might benefit from this procedure and how it compares to the benefits of powerful immune-modulating therapies now available. A phase 3 trial of HSCT is now in planning stages. The Society is engaged with the team planning the trial and is encouraging quick action to design and launch the trial.Read a summary of the results or the paper in JAMA Neurology

In February 2017, results were published from a multi-center, 5-year trial called theHALT MS Study. It tested HSCT in 24 people with MS and active relapsing-remitting disease that was not controlled by disease-modifying medications. Results suggest that after five years, 69.2% of participants experienced no new disease activity after the procedure and did not need disease-modifying therapies to control their disease. All participants experienced severe and/or life threatening adverse events. Most of these occurred within the first 30 days after transplant and were related to low white blood cell counts and infections. This trial, which was funded by the National Institutes of Health, is an important addition to research needed to determine whether this approach to stem cell transplantation is safe and effective in people with MS. A larger, phase 3 trial is in planning stages.Read a summary of the results or the paper in Neurology

In June 2016 researchers in Canada published results of a long-term HSCT trial involving 24 people with aggressive relapsing-remitting MS whose disease was not controlled with available therapies. Three years after the procedure, 70% remained free of disease activity, with no relapses, no new MRI-detected inflammatory brain lesions, and no signs of progression. None of the surviving participants experienced clinical relapses or required MS disease-modifying therapies to control their disease, and 40% experienced reductions in disability. One participant died and another required intensive hospital care for liver complications. All participants developed fevers, which were frequently associated with infections, and other toxicities.Read more about this study

In October 2015, researchers at the University of Genoa and other institutions in Italy reported on a small trial of HSCT in seven people with very active relapsing-remitting MS that was not controlled with MS disease-modifying therapy. They underwent a low-intensity lympho-ablative regimen in which the immune system was suppressed but not completely depleted before the stem cell transplant as an approach to reducing toxicity. The investigators did MRI scans (for 3 years) and clinical evaluations (for 5 years). They found dramatic reductions of MRI-detected inflammation after the procedure, but did not achieve complete absence of inflammation. After 5 years, two participants remained stable, one significantly improved, and four had mild disease progression. One experienced a relapse after treatment. No severe side effects occurred. The authors conclude that the low-intensity regimen they used was not sufficient to treat aggressive MS.Read an abstract from the paper(Multiple Sclerosis 2015 Oct;21(11):1423-30) In January 2015, doctors at Northwestern University published their10-year experience of treating people with HSCT. The report included 123 people with relapsing-remitting MS and 28 with secondary-progressive MS. Their method is nonmyeloblative HSCT, in which the immune system is suppressed but not completely depleted before the stem cell transplant. Individuals were followed from 6 months to 5 years, or an average of 2.5 years. The EDSS disability scores improved, compared to pretreatment, by one point or more in 64% of those followed out to year 4. Relapses and MRI-detected disease activity were also reduced. In evaluating which type of individuals benefited from the therapy, the doctors suggested that people with relapsing-remitting MS who had had MS for ten years or less showed improvements in their disability scores, whereas those with secondary-progressive MS or disease duration greater than ten years did not show improvements on their disability scores. They reported no treatment-related deaths or serious infections. ITP (immune-mediated thrombocytopenia), a potentially serious bleeding disorder, developed in 7 people, and thyroid disorders developed in 7 people.Read a summary of their resultsor thepaper in JAMA (Published onlineJanuary 20, 2015).

Ongoing Research in HSCTAdditional research is focusing on figuring out who might benefit from this procedure and how to reduce its risks. HSCTis being investigated in Canada, the United States, Europe and elsewhere. For example:

Dr. Richard Burt of Northwestern University in Chicago has recently begun a new phase 3 clinical trial at Northwestern to try to determine the optimal protocol for safety and benefit. Read more about this trial on A clinical trial is getting underway at medical centers in Denmark, Netherlands, Norway and Sweden. The trial is testing treatment with HSCT compared with alemtuzumab in people with active relapsing-remitting MS. Read more about this trial on

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Thyroid Hormone Treatment | American Thyroid Association

Thyroid hormone is easy to take. Because it stays in your system for a long time, it can be taken just once a day, and this results in very stable levels of thyroid hormone in the blood stream. When thyroid hormone is used to treat hypothyroidism, the goal of treatment is to keep thyroid function within the same range as people without thyroid problems. Keeping the TSH level in the normal range does this. The best time to take thyroid hormone is probably first thing in the morning on an empty stomach. This is because food in the stomach can affect the absorption of thyroid hormone. However, the most important thing is to be consistent, and take your thyroid hormone at the same time, and in the same way, every day. If you are taking several other medications, you should discuss the timing of your thyroid hormone dose with your physician. Sometimes taking your thyroid hormone at night can make it simpler to prevent your thyroid hormone from interacting with food or other medications.

Do not stop your thyroid hormone without discussing this with your physician. Most thyroid problems are permanent, and therefore most patients require thyroid hormone for life. If you miss a dose of thyroid hormone, it is usually best to take the missed dose as soon as you remember. It is also safe to take two pills the next day; one in the morning and one in the evening. It is very important that your thyroid hormone and TSH levels are checked periodically, even if you are feeling fine, so that your dose of thyroid hormone can be adjusted if needed.

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Thyroid Hormone Treatment | American Thyroid Association

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What is Gene Therapy? | Pfizer: One of the world’s premier …

Gene therapy is a technology aimed at correcting or fixing a gene that may be defective. This exciting and potentially transformative area of research is focused on the development of potential treatments for monogenic diseases, or diseases that are caused by a defect in one gene.

The technology involves the introduction of genetic material (DNA or RNA) into the body, often through delivering a corrected copy of a gene to a patients cells to compensate for a defective one, using a viral vector.

The technology involves the introduction of genetic material (DNA or RNA) into the body, often through delivering a corrected copy of a gene to a patients cells to compensate for a defective one, using a viral vector.

Viral vectors can be developed using adeno-associated virus (AAV), a naturally occurring virus which has been adapted for gene therapy use. Its ability to deliver genetic material to a wide range of tissues makes AAV vectors useful for transferring therapeutic genes into target cells. Gene therapy research holds tremendous promise in leading to the possible development of highly-specialized, potentially one-time delivery treatments for patients suffering from rare, monogenic diseases.

Pfizer aims to build an industry-leading gene therapy platform with a strategy focused on establishing a transformational portfolio through in-house capabilities, and enhancing those capabilities through strategic collaborations, as well as potential licensing and M&A activities.

We're working to access the most effective vector designs available to build a robust clinical stage portfolio, and employing a scalable manufacturing approach, proprietary cell lines and sophisticated analytics to support clinical development.

In addition, we're collaborating with some of the foremost experts in this field, through collaborations with Spark Therapeutics, Inc., on a potentially transformative gene therapy treatment for hemophilia B, which received Breakthrough Therapy designation from the US Food and Drug Administration, and 4D Molecular Therapeutics to discover and develop targeted next-generation AAV vectors for cardiac disease.

Gene therapy holds the promise of bringing true disease modification for patients suffering from devastating diseases, a promise were working to seeing become a reality in the years to come.

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What is Gene Therapy? | Pfizer: One of the world's premier ...

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STAR Gene Therapy | Charcot-Marie-Tooth Association

The CMTA Is Accelerating Research Through Gene Therapy

The CMTA looks forward to a time when doctors are able to use genetic therapies to treat the root cause of CMT rather than prescribing medications or recommending surgery. We are already envisioning the possibilities that gene therapy holds for our community of 2.8 million people worldwide living with CMT. In fact, were leading the pursuit to explore gene therapy in CMT by expanding our Strategy to Accelerate Research (STAR) program and our STAR Advisory Board.

At the CMTA, we are already envisioning the possibilities that gene therapy holds for our community of 2.8 million people worldwide living with CMT. John Svaren, PhD, Chair, CMTA Scientific Advisory Board

Given the increased feasibility and applicability of gene therapy to CMT, the CMTA hosted a Gene Therapy Workshop in 2018. In response to invitations from CMTA board member Dr. Steven Scherer, more than 20 of the top gene therapy experts gathered for the inaugural CMT-centered workshop on gene therapy. This meeting included experts who have worked in related genetic and neuromuscular disease areas, as well as clinicians and scientists spearheading efforts toward gene therapy for CMT2D and CMT4J.

Building on this meeting, the CMTA is assembling the best experts to formulate gene therapy strategies for CMT2 and CMT1 subtypes. Four gene therapy experts, Beverly Davidson, PhD, at the University of Pennsylvania, Kleopas Kleopa, MD, at the Cyprus Institute of Neurology & Genetics, Scott Harper, PhD, at the Ohio State University School of Medicine, and Steven Gray, PhD, at the University of Texas Southwestern Medical Center have now joined the Scientific Advisory Board of the CMTA. Dr. Davidson is an acknowledged leader in the gene therapy field, and her extensive experience includes both academic research and commercial translation gene therapy approaches. Dr. Kleopa has shown proof of concept that gene therapy works in two mouse models of CMT: CMT1X and CMT4C. This strategy can capitalize on the CMT animal models that have been developed and characterized with CMTA support. Dr. Harper is collaborating with Robert Burgess, PhD, at the Jackson Laboratory to develop a gene therapy vector to be used in a treatment for CMT2D. Dr. Grays core expertise is in Adeno-Associated Virus (AAV) gene therapy vector engineering, followed by optimizing approaches to deliver a gene to the nervous system, with application to CMT4J.

Our genes dictate many of our personal characteristics; however, mutations in genes cause genetic diseases, such as CMT. Scientists have been working for decades to modify or replace faulty genes with healthy ones to treat, cure or prevent disease. Fortunately, we are seeing significant progress on these efforts to provide gene therapy options for CMT. In fact, recent studies have provided an effective gene therapy for spinal muscular atrophy (SMA), a devastating disorder that affects the same motor neurons that are affected by CMT.

Sometimes the whole gene is duplicated, as in CMT1A, where a chromosome segment around the PMP22 gene is present in three copies instead of two. Alternatively, a part of a gene is defective or missing from birth, causing many of the other known forms of CMT. Any of these variations can disrupt the structure of the protein that is encoded by the affected gene, causing cellular problems that ultimately lead to disease.

In gene therapy, scientists can do one of several things depending on the problem with the gene. The simplest form of gene therapy is to simply provide a correct copy of the gene, which is the basis of the gene therapy for SMA. In variations of this approach, genes that are causing problems can be suppressed. One example of this was the recent demonstration that antisense oligonucleotides can be used to improve the neuropathy in rodent models of CMT1A. In addition, the exciting new field of genome editing using CRISPR technology has now made it possible to correct disease-causing mutations, and collaborative projects have already been initiated with leaders in this field

In order to insert new genes directly into cells, scientists use a vehicle called a vector that is genetically engineered to deliver the correct version of the gene. For example, viruses have a natural ability to deliver genetic material into cells, and therefore, can be used as vectors. While some viruses cause disease, virus vectors are highly modified to remove their ability to cause disease so that they can be safely used to carry therapeutic genes into human cells.

Gene therapy can be used to modify cells inside or outside the body. When its done inside the body, a doctor will inject the vector carrying the gene directly into the part of the body that has defective cells.

Before a company can market a gene therapy product for use in humans, the gene therapy product has to be tested for safety and effectiveness so that the Food and Drug Administration (FDA) can evaluate whether the risks of the therapy are acceptable in light of its potential benefits. Gene therapies have begun to receive FDA approval, and many gene therapies are in clinical trials.

At the CMTA, we believe gene therapy holds the promise to provide effective therapies for people living with CMT. As we continue to make great strides in this area, the CMTA is committed to helping speed the development of gene therapy approaches by investing in the most promising and groundbreaking gene therapy treatments that have the potential to benefit our community.

We are members of the National Organization for Rare Disorders (NORD), and they have put together a six-minute video to help answer questions frequently asked about gene therapy. We think this video will help you better understand the basics of gene therapy.

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STAR Gene Therapy | Charcot-Marie-Tooth Association

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Testosterone Replacement Therapy For Men – Renue Health

Testosterone is a hormone that is present in both men and women. Testosterone is the androgenic hormone primarily responsible for normal growth and development of male sex and reproductive organs, including the penis, testicles, scrotum, prostate, and seminal vesicles. It facilitates the development of secondary male sex characteristics such as musculature, bone mass, fat distribution, hair patterns, laryngeal enlargement, and vocal chord thickening. Additionally, normal testosterone levels maintain energy level, healthy mood, fertility, and sexual desire.

The number of men diagnosed with hypogonadism, commonly referred to as Low T has grown dramatically in recent years due to an increasing awareness of the importance of hormones in a mans health and well being. Research shows that about 1 out of 4 men over the age of 30 may have low testosterone. Circulating testosterone levels decline progressively with age, starting in the second and third decade of life. Testing for testosterone deficiency requires a comprehensive understanding of the intricacies of hormone balance before one makes a commitment to what may be lifelong therapy.

Low Libido

Gaining fat around the middle

If you have any of these common symptoms, it is recommended you have a proper and thorough set of labs drawnto help determine if you havehypogonadism.

Testosterone replacement therapy is essential for men with hypogonadism. In these men, full replacement of testosterone is necessary. The amount of total testosterone in men can range from 300 to 1100 ng/ml, while the range for free testosterone is 50 to 250 ng/ml. It is more accurate to utilize free testosterone levels instead of total T levels.

Because the range is so broad, testosterone optimization must be individualized. In general, Dr. Rob aims to provide the lowest dose of testosterone that relieves symptoms and causes the man to be in the optimized zone. All while monitoring testosterone and its by-products for any potential unwanted side effects. There are several delivery method options and Dr. Rob presents the pros and cons of each before a mutually agreed upon delivery method is instituted.

It is also important to note that men should not be started on testosterone replacement without a careful endocrine evaluation to determine the cause of the low testosterone. Serious conditions including pituitary tumors can present with low testosterone.

Women have testosterone too

Men have 10 to 20 times higher levels of testosterone than women. Nonetheless, even this small amount of testosterone in women is important for maintaining sexual function, and healthy bladder and vaginal function.

When used in small physiologic doses with monitoring of testosterone blood levels, testosterone in women is well tolerated. High doses must be avoided as they can cause facial hair, loss of scalp hair, deepening of voice, and acne. Just like men, womenshould not be started on testosterone replacement without a careful endocrine evaluation to determine if it will provide a health benefit.

ReNue Healthis located conveniently in Springboro, Ohio with easy access from Dayton International Airport, Cincinnati International Airport or the adjacent Wright Brothers Private Airport (MGY) for those travelling by private aviation.Click here for directions and contact information.

Only one visit is necessary to perform a comprehensive history, interview, and education. Follow up evaluations, adjustments and balancing of hormones are done by phone or written communications and a return visit to Dr. Rob is not necessary. Ongoing testing and adjustment is mandatory and performed through a laboratory convenient to your home.

Its that nagging feeling that something does not feel quite right and you cant put your finger on it. Youre a busy person and your own health is the last thing you have time to think about, but think again!

To learn how the ReNue Health Opportunity may help restore your youth and vitality, simply call937-350-5527or visit us online

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Testosterone Replacement Therapy For Men - Renue Health

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Gene Therapy to Treat Macular Degeneration – AMDF

In Boston, scientists are working at the frontier of genetic research in an attempt to cure Macular Degeneration, the leading cause of blindness in the U.S., an enormous task.

Rajendra Kumar-Singh: There are about 3 billion nucleotides in the human genome and just 1 small mistake is sufficient to cause a problem. And when that problem occurs it can lead to inherited retinal degeneration.

Dean Bok: The promises of gene therapy at this point in time are tremendous. In principal, one can replace a bad gene with a good one. Its easier to replace a gene thats recessive, where you need two bad ones in order to produce the disease, and thats where weve had success. The challenge is for genes that are dominant. You need to get rid of the bad guys before the good guys can do their work.

Rajendra Kumar-Singh: Because the source of inherited retinal degeneration is DNA, it makes sense to be able to deliver normal DNA to correct the defect and hence gene therapy is going to be a key player in trying to develop novel therapies for these inherited retinal degeneration.

Narrator: (Animation) An imbalance in the complement system, which helps to fight many diseases, can cause holes or, macs, to form in the macula. A protein called cd59 normally helps prevent this from occurring. At Tufts University they are seeking a way to increase this protein in people with macular degeneration.

Rajendra Kumar-Singh: We plan to express the same protein but at higher levels on the cells that are normally getting damaged in AMD and theoretically we hope to be able to prevent the formation of these macs on these cells. When we use gene therapy we are in fact putting back in a normal version of the gene, such as the protein that is produced from that is now normal and allows the cell to revert to a normal, healthy looking or healthy functioning cell. We can potentially inject just once directly into the eye and that may serve as a therapeutic for the lifetime of the patient whether it be dry AMD or wet AMD. Science is all about solving problems and I would love to be the one to be able to solve this problem and provide some sort of therapies to people who otherwise might potentially go blind. And I think Ill have fulfilled my role as a scientist if I can achieve that.

Rajendra Kumar-Singh, PhD, Professor of Ophthalmology and NeuroscienceTufts University

Dean Bok, Phd, Distinguished Professor of Neurobiology and OphthalmologyUCLA

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Gene Therapy to Treat Macular Degeneration - AMDF

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Crude versus defined CAR T-cell therapy product

In the race for the most potent CAR T-cell therapy, there is a big interest to the issue of purity and composition of the final cell product. In this post, Ill try to summarize the current knowledge about defined CAR T-cell products, based on two clinical studies, published this week.

What is defined product and why it is important?We can roughly divide CAR T-cell products on bulk T-cell or crude and defined composition. Crude CART products are not purified and contain: different ratios of CD4/CD8 T-cells and their subsets, other than T- contaminating cells and non-CAR cells. Defined composition products could be the following:

There are few good reasons for development of defined CART products:

The later is single most important reason, which begs the question Will defined CAR T-cell products deliver superior therapeutic benefit? As of today, vast majority of CART developers manufacture crude cell products. Manufacturing process usually does not include sorting of T-cells on day 0 or purification of T-cells/ CAR+ cells in-process or on a harvest day. Most of developers release final CAR T-cell product with CD3+ cells >80-90%, highly variable CD4/CD8 ratio and % of CAR+ cells.

Preclinical dataAt least one group of researchers have done a lot of experimental and clinical work on defined composition of CAR T-cell products. Defined product/ process development has been done by Michael Jensen lab, initially at City of Hope and then further adapted and modified at Fred Hutchinson Cancer Center and Seattle Childrens Hospital. Stanly Riddells lab from Hutch did a lot of experimental work to demonstrate potential value of defined CAR T-cell product. All together they have tried all versions of defined composition CAR T-cell products, mentioned above. One of recent and the most comprehensive studies by Riddells lab, showed that (1) combination of both CD4 and CD8 T-cells has superior therapeutic potency and (2) naive CD4 cells and central memory (T-CM) CD8 T-cell subsets were the most potent in vivo. Long-term persistence of human memory T-cells was demonstrated by Riddell and Jensen earlier in mouse and primate models. Importance of CD4+CD8 combo rather than use of potent cytotoxic CD8+ cells alone was also demonstrated in numerous studies (check here, here and here). Therefore, experimental studies created a strong rational for favoring T-CM, naive T-cells (T-N) and CD4+CD8 combo in adoptive cell therapy trials.

Feasibility of manufacturing defined T-CM CAR T-cell productBefore I get to the first clinical results, Id like to look at manufacturing process of defined CAR T-cell product. Jensen started with purified CD8 T-CM or CD4 + CD8 T-CM manufacturing process, which described in details here. It includes sequential 2-step CliniMACS procedure for negative selection of CD14/CD45RA/CD4 or CD14/CD45RA-negative cells, positive selection for CD62L (marker of T-CM) and culture with IL2/IL15 for up to 30 days in bags. After two CliniMACS procedures, cell recovery was as low as 0.4% (in contrast to expected 1.4%). If input cell number was usually 5 billions PBMCs, average output cell number before starting a culture was ~19 millions. T-CM recovery efficiency was 26%. Even though, they typically started culture from 7-15 millions of CD8 T-CM cells, generation of ~3 billions of cells in 3-6 weeks was feasible. This manufacturing process was used in 2 clinical trials: NHL1 and NHL2.

In the modified manufacturing process, designed for NCT01865617 trial, included CliniMACS selection of CD4+ bulk population and 2-step CD8 T-CM (see above) or CD8 bulk selection with 2 parallel 15-20 days cultures and mixing CD4:CD8 as 1:1 before infusion. Importantly, CAR+ cells were selected before infusion by a marker (EGFRt). Interestingly, either CD8 T-CM purified on day 0 or CD8 bulk cells yielded only ~40-50% of CD8+/CAR+ cells with T-CM phenotype (CD45RA-CD62L+).Now, feasibility of manufacturing in NCT01865617. 16/30 (53%) patients have passed threshold of 20 T-CM cells/ ul in screening assay for feasibility of manufacturing. From selected products, T-CM were successfully manufactured in all, but 1 cases. 3 out of 30 infused products were not formulated as 1:1 (10%), due to lack of expansion.Id summarize some of my thoughts of defined CAR T-cell product manufacturing feasibility as the following:

Clinical outcomes of using defined CAR T-cell productsResults of 3 clinical trials (NCT01318317, NCT01815749, NCT01318317), using defined CAR T-cell products have been published so far (here and here). However, the therapeutic benefit of using defined versus crude CAR T-cell product remains unclear. Ideally, defined CAR T-cells should be compared with crude product within one trial settings, because even for the same conditions, clinical protocols are very very different between sites. Also, ideally, CD8 bulk vs. CD T-CM or CD8 alone vs. CD8+CD4 combo should be compared within one trial in exactly the same settings. Unfortunately, none of these ideal comparison conditions were met in 3 published trials, mentioned above.

Even though, it seem like CD4 + CD8 T-CM combo performed better in NHL2 trial (75% progression-free survival at 1-year) than CD8 T-CM alone in NHL1 (50% progression-free survival at 1-year), the difference is not significant, due to low number of patients (n=8 in each trial). On top of it, different CAR vectors were used between these trials, culture duration was shorter and CD25+ T-regs were depleted in NHL2 trial manufacturing protocol. So, data cannot be compared. If we look at results of other CAR T-cell lymphoma trials (narrowing to DLBCL), City of Hope results are not much better than reported from other centers (for example, from Penn). CD8 T-CM persistence was not beneficial, compare to data from other centers. Two excerpts from the study, which demonstrate that assessment of defined CAR T-cell product benefit is impossible:

CD19-CAR T cell activity is difficult to assess by disease response, since 9/16 patients were in CR at start of study, and HSCT can also produce CRs.Thus, a T cell product derived from central-memory enrichment as described in these studies, does not persist longer than what is observed in trials with conventional bulk T cells transduced with CARs bearing CD28 co-stimulatory domains.

Now, moving to B-ALL study, published this week in JCI. First of all, B-ALL is not the best condition to assess a difference by clinical outcome between crude and defined CAR T-cell products, because response rate is too high (close to 90%) across the centers no matter what. The authors about outcome:

The 93% remission rate by flow cytometry and 86% MRD-negative CR rate in our study compares very favorably to that reported by others in which CART cells of undefined composition were manufactured using CD19 CARs that incorporate either a 4-1BB costimulatory domain (children and young adults, 79%) or a CD28 costimulatory domain (adults, 75%; children and young adults, 60%) (1-4)

What about persistence? Theoretically, based on experimental work, CD8 T-CM should have superior long-term persistence. But it was not the case. The study showed persistence only at 1 month time point. What about relapses? Maybe application of T-CM will reduce the rate of relapses? No, 9/30 patients in the study relapsed, half of them (5/9) received CD8 T-CM product. Clinical outcome was significantly improved in the study after implementation of different conditioning regiment (with fludarabine). This change significantly complicates and even make impossible data comparison between CD8 bulk and CD8 T-CM groups:

The high overall rate of BM remission of 93% by flow cytometry in this study and differences in lymphodepletion regimens and infused cell doses do not allow comparison of the efficacy of CART cell products manufactured from CD8+ TCM cells or from bulk CD8+ T cells. Analysis of differences in long-term persistence of cell products that were selected for CD8+ TCM or bulk CD8+ T cells in our study was further complicated by our findings that immune-mediated rejection of CART cells occurs in some patients, which may provide an explanation for the loss of CART cells observed in a subset of patients in other studies

To conclude: Despite the strong experimental evidence and very attractive idea behind of defined CAR T-cell products, it is too early to conclude about their therapeutic benefit and superior potency. With greater number of patients and technical improvements in manufacturing (more efficient clinical cell sorting, IL7+IL15 in culture and other), potential benefit of defined CAR T-cell product may become more obvious. Such benefits as dropping a therapeutic dose, better correlation between dose and in vivo expansion dynamics, decreasing donor variability in manufacturing, we can see today already.

Tagged as:CART, cell product, manufacturing

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Crude versus defined CAR T-cell therapy product

Recommendation and review posted by Bethany Smith

Lick Your Rats – Genetics

In our society, we think of anxious behavior as being a disadvantage. But that's because, for the most part, we live in a nutrient-rich, low-danger environment. In the rat equivalent to our world, the relaxed rat lives a comfortable life. It is likely to reach a high social standing, and it doesn't have to worry about where its next meal is coming from. An anxious rat, on the other hand, doesn't do so well. It is more likely to have a low social standing and suffer from diabetes and heart disease.

In another environment, however, the tables turn. The anxious, guarded behavior of the low-nurtured rat is an advantage in an environment where food is scarce and danger is high. The low nurtured rat is more likely to keep a low profile and respond quickly to stress. In the same environment, a relaxed rat might be a little too relaxed. It may be more likely to let down its guard and be eaten by a predator.

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Lick Your Rats - Genetics

Recommendation and review posted by Bethany Smith

Life Extension Mix, 360 capsules | Life Extension

Studies show that people who eat the most fruits and vegetables enjoy healthier and longer lives, but getting the recommended five servings a day is difficult for even the healthiest diets. That's why we created Life Extension Mix, a daily supplement that provides all the high-potency vitamins and minerals needed to form the cornerstone of a comprehensive health maintenance program.

Benefits at a Glance:

Our formula saves time and money by combining the most important nutrients including unique vegetable, fruit, and botanical extracts into one product, eliminating the need to take dozens of separate supplements.

More facts about Life Extension Mix

Life Extension Mix is a state-of-the-art multi-nutrient formula jam-packed with the purest and most potent forms of vitamins, minerals, amino acids, and unique vegetable, fruit, and botanical extracts. In every daily dose of Life Extension Mix, you'll get an extensive array of nutrients:

Bioactive quercetin phytosome

Life Extension Mix contains 5 mg of quercetin that has been integrated into a phytosome. A phytosome is a phospholipid sphere that encases a botanical compound, aiding in its absorption and making it more bioavailable: this quercetin is up to 50 times more bioavailable than standard quercetin. Quercetin supports cellular health, endothelial health, and healthy immune function.


Found in dark red fruits, delphinidins are potent anthocyanin compounds that activate the production of nitric oxide, promoting vascular relaxation and blood pressure support.14 They can also help inhibit inflammatory factors58 and glycation,9 support immune health, and help maintain healthy blood sugar levels within normal range.

Pyridoxal 5'-phosphate

Glycation is a normal part of the aging process that can affect your health.1014 To help inhibit glycation, each daily dose of Life Extension Mix provides 100 mg of pyridoxal 5'-phosphate a metabolically active B6 that has been shown to help inhibit glycation reactions.15-17

Standardized pomegranate extract

Pomegranate supports healthy cardiovascular function32-37 and DNA structure in prostate cells.18-23 Our pomegranate extract is standardized to provide the biologically active punicalagins that are so unique to this fruit. These punicalagins are 100% water-soluble, have a remarkable 95% absorption rate,24 and are highly potent at inhibiting free radicals.25

Blueberry extracts

Blueberry anthocyanin compounds help inhibit free radicals, while blueberry's other active constituents promote healthy lipid and glucose levels for those already within normal range.26-29 Even more exciting: these blueberry constituents may help protect DNA structure.30-34 Life Extension Mix features the wild blueberry extract packed with active blueberry constituents.

Standardized green tea extract

In recent years, the active polyphenol compounds in green tea have been found to help inhibit LDL oxidation, neuronal peroxidation, and help maintain healthy DNA structure.35-44 Life Extension Mix's daily dose contains 325 mg of a decaffeinated green tea extract standardized to provide 98% of the active polyphenols that scientists attribute to green tea's multiple health benefits.

Standardized vegetable extracts

Life Extension Mix offers a wide array of vegetable extracts, including 8 mg of luteolin, a flavonoid found in parsley, basil, celery, and other foods. Luteolin has been shown to inhibit DNA oxidation45 and to inhibit excess levels of cytokines such as interleukin-4 and interleukin-13.46

Our formula features a concentrated broccoli mixture with standardized extracts of sulforaphane and glucosinolates, compounds attributed to broccoli's detoxification, DNA,47-50 and other health benefits,51-71 as well as chlorophyll.72-83A daily dose also provides 200 mg of calcium D-glucarate (supplying 175 mg of D-glucarate), a phytonutrient found in grapefruit, apples, oranges, broccoli, and Brussels sprouts. D-glucarate supports detoxification processes.84-86

Life Extension Mix also contains lutein and lycopene. Lutein, an extract found in in leafy greens such as kale and spinach, has been shown to help maintain critical pigments in the eye macula.87 Lycopene from tomatoes helps to maintain DNA structure and protect against LDL oxidation.88-98

Standardized fruit extracts

In addition to our standardized pomegranate and wild blueberry extracts, Life Extension Mix also features fruit extracts such as bilberry, grape seed, and citrus bioflavonoids to promote healthy circulation help maintain healthy DNA.

Our unique formula is fortified with maqui berry and tart cherry for their antioxidant benefits for heart health as well as muscle and joint function support.99-118 It also includes a customized blend of blackberry, cranberry, plum, elderberry, persimmon, cherry, and other fruits that studies indicate provide multiple favorable effects on the body.

Numerous studies have pointed toward the many benefits of olive polyphenols, and Life Extension Mix contains an olive extract standardized to provide polyphenols like hydroxytyrosol that have been shown to help inhibit LDL oxidation, free radicals, and promote healthy cell membranes.119-131

Sesame seed lignan extract

Sesame lignans promote healthy levels of gamma tocopherol,132,133 enhance the beneficial effects of fish oils, and helping to maintain already-normal cholesterol/LDL levels.134-143 Life Extension Mix provides 10 mg of a sesame lignan extract to supply the direct benefits of the lignans and to augment the effects of vitamin E174 and other nutrients such as gamma-linolenic acid (GLA).

Nutrients to maintain healthy blood glucose levels

Chromium, magnesium, and biotin help maintain healthy blood sugar for those already within normal range.145-156 In addition to highly absorbable forms of magnesium and biotin, Life Extension Mix contains 500 mcg of Crominex 3+, a biologically active chromium complex. Studies on the benefits of chromium supplementation show that doses exceeding 200 mcg a day are required for optimal effects.157-159

High-potency vitamin D3

Researchers today are concerned that many people are not supplementing with enough vitamin D, a critical nutrient for maintaining bone density and healthy cell division.160-167 Currently, most experts in the field believe that intakes of between 1,000 and 10,000 IU for adults will lead to a more healthy level of serum 25(OH)D, at approximately 50-80 ng/mL.168-170

Each daily dose of Life Extension Mix provides 2,000 IU of vitamin D3. What's more, this formula contains only 500 IU of preformed vitamin A. Preformed (not beta-carotene) vitamin A may interfere with the benefits of vitamin D, yet most multivitamins contain between 5,000 and 25,000 IU of preformed vitamin A.171

Cyanidin-3-glucoside (C3G)

Life Extension Mix contains 1.25 mg of C3G to support eye health. Found in blackberries and black currants, this potent compound promotes healthy levels of rhodopsin a compound that absorbs light in the retina and enhance night vision.172-176

In one study, just 50 mg of a berry extract concentrate containing C3G helped aging individuals see better in the darkness after 30 minutes.177 Bioavailable C3G also supports other body functions,178-191 has potent antioxidant properties,192,193 and supports endothelial cell health.194,195

5-MTHF (5-methyltetrahydrofolate)

Folate helps maintain homocysteine levels within the normal range. One dose of our formula contains 400 mcg of the bioactive 5-MTHF form of folate, which is up to 7 times more bioavailable than ordinary folic acid.

Selenium and Apigenin

Life Extension Mix contains three potent forms of selenium (SelenoExcell, Se-methyl-selenocysteine, and sodium selenite). Also newly included is apigenin, a powerful bioflavonoid found in many vegetables and fruits which boosts cell protection.

Why choose Life Extension Mix?

The ingredients in Life Extension Mix are based on over 35 years of clinical research, and we've selected the purest and most potent forms of plant extracts, vitamins, minerals, and other nutrients for maximum absorption. Discover the extensive benefits of Life Extension Mix!

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Life Extension Mix, 360 capsules | Life Extension

Recommendation and review posted by Bethany Smith

Pluripotent Stem Cells 101 Boston Children’s Hospital

Pluripotent stem cells are master cells. Theyre able to make cells from all three basic body layers, so they can potentially produce any cell or tissue the body needs to repair itself. This master property is called pluripotency. Like all stem cells, pluripotent stem cells are also able to self-renew, meaning they can perpetually create more copies of themselves.

There are several types of pluripotent stem cells, including embryonic stem cells. At Childrens Hospital Boston, we use the broader term because pluripotent stem cells can come from different sources, and each method creates a cell with slightly different properties.

But all of them are able to differentiate, or mature, into the three primary groups of cells that form a human being:

Right now, its not clear which type or types of pluripotent stem cells will ultimately be used to create cells for treatment, but all of them are valuable for research purposes, and each type has unique lessons to teach scientists. Scientists are just beginning to understand the subtle differences between the different kinds of pluripotent stem cells, and studying all of them offers the greatest chance of success in using them to help patients.

Types of pluripotent stem cells:

All four types of pluripotent stem cells are being actively studied at Childrens.

Induced pluripotent cells (iPS cells):Scientists have discovered ways to take an ordinary cell, such as a skin cell, and reprogram it by introducing several genes that convert it into a pluripotent cell. These genetically reprogrammed cells are known as induced pluripotent cells, or iPS cells. The Stem Cell Program at Childrens Hospital Boston was one of the first three labs to do this in human cells, an accomplishment cited as the Breakthrough of the Year in 2008 by the journal Science.

iPS cells offer great therapeutic potential. Because they come from a patients own cells, they are genetically matched to that patient, so they can eliminate tissue matching and tissue rejection problems that currently hinder successful cell and tissue transplantation. iPS cells are also a valuable research tool for understanding how different diseases develop.

Because iPS cells are derived from skin or other body cells, some people feel that genetic reprogramming is more ethical than deriving embryonic stem cells from embryos or eggs. However, this process must be carefully controlled and tested for safety before its used to create treatments. In animal studies, some of the genes and the viruses used to introduce them have been observed to cause cancer. More research is also needed to make the process of creating iPS cells more efficient.

iPS cells are of great interest at Childrens, and the lab of George Q. Daley, MD, PhD, Director of Stem Cell Transplantation Program, reported creating 10 disease-specific iPS lines, the start of a growing repository of iPS cell lines.

Embryonic stem cells:Scientists use embryonic stem cell as a general term for pluripotent stem cells that are made using embryos or eggs, rather than for cells genetically reprogrammed from the body. There are several types of embryonic stem cells:

1. True embryonic stem cell (ES cells)These are perhaps the best-known type of pluripotent stem cell, made from unused embryos that are donated by couples who have undergone in vitro fertilization (IVF). The IVF process, in which the egg and sperm are brought together in a lab dish, frequently generates more embryos than a couple needs to achieve a pregnancy.

These unused embryos are sometimes frozen for future use, sometimes made available to other couples undergoing fertility treatment, and sometimes simply discarded, but some couples choose to donate them to science. For details on how theyre turned into stem cells, visit our page How do we get pluripotent stem cells?

Pluripotent stem cells made from embryos are generic and arent genetically matched to a particular patient, so are unlikely to be used to create cells for treatment. Instead, they are used to advance our knowledge of how stem cells behave and differentiate.

2. Stem cells made by somatic cell nuclear transfer (ntES cells)The term somatic cell nuclear transfer (SCNT) means, literally, transferring the nucleus (which contains all of a cells genetic instructions) from a somatic cellany cell of the bodyto another cell, in this case an egg cell. This type of pluripotent stem cell, sometimes called an ntES cell, has only been made successfully in lower animals. To make ntES cells in human patients, an egg donor would be needed, as well as a cell from the patient (typically a skin cell).

The process of transferring a different nucleus into the egg reprograms it to a pluripotent state, reactivating the full set of genes for making all the tissues of the body. The egg is then allowed to develop in the lab for several days, and pluripotent stem cells are derived from it. (Read more in How do we get pluripotent stem cells?)

Like iPS cells, ntES cells match the patient genetically. If created successfully in humans, and if proven safe, ntES cells could completely eliminate tissue matching and tissue rejection problems. For this reason, they are actively being researched at Childrens.

3. Stem cells from unfertilized eggs (parthenogenetic embryonic stem cells)Through chemical treatments, unfertilized eggs can be tricked into developing into embryos without being fertilized by sperm, a process called parthenogenesis. The embryos are allowed to develop in the lab for several days, and then pluripotent stem cells can be derived from them (for more, see How do we get pluripotent stem cells?)

If this technique is proven safe, a woman might be able to donate her own eggs to create pluripotent stem cells matching her genetically that in turn could be used to make cells that wouldnt be rejected by her immune system.

Through careful genetic typing, it might also be possible to use pES cells to create treatments for patients beyond the egg donor herself, by creating master banks of cells matched to different tissue types. In 2006, working with mice, Childrens researchers were the first to demonstrate the potential feasibility of this approach. (For details, see Turning pluripotent stem cells into treatment).

Because pES cells can be made more easily and more efficiently than ntES cells, they could potentially be ready for clinical use sooner. However, more needs to be known about their safety. Concerns have been raised that tissues derived from them might not function normally.

Read more about pluripotent stem cells by following these links:

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Pluripotent Stem Cells 101 Boston Children's Hospital

Recommendation and review posted by Bethany Smith

Louisville hormone clinic 25 Again sued over diet drug

A popular hormone clinic that was accused in a lawsuit in September of causing a patients death by giving him too much testosterone has been accused in another complaint of prescribing a diet drug banned by the federal government.

In a suit filed Friday in Jefferson Circuit Court, Cindy Kinder-Benge and her husband Mark allege that a nurse at 25 Again gave her human chorionic gonadotropin, or HCG, for weight loss, without disclosing that it is ineffective for that purpose.

In a consumer update headlined HCG Diet Products Are Illegal, the U.S. Food & Drug Administration saidthe hormone is not approved and there is no evidence that it produces weight loss.

The latest suit alleges that a nurse at 25 Agains New Albany clinic provided HCG in conjunction with a 700-calorie-a-day diet, which the FDA says can be dangerous and potentially fatal.

The suitsays "multiple peer-reviewed, prospective, randomized, clinical trials dating back to 1976 have concluded that HCG is ineffective for weight loss and should not be prescribed for that purpose. This information was not shared with the plaintiff."

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Ted Ennenbach, who owns 25 Again, also known as Body Shapes Medical, said in an email that the company "promotes health" anddoes not "endorse or use" either homeopathic HCG or 700-calorie diets. He said he was out of town and hadn't seen the suit and couldn't confirm whetherKinder-Benge was a patient.

The lawsuit follows other legal trouble for the clinic. In the suit filed in September, MelanieLester said the clinic repeatedly administered testosterone to her husband David, even thoughhis levels of it were normal, eventually causing his death from a heart attack.

Two other widows have sued nurse practitioner Karla King, who previously worked in Owensboro, alleging she also gave excessive testosterone to their husbands, who had normal levels of the male hormone, resulting in their deaths.King has denied negligence.

In her complaint Friday, Kinder-Bengesaid she saw ads on TV in which the clinic said its hormone treatments could resolve symptoms of menopause, such as hot flashes, and cause weight loss. She signed up for treatment at an annual rate of $2,388 plus an additional $209 for HCG.

She said blood work showed she had normal thyroid levels but a nurse nonetheless gave her additionalthyroid that caused her to experience severe chest pain and weakness due to her heart racing.

The clinic allegedly continued to tell her she needed extra thyroid, which she took for 22 months.

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From August: Why are nurses fleeing a controversial Louisville hormone treatment clinic 25 Again?

The lawsuit alleges a co-worker had to take her to BaptistHealth Floyd, where she was diagnosed as suffering from atrial fibrillation, an irregular heartbeat that can lead to blood clots, stroke, heart failure and other heart-related complications

Last September, despite being on medication to control her irregular heartbeat, she had chest pains again and hadto be returned by ambulance to the hospital, where she was intubated, placed on a ventilator and spent several days in the intensive care unit, according to the suit.

It asks for unspecified damages for negligence, fraud, lack of informed consent and violations of consumer-protection laws.

The suit,Lesters and the Owensboro complaints werefiled by attorney Ronald Johnson, who says 25 Again prescribes and administers hormones to patients when they are not clinically indicated, do not provide any benefit, and expose patients to risk of harm and death.

The Kentucky Board of Medical Licensure in June prohibited 25 Agains then-medical director, Elizabeth Bates, from practicing hormone medicine after finding her practice violated acceptable and prevailing standards of medicine.

But the agency did not ban others from the practice.

Ennenbach has said the clinic provides safe care to thousands of satisfied patients.

It is a sponsor of University of Louisville mens basketball and advertises heavily on sports talk radio, promising that patients will look younger, feel healthier and feel 25 again.

Andrew Wolfson: 502-582-7189;; Twitter: @adwolfson. Support strong local journalism by subscribing today:

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Louisville hormone clinic 25 Again sued over diet drug

Recommendation and review posted by Bethany Smith

Hypogonadism Causes + 6 Ways to Help Balance … – Dr. Axe

If you or a loved one is struggling with hypogonadism, you may already know that it can be a devastating condition that reduces your quality of life and livelihood. People with hypogonadism can experience muscle loss, low libido, infertility and depressed mood. In fact, these symptoms can make talking about hypogonadism difficult. (1)

Thankfully, research shows that there are ways to balance your hormones, either using hormone replacement therapy, which is the conventional form of treatment for this condition, or natural estrogen and testosterone boosters like exercise, dietary and lifestyle changes, adaptogen herbs and essential oils. But if youve been struggling with the symptoms of hypogonadism, rest assured that there are natural remedies to help support your treatment and improve your quality of life.

Hypogonadism is a condition that occurs when the bodys sex glands, the testes for males and ovaries for females, produce little or no hormones. For males with hypogonadism, low testosterone can affect the development and maintenance of male reproductive organs, including the testes, penis and prostate. In fact, low testosterone levels can lead to issues like reduced muscle strength, hair loss and impotence.

For females, hypogonadism occurs when the ovaries arent producing enough estrogen. Estrogen is responsible for maintaining sex organs like the uterus, vagina, fallopian tubes and mammary glands. But low or little estrogen in the body can lead to infertility, loss of libido, mood swings, loss of menstruation and osteoporosis. (2)

There are two types of hypogonadism, primary or central, or secondary. The definition of these types of hypogonadism depends on the cause of the condition.

Primary hypogonadism: Primary hypothyroidism occurs when theres a problem in a persons testes or ovaries, which are the gonads. The gonads are receiving messages from the brain to produce hormones, but they arent functioning properly.

The symptoms of hypogonadism vary depending on the patients age, sex and type of condition.

Symptoms in Females: Women with hypogonadism may experience the following symptoms:

If a young girl has hypogonadism, she may not menstruate. Plus the condition can affect her height and breast development.

Boys with low testosterone may have growth problems, with a delay in muscle growth and beard development, impaired testicle and penis growth, and enlarged male breasts. Also, low testosterone levels may result in failure of normal pubertal progression.

The cause of hypogonadism depends on the type of condition, either primary or central.

Primary hypogonadism can be caused by any of the following health conditions or factors (5):

Central hypogonadism (also known as hypogonadotropic hypogonadism) occurs when theres an issue with the centers of the brain that control hormone production. The following issues can cause it:

Androgen deficiency of the aging male (known as ADAM) is a cause of secondary hypogonadism. ADAM occurs when a mans testosterone levels decline progressively after age 40, leading to sexual dysfunction and altered body composition, cognition and metabolism. (6) In fact, research published by the International Journal of Clinical Practice indicates that older men are more likely to have low testosterone levels, with the prevalence being 34 percent in men between the ages of 45 and 54, and 50 percent in men over 85 years. (7)

According to research published in the International Journal of Clinical Practice, hypogonadism is significantly associated with various health issues, including Type 2 diabetes, hypertension, obesity, osteoporosis and metabolic syndrome. (8)

Treatment for hypogonadism depends on the cause of the condition. But the most common form of treatment is hormone replacement therapy, which is used to restore hormone levels to the normal range.

For Females: Women with hypogonadism are usually given a combination of estrogen and progesterone. However, research shows that estrogen therapy can increase the risk of heart disease, blood clots and cancer. Progesterone is added to estrogen therapy because it may reduce the risk of endometrial cancer.

1. Reduce Stress

A study conducted at the University of Massachusetts Medical School investigated the association between testosterone levels and stress. Researchers measured the stress levels of participants by taking into account daily hassles, major life events and perceived stress. They found that testosterone levels were significantly associated with stress in both males and females. This study suggests that testosterone levels are reflective of a persons ability to respond to stressors and his or her emotional coping mechanisms. (14)

To support your treatment for hypogonadism, practice some simple stress relievers, like spending time outdoors, meditating, exercising, being social and keeping a journal. Pursuing some form of therapeutic practice, like cognitive behavioral therapy, may also be beneficial because it helps you to better react to stressful situations. Plus, vocalizing your fears and emotions about coping with hypogonadism can be extremely helpful.

2. Address your Weight and Diet

Being overweight and being underweight can both contribute to low sex hormone levels. For the majority of people, before they can maintain a normal body weight to help regulate their hormone levels, they need to change the way they eat. This may be the most important natural remedy to help treat hypogonadism. (15)

In fact, a 2014 study published in the Journal of Neuroinflammation found that low testosterone and diet-induced obesity can contribute to impairments in neural health, increasing the risk of serious disorders like type 2 diabetes and Alzheimers disease. (16) Theres also a childhood obesity epidemic that is causing serious health issues among children, including problems with growth and development.

So if you have low testosterone and youre struggling with weight loss, now is the time to make some serious changes to your diet in order to get well.

First, cut out all of the junk food, the processed, packaged and fast food, the refined carbohydrates and the artificial sweeteners. Focus on eating whole, real foods, including the following:

If you are having trouble staying on track with your diet and eating healthy, consider working with a health coach who can serve as a mentor and help you to reach your weight and health-related goals.

3. Exercise Regularly

Theres plenty of research that proves exercise can regulate or boost low testosterone levels. In fact, one study published in the Indian Journal of Physiology and Pharmacology found that even short-term exercise produces an elevation in serum testosterone levels in adults. (17)

Some of the best forms of exercise to boost testosterone and human growth hormone levels are weight training and high intensity interval training (HIIT workouts). Research shows that even moderate and light weightlifting can increase serum testosterone levels when compared to not doing any exercise at all. (18)

Try lifting weights for at least 30 minutes, three times a week. Doing this in combination with burst training can be even more beneficial in helping to elevate your testosterone levels. Burst training means that you are exercising at 90100 percent of your maximum effort for short, bursts of time (about 30 to 60 seconds), followed by a period of low impact exercise for recovery.

Exercise can also be helpful for women with hypogonadism because it helps to reduce stress and helps you to get to a normal weight. Weighing too little or being overweight are both factors that may cause low estrogen levels. Low-impact exercises like yoga and pilates can be very beneficial in helping to relieve symptoms and reduce some causes of hypogonadism.

4. Supplement with L-arginine

L-arginine is a type of amino acid that we obtain from our diets. It has multiple benefits, including its ability to stimulate the production of growth hormones, correct impotence, and improve erectile dysfunction and male infertility. A study published in The Journal of Endocrinology found that dietary arginine is actually required for the anabolic action of androgens, like testosterone. (19)

Research also shows that L-arginine ingestion enhances growth hormone response, increasing resting human growth hormone (HGH) levels by at least 100 percent. This is beneficial for men with hypogonadism because HGH is a natural testosterone booster. (20)

The best way to help your body make and use more L-arginine is by eating a diet based on whole, real foods, including organic grass-fed beef, wild-caught salmon, cage-free eggs, cultured yogurt, nuts and seeds, sea vegetables and coconut meat.

To supplement with L-arginine in order to improve hypogonadism symptoms, I recommend you take 36 grams per day, divided into two doses.

5. Try Ashwagandha

According to research published in Evidence-Based Complementary and Alternative Medicine, ashwagandha has been used in Ayurvedic medicine as an aphrodisiac that can treat male sexual dysfunction and infertility. Researchers involved in a pilot study found that patients with a low sperm count who were using ashwagandha had a 167 percent increase in sperm count, 53 percent increase in sperm volume and 57 percent increase in sperm motility. The ashwagandha group also showed improved serum hormone levels compared to the placebo group. (21)

To use ashwagandha to boost your libido, improve your hormone levels, increase your endurance and improve your mood, I recommend supplementing with 500 milligrams, one to two times daily. But do this in combination with eating a diet filled with healthy fats, fiber and clean protein.

6. Use Essential Oils

Two essential oils that can help to regulate hormone levels and improve hypogonadism symptoms are clary sage and sandalwood.

Clary sage contains natural phytoestrogens, so it helps to balance estrogen levels. According to a 2017 study published in Neuro Endocrinology Letters, clary sage can be used to alleviate menopausal symptoms caused by declining levels of estrogen secretion. In fact, researchers found that some essential oils, including clary sage, were able to increase estrogen concentration. (22) To use clary sage oil to support your hypogonadism treatment, combine 5 drops with a teaspoon of coconut oil and massage the mixture into your abdomen, wrists and bottoms of your feet.

Sandalwood essential oil can be used to relieve hypogonadism symptoms, like low sex drive, moodiness, stress and cognitive issues. A 2015 study conducted at South Dakota State University shows that sandalwood also has anticancer mechanisms because of its antioxidant and anti-inflammatory properties. Researchers found that sandalwood has anticancer effects against both breast and prostate cancer. (23) You can diffuse 5 drops of sandalwood at home, inhale it directly from the bottle or apply 23 drops to the bottoms of your feet.

Talk to your doctor about the risks and benefits of hormone replacement therapy. There are studies supporting the benefits of hormone replacement therapy, and evidence opposing its use for hypogonadism.

Use the natural remedies discussed in this article to support your treatment for hypogonadism or to naturally boost your low estrogen or testosterone levels. However, make sure that you discuss any supplements that you choose to take with your doctor.

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Hypogonadism Causes + 6 Ways to Help Balance ... - Dr. Axe

Recommendation and review posted by Bethany Smith

Hypopituitarism Symptoms & Causes | Boston Children’s Hospital

We understand that you may have a lot of questions when your child is diagnosed with hypopituitarism. Is it dangerous? Will it affect my child long term? What do we do next? Weve tried to provide some answers to those questions on this site, and our experts can explain your childs condition fully.

Growth hormone is a protein produced by the pituitary gland, which is located near the base of the brain and attached to the hypothalamus (a part of the brain that helps to regulate the pituitary gland). If the pituitary gland or the hypothalamus is malformed or damaged, it may mean that the pituitary gland cant produce some or all of its hormones.

Hypopituitarism in children may be caused by:

Hypopituitarism can also be idiopathic, meaning that no exact cause can be determined.

The symptoms of hypopituitarism will vary depending on two things: which hormones are lacking, and your childs age. Symptoms that newborn babies may have include:

Older infants and children may have these symptoms:

Because the symptoms of hypopituitarism may resemble other conditions or medical problems, you should always consult your child's physician for a diagnosis.

Q: What is hypopituitarism?

A: Hypopituitarism occurs when the anterior (front) lobe of the pituitary gland loses its ability to make hormones, resulting in multiple pituitary hormone deficiencies. Physical symptoms depend on which hormones are no longer being produced by the gland.

Q: What causes hypopituitarism?

A: Hypopituitarism may be caused by many different conditions, including:

Hypopituitarism can also be idiopathic, meaning that no exact cause can be determined.

Q: Is hypopituitarism treatable?

A: Treating hypopituitarism depends both on its cause and on which hormones are missing. The goal of treatment is to restore normal levels of hormones. Treating the underlying condition thats causing your childs hypopituitarism often leads to a full recovery.

Since your childs body is unable to make some or all of these missing hormones, life-long hormone replacement therapy is necessary. Replacement therapy needs to be monitored and adjusted, but the extent of your childs pituitary deficiency will determine how often he will need to see his doctor.

Q: How safe is treatment?

A: While there are many potential side effects, researchers generally agree that hormone replacement therapy is safe and effective.

You and your family are key players in your childs medical care. Its important that you share your observations and ideas with your childs health care provider and that you understand your providers recommendations.

If your child is experiencing symptoms of hypopituitarism and youve set up an appointment, you probably already have some ideas and questions on your mind. But at the appointment, it can be easy to forget the questions you wanted to ask. Its often helpful to jot them down ahead of time so that you can leave the appointment feeling like you have the information you need.

If your child is old enough, you may want to suggest that she write down what she wants to ask her health care provider, too.

Some of the questions you may want to ask include:

Hypopituitarism Symptoms & Causes | Boston Children's Hospital

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Thyroid Disorders | Hormone Health Network

The thyroid is a small butterfly-shaped gland inside the neck, located in front of the trachea (windpipe) and below the larynx (voicebox). It produces two thyroid hormonestriiodothyronine (T3) and thyroxine (T4)that travel through the blood to all tissues of the body.

Thyroid hormones regulate how the body breaks down food and either uses that energy immediately or stores it for the future. In other words, our thyroid hormones regulate our body's metabolism.

Another gland, called the pituitary gland, controls how well the thyroid works. The pituitary gland is located at the base of the brain and produces thyroid-stimulating hormone (TSH). The bloodstream carries TSH to the thyroid gland, where it tells the thyroid to produce more thyroid hormones, as needed.

Thyroid hormones influence virtually every organ system in the body. They tell organs how fast or slow they should work. Thyroid hormones also regulate the consumption of oxygen and the production of heat.

Endocrinologistsphysicians and scientists who study and care for patients with endocrine gland and hormone problemsstudy and treat several major disorders of the thyroid gland. The following is a list of some common thyroid disorders.

Too much thyroid hormone from an overactive thyroid gland is called hyperthyroidism, because it speeds up the body's metabolism. This hormone imbalance occurs in about 1 percent of all women, who get hyperthyroidism more often than men. One of the most common forms of hyperthyroidism is known as Graves' disease. This autoimmune disorder (when your bodys defense system attacks your own cells) tends to run in families. Because the thyroid gland is producing too much hormone in hyperthyroidism, the body develops an increased metabolic state, with many body systems developing abnormal function.

Too little thyroid hormone from an underactive thyroid gland is called hypothyroidism. In hypothyroidism, the body's metabolism is slowed. Several causes for this condition exist, most of which affect the thyroid gland directly, impairing its ability to make enough hormone. More rarely, there may be a pituitary gland tumor, which blocks the pituitary from producing TSH. Whether the problem is caused by the thyroid or by the pituitary gland, the result is that the thyroid is producing too few hormones, causing many physical and mental processes to become sluggish. The body consumes less oxygen and produces less body heat.

A thyroid nodule is a small lump in the thyroid gland. Thyroid nodules are common. These nodules can be either a growth of thyroid tissue or a fluid-filled cyst, which forms a lump in the thyroid gland. Almost half of the population will have tiny thyroid nodules at some point in their lives but, typically, these are not noticeable until they become large and affect normal thyroid size. About 5% of people develop large nodules, more than a half inch across (about 1 centimeter).

Although most nodules are not cancerous, people who have them should seek medical attention to rule out cancer. Also, some thyroid nodules may produce too much thyroid hormone and cause hyperthyroidism, or become too large, interfering with breathing or swallowing or causing neck discomfort.

Other thyroid problems include cancer, thyroiditis (swelling of the thyroid gland), or a goiter, which is an enlargement of the thyroid gland.

July 2018


Bryan Haugen, MD

Leonard Wartofsky, MD, MACP

Ramon Martinez, MD

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Life Extension | SNC-Lavalin

CANDU reactors can operate economically and reliably for up to 60 years. After about 30 years of operation, reactor components are replaced and refurbished, extending the life of a reactor for another 30 years. This process is called life extension.

During life extension, the reactors pressure tubes, calandria tubes and end fitters are removed and replaced. Our experts have designed and delivered multi-tonne, remotely controlled tooling systems to accomplish this in a safe and effective manner. The outage also allows operators to refurbish other key reactor components, and make system upgrades.

All utilities that operate CANDU reactors are currently undergoing or will at some point consider life extension work on their reactors.

One of the worlds top-performing CANDU stations, the Darlington Nuclear Generating Station supplies 20% of Ontarios energy needs. Its refurbishment is crucial to deliver the power required to serve the provinces residents. Refurbishment operations began in the fall of 2016; it is the largest clean energy project in Canada.

This life extension project will allow Argentinas Embalse Nuclear Station to continue producing safe, reliable, low-carbon power for up to another 30 years. The Embalse CANDU 6 reactor began commercial operation in January 1984 and the single-unit has a gross output of 648 Mwe. The station shut down for this project in December 2015; the outage is expected to last until December 2017.

Bruce Power is Ontarios lowest cost source of nuclear, currently generating over 30% of the provinces electricity. Extending the operational life of the Bruce Power Units 3-8 will ensure long-term price stability. We are currently working with Bruce Power to solidify our scope for the Bruce Power major component replacement(MCR) project and look forward to concluding negotiations in late 2016.

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Hormone Replacement Therapy and Testosterone Clinic in Chicago

Bioidentical hormones offer an alternative to Hormone Replacement Therapy and are a way to relieve menopause symptoms. They are chemically identical to those the hormones your body produces. The body cant distinguish the bioidentical hormones from the ones produced by your ovaries. The hormone levels in our bodies decline as we age. By having hormone replacement therapy, your hormones are restored to more youthful levels resulting in more energy, a sharper memory, stronger bones, a healthier heart and an overall more youthful glow. The treatment comes in patch form, a cream form or pill form. Dr. Pavilonis has treated patients for years with bioidentical hormone replacement therapy in Chicago and has had outstanding results with it.

Almost all women over 40 start to experience hormone imbalance. In day to day living, we are exposed to many different toxins from our food to our environment. These toxins start to contribute to our hormone decline as we age. To balance your hormones, it is critical to be evaluated by a highly trained doctor and have the treatment of hormone replacement therapy in Chicago. You will also have comprehensive lab testing and answer an in-depth questionnaire before we create a personalized treatment plan can for you.

Having your hormones out of balance can contribute to many conditions and diseases such as:

As a result of your hormones being out of balance, you may be experiencing several of these classic symptoms of aging:

If you are experiencing any of these symptoms, you may be a candidate for bioidentical hormone therapy.

Estrogen is a womans most important hormone. Studies have shown, without hormone replacement therapy, the loss of estrogen puts her at increased risk for premature ovary failure, osteoporosis, heart disease, colon cancer, Alzheimers disease, tooth loss, impaired vision, Parkinsons disease and diabetes. The longer a woman is without the protection of estrogen, the greater the risk for serious health consequences of these conditions.

There are estrogen receptors in a variety of organs throughout the body. Thats why hormonal imbalance produces different symptoms such as loss of skin elasticity, bone shrinkage, moodiness and cognitive decline. On the other hand, when estrogen levels rise as they do in the first week of menses, their overall effect is to increase the amount of serotonin available in the spaces between the brains nerve cells. That improves mood. Within the brain, estrogen may in fact act as a natural antidepressant and mood stabilizer. It is therefore essential that a woman suffering from premature ovary failure or surgical menopause receive treatment from an HRT physician who understands the many ramifications of the disease and is willing and able to meet her endocrine and emotional needs. This is the reason why you need to look for hormone replacement therapy in Chicago.

Studies have shown, testosterone hormone therapy can provide a woman with mental clarity, increased libido and muscle tone and mass. When this hormone is at low levels, women often complain of mental confusion, weight gain and poor muscle tone, even with regular exercise.

The effect of hormone deficiency on the brain, muscle, bone, heart and metabolism can be significant without hormone replacement therapy for women, and it can be dangerous to long-term health. The brain needs normal amounts of testosterone in balance with estrogen to produce serotonin, which supports emotional balance. When lacking in these hormones, a woman will experience emotional instability that often results in increased anxiety, irritability, sleep disturbances, anger, sadness and depression.

The musculoskeletal system is also adversely affected by the loss of testosterone. By not having bio-identical hormone therapy, the deficiency or imbalance of testosterone can lead to muscle atrophy, osteopenia, osteoporosis, and pain in the muscles and joints. Think upon it once and search for testosterone clinic in Chicago.

Studies have shown, men begin losing testosterone at a rate of 3% to 10% per year beginning at age 30. Current medical research now defines a male equivalent to menopause asandropause. Because the testosterone used is totally natural, it is ideal for men who want s the benefits of a bio-identical hormone without the drawbacks of a synthetic.

Symptoms of testosterone deficiency in men include fatigue, lack of mental acuity, loss of libido, and difficulty achieving or sustaining an erection.Why bio-identical hormone pellet therapy for men? Hormonal needs for men have received national attention, but with marginal treatment options available. Hormonal treatments for men can be expensive, require daily consumption, and, in many cases, need to be carefully timed with their partners needs for normal sexual activities and pleasure.

Bio-identical hormone pellet therapy is the only delivery method of testosterone therapy that gives sustained and consistent testosterone levels throughout the day for four to six months without any roller coaster blood levels of testosterone, which can result in mood and energy fluctuations for the patient.BioTE Medical has had excellent results treating men with bio-identical hormone therapy. There have been only a few reported side effects, which are all minor and treatable.

Men find themselves lacking in sexual desire, gaining weight, losing muscle mass, and feeling sluggish, depressed and irritable. Yet, they believe they must endure these body and hormonal changes as part of aging. It is a high time when you need to consider testosterone clinic in Chicago and enhance your health.

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Bone Marrow Stem Cells Stall Out in Chronic Lymphocytic …

Snow and ice cause cars to stall out on the road to their destination. In patients with CLL, its their stem cells that stall out and researchers want to know why.

For patients who have chronic lymphocytic leukemia, fighting off a serious infection can be difficult and often is just not possible. And a team of Mayo researchers is starting to find out why in a paper published recently in the journal Leukemia.

What is Chronic Lymphocytic Leukemia?

This disease is cancer of an immune cell called a B lymphocyte. These cells form in bone marrow and migrate out to patrol in the blood stream and lymphoid organs. But in chronic lymphocytic leukemia, the immune system is depleted, a state called immunodeficiency. Because of that, people with this type of leukemia are prone to serious infections and the diseases those may cause. They are also prone to developing other types of cancer.

And its those resulting problems that may ultimately contribute to death explains Kay Medina, Ph.D., a Mayo Clinic immunologist. Dr. Medina specializes in how immune cells develop from bone marrow stem cells.

In our bone marrow, stem cells convert to red blood cells, platelets or a variety of immune cells. Those are then sent into the blood stream where they do their job. Red blood cells replace cells that are worn out.

White blood cells patrol the byways of our circulation, chasing down everything from cellular debris to bacteria to virus particles.But not in patients with chronic lymphocytic leukemia.

Joining the Team

Research on chronic lymphocytic leukemia is going on in several labs at Mayo Clinic. Dr. Medina got involved after speaking with colleagues Wei Ding, M.B.B.S, Ph.D., and Neil Kay, M.D., both chronic lymphocytic leukemia physician researchers.

Mayo has a strong tradition of encouraging physician/basic research collaborations to advance knowledge of disease mechanisms, development, and assessment of new treatment approaches, says Dr. Medina.

The basic research helps us understand the cause of the disease, in this case the leukemia cell, but it also helps to understand what the disease does to other parts of the body, such as the lymph nodes, spleen, blood and bone marrow, she says.

Bone marrow is the organ that replenishes all cells in the immune system but has not been evaluated for functional proficiency in CLL patients, explains Dr. Medina.

Checking out the Cells and their Environment

Kay Medina, Ph.D.

Dr. Medinas team, with funding from Mayo Clinics Center for Biomedical Discovery, decided to look at bone marrow stem cells and their ability to generate all blood cell types. Some of the immune deficiency may be the result of treatment, but untreated patients have the same problem. The chronic nature of the disease itself may also dampen immune activity. But Dr. Medina explains that the leukemia cells may promote an environment that suppresses immune function.

Our research seeks to add to the discussion by identifying additional ways patients with CLL are unable to fight off tumors and other diseases, says Dr. Medina.

In a paper published late last year, Dr. Medina and her team, including first author Bryce Manso who is a student in the Mayo Clinic Graduate School of Biomedical Sciences, examined bone marrow and blood samples from chronic lymphocytic leukemia patients and healthy controls to determine the frequency of bone marrow stem cells in each sample and how well they did their job.

Bryce Manso, presenting a poster to a conference attendee.

The authors reported that, in general, samples from patients with chronic lymphocytic leukemia have fewer stem cells in their bone marrow, and those stem cells that remain work less well than stem cells from controls.

Stalled-Out Bone Marrow Stem Cells

As to why this happens, the authors found that it was linked to loosening controls for the on/off switches which regulate this process, proteins called transcription factors. These proteins regulate key functions in the cell, and are out of whack in samples from chronic lymphocytic leukemia patients. They may prevent bone marrow stem cells from pursuing a pathway for development; stalling-out their ability to differentiate, resulting in decreased production of important blood cells that provide the first line of defense against infectious agents.

But, Dr. Medina cautions, there is more to this story.

This is an emerging area of research in that its both a unique explanation for the clinical problem of immune deficiency and it has been minimally studied, says Dr. Medina. Future studies are planned to look at specific transcription factors that control stem cell differentiation as well as how the presence of leukemic cells in the bone marrow alter blood cell development. They will then relate this information to clinically relevant complications reported in chronic lymphocytic leukemia patients, she says.

Basic Research to Improve Patient Care

Dr. Medina, her team, and their clinical colleagues hope that by understanding how bone marrow function is impaired in chronic lymphocytic leukemia patients, they can develop unique strategies to boost bone marrow function or find alternate treatments that do not block or modify marrow function.

Through this work we hope to find ways to reduce infections and the incidence of second cancers in chronic lymphocytic leukemia patients. Our research has the potential to improve quality of life as well as extend the lives of these patients says Dr. Medina.


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Tags: basic science, blood cancer, cancer, Center for Biomedical Discovery, chronic lymphocytic leukemia, Findings, immunology, Kay Medina, leukemia, Mayo Clinic Cancer Center, Neil Kay, News, Progress Updates, Wei Ding

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What is a stem cell or bone marrow transplant? | non …

You might have a stem cell or bone marrow transplant as part of your treatment for non-Hodgkin lymphoma (NHL). Find out how a transplant works and why you might have it.

A transplant allows you to have high doses of chemotherapy and other treatments. The stem cellsare collected from the bloodstream or the bone marrow.

Stem cells are very earlycells made inthe bone marrow. Bone marrow is a spongy material that fills the bones.

These stem cells develop into red blood cells, white blood cells and platelets.

Red blood cells contain haemoglobin which carries oxygen around the body. White blood cells are part of your immune system and help to fight infection. Platelets help to clot the blood to prevent bleeding.

These stem cells develop into red blood cells, white blood cells and platelets.

You have a stem cell transplant after very high doses of chemotherapy. You might have targeted drugs with the chemotherapy. You may also have radiotherapy to your whole body. This is called total body irradiation or TBI.

The radiotherapy and chemotherapy has a good chance of killing the lymphomacells. But it also kills the stem cells in your bone marrow.Soyour team either collects:

After the treatment you have the stem cells into your bloodstreamthrough a drip. The cells find their way back to your bone marrow where theystart making blood cells again and your bone marrow slowly recovers.

The main difference between a stem cell and bone marrow transplant is whether stem cells are collected from the bloodstream or bone marrow.

A stem cell transplant uses stem cells from your bloodstream, or a donors bloodstream. This is also called a peripheral blood stem cell transplant.

A bone marrow transplant uses stem cells from your bone marrow, or a donors bone marrow.

Stem cell transplants are the most common type of transplant. Bone marrow transplants are not used as much. This is because:

You might have a bone marrow transplant if collecting stem cells has been difficult in your situation.

The aim of NHL treatment is usually to put it into remission. Remission means there is no sign of lymphoma.

Your doctor might suggest a transplant if your NHL:

High dose chemotherapy and a transplant aims to cure some types of NHL. Or it might control the lymphoma for longer if a cure is not possible.

Depending on your situation, you might have a transplant using:

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What is a stem cell or bone marrow transplant? | non ...

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Amicus Establishes Global Research and Gene Therapy Center …

New 75,000 sq. ft. State of the Art Facility in uCity Square Adjacent to Penn Campus

Strengthens Amicus Capabilities as a Leading Global Rare Disease Biotechnology Company

CRANBURY, N.J. and PHILADELPHIA, Feb. 26, 2019 (GLOBE NEWSWIRE) -- Amicus Therapeutics (FOLD) today announced it is establishing a new Global Research and Gene Therapy Center of Excellence in uCity Square in Philadelphia, PA, to advance its commitment to world-class science that makes a meaningful difference in the lives of people living with rare metabolic diseases. Philadelphia is a well-regarded ecosystem for biotechnology and gene therapy research and offers an ideal environment for Amicus to advance its pipeline, attract and retain top talent and foster external collaborations within the rare diseases.

John F. Crowley, Chairman and Chief Executive Officer of Amicus Therapeutics, stated, This Amicus Global Research and Gene Therapy Center of Excellence is an important next step in the evolution of our science, research and gene therapy capabilities. In considering locations, Philadelphia became the clear choice as a burgeoning hub for medical breakthroughs. The proximity to our collaborators at the University of Pennsylvania and other major academic centers and hospitals in the area also provides a tremendous opportunity to advance our commitment to gene therapies. Philadelphia is easily accessible to New Jersey, which has been a strong contributor to our success and will remain the location of our global headquarters. As Amicus continues to expand globally, my hope is that the great science to come from our research in Philadelphia will one day soon lead to medicines with the potential to alleviate an enormous amount of suffering. This is our mission at Amicus and we are honored to be a part of the exciting Philadelphia research community.

Under the leadership of Jeff Castelli, PhD, Chief Portfolio Officer and newly appointed Head of Gene Therapy, and Hung Do, PhD, Chief Science Officer, the new facility will be located at 3675 Market Street in uCity Square, a 6.5 million square-foot, mixed-use knowledge community consisting of office, laboratory, clinical, residential and retail space designed to enable university and corporate research, entrepreneurial activity and community engagement.

An initial group of Amicus research employees has moved into temporary space in the building at BioLabs@CIC Philadelphia during construction of the permanent space. The new 75,000 sq. ft. Center will be completed in the second half of 2019 and will serve as the headquarters for the global Amicus science organization and the gene therapy leadership team. Amicus expects up to 200 employees to eventually be based at the new Philadelphia facility. The Company is maintaining global business operations in Cranbury, NJ, and international headquarters in Marlow, UK.

J. Larry Jameson, MD, PhD, Executive Vice President for the Health System and Dean of the Raymond and Ruth Perelman School of Medicine stated, On behalf of Penn Medicine, I would like to welcome Amicus Therapeutics to Philadelphia. Amicus is working to pioneer significant advancements in gene therapy, which includes a collaboration with Dr. James Wilson and his team at our Orphan Disease Center. This relationship reflects how the innovation ecosystem at Penn brings together researchers, innovators, and entrepreneurs to accelerate research discoveries to patients as quickly as possible. The close proximity between the Amicus Center of Excellence and our campus will further strengthen this relationship and create additional opportunities to work together.

Jim Kenney, Mayor of Philadelphia, commented, The City of Philadelphia is committed to fostering innovative companies, academic institutions, and hospitals that are focused on the latest advancements in research and development, while also elevating the patient experience within our healthcare systems. Amicus Therapeutics is an established leader in biotechnology with a unique and intense patient-dedicated mission. The Companys presence and investment in Philadelphia will create additional opportunities that will be highly influential as our city continues its transformation into a major global biotech hub.

About Amicus Therapeutics Amicus Therapeutics (FOLD) is a global, patient-dedicated biotechnology company focused on discovering, developing and delivering novel high-quality medicines for people living with rare metabolic diseases. With extraordinary patient focus, Amicus Therapeutics is committed to advancing and expanding a robust pipeline of cutting-edge, first- or best-in-class medicines for rare metabolic diseases. For more information please visit the companys website at, and follow us on Twitter and LinkedIn.

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Forward-Looking StatementsThis press release contains "forward- looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 Words such as, but not limited to, look forward to, believe, expect, anticipate, estimate, intend, "confidence," "encouraged," potential, plan, targets, likely, may, will, would, should and could, and similar expressions or words identify forward-looking statements. The forward looking statements included in this press release are based on management's current expectations and belief's which are subject to a number of risks, uncertainties and factors. In addition, all forward looking statements are subject to the other risks and uncertainties detailed in our Annual Report on Form 10-K for the year ended December 31, 2017 and Quarterly Report on 10-Q for the Quarter ended September 30, 2018. As a consequence, actual results may differ materially from those set forth in this press release. You are cautioned not to place undue reliance on these forward looking statements, which speak only of the date hereof. All forward looking statements are qualified in their entirety by this cautionary statement and we undertake no obligation to revise this press release to reflect events or circumstances after the date hereof.


Investors/Media:Amicus TherapeuticsSara Pellegrino, IRCVice President, Investor Relations & Corporate (609) 662-5044

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Women’s Contributions to Early Genetics Studies Were …

As a postdoctoral researcher at the University of California, Berkeley, Emilia Huerta-Snchez noticed something strange in the fine print of an old population genetics study. In the acknowledgements, the studys author, a well-known geneticist, wrote, I wish to thank Mrs. Jennifer Smith for ably programming and executing all the computations.

Huerta-Snchez showed the odd credit line to fellow postdoc Rori Rohlfs. Smiths level of computing, she remarked, would normally warrant authorship today. In all likelihood, the two scientists mused privately, other womens contributions to the burgeoning field of population genetics had also been relegated to the footnotes.

Years later, after watching the 2016 movie Hidden Figures, which depicts the black female mathematicians behind NASAs human spaceflight program, Huerta-Snchez and Rohlfsnow with university appointments of their owndiscussed the idea again. This time, they wanted to test the hypothesis. How many programmers had been left in the footnotes of their field, they wondered, and how many of those less-acknowledged contributors were women?

Huerta-Snchez and Rohlfs assembled a team of student researchers to flip through the archival pages of 20 years worth of articles in the programming-heavy journal Theoretical Population Biology, documenting the authors and the names in the acknowledgements and categorizing them by gender. After the group reviewed 800-plus articles by over 1,000 authors (about 93 percent of whom were men), Huerta-Snchezs initial suspicion proved correct. Women whod contributed to influential studies tended to receive a hat-tip in the acknowledgements rather than full authorship.

In a recent study published in the journal Genetics, the San Francisco State University and Brown University researchers found that just under half of the 46 acknowledged programmers they identified in theoretical population genetics studies were women, in contrast to only about seven percent of credited authors. Ezequiel Lopez Barragan, one of the San Francisco State University students who worked on (and got authorship) for the new study, says he felt the skewed acknowledgement of women as programmers was just not fair, not equitable.

By identifying the biases in old research conventions, the team hopes to draws attention to who doesand does notreceive acknowledgement in scientific papers today.

Population genetics, which sprouted up in the first half of the 20th century after the rediscovery of Gregor Mendels foundational work in genetics, is a computation-heavy field that looks at genetic variation to better understand how natural selection and population makeup influence evolution. By the 1970s, one of the decades reviewed in the new study, computer-generated models had become accessible tools for scientists, and technological advances made it possible to gather detailed protein variation data. The field of population genetics took off, Rohlfs says.

Some of the data couldnt be analyzed by hand, which is where the acknowledged programmers came in, computing on the new machines to conduct numerical analysis. These programming roles were often carried out by women, but the researchers crunching the numbers didnt receive the same acknowledgment in published research that they might expect today.

The practice of downplaying womens scientific contributions isnt anything new, says historian Marsha Richmond, who studies womens early contributions to academic biology. Instead, she says, it follows a long trend that was probably first established in astronomy. The Harvard computers, for example, who calculated the positions and characteristics of thousands of stars at Harvard Observatory at the turn of the 20th centuryand made many important discoveries in astronomy along the waymirrored the mathematical roles that women played at NASA more than half a century later.

Historically, women tended to enter emerging fields like ecology or radiation science, and as employees, they were cheaper to hire than their male counterparts. But once the field develops, they get rather marginalized and the men take over, Richmond says. Although the 1960s and 70s heralded increased visibility for some female scientists, like ecologist Rachel Carson and geneticist Charlotte Auerbach, both genetics and the initially pink-collar field of programming followed the pattern of sidelining women contributors. The proportion of female acknowledged programmers in the new study, for instance, decreased between the 1970s and 1980s as the field became more male-dominated and lucrative.

Richmond calls Huerta-Snchez and Rohlfs paper exciting. It was the first shed learned of women involved in this era of evolutionary biology. The lack of female scientists and programmers in the historic record, Richmond says, is not just a problem of science and society but also of historians. Historians have tended to gravitate towards the males who are considered geniuses.

Both Richmond and the studys principal investigators emphasized that uncovering the presence of women in population genetics could inspire future scientists and guard against the negative impact of gender stereotypes in science. Such work reveals paths to success in a field thats still relatively male-dominated. The more we see women doing science, the more its normal, Rohlfs says, and we hope that will lead to change.

Margaret Wu is an early contributor to population genetics and one of the acknowledged programmers whose name cropped up repeatedly in the new study. As the Atlantics Ed Yong explains, her work help develop a statistical toolstill used todaythat approximates the level of genetic diversity in a population.

But when the team behind the study finally reached Wu, she initially thought theyd contacted the wrong person. Wu, after working as a research assistant at Monash University in Australia, has gone on to specialize in educational statistics, not population genetics. She earned a PhD almost 30 years after the highly-cited study that she contributed numerical work to, and she is now on the faculty of the University of Melbourne.

I was in no way frustrated about the authorship. I didnt even think I should be acknowledged that was the norm in those days, Wu writes in an email. But she also says shes observed and experienced gender discrimination throughout her career in academia. My conclusion was that men are often mates (to use an Australian term), she says, and they unite and are unwilling to contradict each other even though someone is not doing the right thing.

Upon reading about Margaret Wu in the Atlantic, Jess Wade, a physics postdoc at Imperial College London whos created around 510 Wikipedia pages for female scientists, made Wu a Wikipedia page. Wade says via Twitter that her first reaction to the study was anger. I made [the Wikipedia page] because Im sick of these people being written out of history.

Rohlfs also pointed to norms, not individuals, as being responsible for the lack of acknowledgement for women. Because authorship, which is totally crucial for career advancement, can be distributed subjectively, its subject to all the biases we have, she says. Today, for instance, the contributions of technicians might be overlooked, and technicians, Rohlfs says, are more often women and people of color.

Everybody just thought it was okay that these women didnt get authorship, she says. I think that leads us directly then to think about what are our authorship norms today, and who are we excluding because we just tacitly agree that its right to exclude those people.

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What is Crispr Gene Editing? The Complete WIRED Guide | WIRED

In the early days of gene editing, biologists had a molecular tool kit that was somewhat akin to a printing press. Which is to say, altering DNA was a messy, labor-intensive process of loading genes onto viruses bound for target cells. It involved more than a fair amount of finger-crossing. Today, scientists have the genetic equivalent of Microsoft Word, and they are beginning to edit DNA almost as easily as software engineers modify code. The precipitating event? Call it the Great Crispr Quake of 2012.

If youre asking, whats Crispr? the short answer is that its a revolutionary new class of molecular tools that scientists can use to precisely target and cut any kind of genetic material. Crispr systems are the fastest, easiest, and cheapest methods scientists have ever had to manipulate the code of life in any organism on Earth, humans included.

The long answer is that Crispr stands for Clustered Regularly Interspaced Palindromic Repeats. Crispr systems consist of a protein with sequence-snipping capabilities and a genetic GPS guide. Such systems naturally evolved across the bacterial kingdom as a way to remember and defend against invading viruses. But researchers recently discovered they could repurpose that primordial immune system to precisely alter genomes, setting off a billion-dollar boom in DNA hacking.

Every industry is throwing mad money at Crisprpharma, agriculture, energy, materials manufacturing, you name it. Even the weed guys want in. Companies are using it to make cancer-curing medicines, climate-change-fighting crops, biofuel-oozing algae, and self-terminating mosquitoes. Academic researchers have almost universally adopted Crispr to more deeply understand the biology of their model organisms. Supporting this biohacking bonanza is an increasingly crowded Crispr backend supply chain; businesses building gene-editor design tools and shipping synthetic guide RNAs or pre-Crisprd cell lines to these companies doors. So far, though, very few Crispr-enhanced products have made it into the hands of actual consumers. In their place, hyperbolic headlines have bugled societys greatest hopes and fears for the technology, from saving near-extinct species to igniting a superbaby arms race.

Crispr isnt going to end disease or hunger or climate change any time soon. Maybe it never will. Nor is it about to deliver designer children or commit genetic genocide. (Though its never too early to start talking about the ethical dilemmas such a powerful technology could pose.) Crispr is, however, already beginning to reshape the physical world around us in much less radical ways, one base pair at a time.

It all started with yogurt. To make it, dairy producers have long employed the help of Streptococcus thermophilus, a bacteria that gobbles up the lactose in milk and poops out lactic acid. It wasnt until 2005, though, that a young microbiologist named Rodolphe Barrangou discovered that S. thermophilus contained odd chunks of repeating DNA sequencesCrisprsand that those sequences were keeping it safe from the viruses that attack it and result in spoilage. (If the thermophilus is gone, nastier bacteria can move in and feed off the lactose, ruining the product.)

Before long, DuPont bought the Danish company that Barrangou worked for and began using Crispr to protect all of its yogurt and cheese cultures. Since DuPont owns about 50 percent of the global dairy culture market, that means youve probably already eaten Crispr-optimized cheese on your pizza.

Viruses work by turning your cells into little factories for their DNA. A Crispr-based test could pick out that foreign DNA from just a drop of blood, spit, or urine and tell you in minutes if youve got the Zika virus, dengue, or yellow fever circulating in your body.

Every year, fungi wipe out a third of all crops. Crispr panels tuned to identify the worst offenders could help farmers save their harvests before the blight sets in.

Thanks to overuse, the worlds antibiotic arsenal is losing its effectiveness. New Crispr-based drugs that only target bad bugs would leave your microbiome intact and help fight antibiotic resistance.

All the while, gene sequencing costs were plummeting and research scientists around the world were assembling the genomes of bacteria. As they did, they found Crisprs everywheremore than half of the bacterial kingdom turned out to have them. Oftentimes those sequences were flanked by a set of genes coding for a class of strand-cutting enzymes called endonucleases. Scientists suspected they were involved in this primitive immune system, but how exactly?

The key insight came from a particularly nasty bugthe one that causes strep throat. Its Crispr system made two RNA sequences that attached to a clam-shaped endonuclease called Cas9. Like a genetic GPS, those sequences directed the enzyme to a strand of DNA complementary to the RNA sequences. When it got there, Cas9 changed shape, grabbing the DNA and slicing it in two. The molecular biologists who made this discoveryJennifer Doudna and Emmanuelle Charpentierpublished their work on bacteria in Science in 2012. But not before patenting the technology as a tool for genetic engineering. If you just switch out the RNA guide, you can send Cas9 anywhereto the gene that causes Huntingtons disease, say, and snip it out. Crispr, they realized, would be a molecular biologists warp drive.

Six months later, a molecular biologist at the Broad Institute of MIT and Harvard named Feng Zhang published a paper in Science showing how Crispr-Cas9 could edit human cells too. In fact, with the right genetic guides, you can Crispr pretty much anything. That meant it might be put to work on next-generation medicines that could do things like erase genetic defects and supercharge the bodys natural defenses against cancer. And that meant big money.

Perhaps predictably, a patent battle ensuedone that is still going on today. Crisprs early pioneers founded three companies with exclusive licenses to exploit Crispr/Cas9 to cure human diseases; the first clinical trials are expected to begin in the US in 2018. Uncertainty over who will ultimately own the technology has done little to slow the appetite for all things Crispr. If anything, it has unleashed a flood of interest in developing competing and adjacent tools that promise to further refine and expand Crisprs already ample potential.

For now, Crispr is still a biologist's buzzword. But just as computers evolved from a nerdy, niche tool for math geeks to a ubiquitous, invisible extension of our own bodies, so Crispr will one day weave seamlessly into the fabric of our physical reality. It will simply be the way to solve a problem, if that problem is remotely biological in nature.

Take industrial fermentation for example. With the help of old-school genetic engineering techniques, scientists have already reprogrammed microbes like E. Coli and brewers yeast into factories that can make everything from insulin to ethanol. Crispr will rapidly enlarge the catalog of designer chemicals, molecules, and materials that biorefineries can produce. Self-healing concrete? Fire-resistant, plant-based building materials lighter than aluminum? Fully biodegradable plastics? Crispr not only makes all these possible, it makes it possible to produce them at scale.

But we wont get there with the tools weve currently got. Which is why researchers are now racing to chart the full expanses of the Crispr universe. At this moment theyre scouring the globe for obscure bacteria to sequence, and theyre tinkering with the systems that have already been discovered. Theyre filing patents on every promising new nuclease they come across, adding to a list that is sure to expand in the coming decade. Each new enzyme will not only advance Crisprs gene editing powers, but extend its capabilities far beyond DNA manipulation. You see, slicing and dicing isnt the only interesting thing to do to DNA. Tricked out new Crispr systems could temporarily toggle genes on and off or surveil the genome to fix mutations as they happen in real time, no snipping required. The first would let scientists treat human diseases where theres too much or too little of a certain substancesay insulinwithout permanently altering a patients DNA. The second could one day prevent diseases like cancer from occurring altogether. The specificity of Crispr, perhaps more than its actual cutting mechanism, will inspire applications we cant yet imagine.

Good at cutting DNA, great for knockouts. Already being replaced by newer base pair editors with more fine-tuned control.

Like Cas9 but not as sloppy. It leaves sticky DNA ends, which are easier to work with when making edits.

Cuts RNA not DNA. Could knock down protein levels without permanently changing your genome. Pair it with a reporter signal and youve got a diagnostic.

Cas3 gives zero f***. It offers no repair mechanismonce it finds that target DNA sequence it just starts cutting till there aint no DNA left.

Just discovered in an abandoned silver mine, we dont know yet what these tiny enzymes superpowers will be.

Meanwhile, consumers can expect to see their first Crisprd products lining grocery store shelves very soon. Because Crispr doesnt use plant pathogens to manipulate DNA (the old GMO-generating method), the USDA has given a free regulatory pass to gene-edited crops, allowing drought-tolerant soybeans and extra-starchy corn to ease into your favorite processed foods. Specialty fruits and vegetables will likely follow the commodity crops; the reduced regulatory burden and the cheapness of Crispr will allow companies appealing to consumers senses rather than farmers bottom lines to enter the market. Already a dozen or so startups have popped up to challenge the Bayer/Monsanto, DowDupont/Pioneers of the world.

This democratizing aspect of Crispr-based tech, combined with its nearly limitless commercial possibilities, make today a great time to be a molecular biologist. Want to make antibiotics that only target bad bugs without wiping out the entire microbiome? There are companies doing that. Want to make paper-based diagnostics that doctors can take into the field to test for diseases like dengue and Zika? There are research labs and startups doing that too. And as more tools come online, the backend Crispr ecosystem will continually expand to support, supply, and optimize them.

Crispr applications are only going to become more powerful, and when they do they will rightly invite more scrutiny, and probably more regulation. Were going to have to figure out if its OK to wipe out an entire species in the name of conservation and bring other ones back from extinction. Well have to wrestle with the possibility that gene editing tools might be used to produce biological weapons of unfathomable destruction. And yes, well eventually have to talk about designer babies; when is it acceptable to fix a genetic mutation? Would we ever start adding features? Where do we draw the line? Crispr, and all the tools that will one day make up the Crispr universe will undoubtedly force societiesnot just scientiststo confront these questions and ponder the oldest one of all; what does it mean to be human?

Everything You Need To Know About Crispr Gene EditingOkay, you get it, Crisprs a big deal. But now, arent you curious to know exactly how it works? You dont have to be a microbiologist to understand this step-by-step look inside the molecular multitool of the century.

What Good Is Crispr If It Cant Get Where It Needs To Go?It doesnt matter how good Crispr gets, in order to actually snip away humanitys worst diseases, it first has to get to the right cells. And thats way harder said than done. Its time to talk about Crisprs delivery problem.

First Human-Pig Chimera Is a Step Toward Custom OrgansScientists have long been dreaming of xenotransplantationputting animal organs into peopleas a possible solution to the current human organ shortage. But almost all attempts to do so have failed. Heres how Crispr is bringing new hope to the dream of animal organ farms.

Read This Before You Freak Out Over Gene-Edited SuperbabiesIn the last few years, scientists in the US and China have used Crispr to fix genetic mutations in human embryos, prompting concerns over the imminent takeover of genetically superior designer children. Breathe, people: You dont need to worry about that for a long, long, long time.

America Needs To Figure Out the Ethics of Gene Editing NowStill. All that successful human embryo modification has scientists around the world calling for varying levels of caution against it. And while pretty much everyone agrees on avoiding a Gattaca-type situation, thats where the consensus ends.

Process of EliminationFor decades conservationists have used medieval methods for eradicating invasive island predators like rats. And all those traps and guns and poisons still havent gotten the job done. Local species are still under threat of extinction. Now some scientists are turning to Crispr gene drives, a particularly potent genetic tool that could forever transform our power over nature. Emma Marris went to the Galapagos to see how they might work in the wild.

The FDA Wants to Regulate Gene-Edited Animals as DrugsWe get it. Its hard to contort the USs 1938 patchwork of laws around 21st century technology. But companies making hornless cows and tailless pigs and all-male beef cattle are pissed at the FDAs new interpretation of the rules, and talking about taking their tech elsewhere.

Easy DNA Editing Will Remake the World. Buckle Up.Still havent had enough Crispr? Amy Maxmens 2015 cover story is the definitive survey of this gene-editing technology; from its humble bacterial beginnings, to the trenches of its ferocious patent battle, to inside the companies already churning toward our Crispr-created future.

Plus! Crispr uploads a galloping horse GIF into a living bacteria and more WIRED gene editing coverage.

This guide was last updated on April 26, 2018.

Enjoyed this deep dive? Check out more WIRED Guides.

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Gene Therapy: The Future of Vision Treatment

Leber congenital amaurosis is an inherited retinal disease that can cause blindness. This rare eye disorder can cause severe vision loss among infants, affecting two to three infants per 100,000 births. Fortunately, new medical treatment for this condition has recently been developed. In todays post, your glaucoma doctor from EyeSite of The Villages discusses how gene therapy can help treat inherited retinal problems.

Understanding Leber Congenital Amaurosis

The retina is a specialized tissue at the back of the eye that detects light and color. Leber congenital amaurosis attacks this part of the eye, causing severe visual impairment. Its considered an inherited degenerative disease, wherein both of the parents of the affected child carry a defective gene, including the RPE65 gene. Scientists have identified 14 genes with mutations that can cause this eye condition.

Patients diagnosed with Leber congenital amaurosis have reduced vision at birth. During infancy, parents may notice a lack of visual responsiveness and unusual eye movement. Typical eye exams conducted by a cataract doctor, however, may reveal normal retinas during eye exams. Electroretinography tests, however, may detect little if any activity in the retina.

Introduction to Gene Therapy

In 2009, Israeli researchers found a herd of Awassi sheep that suffered from day blindness. They began gene therapy trials for the sheep. The treatment included injecting a virus that carries a normal copy of the missing gene. The treated sheep regained their day vision, while the untreated remained visually impaired.

How Gene Therapy Can Help

After successful clinical trials, gene therapy has been approved by the Food and Drug Administration to treat Leber congenital amaurosis. This therapy doesnt restore normal eyesight; instead, it allows patients to see shapes and light. It involves injecting a healthy version of the affected gene in the retina, which helps detect light and convert it into visual signals for the brain to interpret.

Turn to the EyeSite of The Villages glaucoma doctor to help diagnose different eye conditions. We offer comprehensive eye exams to gauge your vision health. Call us today at (352) 504-4560 to schedule an appointment. We serve residents of Lady Lake and Fruitland Park, FL.

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Genetics and Male Infertility –

The development of in vitro fertilitzation (IVF) has allowed many couples to have the families they might otherwise have been unable to create independently. At the same time, this technology has allowed researchers to study the genetic make-up of the earliest stages of embryos. These advances are providing insights into the link between genetics and infertility and how defects (mutations) in specific genes may result in male or female infertility. It is possible that many cases of unexplained infertility will one day be found to have a clear genetic basis.

What has been learned in the last two decades of assisted reproduction is that some cases of severe male factor infertility are clearly related to gene deletions, mutations or chromosomal abnormalities.

Some men with very severe male factor infertility will be found, upon testing their blood chromosomes (known as a "karyotype") to have an extra X chromosome. That is, instead of having a 46 XY karyotype, they have a 47 XXY karyotype. This condition is known as "Klinefelter Syndrome" and can result in failure to achieve puberty or even when puberty is achieved, these men often have male infertility. Some men with Klinefelter Syndrome can father pregnancies through the use of in vitro fertilitzation (IVF) with Intra-Cytoplasmic Sperm injection (ICSI). So far, we are not seeing an increased risk of Klinefelter Syndrome or other chromosome abnormalities in the offspring achieved in these cases.

Also discovered in recent years is that some men with very severe low sperm counts will be found to have deletions in a certain part of their Y chromosome, known as the DAZ gene. Their karyotype is normal (46 XY) but close inspection of the Y chromosome shows there are sections of the chromosome that are missing. A portion of these men will have no recoverable sperm in the ejaculate or on testicular surgery and donor sperm is the only option. With other deletions in the DAZ gene, there is a small amount of sperm present and conception with IVF-ICSI is possible. In these cases, the male offspring which will always inherit their father's Y chromosome, will also have this deletion, and will themselves be infertile.

A single gene mutation in the gene for Cystic Fibrosis (CF) is associated with absence of the part of the tube (the "vas deferens") that leads from the testicle to the urethra in the penis. These men are usually carriers for the CF gene mutation and do not themselves have the disease of Cystic Fibrosis. Sperm can be recovered from the testicles in these men to be used for IVF with ICSI but it is imperative that their wife (or egg provider) be fully tested for CF mutations as well, otherwise there is significant risk of having a child with Cystic Fibrosis.

For men with sperm counts routinely in the less than 5 million total motile sperm range, testing for genetic conditions is warranted so that these men or couples can be made aware of the genetic issues and how these issues might affect their offspring.

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Biology and sexual orientation – Wikipedia

The relationship between biology and sexual orientation is a subject of research. While scientists do not know the exact cause of sexual orientation, they theorize that a combination of genetic, hormonal, and social factors determine it.[1][2][3] Hypotheses for the impact of the post-natal social environment on sexual orientation, however, are weak, especially for males.[4]

Biological theories for explaining the causes of sexual orientation are favored by scientists[1] and involve a complex interplay of genetic factors, the early uterine environment and brain structure.[5] These factors, which may be related to the development of a heterosexual, homosexual, bisexual, or asexual orientation, include genes, prenatal hormones, and brain structure.

A number of twin studies have attempted to compare the relative importance of genetics and environment in the determination of sexual orientation. In a 1991 study, Bailey and Pillard conducted a study of male twins recruited from "homophile publications", and found that 52% of monozygotic (MZ) brothers (of whom 59 were questioned) and 22% of the dizygotic (DZ) twins were concordant for homosexuality.[6] 'MZ' indicates identical twins with the same sets of genes and 'DZ' indicates fraternal twins where genes are mixed to an extent similar to that of non-twin siblings. In a study of 61 pairs of twins, researchers found among their mostly male subjects a concordance rate for homosexuality of 66% among monozygotic twins and a 30% one among dizygotic twins.[7] In 2000 Bailey, Dunne and Martin studied a larger sample of 4,901 Australian twins but reported less than half the level of concordance.[8] They found 20% concordance in the male identical or MZ twins and 24% concordance for the female identical or MZ twins. Self reported zygosity, sexual attraction, fantasy and behaviours were assessed by questionnaire and zygosity was serologically checked when in doubt. Other researchers support biological causes for both men and women's sexual orientation.[9]

Bearman and Brckner (2002) criticized early studies concentrating on small, select samples[10] and non-representative selection of their subjects.[11] They studied 289 pairs of identical twins (monozygotic, or from one fertilized egg) and 495 pairs of fraternal twins (dizygotic, or from two fertilized eggs) and found concordance rates for same-sex attraction of only 7.7% for male identical twins and 5.3% for females, a pattern which they say "does not suggest genetic influence independent of social context".[10]

A 2010 study of all adult twins in Sweden (more than 7,600 twins)[12] found that same-sex behavior was explained by both heritable factors and individual-specific environmental sources (such as prenatal environment, experience with illness and trauma, as well as peer groups, and sexual experiences), while influences of shared-environment variables such as familial environment and social attitudes had a weaker, but significant effect. Women showed a statistically non-significant trend to weaker influence of hereditary effects, while men showed no effect of shared environmental effects. The use of all adult twins in Sweden was designed to address the criticism of volunteer studies, in which a potential bias towards participation by gay twins may influence the results;

Biometric modeling revealed that, in men, genetic effects explained .34.39 of the variance [of sexual orientation], the shared environment .00, and the individual-specific environment .61.66 of the variance. Corresponding estimates among women were .18.19 for genetic factors, .16.17 for shared environmental, and .64.66 for unique environmental factors. Although wide confidence intervals suggest cautious interpretation, the results are consistent with moderate, primarily genetic, familial effects, and moderate to large effects of the nonshared environment (social and biological) on same-sex sexual behavior.[12]

Twin studies have received a number of criticisms including self-selection bias where homosexuals with gay siblings are more likely to volunteer for studies. Nonetheless, it is possible to conclude that, given the difference in sexuality in so many sets of identical twins, sexual orientation cannot be attributed solely to genetic factors.[13]

Another issue is the finding that even monozygotic twins can be different and there is a mechanism which might account for monozygotic twins being discordant for homosexuality. Gringas and Chen (2001) describe a number of mechanisms which can lead to differences between monozygotic twins, the most relevant here being chorionicity and amniocity.[14] Dichorionic twins potentially have different hormonal environments because they receive maternal blood from separate placenta, and this could result in different levels of brain masculinisation. Monoamniotic twins share a hormonal environment, but can suffer from the 'twin to twin transfusion syndrome' in which one twin is "relatively stuffed with blood and the other exsanguinated".[15]

Chromosome linkage studies of sexual orientation have indicated the presence of multiple contributing genetic factors throughout the genome. In 1993 Dean Hamer and colleagues published findings from a linkage analysis of a sample of 76 gay brothers and their families.[16] Hamer et al. found that the gay men had more gay male uncles and cousins on the maternal side of the family than on the paternal side. Gay brothers who showed this maternal pedigree were then tested for X chromosome linkage, using twenty-two markers on the X chromosome to test for similar alleles. In another finding, thirty-three of the forty sibling pairs tested were found to have similar alleles in the distal region of Xq28, which was significantly higher than the expected rates of 50% for fraternal brothers. This was popularly dubbed the "gay gene" in the media, causing significant controversy. Sanders et al. in 1998 reported on their similar study, in which they found that 13% of uncles of gay brothers on the maternal side were homosexual, compared with 6% on the paternal side.[17]

A later analysis by Hu et al. replicated and refined the earlier findings. This study revealed that 67% of gay brothers in a new saturated sample shared a marker on the X chromosome at Xq28.[18] Two other studies (Bailey et al., 1999; McKnight and Malcolm, 2000) failed to find a preponderance of gay relatives in the maternal line of homosexual men.[17] One study by Rice et al. in 1999 failed to replicate the Xq28 linkage results.[19] Meta-analysis of all available linkage data indicates a significant link to Xq28, but also indicates that additional genes must be present to account for the full heritability of sexual orientation.[20]

Mustanski et al. (2005) performed a full-genome scan (instead of just an X chromosome scan) on individuals and families previously reported on in Hamer et al. (1993) and Hu et al. (1995), as well as additional new subjects. In the full sample they did not find linkage to Xq28.[21]

Results from the first large, comprehensive multi-center genetic linkage study of male sexual orientation were reported by an independent group of researchers at the American Society of Human Genetics in 2012.[22] The study population included 409 independent pairs of gay brothers, who were analyzed with over 300,000 single-nucleotide polymorphism markers. The data strongly replicated Hamer's Xq28 findings as determined by both two-point and multipoint (MERLIN) LOD score mapping. Significant linkage was also detected in the pericentromeric region of chromosome 8, overlapping with one of the regions detected in the Hamer lab's previous genomewide study. The authors concluded that "our findings, taken in context with previous work, suggest that genetic variation in each of these regions contributes to development of the important psychological trait of male sexual orientation". Female sexual orientation does not seem to be linked to Xq28,[18][23] though it does appear moderately heritable.[24]

In addition to sex chromosomal contribution, a potential autosomal genetic contribution to the development of homosexual orientation has also been suggested. In a study population composed of more than 7000 participants, Ellis et al. (2008) found a statistically significant difference in the frequency of blood type A between homosexuals and heterosexuals. They also found that "unusually high" proportions of homosexual males and homosexual females were Rh negative in comparison to heterosexuals. As both blood type and Rh factor are genetically inherited traits controlled by alleles located on chromosome 9 and chromosome 1 respectively, the study indicates a potential link between genes on autosomes and homosexuality.[25][26]

The biology of sexual orientation has been studied in detail in several animal model systems. In the common fruit fly Drosophila melanogaster, the complete pathway of sexual differentiation of the brain and the behaviors it controls is well established in both males and females, providing a concise model of biologically controlled courtship.[27] In mammals, a group of geneticists at the Korea Advanced Institute of Science and Technology bred a female mice specifically lacking a particular gene related to sexual behavior. Without the gene, the mice exhibited masculine sexual behavior and attraction toward urine of other female mice. Those mice who retained the gene fucose mutarotase (FucM) were attracted to male mice.[28]

In interviews to the press, researchers have pointed that the evidence of genetic influences should not be equated with genetic determinism. According to Dean Hamer and Michael Bailey, genetic aspects are only one of the multiple causes of homosexuality.[29][30]

In 2017, Nature published an article with a genome wide association study on male sexual orientation. The research consisted of 1,077 homosexual men and 1,231 heterosexual men. A gene named SLITRK6 on chromosome 13 was identified.[31] The research supports another study which had been done by Simon LeVay. LeVay's research suggested that the hypothalamus of gay men is different from straight men.[32] The SLITRK6 is active in the mid-brain where the hypothalamus is. The researchers found another gene, named "thyroid stimulating hormone receptor" (TSHR) on chromosome 14 which dna sequence is different also for gay men.[31] TSHR stimulates thyroid and grave disease interrupted the function of TSHR. The previous research also indicated that grave disease had been seen more in gay men than in straight men.[33] Research indicated that gay people have lower body weight than straight people. It had been presumed that the overactive TSHR hormone lowered body weight in gay people.[34][35]

In 2018, Ganna et al. performed another genome wide association study on sexual orientation of men and women with data from 26,890 people who had at least one same-sex partner and 450,939 controls. The data in the study was meta-analyzed and obtained from the UK Biobank study and 23andMe. The researchers identified four variants more common in people who reported at least one same-sex experience on chromosomes 7, 11, 12, and 15. The variants on chromosomes 11 and 15 were specific to men, with the variant on chromosome 11 located in an olfactory gene and the variant on chromosome 15 having previously been linked to male-pattern baldness. The four variants were also correlated with mood and mental health disorders; major depressive disorder and schizophrenia in men and women, and bipolar disorder in women. However, none of the four variants could reliably predict sexual orientation.[36]

A study suggests linkage between a mother's genetic make-up and homosexuality of her sons. Women have two X chromosomes, one of which is "switched off". The inactivation of the X chromosome occurs randomly throughout the embryo, resulting in cells that are mosaic with respect to which chromosome is active. In some cases though, it appears that this switching off can occur in a non-random fashion. Bocklandt et al. (2006) reported that, in mothers of homosexual men, the number of women with extreme skewing of X chromosome inactivation is significantly higher than in mothers without gay sons. 13% of mothers with one gay son, and 23% of mothers with two gay sons, showed extreme skewing, compared to 4% of mothers without gay sons.[37]

Blanchard and Klassen (1997) reported that each additional older brother increases the odds of a man being gay by 33%.[38][39] This is now "one of the most reliable epidemiological variables ever identified in the study of sexual orientation".[40] To explain this finding, it has been proposed that male fetuses provoke a maternal immune reaction that becomes stronger with each successive male fetus.This maternal immunization hypothesis (MIH) begins when cells from a male fetus enter the mother's circulation during pregnancy or while giving birth.[41]Male fetuses produce H-Y antigens which are "almost certainly involved in the sexual differentiation of vertebrates".These Y-linked proteins would not be recognized in the mother's immune system because she is female, causing her to develop antibodies which would travel through the placental barrier into the fetal compartment. From here, the anti-male bodies would then cross the blood/brain barrier (BBB) of the developing fetal brain, altering sex-dimorphic brain structures relative to sexual orientation, increasing the likelihood that the exposed son will be more attracted to men than women.[41]It is this antigen which maternal H-Y antibodies are proposed to both react to and 'remember'. Successive male fetuses are then attacked by H-Y antibodies which somehow decrease the ability of H-Y antigens to perform their usual function in brain masculinisation.[38]

However, the maternal immune hypothesis has been criticized because the prevalence of the type of immune attack proposed is rare compared with the prevalence of homosexuality.[42]

The "fraternal birth order effect" however, cannot account for between 71-85% of male homosexual preference.[43] Additionally, it does not explain instances where a firstborn child displays male homosexual preference (MHP).[44]

In 2017, researchers discovered a biological mechanism of gay people who tend to have older brothers. They think Neuroligin 4 Y-linked protein is responsible for a later son being gay. They found that women had significantly higher anti-NLGN4Y levels than men. The result also indicates that number of pregnancies, mothers of gay sons, particularly those with older brothers, had significantly higher anti-NLGN4Y levels than did the control samples of women, including mothers of heterosexual sons.[45]

In 2004, Italian researchers conducted a study of about 4,600 people who were the relatives of 98 homosexual and 100 heterosexual men. Female relatives of the homosexual men tended to have more offspring than those of the heterosexual men. Female relatives of the homosexual men on their mother's side tended to have more offspring than those on the father's side. The researchers concluded that there was genetic material being passed down on the X chromosome which both promotes fertility in the mother and homosexuality in her male offspring. The connections discovered would explain about 20% of the cases studied, indicating that this is a highly significant but not the sole genetic factor determining sexual orientation.[46][47]

Research conducted in Sweden[48] has suggested that gay and straight men respond differently to two odors that are believed to be involved in sexual arousal. The research showed that when both heterosexual women and gay men are exposed to a testosterone derivative found in men's sweat, a region in the hypothalamus is activated. Heterosexual men, on the other hand, have a similar response to an estrogen-like compound found in women's urine.[49] The conclusion is that sexual attraction, whether same-sex or opposite-sex oriented, operates similarly on a biological level. Researchers have suggested that this possibility could be further explored by studying young subjects to see if similar responses in the hypothalamus are found and then correlating these data with adult sexual orientation.[citation needed]

A number of sections of the brain have been reported to be sexually dimorphic; that is, they vary between men and women. There have also been reports of variations in brain structure corresponding to sexual orientation. In 1990, Dick Swaab and Michel A. Hofman reported a difference in the size of the suprachiasmatic nucleus between homosexual and heterosexual men.[50] In 1992, Allen and Gorski reported a difference related to sexual orientation in the size of the anterior commissure,[51] but this research was refuted by numerous studies, one of which found that the entirety of the variation was caused by a single outlier.[52][53][54]

Research on the physiologic differences between male and female brains are based on the idea that people have male or a female brain, and this mirrors the behavioral differences between the two sexes. Some researchers state that solid scientific support for this is lacking. Although consistent differences have been identified, including the size of the brain and of specific brain regions, male and female brains are very similar.[55][56]

Simon LeVay, too, conducted some of these early researches. He studied four groups of neurons in the hypothalamus called INAH1, INAH2, INAH3 and INAH4. This was a relevant area of the brain to study, because of evidence that it played a role in the regulation of sexual behaviour in animals, and because INAH2 and INAH3 had previously been reported to differ in size between men and women.[57]

He obtained brains from 41 deceased hospital patients. The subjects were classified into three groups. The first group comprised 19 gay men who had died of AIDS-related illnesses. The second group comprised 16 men whose sexual orientation was unknown, but whom the researchers presumed to be heterosexual. Six of these men had died of AIDS-related illnesses. The third group was of six women whom the researchers presumed to be heterosexual. One of the women had died of an AIDS-related illness.[57]

The HIV-positive people in the presumably heterosexual patient groups were all identified from medical records as either intravenous drug abusers or recipients of blood transfusions. Two of the men who identified as heterosexual specifically denied ever engaging in a homosexual sex act. The records of the remaining heterosexual subjects contained no information about their sexual orientation; they were assumed to have been primarily or exclusively heterosexual "on the basis of the numerical preponderance of heterosexual men in the population".[57]

LeVay found no evidence for a difference between the groups in the size of INAH1, INAH2 or INAH4. However, the INAH3 group appeared to be twice as big in the heterosexual male group as in the gay male group; the difference was highly significant, and remained significant when only the six AIDS patients were included in the heterosexual group. The size of INAH3 in the homosexual men's brains was comparable to the size of INAH3 in the heterosexual women's brains.

However, other studies have shown that the sexually dimorphic nucleus of the preoptic area, which include the INAH3, are of similar size in homosexual males who died of AIDS to heterosexual males, and therefore larger than female. This clearly contradicts the hypothesis that homosexual males have a female hypothalamus. Furthermore, the SCN of homosexual males is extremely large (both the volume and the number of neurons are twice as many as in heterosexual males). These areas of the hypothalamus have not yet been explored in homosexual females nor bisexual males nor females. Although the functional implications of such findings still haven't been examined in detail, they cast serious doubt over the widely accepted Drner hypothesis that homosexual males have a "female hypothalamus" and that the key mechanism of differentiating the "male brain from originally female brain" is the epigenetic influence of testosterone during prenatal development.[58][59]

William Byne and colleagues attempted to identify the size differences reported in INAH 14 by replicating the experiment using brain sample from other subjects: 14 HIV-positive homosexual males, 34 presumed heterosexual males (10 HIV-positive), and 34 presumed heterosexual females (9 HIV-positive). The researchers found a significant difference in INAH3 size between heterosexual men and heterosexual women. The INAH3 size of the homosexual men was apparently smaller than that of the heterosexual men, and larger than that of the heterosexual women, though neither difference quite reached statistical significance.[60]

Byne and colleagues also weighed and counted numbers of neurons in INAH3 tests not carried out by LeVay. The results for INAH3 weight were similar to those for INAH3 size; that is, the INAH3 weight for the heterosexual male brains was significantly larger than for the heterosexual female brains, while the results for the gay male group were between those of the other two groups but not quite significantly different from either. The neuron count also found a male-female difference in INAH3, but found no trend related to sexual orientation.[60]

A 2010 study, Garcia-Falgueras and Swaab asserted that "the fetal brain develops during the intrauterine period in the male direction through a direct action of testosterone on the developing nerve cells, or in the female direction through the absence of this hormone surge. In this way, our gender identity (the conviction of belonging to the male or female gender) and sexual orientation are programmed or organized into our brain structures when we are still in the womb. There is no indication that social environment after birth has an effect on gender identity or sexual orientation."[61]

The domestic ram is used as an experimental model to study early programming of the neural mechanisms which underlie homosexuality, developing from the observation that approximately 8% of domestic rams are sexually attracted to other rams (male-oriented) when compared to the majority of rams which are female-oriented. In many species, a prominent feature of sexual differentiation is the presence of a sexually dimorphic nucleus (SDN) in the preoptic hypothalamus, which is larger in males than in females.

Roselli et al. discovered an ovine SDN (oSDN) in the preoptic hypothalamus that is smaller in male-oriented rams than in female-oriented rams, but similar in size to the oSDN of females. Neurons of the oSDN show aromatase expression which is also smaller in male-oriented rams versus female-oriented rams, suggesting that sexual orientation is neurologically hard-wired and may be influenced by hormones. However, results failed to associate the role of neural aromatase in the sexual differentiation of brain and behavior in the sheep, due to the lack of defeminization of adult sexual partner preference or oSDN volume as a result of aromatase activity in the brain of the fetuses during the critical period. Having said this, it is more likely that oSDN morphology and homosexuality may be programmed through an androgen receptor that does not involve aromatisation. Most of the data suggests that homosexual rams, like female-oriented rams, are masculinized and defeminized with respect to mounting, receptivity, and gonadotrophin secretion, but are not defeminized for sexual partner preferences, also suggesting that such behaviors may be programmed differently. Although the exact function of the oSDN is not fully known, its volume, length, and cell number seem to correlate with sexual orientation, and a dimorphism in its volume and of cells could bias the processing cues involved in partner selection. More research is needed in order to understand the requirements and timing of the development of the oSDN and how prenatal programming effects the expression of mate choice in adulthood.[62]

The early fixation hypothesis includes research into prenatal development and the environmental factors that control masculinization of the brain. Some studies have seen pre-natal hormone exposures as the primary factor involved in determining sexual orientation.[63][64][65] This hypothesis is supported by both the observed differences in brain structure and cognitive processing between homosexual and heterosexual men. One explanation for these differences is the idea that differential exposure to hormone levels in the womb during fetal development may change the masculinization of the brain in homosexual men. The concentrations of these chemicals is thought to be influenced by fetal and maternal immune systems, maternal consumption of certain drugs, maternal stress, and direct injection. This hypothesis is connected to the well-measured effect of fraternal birth order on sexual orientation.

Daryl Bem, a social psychologist at Cornell University, has theorized that the influence of biological factors on sexual orientation may be mediated by experiences in childhood. A child's temperament predisposes the child to prefer certain activities over others. Because of their temperament, which is influenced by biological variables such as genetic factors, some children will be attracted to activities that are commonly enjoyed by other children of the same gender. Others will prefer activities that are typical of another gender. This will make a gender-conforming child feel different from opposite-gender children, while gender-nonconforming children will feel different from children of their own gender. According to Bem, this feeling of difference will evoke psychological arousal when the child is near members of the gender which it considers as being 'different'. Bem theorizes that this psychological arousal will later be transformed into sexual arousal: children will become sexually attracted to the gender which they see as different ("exotic"). This proposal is known as the "exotic becomes erotic" theory.[66]

Bem sought support from published literature but did not present new data testing his theory.[67] Research cited by him as evidence of the "exotic becomes erotic" theory includes the study Sexual Preference by Bell et al. (1981)[67] and studies showing the frequent finding that a majority of gay men and lesbians report being gender-nonconforming during their childhood years. A meta-analysis of 48 studies showed childhood gender nonconformity to be the strongest predictor of a homosexual orientation for both men and women.[68] In six "prospective" studiesthat is, longitudinal studies that began with gender-nonconforming boys at about age 7 and followed them up into adolescence and adulthood 63% of the gender nonconforming boys had a homosexual or bisexual orientation as adults.[69]

Sexual practices that significantly reduce the frequency of heterosexual intercourse also significantly decrease the chances of successful reproduction, and for this reason, they would appear to be maladaptive in an evolutionary context following a simple Darwinian model (competition amongst individuals) of natural selectionon the assumption that homosexuality would reduce this frequency. Several theories have been advanced to explain this contradiction, and new experimental evidence has demonstrated their feasibility.[70]

Some scholars[70] have suggested that homosexuality is indirectly adaptive, by conferring a reproductive advantage in a non-obvious way on heterosexual siblings or their children. By way of analogy, the allele (a particular version of a gene) which causes sickle-cell anemia when two copies are present, also confers resistance to malaria with a lesser form of anemia when one copy is present (this is called heterozygous advantage).[71]

Scholars have also pointed out that Darwin himself described kin selection in The Origin of Species, so under a Darwinian model of evolution, not only individuals, but family groups (bloodlines) can compete for selection.

Brendan Zietsch of the Queensland Institute of Medical Research proposes the alternative theory that men exhibiting female traits become more attractive to females and are thus more likely to mate, provided the genes involved do not drive them to complete rejection of heterosexuality.[72]

In a 2008 study, its authors stated that "There is considerable evidence that human sexual orientation is genetically influenced, so it is not known how homosexuality, which tends to lower reproductive success, is maintained in the population at a relatively high frequency." They hypothesized that "while genes predisposing to homosexuality reduce homosexuals' reproductive success, they may confer some advantage in heterosexuals who carry them". Their results suggested that "genes predisposing to homosexuality may confer a mating advantage in heterosexuals, which could help explain the evolution and maintenance of homosexuality in the population".[73]

However, in the same study, the authors noted that "nongenetic alternative explanations cannot be ruled out" as a reason for the heterosexual in the homosexual-heterosexual twin pair having more partners, specifically citing "social pressure on the other twin to act in a more heterosexual way" (and thus seek out a greater number of sexual partners) as an example of one alternative explanation. Also, the authors of the study acknowledge that a large number of sexual partners may not lead to greater reproductive success, specifically noting there is an "absence of evidence relating the number of sexual partners and actual reproductive success, either in the present or in our evolutionary past".

The heterosexual advantage hypothesis was given strong support by the 2004 Italian study demonstrating increased fecundity in the female matrilineal relatives of gay men.[46][47] As originally pointed out by Hamer,[74] even a modest increase in reproductive capacity in females carrying a "gay gene" could easily account for its maintenance at high levels in the population.[47]

The "gay uncle hypothesis" posits that people who themselves do not have children may nonetheless increase the prevalence of their family's genes in future generations by providing resources (e.g., food, supervision, defense, shelter) to the offspring of their closest relatives.

This hypothesis is an extension of the theory of kin selection, which was originally developed to explain apparent altruistic acts which seemed to be maladaptive. The initial concept was suggested by J. B. S. Haldane in 1932 and later elaborated by many others including John Maynard Smith, W. D. Hamilton and Mary Jane West-Eberhard.[75] This concept was also used to explain the patterns of certain social insects where most of the members are non-reproductive.

Vasey and VanderLaan (2010) tested the theory on the Pacific island of Samoa, where they studied women, straight men, and the fa'afafine, men who prefer other men as sexual partners and are accepted within the culture as a distinct third gender category. Vasey and VanderLaan found that the fa'afafine said they were significantly more willing to help kin, yet much less interested in helping children who aren't family, providing the first evidence to support the kin selection hypothesis.[76][77]

The hypothesis is consistent with other studies on homosexuality, which show that it is more prevalent amongst both siblings and twins.[76][77][78][bettersourceneeded] Since both twins and non-twin siblings share genes and therefore have a higher factor of genetic redundancy, there is less genetic familial risk if the strategy is expressed. It is speculated that environmental and hormonal stress factors (linked to resource feedbacks) may act as triggers.

Since the hypothesis solves the problem of why homosexuality has not been selected out over thousands of years, despite it being antithetical to reproduction, many scientists consider it the best explanatory model for non-heterosexual behaviour such as homosexuality and bisexuality. The natural bell curve variation that occurs in biology and sociology everywhere, explains the variable spectrum of expression.

Vasal and VanderLaan (2011) provides evidence that if an adaptively designed avuncular male androphilic phenotype exists and its development is contingent on a particular social environment, then a collectivistic cultural context is insufficient, in and of itself, for the expression of such a phenotype.[79]

Some studies have found correlations between physiology of people and their sexuality; these studies provide evidence which suggests that:

Whether genetic or other physiological determinants form the basis of sexual orientation is a highly politicized issue. The Advocate, a U.S. gay and lesbian newsmagazine, reported in 1996 that 61% of its readers believed that "it would mostly help gay and lesbian rights if homosexuality were found to be biologically determined".[106] A cross-national study in the United States, the Philippines, and Sweden found that those who believed that "homosexuals are born that way" held significantly more positive attitudes toward homosexuality than those who believed that "homosexuals choose to be that way" or "learn to be that way".[107][108]

Equal protection analysis in U.S. law determines when government requirements create a suspect classification" of groups and therefore eligible for heightened scrutiny based on several factors, one of which is immutability.

Evidence that sexual orientation is biologically determined (and therefore perhaps immutable in the legal sense) would strengthen the legal case for heightened scrutiny of laws discriminating on that basis.[109][110][111]

The perceived causes of sexual orientation have a significant bearing on the status of sexual minorities in the eyes of social conservatives. The Family Research Council, a conservative Christian think tank in Washington, D.C., argues in the book Getting It Straight that finding people are born gay "would advance the idea that sexual orientation is an innate characteristic, like race; that homosexuals, like African-Americans, should be legally protected against 'discrimination;' and that disapproval of homosexuality should be as socially stigmatized as racism. However, it is not true." On the other hand, some social conservatives such as Reverend Robert Schenck have argued that people can accept any scientific evidence while still morally opposing homosexuality.[112] National Organization for Marriage board member and fiction writer Orson Scott Card has supported biological research on homosexuality, writing that "our scientific efforts in regard to homosexuality should be to identify genetic and uterine causes... so that the incidence of this dysfunction can be minimized.... [However, this should not be seen] as an attack on homosexuals, a desire to 'commit genocide' against the homosexual community.... There is no 'cure' for homosexuality because it is not a disease. There are, however, different ways of living with homosexual desires."[113]

Some advocates for the rights of sexual minorities resist linking that cause with the concept that sexuality is biologically determined or fixed at birth. They argue that sexual orientation can shift over the course of a person's life.[114] At the same time, others resist any attempts to pathologise or medicalise 'deviant' sexuality, and choose to fight for acceptance in a moral or social realm.[112] Chandler Burr has stated that "[s]ome, recalling earlier psychiatric "treatments" for homosexuality, discern in the biological quest the seeds of genocide. They conjure up the specter of the surgical or chemical "rewiring" of gay people, or of abortions of fetal homosexuals who have been hunted down in the womb."[115] LeVay has said in response to letters from gays and lesbians making such criticisms that the research "has contributed to the status of gay people in society".[112]

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Biology and sexual orientation - Wikipedia

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