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CRISPR gene editing is coming to the clinic | Chemical …


The CRISPR system uses a guide RNA (yellow) to direct the Cas9 enzyme (white) to a specific location in a cells DNA (blue) for cutting.

Credit: CRISPR Therapeutics

The gene editing technology CRISPR is one step closer to treating genetic diseases in humans. Last week, Crispr Therapeutics filed an application with European regulatory authorities to begin clinical trials for its CRISPR therapy CTX001 in a genetic blood condition called beta-thalassemia. The biotech firm expects to begin the trialthe first industry-sponsored study of a CRISPR drugnext year.

Samarth Kulkarni, CRISPR Therapeutics CEO

It is a momentous occasion for both our company and the field, says Samarth Kulkarni, CEO of Crispr Therapeutics. In early 2018, the firm will also ask the U.S. Food & Drug Administration for permission to use CTX001 to treat sickle cell disease. Vertex Pharmaceuticals today announced a 50-50 partnership with CRISPR Therapeutics to develop the drug in both beta-thalassemia and sickle cell.

Promising preclinical data presented at the American Society of Hematology (ASH) meeting in Atlanta this past weekend offered a glimpse of the strategies that Crispr Therapeutics and its many competitors are taking to treat the genetic blood diseases.

Since its conception in 2012, CRISPR has been swiftly adopted in research labs. By 2014, three biotech firms, each partly founded by one of the three inventors of CRISPR, had launched to transform the tool into a therapy. These three companies are now gearing up for their first-in-human studies, a breakneck pace for drug development.

CRISPR requires at least two basic components to edit genes: a guide RNA, which carries the code that specifies where to edit a genome, and an enzyme called Cas, which follows the guide RNA to make a cut in a cells DNA. Sometimes this cut is enough for a potential therapy. But to change the DNA or insert a new sequence, a third component, a template DNA, is required.

Both sickle cell disease and beta-thalassemia are caused by mutations in a gene that makes part of hemoglobin, the protein that carries oxygen throughout the blood. In sickle cell, the mutation causes normally donut-shaped red blood cells to warp into a crescent shape; the cells get stuck inside blood vessels, depriving tissues of oxygen. Beta-thalassemia is caused by mutations that prevent the production of fully functional hemoglobin, which for some people can cause severe anemia.

Instead of trying to fix the faulty DNA, Crispr Therapeutics and other companies are using the technology to reactivate a kind of hemoglobin found in infants. Everyone is born with high levels of a protein called fetal hemoglobin, which is mostly replaced with adult hemoglobin by three months of agethe same time that symptoms of sickle cell and beta-thalassemia appear. A gene called BCL11A represses the fetal hemoglobin production, but a rare genetic mutation in this gene is known to allow fetal hemoglobin production to continue.

Crispr Therapeutics lead drug candidate, CTX001, works by simply cutting BCL11A, basically removing the brakes on fetal hemoglobin production, Kulkarni says. On Sunday, the company presented results showing that its method edited over 90% of blood stem cells removed from patients with beta-thalassemia, dramatically increasing fetal hemoglobin in these cells.

Kulkarni says that extensive computer prediction, followed by cell and animal testing, has led them to a guide RNA in the CRISPR therapy that has no detectable off-target activitya potential side effect in which CRISPR accidently cuts the DNA in the wrong location. Stuart Orkin, a hematologist-oncologist at the Boston Childrens Hospital, says that off-target activity is one of the biggest safety concerns for gene editing in humans.

Crispr Therapeutics isnt the only company trying to increase fetal hemoglobin by targeting BCL11A. Intellia Therapeutics and Novartis have a partnership to do this with CRISPR. And Sangamo Therapeutics and Bioverativ are developing a similar therapy together using a different gene editing technology called zinc finger nucleases.

Meanwhile, Editas Medicine, another CRISPR company, presented an update at ASH on using its proprietary Cas enzyme, called Cpf1, to fix the mutation in the gene for adult hemoglobin. Charles Albright, chief scientific officer of Editas, says the company is simultaneously working on the fetal hemoglobin approach, but did not provide a timeline for when the sickle cell therapy would make it into clinical studies.

The hematology meeting also showcased many firms working on therapies for sickle cell and beta-thalassemia that dont require gene editing. Bluebird Bio, a gene therapy company, has ongoing clinical trials for both conditions using a virus to deliver a healthy copy of the hemoglobin gene into cells. Drug companies are also trying to treat sickle cell with small molecule drugs. Global Blood Therapeutics compound voxelotor, which increases hemoglobins ability to bind oxygen, is in Phase II and III clinical trials currently. And Epizyme is developing an inhibitor of an enzyme called histone methyltransferase, which could be another way to release the brakes on fetal hemoglobin production.

Everyone is working on these diseases because we know exactly what to do, and there are multiple different ways to get to the same end, a treatment, Orkin says. We dont know yet which program will be the bestBut the first one that is shown to be very effective and safe, could crowd out the others.

As it prepares to launch its first trial, Crispr Therapeutics has secured a contract manufacturer in Europe which will receive patient blood cells, edit them, and then ship them back to the clinical trial sites. Patients will then undergo chemotherapy or irradiation in preparation for their edited blood stem cells to be transplanted into the bone marrow, where they will hopefully produce healthier blood cells for life.

It is important that they do this very carefully, Orkin says. Because if there is a mistake or bad effect [from CRISPR], it will have repercussions beyond a single patient.

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CRISPR gene editing is coming to the clinic | Chemical ...

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Male hypogonadism – Diagnosis and treatment – Mayo Clinic


Your doctor will conduct a physical exam during which he or she will note whether your sexual development, such as your pubic hair, muscle mass and size of your testes, is consistent with your age. Your doctor may test your blood level of testosterone if you have any of the signs or symptoms of hypogonadism.

Early detection in boys can help prevent problems from delayed puberty. Early diagnosis and treatment in men offer better protection against osteoporosis and other related conditions.

Doctors base a diagnosis of hypogonadism on symptoms and results of blood tests that measure testosterone levels. Because testosterone levels vary and are generally highest in the morning, blood testing is usually done early in the day, before 10 a.m.

If tests confirm you have low testosterone, further testing can determine if a testicular disorder or a pituitary abnormality is the cause. Based on specific signs and symptoms, additional studies can pinpoint the cause. These studies may include:

Testosterone testing also plays an important role in managing hypogonadism. This helps your doctor determine the right dosage of medication, both initially and over time.

Treatment for male hypogonadism depends on the cause and whether you're concerned about fertility.

Hormone replacement. For hypogonadism caused by testicular failure, doctors use male hormone replacement therapy (testosterone replacement therapy, or TRT). TRT can restore muscle strength and prevent bone loss. In addition, men receiving TRT may experience an increase in energy, sex drive, erectile function and sense of well-being.

If a pituitary problem is the cause, pituitary hormones may stimulate sperm production and restore fertility. Testosterone replacement therapy can be used if fertility isn't an issue. A pituitary tumor may require surgical removal, medication, radiation or the replacement of other hormones.

In boys, testosterone replacement therapy (TRT) can stimulate puberty and the development of secondary sex characteristics, such as increased muscle mass, beard and pubic hair growth, and growth of the penis. Pituitary hormones may be used to stimulate testicle growth. An initial low dose of testosterone with gradual increases may help to avoid adverse effects and more closely mimic the slow increase in testosterone that occurs during puberty.

Several testosterone delivery methods exist. Choosing a specific therapy depends on your preference of a particular delivery system, the side effects and the cost. Methods include:

Injection. Testosterone injections (testosterone cypionate, testosterone enanthate) are safe and effective. Injections are given in a muscle. Your symptoms might fluctuate between doses depending on the frequency of injections.

You or a family member can learn to give TRT injections at home. If you're uncomfortable giving yourself injections, a nurse or doctor can give the injections.

Testosterone undecanoate (Aveed), an injection recently approved by the Food and Drug Administration, is injected less frequently but must be administered by a health care provider and can have serious side effects.

Gel. There are several gel preparations available with different ways of applying them. Depending on the brand, you either rub testosterone gel into your skin on your upper arm or shoulder (AndroGel, Testim, Vogelxo), apply with an applicator under each armpit (Axiron) or pump on your front and inner thigh (Fortesta).

As the gel dries, your body absorbs testosterone through your skin. Gel application of testosterone replacement therapy appears to cause fewer skin reactions than patches do. Don't shower or bathe for several hours after a gel application, to be sure it gets absorbed.

A potential side effect of the gel is the possibility of transferring the medication to another person. Avoid skin-to-skin contact until the gel is completely dry or cover the area after an application.

Oral testosterone isn't recommended for long-term hormone replacement because it might cause liver problems.

Testosterone therapy carries various risks, including contributing to sleep apnea, stimulating noncancerous growth of the prostate, enlarging breasts, limiting sperm production, stimulating growth of existing prostate cancer and blood clots forming in the veins. Recent research also suggests testosterone therapy might increase your risk of a heart attack.

Reduce stress. Talk with your doctor about how you can reduce the anxiety and stress that often accompany these conditions. Many men benefit from psychological or family counseling.

Support groups can help people with hypogonadism and related conditions cope with similar situations and challenges. Helping your family understand the diagnosis of hypogonadism also is important.

Although you're likely to start by seeing your family doctor or general practitioner, you may need to consult a doctor who specializes in the hormone-producing glands (endocrinologist). If your primary care doctor suspects you have male hypogonadism, he or she may refer you to an endocrinologist. Or, you can ask for a referral.

Here's some information to help you get ready for your appointment and know what to expect from your doctor.

Preparing a list of questions for your doctor will help you make the most of your time together. For male hypogonadism, some basic questions to ask your doctor include:

Don't hesitate to ask other questions you have.

Your doctor is likely to ask you a number of questions, such as:

Sept. 29, 2016

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Male hypogonadism - Diagnosis and treatment - Mayo Clinic

Recommendation and review posted by Bethany Smith

CRISPR Timeline CRISPR Update

1987: CRISPR repeats were observed in bacterial genomes. The authors concluded, no sequence homologous to these has been found elsewhere in procaryotes, and the biological significance of these sequences is not known. Ishino et al. J. Bacteriology (1987) 169:5429-5433.

2002: The term CRISPR was coined to describe the repetitive repeats observed in bacterial and archaeal genomes. Genes usually found associated with the CRISPR repeats were identified and named CRISPR Associated Proteins or Cas. Jansen et al. Mol. Microbiology. (2002) 43:1565-1575.

2005: CRISPR spacer sequences were matched to foreign DNA. Bolotin et al. Microbiology (2005) 151:2551-2561.

2006: CRISPR was first proposed to be a bacterial adaptive immune system. Makarova et al. Biol Direct (2006) 1:7.

2007: CRISPR loci were found to impart phage resistance in bacteria. It was determined that CRISPR sequences together with the Cas genes impart resistance and that resistance to specific phages was determined by the spacer sequences found between CRISPR repeats. Barrangou et al. Science. (2007) 315:1709-1712.

2009: RNA guided RNA cleavage is first described. Hale et al. RNA (2008) 2:2572-2579.

2010: The CRISPR/Cas system was identified as a bacterial and archeal immune system that targets and cleaves phage DNA. This system was found to be dependent on the bacteria containing CRISPR spacer sequences that match the phage DNA. Additionally researchers discovered that new spacer sequences could be inserted into the bacterial/archeal chromosome making the CRISPR/Cas system an adaptive immune system. Garneau et al. Nature. (2010) 468:67-71.

2011: Cas9 from Streptococcus pyogenes was found to associate with two RNA molecules coined crRNA and tracrRNA and that all these components are required for protection against phage infection. Deltcheva et al. Nature (2011) 471:602-607.

2012: Cas9 was found to be an endonuclease capable of introducing DSB in DNA and that this process is dependent on complementary binding of the crRNA to the target DNA. Two nuclease domains were found in Cas9 with the HNH domain cleaving the complementary strand and the RuvC-like domain cutting the non-complementary strand. Jinek et al. Science (2012) 337:816-821.

2013: The CRISPR/Cas9 system was used to edit targeted genes in both human and mouse cells using designed crRNA sequences. Cong et al. Science (2013) 339:819-823.

First use in plants. Li et al. Nat Biotechnol (2013) 8:688-691.

Also first use in plants ? Nekrasov et al. Nat Biotechnol (2013) 8:691-693.

2014: The crystal structure of Cas9 complexed with both gRNA and targeted DNA was elucidated. Nishimasu et al. Cell (2014) 156:935-949.

PAMs are identified as a key component of DNA target integration. Anders et al. Nature (2014) 513:569-573.

sgRNA and Cas9 are directly delivered into cells without the use of a vector intermediate. Ramakrishna et al. Genome Res (2014) 24:1020-1027.

2015: CRISPR/Cas9 was used to edit tri-chromosomal pre-implantation human embryos. Researchers attempted to repair the HBB locuswhich, when mutated, results in -thalassemia blood disorders. The researchers were unable to effectively repair the mutated locus and many off-target cleavages were observed. Liang et al. Protein and Cell (2015) 6:363-372.

2015: An international moratorium is called for making heritable changes to the human genome using gene editing.At an international meeting convened by the National Academy of Science of the United States, the Institute of Medicine, The Chinese Academy of Sciences, and the Royal Society of London scientists called for a moratorium on making inheritable changes to the human genome. None of these groups have regulatory authority to prevent such research from taking place, however previous moratoriums where widely accepted in 1975 when an international group met in California to discuss gene editing in all species.

2016: The USDA determines CRISPR/Cas9 edited crops will not be regulated as GMOs. Due to the lack of foreign DNA and the inability to distinguish CRISPR modified crops from those created by traditional plant breeding the USDA has determined that gene edited crops will not be regulated like traditional GMOs.

2016: The first human trial to use CRISPR gene editing gets approval from the NIH. A National Institute of Health advisory committee approved the use of CRISPR/Cas9 gene editing in a cancer therapy trial. The treatment will use CRISPR/Cas9 technology to edit the patients own T cells to target cancer.

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CRISPR Timeline CRISPR Update

Recommendation and review posted by Bethany Smith

Gene Therapy Consortium – Rett Syndrome Research Trust

$3,595,265 AWARDED

Rett Syndrome, as awful as the symptoms may be, provides us with several enormous advantages. First we know the cause: mutations in a single gene: MECP2. Second, Rett is not degenerative brain cells dont die. Third, work from RSRT trustee, Adrian Bird, suggests that the symptoms of Rett need not be permanent. These three facts make gene therapy an attractive therapeutic strategy.

In 2014 we launched a bold international collaboration of two gene therapy labs, Brian Kaspar and Steven Gray, and two MECP2 labs, Gail Mandel and Stuart Cobb. Together these labs brought together all the necessary skills and experience to determine if gene therapy is a viable therapeutic.

The Consortium worked through numerous challenges involving vector optimization (the Trojan horse that delivers the gene into a cell), gene construct optimization (what you package into the vector that regulates MeCP2 protein production), gene therapy dosage, and the best route to deliver it.

The data generated by the Consortium exceeded our expectations. They were able to develop a gene therapy product candidate with impressive efficacy, safety and delivery characteristics. Importantly, the magnitude of improvement in the mouse models of Rett is much greater than that of any drug tested and suggests that significant benefit may be achieved in people. We expect improvements, at least to some degree, regardless of age.

Based on the Consortium data the biotech company, AveXis, has now committed to advancing a gene therapy candidate into clinical trials. The company will announce before the end of 2017 what their timeline for trials will be.

Technological advances in gene therapy are happening quickly with more effective vectors being discovered that can carry larger DNA cargos and target a greater percentage of brain cells. While we anticipate encouraging results with our first clinical trial there will undoubtedly be room to improve. We have therefore recently awarded continued funding to the Gene Therapy Consortium to support second-generation gene therapy programs to leverage all technological advances.

Targeting the root problem in Rett, MECP2, can be done either at the DNA level (gene therapy or MECP2 Reactivation), the mRNA level or protein level.

Both the DNA and protein approaches carry a risk of potential dosage problems (too much MeCP2 may be harmful). An alternative approach is to use a technology called Spliceosome-Mediated RNA Trans-Splicing (SMaRT). This technology allows a mutation to be spliced out and repaired in RNA. The advantage is that this approach avoids any potential over-expression issues. Consortium member, Stuart Cobb, is working on this approach.

Gail Mandel of the Consortium is working on yet another approach, RNA editing. The possibility of correcting mutations in RNA has profound therapeutic potential, but had remained largely theoretical. Our focused investments have already demonstrated the potential for correcting MECP2 mutations in RNA in cells. We are currently increasing our investment to improve the editing efficiency and to identify optimal delivery methods.

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Gene Therapy Consortium - Rett Syndrome Research Trust

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Twin Genetics and Heredity – Understanding Genetics

-A curious adult

June 25, 2014

That is a very interesting question! And one that many people wonder about. In fact, we answered a very similar question many years ago.

Twin genetics depend on what kind of twins we are talking about. Having identical twins is not genetic. On the other hand, fraternal twins can run in families.

Genetics can definitely play a role in having fraternal twins. For example, a woman that has a sibling that is a fraternal twin is 2.5 times more likely to have twins than average!

However, for a given pregnancy, only the mothers genetics matter. Fraternal twins happen when two eggs are simultaneously fertilized instead of just one. A fathers genes cant make a woman release two eggs.

It sounds like fraternal twins do indeed run in your family! But, since your son is the father, his genes are on the wrong side of the family tree. So, your family history likely didnt play a role in his wifes twin pregnancy.

The answer would be different if you were asking about a daughter. Also, although your sons family history of twins cant increase his wifes chance of having twins, he can pass those genes down to your granddaughter. With your strong family history of fraternal twins, this just might increase the chances of your granddaughter having twins!

But, your daughter-in-law is not necessarily having twins because of her genetics. Other things like environment, nutrition, age, and weight have also been linked to having twins as well. And there is always simple chanceevery woman has a chance at having fraternal twins. It is just that some women have a higher or lower chance.

Huh? Help Me Understand the Genetics!

Wait a minute. One type of twins has a genetic basis and the other does not? And, only the moms genetics matter? How is that possible?

Dont worry. It makes a lot of sense once we break down the biology.

The important difference between identical and fraternal twins is the number of fertilized eggs involved. Identical twins come from a single fertilized egg. Fraternal twins come from two different ones.

Identical twins happen when a single embryo splits in two soon after fertilization. This is why identical twins have identical DNA. They came from the same fertilized egg.

Since embryo splitting is a random event that happens by chance, it doesnt run in families. Genes are not involved. The same is not true for fraternal twins.

Fraternal twins happen when two independent eggs are each fertilized by different sperm. This is why the DNA of fraternal twins is different. In fact, fhe DNA of fraternal twins is no more similar than the DNA any other sibling pair.

Usually, a woman only releases a single egg at a time. Fraternal twins can only happen if a mother releases two eggs in one cycle. This is called hyperovulation.

Unlike embryo splitting, ovulation is a normal biological process that is controlled by our genes. And, different women can have different versions of these ovulation genes.

Some women have versions (called alleles) of these genes that make them more likely to hyperovulate. This means there is a higher chance that two eggs could get fertilized at once, leading to fraternal twins.

The gene versions that increase the chance of hyperovulation can be passed down from parent to child. This is why fraternal twins run in families.

However, only women ovulate. So, the mothers genes control this and the fathers dont.

This is why having a background of twins in the family matters only if it is on the mothers side. And why your sons family genetics did not play a role in his twins.

We went over a lot of this stuff in our previous answer, but your question got me thinking. Our last answer on twins was done so long ago. Has recent research discovered anything new on this fascinating topic? They have indeed at least if you are a sheep!

Counting Sheep can Teach us about Twins

Scientists often turn to animals when they want to study a biological process. Some of the newest information we have about twin genetics comes from studying sheep.

Sheep were chosen because, like people, they typically give birth to a single lamb. However, they can sometimes have twins and triplets.

Different breeds of sheep naturally have higher or lower twin rates. These different breeds have different versions (called alleles) of some of their genes. Specific alleles can make certain breeds more likely to have twins.

We can compare the genes between these different breeds to try to find the genes controlling twinning. And, this is just what scientists did.

A thorough search for genes controlling twining in sheep identified several interesting ones. The breeds with higher twin rates had different alleles of these genes!

Three key sheep genes identified were named BMP15, GDF9, and BMPR1B. The specific gene names are not really important. Just know that all of these genes are involved in controlling ovulation. Which makes sense!

Remember, hyperovulation increases the chance of having fraternal twins. The sheep breeds with higher than average twin rates had versions of the genes that increase ovulation.

Sheep are a great tool to help us study twin genetics. The tricky part is connecting these findings to people.

It is harder to study humans. Scientists have tried to find links between the genes identified in sheep and human twin genetics. So far theyve found that some match up and some dont. This, in and of itself, is interesting!

Another gene called follicle-stimulating hormone, or FSH for short, has also been linked to twins in humans. Like the other three genes identified, this FSH is also involved in promoting ovulation, and mothers of fraternal twins often have high levels of it.

It seems that twin genetics is more complicated in humans than in sheep. More genes are likely involved. But, each new bit of information about the genes involved adds another puzzle piece to the complete genetic picture.

Maybe someday we will know all the genes that cause fraternal twins in people. But for now, you can just tell your son that his genetics likely didnt cause his twins. Scientists are still trying to figure out which, if any, genes on his wifes side could possibly be the culprits!

By Dr. Anja Scholze, Stanford University

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Twin Genetics and Heredity - Understanding Genetics

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Small viruses could accelerate cell and gene therapy research

Interest in the field of genome editing continues to heat up, fueled by technological advances and the first approval of a gene therapy in the United States. The latest development in this exciting frontier of science involves small viruses called AAVs (short for adeno-associated viruses) that have the power to overwrite DNA in human cells.

AAV biology is one of the most febrile areas of basic research, and were planning to explore its therapeutic potential through a new collaboration, says Craig Mickanin, who focuses on new tools and technologies as a director at the Novartis Institutes for BioMedical Research (NIBR).

Novartis will work with Homology Medicines, a biotech company with a proprietary AAV platform, to adapt and refine the technology for the treatment of a blood disorder and certain eye diseases. Novartis biologists with expertise in these conditions will work side-by-side with Homology scientists over the course of the collaboration announced November 13 to move projects toward clinical testing.

The collaboration is designed to accelerate an initiative at NIBR that engages researchers across the company who are involved in projects with a common denominator: the genetic reprogramming of cells. Homologys AAV technology may aid their work.

It is our hope that this collaboration will help advance our Cell and Gene Therapy initiative, says Susan Stevenson, an executive director at NIBR who leads the initiative.

AAV biology is one of the most febrile areas of basic research, and were planning to explore its therapeutic potential through a new collaboration.

Craig Mickanin, a director at NIBR who focuses on new tools and technologies

AAVs are unusual in one key respect. In contrast to larger viruses, they dont seem to cause illness. This built-in safety feature makes AAVs attractive tools for genome editing.

The benign viruses can be engineered to carry a specific genetic sequence, and they can be programmed to home in on a target site in the genome. When they arrive, AAVs trigger a process called homologous recombination, which overwrites a particular portion of a gene or even replaces an entire gene. In this way, AAVs can be used to correct genetic defects.

Homologous recombination may give AAVs an edge over other genome editing tools such as CRISPR in certain contexts.

Unlike AAVs, CRISPR employs molecular scissors to generate double-stranded breaks in DNA. The breaks can be repaired one of two ways. The repair mechanism that tends to dominate called non-homologous end joining results in the insertion or deletion of short DNA sequences, which typically break the original gene. As a result, its relatively easy for researchers to disrupt a gene with CRISPR, but its harder for them to fix an error in a gene.

We aim to select the right tool for the right project, says Mickanin, the technology specialist. In some cases, that will mean using AAVs to correct a genetic defect rather than disabling a gene.

The collaboration with Homology includes three work streams. The first focuses on a blood disorder. The Novartis-Homology team hopes to design a single AAV reagent that can be injected directly into the bloodstream of any patient with a defective gene to cure the disease. We want to figure out if these AAVs are safe enough to inject directly into the bloodstream and if we can use them to fix a defective gene once and for all, says Stevenson, the cell and gene therapy expert.

The second work stream involves diseases of the eye, a testing ground for gene editing therapies because such therapies can be delivered locally. Gene editing agents can be injected directly under the retina, for example, where researchers hope they will work without affecting the rest of the body. The fact that we can directly observe the treatment and its effects in the eye gives us an important opportunity for assessing gene editing efficacy and helping patients with eye disease, explains Cynthia Grosskreutz, Global Head of Ophthalmology at NIBR.

The final work stream is exploratory. Researchers from across NIBR will be able to nominate projects that could benefit from Homologys AAV technology. Homologys viruses will be tested on a variety of cell types and model systems, potentially exposing new opportunities for therapeutic applications.

This technology could be applied to many different diseases, Mickanin says. Were excited to work with the Homology team to explore the possibilities.

In addition to collaborating with Homology Medicines, Novartis has made an equity investment in the company.

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Small viruses could accelerate cell and gene therapy research

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Germline Gene Transfer – National Human Genome Research …

Germline Gene Transfer

Gene transfer represents a relatively new possibility for the treatment of rare genetic disorders and common multifactorial diseases by changing the expression of a person's genes. Typically gene transfer involves using a vector such as a virus to deliver a therapeutic gene to the appropriate target cells. The technique, which is still in its infancy and is not yet available outside clinical trials, was originally envisaged as a treatment of monogenic disorders, but the majority of trials now involve the treatment of cancer, infectious diseases and vascular disease. Human gene transfer raises several important ethical issues, in particular the potential use of genetic therapies for genetic enhancement and the potential impact of germline gene transfer on future generations.

Gene transfer can be targeted to somatic (body) or germ (egg and sperm) cells. In somatic gene transfer the recipient's genome is changed, but the change is not passed on to the next generation. In germline gene transfer, the parents' egg and sperm cells are changed with the goal of passing on the changes to their offspring. Germline gene transfer is not being actively investigated, at least in larger animals and humans, although a great deal of discussion is being conducted about its value and desirability.

Many people falsely assume that germline gene transfer is already routine. For example, news reports of parents selecting a genetically tested egg for implantation or choosing the sex of their unborn child may lead the public to think that gene transfer is occurring, when actually, in these cases, genetic information is being used for selection, with no cells being altered or changed. In addition, in 2001 scientists confirmed the birth of 30 genetically altered children whose mothers had undergone a procedure called ooplasmic transfer. In this process, doctors injected some of the contents of a healthy donor egg into an egg from a woman with infertility problems. The result was an egg with two types of mitochondria, cellular structures that contain a minuscule amount of DNA and that provide energy for the cell. The children born following this procedure thus have three genetic parents, since they carry DNA from the donor as well as the mother and father. Although the researchers announced this as the "first case of human germline genetic modification," the gene transfer was an inadvertent side effect of the infertility procedure.

Many factors have prevented researchers from developing successful gene transfer techniques in both somatic and germline attempts (the latter in animals). The first hurdle is the gene delivery tool. The new gene is inserted into the body through vehicles called vectors (gene carriers), which deliver therapeutic genes to the patients' cells. Currently, the most common vectors are viruses, which have evolved a mechanism to encapsulate and deliver their genes to human cells in a pathogenic manner. Scientists have tried to take advantage of the virus's biology and manipulate its genome to remove human disease-causing genes and insert therapeutic genes. However, viruses, while effective, introduce other problems to the body, such as toxicity, immune and inflammatory responses, and gene control and targeting issues. Complexes of DNA with lipids and proteins provide an alternative to viruses, and researchers are also experimenting with introducing a 47th (artificial human) chromosome to the body that would exist autonomously along side the standard 46 chromosomes, presumably not affecting their functioning or causing any mutations. An additional chromosome would be a large vector capable of carrying substantial amounts of genetic code, and it is anticipated that, because of its construction and autonomy, the body's immune systems would not attack it.

Some of the concerns raised about somatic gene transfer are related to the possibility that it could inadvertently lead to germline gene transfer. The possibility of germline modification through these techniques is the result of the hit-or-miss nature of the current technologies. It is always possible that a vector will introduce the gene into a cell other than that for which it is supposed to be targeted (e.g., a spermatocytic cell) or that through a secondary mechanism target cells that have taken up the new gene will through some independent natural process (such as transfection) transfer the gene to a germline cell. Moreover, if somatic gene transfer were to be conducted in utero, especially before the second trimester, it would increase the likelihood that some of the cells into which the gene is taken up will become part of the germline. It is possible that to effectively treat certain diseases using gene transfer, it might be necessary to apply somatic techniques early in development so that germline transfer is inevitable.

In contrast to inadvertent germline transfer following somatic gene transfer, intentional germline gene transfer would involve the deliberate introduction of new genetic material into either germ cells (sperm or oocytes) or into zygotes in vitro prior to fertilization or implantation. Currently, this technology has not been applied to humans; however, it has been successfully applied to some plants and animals. The aim of this process is to produce a developing embryo in which each cell (including those that will develop into gametes in the future) carries the newly inserted gene as part of its genetic make-up.

Current efforts in animals have demonstrated the difficulty of this approach. Some cells do not acquire the gene or acquire multiple or partial copies of the gene. In addition, it is not yet possible to specify with any accuracy where in the genome the new gene will be introduced, and some insertion locations may interfere with other important genes. If these kinds of errors are detected, then theoretically embryos with these defects could be "selected out." However, should germline gene transfer be attempted in humans, it is likely that not all errors introduced as a result of the gene transfer will be detected.

Currently, however, animal studies have shown that gene transfer approaches that involve the early embryo can be far more effective than somatic cell gene therapy methodologies used later in development, depending on the complexity of the trait that is being improved or eliminated. Embryo gene transfer affords the opportunity to transform most or all cells of the organism and thus overcome the inefficient transformation that plagues somatic cell gene transfer protocols. Gene transfer selects one relevant locus for a trait (when in fact there might be many interactive loci) and then attempts to improve the trait in isolation. This approach, while potentially more powerful and efficient than conventional breeding techniques, involves more uncertainty risks.

Thus, both kinds of studies - germline gene transfer at the gamete and zygote stages - have significant risks. In cases in which the gene has failed to be introduced or fails to be activated, the resulting child would likely be no worse off than he or she would have been without the attempted gene transfer. However, those with partial or multiple copies of a gene could be in significantly worse condition. The problems resulting from errors caused by the gene insertion could be severe - even lethal - or they might not be evident until well after the child has been born, perhaps even well into adulthood, when the errors could be passed on to future generations. For these reasons, given the limits of current technology, germline gene transfer has been considered ethically impermissible.

Beyond the medical risks to the potential child, a number of long-standing ethical concerns exist regarding the possible practice of germline gene transfer in both human and nonhuman cases. Such modifications in human beings raise the possibility that we are changing not merely a single individual but a host of future individuals as well, with potential for harm to occur to those individuals and perhaps to humanity as a whole. Concerns involve issues ranging from the autonomy of future individuals to distributive justice, fairness, and the application of these technologies to "enhancement" rather than treating disease. In germline gene transfer, the persons being affected by the procedure - those for whom the procedure is undertaken - do not yet exist. Thus, the potential beneficiaries are not in a position to consent to or refuse such a procedure.

Gene transfer clinical trials have a unique oversight process that is conducted by the National Institutes of Health (NIH) through the Recombinant DNA Advisory Committee (RAC) and the NIH Guidelines for Research Involving Recombinant DNA Molecules, and by the Food and Drug Administration (FDA) through regulation (including scientific review, regulatory research, testing, and compliance activities, including inspection and education). Of note, FDA regulations apply to all clinical gene transfer research, while NIH governs gene transfer research that is supported with NIH funds or that is conducted at or sponsored by institutions that receive funding for recombinant DNA research. Currently, the majority of somatic cell gene transfer research is subject to the NIH Guidelines; however RAC will not currently consider protocols using germline gene transfer.

In addition, NIH has added to its guidelines the following statement:

The RAC continues to explore the issues raised by the potential of in utero gene transfer clinical research. However, the RAC concludes that, at present, it is premature to undertake any in utero gene transfer clinical trial. Significant additional preclinical and clinical studies addressing vector transduction efficacy, biodistribution, and toxicity are required before a human in utero gene transfer protocol can proceed. In addition, a more thorough understanding of the development of human organ systems, such as the immune and nervous systems, is needed to better define the potential efficacy and risks of human in utero gene transfer. Prerequisites for considering any specific human in utero gene transfer procedure include an understanding of the pathophysiology of the candidate disease and a demonstrable advantage to the in utero approach. Once the above criteria are met, the RAC would be willing to consider well rationalized human in utero gene transfer clinical trials.

Prepared by Kathi E. Hanna, M.S., Ph.D., Science and Health Policy Consultant

Last Reviewed: March 2006

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Regeneration of the entire human skin using transgenic …

Epidermolysis bullosais is rare, but the charity DEBRA, which campaigns for EB patients, estimates half a million people are affected around the world.

There are different forms of epidermolysis bullosa, including simplex, dystrophic and, as in this case, junctional.

Each is caused by different genetic faults leading to different building blocks of skin being missing.

Prof Michele De Luca, from the University of Modena and Reggio Emilia, told the BBC: The gene is different, the protein is different and the outcome may be different [for each form of EB] so we need formal clinical trials.

But if they can make it work, it could be a therapy that lasts a lifetime.

An analysis of the structure of the skin of the first patient to get 80% of his replaced has discovered a group of long-lived stem cells are that constantly renewing his genetically modified skin.

Genetically modified skin cells were grown to make skin grafts totalling 0.85 sq m (9 sq ft). It took three operations over that winter to cover 80% of the childs body in the new skin. But 21 months later, the skin is functioning normally with no sign of blistering.

Nature Regeneration of the entire human epidermis using transgenic stem cells

Junctional epidermolysis bullosa (JEB) is a severe and often lethal genetic disease caused by mutations in genes encoding the basement membrane component laminin-332. Surviving patients with JEB develop chronic wounds to the skin and mucosa, which impair their quality of life and lead to skin cancer. Here we show that autologous transgenic keratinocyte cultures regenerated an entire, fully functional epidermis on a seven-year-old child suffering from a devastating, life-threatening form of JEB. The proviral integration pattern was maintained in vivo and epidermal renewal did not cause any clonal selection. Clonal tracing showed that the human epidermis is sustained not by equipotent progenitors, but by a limited number of long-lived stem cells, detected as holoclones, that can extensively self-renew in vitro and in vivo and produce progenitors that replenish terminally differentiated keratinocytes. This study provides a blueprint that can be applied to other stem cell-mediated combined ex vivo cell and gene therapies

SOURCES BBC News, Nature

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Fully Functional Skin Grown From Stem Cells Could Double …

If theres one thing skin can do well, its grow. Each month our body replaces its skin,nearly 19 million skin cells per inch a feat thats been far less successful in the lab. However, the days of lab-grown skin may not be too far off:Recently, a team of Japanese scientists not only grew fully functional skin tissue, but also transplanted it successfully onto living organisms.

Though the technique has only been tested on mice so far, the team predicts it could one day revolutionize treatments for burn victims, or other patients that have suffered catastrophic skin damage. On a less gruesome note, the team says it may also be useful in treating a more common condition: baldness.

The study, published online in Science Advances, involved researchers from the Riken Center for Developmental Biology and Tokyo University of Science, among other Japanese institutions. The researchers first step was to transform cells from the gums of mice into induced pluripotent stem cells, or adult cells that have been genetically reprogrammed back into an embryonic stem cell state. This is done by forcing the cells to express genes associated with embryonic stem cells. Once transformed into stem cells, they can then be manipulated to become any type of cell in the body.

Next, the team placed the stem cells into a petri dish, where they added the molecule Wnt10b, which coaxed the stem cells to form into clusters that resembled a developing embryo. These clusters were then transplanted into mice bred without a fully functional immune system, which ensured that their bodies did not reject the transplant. Here, they underwent cell differentiation, the process by which unspecialized cells become specialized. In this case, they were becoming skin cells, and once the process had begun, the cells were transplanted again onto the skin of new mice, where they made normal connections with surrounding nerve and muscle tissue to become fully functional skin.

Skin is one of the largest and most important organs in the human body, yet its also one of the most difficult to treat when its damaged. Current treatment options involve painful skin grafts or barely functional artificial skin. According to the new study, however, being able to grow skin in the lab will account for more than just skin's use in protecting our inner bodies. The lab-grown skin also showed the ability to develop hair follicles and sweat glands, which play a role in controlling body temperature and keeping the skin moisturized it's in these areas that skin repair has often fallen short.

"Up until now, artificial skin development has been hampered by the fact that the skin lacked the important organs, such as hair follicles and exocrine glands, lead researcher, Takashi Tsuji of the RIKEN Center for Developmental Biology,said in a recent statement. With this new technique, we have successfully grown skin that replicates the function of normal tissue.

In addition to revolutionizing skin repair, the technique may also help those with certain types of hair loss. The study noted that using Wnet10b on the stem cells resulted in the production of a higher number of hair follicles than previous attempts at growing skin. Within two weeks of receiving the transplanted skin, the mice began to grow hair. Dr. Seth Orlow, chair of dermatology at NYU School of Medicine in New York City, told U.S. News Health that this feature of the lab-grown skin could be manipulated to help patients with both alopecia and pattern baldness.

In theory, we may eventually be able to create structures like hair follicles and other skin glands that could be transplanted back to people who need them, Orlow told U.S. Health News.

According to The Washington Post, the technique is still about five to 10 years away from being safe and effective enough to be used on humans. But with about 95 percent of men and 50 percent of women experiencing some degree of baldness over the course of their lives, its a safe bet that there will be no shortage of eager customers ready to get their hair back when the treatment is approved for use in doctors offices.

Source: Takagi R, Ishimaru J, Sugawara A, et al. Bioengineering a 3D integumentary organ system from iPS cells using an in vivo transplantation model. Science Advances . 2016

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Hypogonadism Causes & Information | Cleveland Clinic

What is hypogonadism?

Hypogonadism is a condition in which the testicles are not working the way they should.

In an adult, the testicles have two main functions: to make testosterone (the male hormone) and sperm. These activities are controlled by a part of the brain called the pituitary. The pituitary sends signals (called gonadotropins) to the testicles that, under normal conditions, cause the testicles to produce sperm and testosterone.

The pituitary signals can change based on the feedback signals that the brain receives from the testicle. Hypogonadism can therefore be divided into two main categories:

These categories are important because they may influence the way that hypogonadism is treated, and play a role in the results.

Testicular failure occurs when the brain is signaling the testicle to make testosterone and sperm, but the testicles are not responding correctly. As a result, the brain increases the amount of the gonadotropins signals, which causes a higher-than-normal level of these signals in the blood. For this reason, this condition is also referred to as hypergonadotropic hypogonadism. This is the most common category of hypogonadism.

Secondary hypogonadism (also called hypogonadotropic hypogonadism) occurs when the brain fails to signal the testicles properly. In men who have secondary hypogonadism, the testosterone levels may be very low, and sperm are usually missing from the semen. Some boys are born with this condition. In most cases, it is discovered when a boy fails to go through puberty.

Causes of primary hypogonadism include:

Causes of secondary hypogonadism include:

Low testosterone: Hypogonadism may be diagnosed when a man has symptoms of low testosterone, including low energy, fatigue, and a lower sexual drive.

Patients with secondary hypogonadism are usually diagnosed during their teen years because they have not started puberty. These patients may not develop the body type, muscle build, or hair pattern seen in adult males. Some men will also have a poor sense of smell.

Infertility: Hypogonadism may be diagnosed when a man has a problem with fertility (cannot father a child) and is found to have no sperm or only a very low number of sperm in the semen.

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Hypogonadism Causes & Information | Cleveland Clinic

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CRISPR breakthrough treats diseases like diabetes without …

The CRISPR-Cas9 gene editing tool shows incredible promise in treating a wide range of diseases, from HIV to cancer. But the technology isn't without controversy, as the long term effects of cutting DNA in living organisms isn't fully known. Now, scientists from the Salk Institute have modified CRISPR to work without making any cuts, switching targeted genes on and off instead, and demonstrated its effectiveness by treating diabetes, muscular dystrophy and other diseases in mice.

The CRISPR gene-editing tool is one of the most important scientific breakthroughs in years, with the potential to reverse the effects of disease or even snip them out of the genome at the embryo stage. But as exciting as it is, a recent study found that the cut-and-paste method may introduce unintentional mutations into the genome, and although this study was later contested, safety remains a concern at this early stage in the technology.

"Although many studies have demonstrated that CRISPR-Cas9 can be applied as a powerful tool for gene therapy, there are growing concerns regarding unwanted mutations generated by the double-strand breaks through this technology," says Juan Carlos Izpisua Belmonte, senior author of the study. "We were able to get around that concern."

The Salk scientists adapted the regular CRISPR mechanism to influence gene activation without actually changing the DNA itself. The Cas9 enzyme normally does the cutting, so the team used a dead form of it called dCas9 that can still target genes but doesn't damage them. The active ingredients this time are transcriptional activation domains, which act like molecular switches to turn specific genes on or off. These are coupled to the dCas9, along with the usual guide RNAs that help them locate the desired section of DNA.

There's just one problem with this technique: normally the CRISPR system is loaded into a harmless virus called an adeno-associated virus (AAV), which carries the tool to the target. But the entire protein, consisting of dCas9, the switches and the guide RNAs, is too big to fit inside one of these AAVs. To work around that issue, the researchers split the protein into two, loading dCas9 into one virus and the switches and guide RNAs into another. The guide RNAs were tweaked to make sure both parts still ended up at the target together, and to make sure the gene was strongly activated.

To test how well the new technique worked, the researchers experimented with mice that had three different diseases kidney damage, type 1 diabetes and muscular dystrophy. In each case, the mice were treated with specialized CRISPR systems to increase the expression of certain genes, which would hopefully reverse the symptoms.

In the kidney-damaged mice, the team targeted two genes that play a role in kidney function. Sure enough, there was an increase in the levels of a protein linked to those genes, and kidney function improved. In the diabetic mice, the targeted genes were those that promote the growth of insulin-producing cells, and after treatment, the mice were found to have lower blood glucose levels. And finally, the treatment also worked to reverse the symptoms of muscular dystrophy.

After that promising start, further work is underway on the system. The researchers plan to try to apply the technique to other cell types to help treat other diseases, and conduct more safety tests before human trials can begin.

The research was published in the journal Cell.

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The best and worst analogies for CRISPR, ranked


RISPR-Cas9 is complicated.

Thats why scientists, entrepreneurs, and journalists like me have spent the past few years reaching for metaphors to try to make the mechanics of the revolutionary genome-editing technology easier for laypeople to understand. In text and imagery, weve drawn parallels to everything from garage tools to divine interventions.

But it must be said: Some of these analogies are better than others. To compile the definitive ranking, I sat down with STATs senior science writer Sharon Begley, a wordsmith who has herself compared CRISPR to 1,000 monkeys editing a Word document and the kind of dog you can train to retrieve everything from Frisbees to slippers to a cold beer.


Sharon and I evaluated each of the metaphors we found by considering these three questions: Is it creative? Is it clear? And is it accurate? Below, our rankings of CRISPR analogies, ordered from worst to best:

This is not how it works. This is not at all how it works.

We see where these marketers got started with their pun: Genetics researchers do indeed use the term knock out to refer to eliminating an existing gene in, say, a mouse.

But a blunt instrument like a boxing glove vastly undersells CRISPRs precision. It also suggests, wrongly, that CRISPRs powers extend to leaving genes bruised and battered. For these reasons, this ad wins the ignoble prize as the worst CRISPR metaphor we could track down.

The hand of God is a familiar trope to describe advances in biotech. Elucidating CRISPR this way is sinful.

If God were in the business of editing the genome, we expect that She would make fewer mistakes than CRISPR, which is known foroff-target effects. Were wondering, too, if the holy light emanating from the hand of a CRISPR-ing God is meant to imply that She is among those researchers interested in combining CRISPR with optogenetics?

Most damningly, though, this metaphor does nothing to explain how CRISPR actually works.

The framing of CRISPR as a method to remove ticking time bombs lurking within our DNA is true enough: Researchers do want to use the technology to take out genetic mutations that cause deadly diseases.

But this visual metaphor confuses the biology. The destructive power in DNA lies in the base pairs themselves, not in between them, where this red canister is placed. And again, this does nothing to shine light on CRISPRs mechanism of action.

We had high hopes for this analogy, which came courtesy of the National Institutes of Health. But alas, it mostly disappoints.

The idea, as we understand it, is that CRISPR-Cas9 acts to modify precisely the correct segments of DNA, similar to how a handyman uses a particular wrench to loosen or tighten a nut or bolt of a specific size and shape.

But were scratching our heads to come up with a real-life construction scenario where whats visualized here would actually happen.We get the sense that someone in pursuit of a fresh analogy came up with this one only after concluding that all the good analogies were already taken.

This analogy is so 2012. Sure, an eraser is a fine way to think about CRISPRs powers to delete. But that only goes halfway what about CRISPRs powers to add or replace? And it loses the physicality of CRISPR-Cas9s cutting action for no good reason. (In the interests of full disclosure, we must admit that STAT has used this one in the past. Apologies.)

The notion of CRISPR as a surgeons scalpel nicely captures its cutting action. But points are deducted for the suggestion that CRISPR is as precise as a surgeons tool must be.

We like the simple explanatory power of a plain-old pair of scissors to describe CRISPR-Cas9s cutting action. Its better than the scalpel metaphor at conveying the technology isablunt instrument. But points are deducted for not addressing CRISPRs powers to add or replace.

This analogy comes by way ofthe authority:Feng Zheng, the groundbreaking Massachusetts Institute of Technology scientist who helped create CRISPR-Cas9.

Zhengs comparison is a good one overall especially when he explains how it works with the song Twinkle Twinkle Little Star. But its still an imperfect one, because it implies greater precision than CRISPR actually allows.

To continue the analogy: If you use CRISPR to search for the and replace it with this, it would work as intended sometimes. But because CRISPR sometimes finds something it shouldnt, you might also wind up with jumbled words describing the study of the divine as thisology and a book of synonyms as athissaurus.

We really like this comparison, exemplified bywriter Aime Lutkins turn of phrase describing CRISPR assort of like organic matter Photoshop.

To be sure, youre not literally cutting anything, as CRISPR-Cas9 does, when you use the Adobe image editing software. But we saw explanatory power in the fact that Photoshop lets you make zoomed-in changes, down to the level of a single pixel just as CRISPR can make changes at the level of the As, Ts, Cs, and Gs that make up the genetic code.

And as anyone whos been victim of a bad Photoshop job knows, theres plenty of room for the tool to go awry.

Folks, we have a winner: A Swiss Army knife is the best analogy we found for what CRISPR can and cant do.

Like the other cutting instruments on our list, a Swiss Army knife gets points as a good visual because CRISPR-Cas9 literally cuts DNA. But a Swiss Army knife breaks out of the pack because it has different blades for different tasks comparable to CRISPRs ability to cut something out, introduce a single one-letter change, or make an insertion without a deletion. Swiss Army knives also strike the right middle ground between a precise cut and a blunt cut, a good way to think about CRISPRs capabilities.

And if thats not enough: Both CRISPR and Swiss Army knives have recently been at the center of heated legalfights over intellectual property.

Business Reporter

Rebecca covers the business of biopharma.

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How Does Crispr Gene Editing Work? | WIRED

In the last five years, biology has undergone a seismic shift as researchers around the globe have embraced a revolutionary technology called gene editing. It involves the precise cutting and pasting of DNA by specialized proteinsinspired by nature, engineered by researchers. These proteins come in three varieties, all known by their somewhat clumsy acronyms: ZFNs, TALENs, and CRISPRs. But its Crispr, with its elegant design and simple cell delivery, thats most captured the imagination of scientists. Theyre now using it to treat genetic diseases, grow climate-resilient crops, and develop designer materials, foods, and drugs.

So how does it work?

When people refer to Crispr, they're probably talking about Crispr-Cas9, a complex of enzymes and genetic guides that together finds and edits DNA. But Crispr on its own just stands for Clustered Regularly Interspaced Palindromic Repeatschunks of regularly recurring bits of DNA that arose as an ancient bacterial defense system against viral invasions.

Viruses work by taking over a cell, using its machinery to replicate until it bursts. So certain bacteria evolved a way to fight back. They deployed waves of DNA-cutting proteins to chop up any viral genes floating around. If the bacteria survived the attacks, they'd incorporate tiny snippets of virus DNA into their own genomeslike a mug shot of every foe theyd ever come across, so they could spot each one quicker in the future. To keep their genetic memory palace in order, they spaced out each bit of viral code (so-called guide RNAs) with those repetitive, palindromic sequences in between. It doesn't really matter that they read the same forward and backward; the important thing is that they helped file away genetic code from viral invaders past, far away from more essential genes.

And having them on file meant that the next time a virus returned, the bacteria could send out a more powerful weapon. They could equip Cas9a lumpy, clam-shaped DNA-cutting proteinwith a copy of that guide RNA, pulled straight out of storage. Like a molecular assassin, it would go out and snip anything that matched the genetic mug shot.

Thats what happens in the wild. But in the lab, scientists have harnessed this powerful Crispr system to do things other than fight off the flu. The first step is designing a guide RNA that can sniff out a particular block of code in any living cellsay, a genetic defect, or an undesirable plant trait. If that gene consists of a string of the bases A, A, T, G, C, scientists make a complementary strand of RNA: U, U, A, C, G. Then they inject this short sequence of RNA, along with Cas9, into the cell theyre trying to edit. The guide RNA forms a complex with Cas9; one end of the RNA forms a hairpin curve that keeps it stuck in the protein, while the other endthe business enddangles out to interact with any DNA it comes across.

Once in the cell's nucleus, the Crispr-Cas9 complex bumps along the genome, attaching every time it comes across a small sequence called PAM. This protospacer adjacent motif is just a few base pairs, but Cas9 needs it to grab onto the DNA. And by grabbing it, the protein is able to destabilize the adjacent sequence, unzipping just a little bit of the double helix. That allows the guide RNA to slip in and sniff around to see if it's a match. If not, they move on. But if every base pair lines up to the target sequence, the guide RNA triggers Cas9 to produce two pincer-like appendages, which cut the DNA in two.

The process can stop there, and simply take a gene out of commission. Or, scientists can add a bit of replacement DNAto repair a gene instead of knocking it out.

And they don't have to limit themselves to just Cas9. There's a whole bunch of proteins that can use an RNA guide. There's Cas3, which gobbles up DNA Pac-Man style. Scientists are using it to develop targeted antibiotics that can wipe out a strain of C. diff, while leaving your gut microbiome intact. And there's an enzyme called Cas13 that works with a guide that gloms onto RNA, not DNA. Called Sherlock, the system is being used to develop sensitive tests for viral infections. Researchers are working hard to add more implements to the Crispr toolkit, but at least right now, Cas9 is still the most widely used.

Crispr isnt perfect; sometimes the protein veers off course and makes cuts at unintended sites. So scientists are actively working on ways to minimize these off-target effects. And as it gets better, the ethical questions surrounding the technology are going to get a lot thornier. Hello, designer babies?! Figuring out where those lines get drawn is going to take more than science; it will require policymakers and the public coming to the table. Because pretty soon with Crispr, the question wont be can we do it, but should we?

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How Does Crispr Gene Editing Work? | WIRED

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Gene therapy at OHSU Casey Eye Institute | Casey Eye …

Ongoing gene therapy trials open to enrollment

These studies are actively seeking new participants.

The purpose of this study is to learn about a new gene therapy that may help patients with Achromatopsia. This is the first study that aims to treat Achromatopsia disease by gene therapy. The study investigators want to find out whether it is safe for use in humans. The gene therapy is given by a surgical injection into the retina (the lining of the back of the eye that detects light) of one eye. The eye with worse vision will receive the gene therapy.

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The purpose of this study is to learn about a new gene therapy that may help patients with Achromatopsia. The study investigators want to find out whether it is safe for use in humans. The gene therapy is given by a surgical injection into the retina (the lining of the back of the eye that detects light) of one eye. The eye with worse vision will receive the gene therapy.

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The purpose of this study is to learn about a new gene therapy that may help patients with X-Linked Retinoschisis (XLRS).This is the first study that aims to treat XLRS disease by gene therapy. The study investigators want to find out whether it is safe for use in humans. The gene therapy is given by a surgical injection into the vitreous (a thick, gel-like transparent substance that fills the center of the eye) of one eye. The eye with worse vision will receive the gene therapy.

Contact 503 494-0020 or email the ORDC.

The purpose of this study is to learn about a new gene therapy being studied in patients with Retinitis Pigmentosa (RP) as a result of Usher Syndrome.This is the first study that aims to treat RP due to Usher Syndrome by gene therapy.The study investigators want to find out if UshStat is safe for use in humans.The gene therapy is given by surgical injection underneath the retina of one eye.The eye with worse vision will receive the gene therapy

Contact 503 494-0020 or email the ORDC.

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The purpose of this study is to learn about a new gene therapy that may help patients with Stargardt's Macular Degeneration (SMD). This is the first study that aims to treat Stargardt's disease by gene therapy. The study investigators want to find out whether it is safe for use in humans. The gene therapy is given by a surgical injection underneath the retina of one eye. The eye with worse vision will receive the gene therapy.

Contact 503 494-0020 or email the ORDC.

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Purpose: To evaluate the safety and dosing levels of a gene-based treatment, RetinoStat, for wet AMD. In this study, two helpful genes are delivered directly to the retina, where they "turn on" proteins that block abnormal blood vessel growth in a sustained fashion. Enrollment is completed and study patients are being followed.

Contact: Ann Lundquist, 503 494-6364.

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Gene Therapy Advisory Committee – Health Research Authority

If your application is for ethical approval of a gene therapy clinical trial you must apply to the Gene Therapy Advisory Committee (GTAC).

GTAC is the UK national REC for gene therapy clinical research according to regulation 14(5) of The Medicines for Human Use (Clinical Trials) Regulations 2004.

You may book applications to the following RECs:

Once a booking is accepted, you must electronically submit your application and supporting documentation on the same day. If your application is valid, you will be sent an acknowledgement within five days of receipt and arrangements subsequently made for you to attend the REC meeting.

Historically, GTAC would send applications for external peer review. In future, as with all other RECs, the responsibility for providing peer review will rest with the sponsor.

We will seek to work in partnership with other organisations to determine whether it is possible to develop some agreed standards. More information can be found here.

You are no longer required to seek pre-application regulatory advice from GTAC. The MHRA will continue to provide this service to commercial companies, and will consider requests for advice from academic researchers.

Members of the research community have requested clarity on the type of application that needs to be submitted to GTAC.

Legally, all gene therapy applications must be submitted to a GTAC that is able to transfer to other designated RECs.

To make it easier for researchers and sponsors to identify other studies needing review, other applications that involve cell therapy and/or that are submitted to the MHRA Clinical Trials Expert Advisory Group must also be submitted to GTAC.

All gene therapy and cell therapy applications for Clinical Trials Authorisation will be assessed by the MHRA and, where appropriate will now be submitted to the MHRA Clinical Trials Expert Advisory Group for review. This review will assure the RECs that appropriate scrutiny of the safety of the application has been carried out.

The REC will raise any concerns directly with the MHRA.

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Gene Therapy Advisory Committee - Health Research Authority

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CRISPR: can gene-editing help nature cope with climate change?

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Life Extension Reviews – Is it a Scam or Legit?

About Life Extension

Life Extension is a dietary supplements manufacturer that claims to offer the highest quality award-winning, science-based vitamins and supplements. As their name suggests, they and their Life Extension Foundation (more about this in the following section) are focused on anti-aging research and integrative health, and many of their supplements reflect this.

Life Extension is based out of Fort Lauderdale, FL, and claims to have been in business for more than 34 years. During this time, they claim to have reinvested $125 million into helping find cures for age-related diseases. The company is listed with the Better Business Bureau under Life Extension Foundation Buyers Club, Inc., and has an A+ rating, with just one closed complaint over the past three years. Unusually, despite the length of time the company has been in business, we were unable to locate any online customer reviews during our research.

By sourcing only the highest quality raw materials from all over the world, Life Extension claims to manufacture over 350 of the highest quality supplements available on the market, all of which are clinically validated and tested. In addition, the company claims that their supplements are created by scientists who analyze thousands of scientific studies every week, and who are on the forefront of medical research. In fact, the company claims to maintain a Certificate of Analysis on file for each one of their products, which guarantees potency and purity.

When talking about the company, its important to remember that the Life Extension Buyers Club is the consumer-focused portion, while the nonprofit Life Extension Foundation is an organization dedicated to extending human life, controlling aging, and eradicating disease.

At the time of this writing, the most popular Life Extension supplements included:

According to the companys website, all Life Extension products are GMP certified, and include dosages that accurately replicate the most successful results obtained in scientific studies for maximum efficacy.

In addition to products, Life Extension also offers blood testing services, as well as cutting-edge clinical trials that you can apply for, most of which are compensated.


With more than 350 products in their catalog, Life Extension supplements can vary greatly in price. However, based on a moderate sample size, most supplements appear to range between $10 and $82. Keep in mind that the more you buy, the lower per-bottle price youll pay.

During the checkout process, youll be required to become a Life Extension member in order to complete the purchase. As such, youll have six different options:

Whichever option you choose, membership allows you to save 25%-50% when compared to health food store prices. All options other than a monthly membership will also give you access to two free bonuses:

Disease Prevention & Treatment, a 1,400-page book that bridges the gap between cutting-edge science and mainstream medicine.Life Extension Directory, which details all of the companys supplements.

US-based basic shipping costs $5.50, while 2nd Day Air is priced at $12.50 and Overnight at $21.50.

All Life Extension products come with a one-year, 100% satisfaction guarantee. You can also sign up for VIP AutoShip, which allows you to receive your favorite supplements on a recurring basis.

To set yourself up on the AutoShip program or to begin the refund process, youll need to contact customer service at 800-226-2370, or use their online contact form.

With all of this in mind, whats the bottom line: Is Life Extension a scam? While nothing we encountered during our research would lead us to believe this is the case, keep the following in mind:

First, Life Extension is a very big company, and has been in business for more than 34 years, so its products clearly resonate with a large percentage of the population. To drive home this fact, according to this article, as of 2009 it had assets of over $25 million andnetted more than $3 million on revenue of more than $18 million that year.

Regardless of the companys size though, the nutritional supplements industry is rife with unsubstantiated claims. For those with clinical studies that appear to support their claims, many are based on thin science, or on studies not conducted on humans. Were not saying this is the case with Life Extension, but its a rampant problem within the industry. Also, when factoring in the specific makeup of individuals, keep in mind that not all supplements will work for every consumer.

Furthermore, the Life Extension Foundation has a long history of legal woes in its relationship with the FDA, many of which date back more than 25 years. On top of this, the Foundations tax exempt status was revoked in May 2013, although this appears to have more to do with funding than it does with anything related to their products.

Finally, we were unable to locate any legitimate online customer reviews about Life Extension, which is surprising considering the companys age. However, the good news is that you can be a star by writing about your experience with Life Extension. So go ahead and share your experience with the world now!


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Life Extension Reviews - Is it a Scam or Legit?

Recommendation and review posted by sam

What are genome editing and CRISPR-Cas9?

Genome editing (also called gene editing) is a group of technologies that give scientists the ability to change an organism's DNA. These technologies allow genetic material to be added, removed, or altered at particular locations in the genome. Several approaches to genome editing have been developed. A recent one is known as CRISPR-Cas9, which is short for clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9. The CRISPR-Cas9 system has generated a lot of excitement in the scientific community because it is faster, cheaper, more accurate, and more efficient than other existing genome editing methods.

CRISPR-Cas9 was adapted from a naturally occurring genome editing system in bacteria. The bacteria capture snippets of DNA from invading viruses and use them to create DNA segments known as CRISPR arrays. The CRISPR arrays allow the bacteria to "remember" the viruses (or closely related ones). If the viruses attack again, the bacteria produce RNA segments from the CRISPR arrays to target the viruses' DNA. The bacteria then use Cas9 or a similar enzyme to cut the DNA apart, which disables the virus.

The CRISPR-Cas9 system works similarly in the lab. Researchers create a small piece of RNA with a short"guide" sequence that attaches (binds) to a specific target sequence of DNA in a genome. The RNA also binds to the Cas9 enzyme. As in bacteria, the modified RNA is used to recognize the DNA sequence, and the Cas9 enzyme cuts the DNA at the targeted location. Although Cas9 is the enzyme that is used most often, other enzymes (for example Cpf1) can also be used. Once the DNA is cut, researchers use the cell's own DNA repair machinery to add or delete pieces of genetic material, or to make changes to the DNA by replacing an existing segment with a customized DNA sequence.

Genome editing is of great interest in the prevention and treatment of human diseases. Currently, most research on genome editing is done to understand diseases using cells and animal models. Scientists are still working to determine whether this approach is safe and effective for use in people. It is being explored in research on a wide variety of diseases, including single-gene disorders such as cystic fibrosis, hemophilia, and sickle cell disease. It also holds promise for the treatment and prevention of more complex diseases, such as cancer, heart disease, mental illness, and human immunodeficiency virus (HIV) infection.

Ethical concerns arise when genome editing, using technologies such as CRISPR-Cas9, is used to alter human genomes. Most of the changes introduced with genome editing are limited to somatic cells, which are cells other than egg and sperm cells. These changes affect only certain tissues and are not passed from one generation to the next. However, changes made to genes in egg or sperm cells (germline cells) or in the genes of an embryo could be passed to future generations. Germline cell and embryo genome editing bring up a number of ethical challenges, including whether it would be permissible to use this technology to enhance normal human traits (such as height or intelligence). Based on concerns about ethics and safety, germline cell and embryo genome editing are currently illegal in many countries.

Gupta RM, Musunuru K. Expanding the genetic editing tool kit: ZFNs, TALENs, and CRISPR-Cas9. J Clin Invest. 2014 Oct;124(10):4154-61. doi: 10.1172/JCI72992. Epub 2014 Oct 1. Review. PubMed: 25271723. Free full-text available from PubMed Central: PMC4191047.

Hsu PD, Lander ES, Zhang F. Development and applications of CRISPR-Cas9 for genome engineering. Cell. 2014 Jun 5;157(6):1262-78. doi:10.1016/j.cell.2014.05.010. Review. PubMed: 24906146. Free full-text available from PubMed Central: PMC4343198.

Komor AC, Badran AH, Liu DR. CRISPR-Based Technologies for the Manipulation of Eukaryotic Genomes. Cell. 2017 Apr 20;169(3):559. doi:10.1016/j.cell.2017.04.005. PubMed: 28431253.

Lander ES. The Heroes of CRISPR. Cell. 2016 Jan 14;164(1-2):18-28. doi:10.1016/j.cell.2015.12.041. Review. PubMed: 26771483.

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What are genome editing and CRISPR-Cas9?

Recommendation and review posted by Bethany Smith

"Latest Stem Cells News" – news from the world about stem …

To meet the industry needs and to benefit students and research scholars, Nitte University has set up the a centre for stem cell research at K S Hedge Medical Academy (Kshema).

The Nitte University Centre for Stem Cell Research and Regenerative Medicine (NUCSReM), has been established to further advance the understanding of stem cell biology and to facilitate clinical application of stem cells to treat patients with various ailments, says N Vinaya Hegde, chancellor, Nitte University.

Gianvito Martino, the head of the Neurosciences division at the Institute of San Raffaele in Milan in a speech at Multiple Sclerosis Week, which took place from May 23-31, warned against trips of hope to clinics that promise effective treatments using stem cells.

According to Martino, who coordinated a Consensus Conference on last Tuesday in London on the neurodegenerative disease, where the guidelines for pre-clinical studies and clinical treatments with stem cells were defined, hundreds of Italian patients each year go on these trips due to cures that are promised. In the best-case scenario, these patients return in the Read More

Scientists have claimed they would serve the worlds first test tube hamburger this October.

A team, led by Prof Mark Post of Maastricht University in the Netherlands, says it has already grown artificial meat in the laboratory, and now aims to create a hamburger, identical to a real stuff, by generating strips of meat from stem cells.

The finished product is expected to cost nearly 220,000 pounds, The Daily Telegraph reported.

Prof Post said his team has successfully replicated the process with cow cells and calf serum, bringing the first artificial burger a step closer.

In October we are going to provide a Read More

Studies begun by Harvard Stem Cell Institute (HSCI) scientists eight years ago have led to a report published today that may be amount to a major step in developing treatments for amyotrophic lateral sclerosis (ALS), also known as Lou Gehrigs disease.

The findings by Kevin Eggan, a professor in Harvards Department of Stem Cell and Regenerative Biology (HSCRB), and colleagues also has produced functionally identical results in human motor neurons in a laboratory dish and in a mouse model of the disease, demonstrating that modeling the human disease with customized stem cells in the laboratory could relatively soon eliminate some Read More

Frank LaFerla, left, Mathew Blurton-Jones and colleagues found that neural stem cells could be a potential treatment for advanced Alzheimer's disease

UC Irvine scientists have shown for the first time that neural stem cells can rescue memory in mice with advanced Alzheimers disease, raising hopes of a potential treatment for the leading cause of elderly dementia that afflicts 5.3 million people in the U.S.

Mice genetically engineered to have Alzheimers performed markedly better on memory tests a month after mouse neural stem cells were injected into their brains. The stem cells secreted a protein that created more neural connections, improving Read More

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"Latest Stem Cells News" - news from the world about stem ...

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Low Testosterone | Hormone Health Network

What is the role of testosterone in mens health?

Testosterone is the most important sex hormone that men have. It is responsible for the typical male characteristics, such as facial, pubic, and body hair as well as muscle. This hormone also helps maintain sex drive, sperm production, and bone health. The brain and pituitary gland (a small gland at the base of the brain) control the production of testosterone by the testes.

In the short term, low testosterone (also called hypogonadism) can cause:

Over time, low testosterone may cause a man to lose body hair, muscle bulk, and strength and to gain body fat. Chronic (long-term) low testosterone may also cause weak bones (osteoporosis), mood changes, less energy, and smaller testes. Signs and symptoms (what you see and feel) vary from person to person.

Low testosterone can result from:

Low testosterone is common in older men. In many cases, the cause is not known.

During a physical exam, your doctor will examine your body hair, size of your breasts and penis, and the size and consistency of the testes and scrotum. Your doctor may check for loss of side vision, which could indicate a pituitary tumor, a rare cause of low testosterone.

Your doctor will also use blood tests to see if your total testosterone level is low. The normal range is generally 300 to 1,000 ng/dL, but this depends on the lab that conducts the test. To get a diagnosis of low testosterone, you may need more than one early morning (710 AM) blood test and, sometimes, tests of pituitary gland hormones.

If you have symptoms of low testosterone, your doctor may suggest that you talk with an endocrinologist. This expert in hormones can help find the cause. Be open with your doctor about your medical history, all prescription and nonprescription drugs you are now taking, sexual problems, and any major changes in your life.

Testosterone replacement therapy can improve sexual interest, erections, mood and energy, body hair growth, bone density, and muscle mass. There are several ways to replace testosterone:

The best method will depend on your preference and tolerance, and the cost.

There are risks with long-term use of testosterone. The most serious possible risk is prostate cancer. African American men, men over 40 years of age who have close relatives with prostate cancer, and all men over 50 years of age need monitoring for prostate cancer during testosterone treatment. Men with known or suspected prostate cancer, or with breast cancer, should not receive testosterone treatment.

Other possible risks of testosterone treatment include:

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Low Testosterone | Hormone Health Network

Recommendation and review posted by simmons

Budgie Parakeet Colors, Varieties, Mutations, Genetics

Budgie parakeets come in so many colors and mutations they remind me of jellybeans! These birds are part of our family flock.

Original Australian wild type green budgerigar parakeet

In the wild, Budgie Parakeets are green with yellow, with black stripes and markings, and dark blue-green-black flight and tail feathers. Captive breeding programs, however, have produced Budgies in almost every color of the rainbow, except red and pink. They are so colorful, they remind me of jellybeans!

All captive budgerigars are divided into two basic series of colors: white-based (includes skyblue, cobalt, mauve, gray, violet, and white) and yellow-based (includes light-green, dark-green, gray-green, olive, and yellow). Green (yellow base) is dominant and blue (white base) is recessive.There are at least 32 primary mutations in the budgerigar, enabling hundreds of possible secondary mutations and color varieties!

One of my all time personal favorite mutation combinations is pictured below I call it a Rainbow Spangle. Toto, a budgie raised by us, is a yellow-face type 2 sky-blue opaline spangle.

A combination of several mutations, I call this a Rainbow Spangle.

Green (yellow base) is dominant and blue (white base) is recessive.

There are 3 color variations for both the white base colorand the yellow base color. In the yellow base color, the dark factor genes make these color variations:

Yellow Base Color:0 dark factors = light green1 dark factors = dark green2 dark factors = olive

Mutations like Lutinos and Double-Factor Spangles still have dark factors but they are not seen visually.


Light-Green (additional mutations present: Opaline, Spangle)


Dark Factor budgie parakeet breeding punnett square

Blue (white base) is recessive to green (yellow base).

There are 3 color variations for both the white (blue) series and the yellow (green) series birds. In the white series, the dark factor genes make these color variations:

White (blue) series:0 dark factors = skyblue1 dark factors = cobalt2 dark factors = mauve

Albinos and Double-Factor Spangles still have dark factors but they are not seen visually.


Skyblue (other mutation present: Cinnamon-Wing)

Cobalt(other mutation present:Yellowface type 1)

The violet factor affects both white-based (blue) and yellow-based (green) colors.

Violet (other mutation present: Sky-blue, Greywing)

Violet (other mutations present: Sky-blue, Opaline, Spangle)

Violet (other mutations present: Cobalt)

Violet Factor budgie parakeet breeding punnett square

The gray factor affects both white-based (blue) and yellow-based (green) colors.

Gray normal English x American budgie

Gray yellowface spangle budgie parakeet

Gray-green opaline baby English Budgie

Gray factor budgie parakeet breeding punnett square

In addition to a dark factor, budgies may also have a degree of dilution. There are four types of dilution: Greywing, Full-Body-Color Greywing, Clearwing, and Dilute.

Dilute blue opaline American parakeet

When a budgie has two of the recessive Dilute genes, its markings and color are about 70% washed out when compared to a normal.

Greywing blue American Parakeet

Greywing light-green American parakeet

A homozygous Greywing (or a Greywing budgie with the recessive Dilute gene) has gray wing markings and a 50% diluted body color.

Full-Body-Color Greywing light green American parakeet

When a budgie has both the Greywing and Clearwing gene, it is a Full-Body-Color Greywing with grey wing markings and bright body color.

Clearwing dark green American parakeet

A homozygous Clearwing (or a Clearwing budgie with the recessive Dilute gene) has less pigment in the wings, causing very light markings, and more pigment in the body feathers, causing a bright body color.

Normal = dominantGreywing = recessive, co-dominant with clearwingClearwing = recessive, co-dominant with greywingDilute= recessive

normal + normal = normalnormal + greywing = normal split for greywingnormal + clearwing = normal split for clearwingnormal + dilute = normal split for dilutegreywing + greywing = greywinggreywing + clearwing = full body color greywinggreywing + dilute = greywing split for diluteclearwing + clearwing = clearwingclearwing + dilute = clearwing split for dilutedilute + dilute = dilute

Two full body color greywings =50% full body color greywing25% greywing25% clearwing

Dilute budgie parakeet breeding punnet square

Lutino American parakeet (solid yellow with red/pink eyes)

Albino American parakeet (solid white with red/pink eyes)

The ino gene removes all the melanin (the substance that creates all the dark colors) removed, so a blue series budgie becomes white (Albino) and a green series one become yellow (Lutino). The gene also removes the dark shade from the skin and beak leaving them with pink legs and an orange beak. The dark color of the eye is also gone leaving a red eye with a white iris ring, and the cheek patches are silvery white. It removes the blue shade from the cocks cere too so hell have a pink/purple colored cere; the hens cere is the usual white to brown shade. Because usually only the white and yellow colors are left, an ino can hide the fact that it also has other varieties present genetically. The only varieties that show are the yellow faces or golden faces and they are only obvious on an albino budgie.

The ino gene is sex-linked and recesssive:

ino x ino =100% ino

ino cock x normal hen =50% normal split for ino cocks50% ino hens

normal cock x ino hen =50% normal split for ino cocks50% normal hens

normal split for ino cock x normal hen =25% normal cocks25% normal split for ino cocks25% ino hens25% normal hens

Albino / Lutino / Ino budgie parakeet breeding punnett square

Yellowface type 1 blue English budgie

Yellow face gray dominant pied English budgie

Yellowface budgies are in between yellow-based budgies and white-based budgies and the genetics are complicated. There are different degrees of the level of yellow pigment but it is less than the yellow-based variety. The double factor birds contain less yellow than single factor birds. The Yellowface mutation is possible in all of the blue series birds, including Albinos, Dark-Eyed Clears, Grays, Violets and in all their three depths of shade (ie. Skyblue, Cobalt, Mauve). Green series birds can mask a Yellowface character, and they can carry both Yellowface and Blue splits at the same time. Visually, there are two types of Yellowface: Type 1 and Type 2:

Yellowface type 1 skyblue single-factor violet clearflight pied opaline American parakeet

In Type 1, the yellow is confined to the mask feathers, plus maybe the peripheral tail feathers, only. The body feathers are normally colored.

Yellowface type 2 skyblue Greywing American Parakeet. The Yellowface type 2 mutation bleeds down into the blue body color, creating a seafoam-green effect.

Yellow face type 2 American parakeet. With the YF 2 mutation, the yellow spreads into the blue body color to create turquoise.

Type 2 Yellowface budgies have yellow in the mask feathers and tail, just like the Type 1. However, after the first molt at around 3 months of age, the yellow diffuses into the body color and creates a new color, depending on the original color. The single factor (SF) Yellowface 2 Skyblue variety is like a normal Light Green but has a very bright body color midway between blue and green a shade often called sea-green or turquoise. The body feathers of the SF Yellowface 2 Cobalt are bottle-green and in the SF Yellowface 2 Mauve they are a mixture of mauve and olive. The double factor (DF) Yellowface 2 Skyblue variety is very similar to the Yellowface 1 Skyblue, but the yellow pigmentation is brighter, and tends to leak into the body feathers to a greater extent.

In combination with the Blue, Opaline and Clearwing mutations, the single factor (SF) Yellowface 2 mutation produces the variety called Rainbow.

The yellowface type 2 gene is dominant to the yellowface type 1, meaning that it is visually expressed and the type 1 is masked in a genotypically type 1 x type 2 bird. When two yellowface type 1 skyblues are paired together, half the chicks will be yellowface type 1 skyblues and half will be normal skyblues in appearance. But half of these apparent skyblues will be double factor (DF) yellowface 1s. Here are the breeding expectations using punnett squares:

Yellowface budgie parakeet breeding punnett square

Cinnamon-Wing gray-green English Budgie baby

Cinnamon-wing sky-blue English budgie hen

All the markings which appear black or dark gray in the Normal appear brown in the Cinnamon. The Cinnamon markings on cocks tend to be darker than on hens. The long tail feathers are lighter than Normals. The body color and cheek patches are much paler, being about half the depth of color of the Normal. The feathers of Cinnamons appear tighter than Normals, giving a silky appearance. The eyes of the newly-hatched Cinnamon are not black like the eyes of Normals, but deep plum-colored. This color can be seen through the skin before the eyes open. A few days after the eyes open, the eye darkens and is then barely distinguishable from the that of a Normal chick, but by this time the difference in down color is visible: Normal chicks have gray down, but Cinnamon (and Opaline and Ino) chicks have white. The skin of Cinnamon chicks is also redder than Normals, and this persists into adulthood: the feet of Cinnamons are always pink rather than bluey-gray. The beak tends to be more orange in color.

In birds, the cock has two X chromosomes and the hen has one X and one Y chromosome. So in hens whichever allele is present on the single X chromosome is fully expressed in the phenotype. Hens cannot be split for Cinnamon (or any other sex-linked mutation). In cocks, because Cinnamon is recessive, the Cinnamon allele must be present on both X chromosomes (homozygous) to be expressed in the phenotype. Cocks which are heterozygous for Cinnamon are identical to the corresponding Normal. Such birds are said to be split for Cinnamon. The Cinnamon with Ino can create the Lacewing variety.

Cinnamon is a sex-linked recessive gene:

cinnamon x cinnamon =100% cinnamon

cinnamon cock x normal hen =50% normal split for cinnamon cocks50% cinnamon hens

normal cock x cinnamon hen =50% normal split for cinnamon cocks50% normal hens

normal split for cinnamon cock x normal hen =25% normal cocks25% normal split for cinnamon cocks25% cinnamon hens25% normal hens

normal split for cinnamon cock x cinnamon hen =25% normal cocks25% normal split for cinnamon cocks25% cinnamon hens25% normal hens

Cinnamon-wing budgie parakeet breeding punnett square

Opaline parakeet on the right, normal on the left.

The striping pattern on the head feathers is reversed so that there are thicker white areas and thinner black stripes. Another feature of this mutation is that the body feather color runs through the stripes on the back of the neck and down through the wing feathers. Opaline budgies tails are characteristically patterned with light and colored areas running down the tail feather. Most Opalines show a brighter body color than the corresponding non-Opaline, particularly in nest feather and in the rump area. The Opaline (and the Cinnamon) can be identified at a very early age because the color of the down feathers of the young nestling are white instead of the usual gray.

Opaline is a sex-linked recessive gene:

opaline x opaline =100% opaline

opaline cock x normal hen =50% normal split for opaline cocks50% opaline hens

normal cock x opaline hen =50% normal split for opaline cocks50% normal hens

normal split for opaline cock x normal hen =25% normal cocks25% normal split for opaline cocks25% opaline hens25% normal hens

normal split for opaline cock x opaline hen =25% normal cocks25% normal split for opaline cocks25% opaline hens25% normal hens

Single Factor Spangle violet opaline American parakeet x English budgie cross

Double Factor Spangle English budgie

SINGLE Factor Spangle: The markings on the wings, the throat spots and the tail feathers are altered on the single factor Spangle. The feathers have a white or yellow edge, then a thin black pencil line, then the center of the feather is yellow or white. The throat spots are often all or partly missing but if present look like targets, with a yellow or white center. The long tail feathers can be like the wing feathers with a thin line near the edge, or they may be plain white, yellow or solid dark blue as in a normal.

DOUBLE Factor Spangle: Pure white or yellow bird, though sometimes with a slight suffusion of body color.

Both types of Spangle have normal dark eyes with a white iris ring and normal ceres. Their feet and legs can be gray or fleshy pink. They can have either violet or silvery white cheek patches (or a mixture of both).

Spangle Breeding Outcomes:

Spangle is an incomplete dominant gene. This means it has three forms: the non-spangle, the single factor spangle and the double factor spangle. Spangle genetics sometimes do not act as expected.

normal x single factor spangle =50% normal50% single factor spangle

normal x double factor spangle =100% single factor spangle

single factor spangle x single factor spangle =25% normal50% single factor spangle25% double factor spangle

single factor spangle x double factor spangle =50% single factor spangle50% double factor spangle

double factor spangle x double factor spangle =100% double factor spangle

Spangle budgie parakeet breeding punnett square

All pied budgerigars are characterized by having irregular patches of completely clear feathers appearing anywhere in the body, head or wings. These clear feathers are pure white in blue-series birds and yellow in birds of the green series. Such patches are completely devoid of black melanin pigment. The remainder of the body is colored normally.

Dominant Pied (single factor) yellow face type 2 skyblue English budgie

Dominant pied (single factor) skyblue American parakeet

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Budgie Parakeet Colors, Varieties, Mutations, Genetics

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Genetic Testing in San Antonio, Texas | Start Center for …

More and more, the leading edge of modern cancer care is about targeted and individualized therapies treatments that are designed around the unique characteristics of each cancer patient and his or her cancer. Put simply, different people respond differently to certain treatments, and the same goes for their cancer.

At the START Center for Cancer Care, we are the first cancer-treatment provider in South Texas to offer comprehensive genetic testing of tumors, which is the key to providing state-of-the-art, individualized treatment. Through this genetic testing, our board certified and highly trained cancer specialists are able to look for specific genetic markers that are associated with existing data about the appropriateness and effectiveness of the various treatments.

Through research and genetic profiling of tumor tissue from prior patients, weare now able to see that one anti-cancer drug is likely to work better (or worse)for you than another. For instance, a particular genetic marker is associated with better results with anti-cancer Drug A, while anti-cancer Drug B has shown much lower effectiveness.

In this way, we are able to skip treatments that are likely to have a lower chance of benefiting you. Also, knowing that cancer treatment is itself challenging and burdensome, looking for and finding these genetic markers can spare you many weeks of treatment and side effects with a therapy that isnt going to work. Instead, genetic testing helps us go straight to treatments that have a higher probability of working for you or your loved one.

At START, we provide comprehensive genetic testing of patients tumors. Genetic tumor testing is an invaluable resource in cancer care because of its ability to direct cancer doctors in the informed, science-based selection of targeted therapies, whether for conventional therapies or investigational drugs via clinical trials. With the help of a leading East Texas pathology reference laboratory, we are proud to help our patients as part of our commitment to both world-class care and a new era in cancer treatment.

For more information about genetic testing and how it can improve the efficacy of your individual cancer treatment or to schedule an appointment call the START Center at 210-745-6841. Also, feel free to request an appointment using our easy online form.

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Genetic Testing in San Antonio, Texas | Start Center for ...

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Glossary of Terms | Aplastic Anemia and MDS International …

acute myelogenous leukemia

(uh-KYOOT my-uh-LAH-juh-nuss loo-KEE-mee-uh) A cancer of the blood cells. It happens when very young white blood cells (blasts) in the bone marrow fail to mature. The blast cells stay in the bone marrow and become to numerous. This slows production of red blood cells and platelets. Some cases of MDS become AML. But most do not. Also called AML, acute myeloblastic leukemia, acute myelocytic leukemia, acute myeloid leukemia.

A procedure where bone marrow stem cells are taken from a genetically matched donor (a brother, sister, or unrelated donor) and given to the patient through an intravenous (IV) line. In time, donated stem cells start making new, healthy blood cells.

See complementary and alternative medicine.

(an-uh-fuh-LAK-suss) A very severe allergic reaction to a foreign protein, as in a bee sting, or to a medicine. This reaction causes the blood pressure to drop and trouble breathing. Before a patient receives ATG, a treatment for aplastic anemia, a skin test is given to find out if they are likely to develop anaphylaxis. Also known as anaphylactic shock.

An approach to treating bone marrow failure using natural male hormones. Androgen therapy can help the bone marrow make more blood cells. This is an older treatment for bone marrow failure that is rarely used because of the side effects. Scientists are studying these medicines to try to better understand why they work in some cases of acquired and genetic bone marrow failure.

(uh-NEE-mee-uh) A condition in which there is a shortage of red blood cells in the bloodstream. This causes a low red blood cell count. Symptoms of anemia are fatigue and tiredness.

(an-tee-by-AH-tik) A medicine that fights bacterial infections. When a person with bone marrow failure does not have enough neutrophils, the white blood cells that fight infection, antibiotics may help to prevent and fight infection.

(ant-i-ko-AG-yuh-lunt) See blood thinner.

(ay-PLASS-tik uh-NEE_mee-uh) A rare and serious condition in which the bone marrow fails to make enough blood cells: red blood cells, white blood cells, and platelets. The term aplastic is a Greek word meaning not to form. Anemia is a condition that happens when red blood cell count is low. Most scientists believe that aplastic anemia happens when the immune system attacks the bone marrow stem cells. Aplastic anemia can be acquired (begin any time in life) or can be hereditary (less common, passed down from parent to child).

Programmed cell death.

(uh-SITE-eez) Extra fluid and swelling in the belly area (abdomen). Also called hydroperitoneum.

Any condition that happens when the immune system attacks the body's own normal tissues by mistake.

A procedure in which some of the patient's own bone marrow stem cells are removed, frozen, and then returned to the through an intravenous (IV) line. In time, the stem cells start making new, healthy blood cells.

Describes one of several ways that a trait or disorder can be inherited, or passed down through families. "Autosomal" means that the mutated, or abnormal, gene is located on one of the numbered, or non-sex, chromosomes. "Dominant" means that only one copy of the mutated gene is enough to cause the disease. Dyskeratosis congenita is a rare cause of bone marrow failure disease. It may have an autosomal dominant, autosomal recessive or x-linked pattern of inheritance.

Describes one of several ways that a trait or disorder can be inherited, or passed down through families. "Autosomal" means that the mutated, or abnormal, gene is located on one of the numbered, or non-sex, chromosomes. "Recessive" means that two copies of a mutated gene must be present to cause the disease. Dyskeratosis congenita is a rare cause of bone marrow failure. It may have an autosomal dominant, autosomal recessive or x-linked pattern of inheritance.

The study of a subject to increase knowledge and understanding about it. The goal of basic research in medicine is to better understand disease. In the laboratory, basic research scientists study changes in cells and molecules linked to disease. Basic research helps lead to better ways of diagnosing, treating, and preventing disease. Also called basic science research.

A type of white blood cell that plays a role in allergic reactions.

A chemical that is widely used by the chemical industry in the United States to make plastics, resins, nylon and synthetic fibers. Benzene is found in tobacco smoke, vehicle emissions, and gasoline fumes. Exposure to benzene may increase the risk of developing a bone marrow failure disease. Benzene can affect human health by causing bone marrow stem cells not to work correctly.

(bil-i-ROO-bun) A reddish yellow substance formed when red blood cells break apart. It is found in the bile and in the blood. Yellowing of the skin and eyes can occur with high levels of bilirubin. Also called total bilirubin.

A substance made from a living system, such as a virus, and used to prevent or treat disease. Biological drugs include antibodies, globulin, interleukins, serum, and vaccines. Also called a biologic or biological drug.

A young white blood cell. The number of blast cells in the bone marrow helps define how severe MDS is in a person. When 20 out of 100 cells in the bone marrow are blasts, this is considered acute myeloid leukemia.

See Blast Cells.

A mass of blood that forms when platelets stick together. Harmful blood clots are more likely to happen in PNH. The term thrombus describes a blood clot that develops and attaches to a blood vessel. The term embolus describes a blood clot or other foreign matter that gets into the bloodstream and gets stuck in a blood vessel.

A medicine used to stop blood clots from forming. Blood thinners can be used to treat or prevent clots. Some common blood thinners are enoxaprin (Lovenox), heparin (Calciparine or Liquaemin), and warfarin (Coumadin). Also called and anticoagulant or thrombopoiesis inhibitor.

A procedure in which whole blood or one of its components is given to a person through an intravenous (IV) line into the bloodstream. A red blood cell transfusion or a platelet transfuson can help some patients with low blood counts.

The soft, spongy tissue inside most bones. Blood cells are formed in the bone marrow.

A medical procedure to remove of a small amount of liquid bone marrow through a needle inserted into the back of the hip. The liquid bone marrow is examined for abnormalities in cell size, shape, or look. Tests may also be run on the bone marrow cells to look for any genetic abnormalities.

A medical procedure to remove a small piece of solid bone marrow using a needle that goes into the marrow of the hip bone. The solid bone marrow is examined for cell abnormalities, the number of different cells and checked for scaring of the bone marrow.

A condition that occurs when the bone marrow stops making enough healthy blood cells. The most common of these rare diseases are aplastic anemia, myelodysplastic syndromes (MDS) and paroxysmal nocturnal hemoglobinuria (PNH). Bone marrow failure can be acquired (begin any time in life) or can be hereditary (less common, passed down from parent to child).

A procedure where bone marrow stem cells are collected from marrow inside the donor's hipbone and given to the patient through an intravenous (IV) line. In time, donated stem cells start making new, healthy blood cells.

(bud-kee-AR-ee SIN-drome) A blood clot in the major vein that leaves the liver (hepatic vein). The liver and the spleen may become enlarged. Budd-Chiari syndrome can occur in PNH.

How much of the bone marrow volume is occupied by various types of blood cells.

(kee-moe-THER-uh-pee) The use of medicines that kill cells (cytotoxic agents). People with high-risk or intermediate-2 risk myelodysplastic syndrome (MDS) may be given chemotherapy to kill bone marrow cells that have an abnormal size, shape, or look. Chemotherapy hurts healthy cells along with abnormal cells. If chemotherapy works in controlling abnormal cells, then relatively normal blood cells will start to grow again. Low-dose chemotherapy agents include: cytarabine (Ara-C) and hydroxyurea (Hydrea). High-dose chemotherapy agents include: daunorubicin (Cerubidine), idarubicin (Idamycin), and mitoxanrone (Novantrone).

The part of the cell that contains our DNA or genetic code.

A medical condition that lasts a long time. A chronic illness can affect a person's lifestyle, ability to work, physical abilities and independence.

A person who gives advice, or counsel, to people who are coping with long-term illness. A chronic illness counselor helps people understand their abilities and limitations, cope with the stress, pain, and fatigue associated with long-term illness. A chronic illness counselor can often be located by contacting a local hospital.

A type of research that involves individual persons or a group of people. There are three types of clinical research. Patient-oriented research includes clinical trials which test how a drug, medical device, or treatment approach works in people. Epidemiology or behavioral studies look at the patterns and causes of disease in groups of people. Outcomes and health services research seeks to find the most effective treatments and health services.

A type of research study that tests how a drug, medical device, or treatment approach works in people. There are several types of clinical trials. Treatment trials test new treatment options. Diagnostic trials test new ways to diagnose a disease. Screening trials test the best way to detect a disease or health problem. Quality of life (supportive care) trials study ways to improve the comfort of people with chronic illness. Prevention trials look for better ways to prevent disease in people who have never had the disease.

Trials are in four phases: Phase I tests a new drug or treatment in a small group to see if it is safe. Phase II expands the study to a larger group of people to find out if it works. Phase III expands the study to an even larger group of people to compare it to the standard treatment for the disease; and Phase IV takes place after the drug or treatment has been licensed and marketed to find out the long-term impact of the new treatment.

To make copies. Bone marrow stem cells clone themselves all the time. The cloned stem cells eventually become mature blood cells that leave the bone marrow and enter the bloodstream.

To thicken. Normal blood platelets cause the blood to coagulate and stop bleeding.

A group of proteins that move freely in the bloodstream. These proteins support (complement) the work of white blood cells by fighting infections.

A medical approach that is not currently part of standard practice. Complementary medicine is used along with standard medicine. Alternative medicine is used in place of standard medicine. Example of CAM therapies are acupuncture, chiropractic, homeopathic, and herbal medicines. There is no complementary or alternative therapy that effectively treats bone marrow failure. Some CAM therapies may even hinder the effectiveness of standard medical care. Patients should talk with their doctor if they are currently using or considering using a complementary or alternative therapy.

A group of tests performed on a small amount of blood. The CBC measures the number of each blood cell type, the size of the red blood cells, the total amount of hemoglobin, and the fraction of the blood made up of red blood cells. Also called a CBC.

A procedure where umbillical cord stem cells are given to the patient through an intravenous (IV) line. Stem cells are collected from an umbilical cord right after the birth of a baby. They are kept frozen until needed. In time, donated stem cells given to the patient begin making new, healthy blood cells.

An imaging technique using x-ray technology and computerization to create a three-dimentional image of a body part. Also called a CT scan, it can be used to locate a blood clot in the body.

A response to treatment indicating that no sign of abnormal chromosomes are found. When a test is done on a patient with 5q deletion MDS, and there are no signs of an abnormal chromosome 5, then that patient has achieved a cytogenetic remission. Also called cytegenetic response.

(sie-toe-juh-NEH-tiks) The study of chromosomes (DNA), the part of the cell that contains genetic information. Some cytogenetic abnormalities are linked to different forms of myelodysplastic syndromes (MDS).

(sie-tuh-PEE-nee-uh) A shortage of one or more blood cell types. Also called a low blood count.

(sie-tuh-TOK-sik) A medicine that kills certain cells. Chemotherapy for MDS patients often involves the use of cytotoxic agents.

A test that helps doctors find out if a person has a problem with blood clotting.

(di-NO-vo) Brand new, referring to the first time something occurs. MDS that is untreated or that has no known cause is called de novo MDS.

The death of part of the intestine. This can happen if the blood supply in the intestine is cut off, for example, from a blood clot in the abdomen. Also called intestinal necrosis, ischemic bowel, dead gut.

A rare form of pure red cell aplasia that can be passed down from parent to child. Diamond-Blackfan anemia (DBA) is characterized by low red blood cell counts detected in the first year of life. Some people with DBA have physical abnormalities such as small head size, low frontal hairline, wide-set eyes, low-set ears. Genetic testing is used to diagnose DBA.

Vitamins, minerals, herbs and other substances meant to improve your nutritional intake. Dietary supplements are taken by mouth in the form of a pill, capsule, tablet or liquid.

To become distinct or specialized. In the bone marrow, young parent cells (stem cells) develop, or differentiate, into specific types of blood cells (red cells, white cells, platelets).

The gene that always expresses itself over a recessive gene. A person with a dominant gene for a disease has the symptoms of the disease. They can pass the disease on to children.

An inherited disease that may lead to bone marrow failure.

Refers to how well a graft (donor cells) is accepted by the host (the patient) after a bone marrow or stem cell transplant. Several factors contribute to better engraftment: physical condition of the patient, how severe the disease is, type of donor available, age of patient. Successful engraftment results in new bone marrow that produces healthy blood cells.

A type of white blood cell that kills parasites and plays a role in allergic reactions.

The study of patterns and causes of disease in groups of people. Epidemiology researchers study how many people have a disease, how many new cases are diagnosed each year, where patients are located, and environmental or other factors that influence disease.

(i-RITH-ruh-site) See red blood cell.

(i-rith-row-POY-uh-tun) A protein made by the kidneys. Erythropoietin, also called EPO, is created in response to low oxygen levels in the body (anemia). EPO causes the bone marrow to make more red blood cells. A shortage of EPO can also cause anemia.

A medicine used to help the bone marrow make more red blood cells. Epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp) are erythropoietin-stimulating agents that can help boost the red blood cell count of some bone marrow failure patients. Also called red blood cell growth factor.

A form of estrogen, it is the most potent female hormone. It is also present in males. Estradiol is involved in many body functions beyond the reproductive system. Researchers are investigating the role of estradiol in the treatment of genetic bone marrow failure.

The cause or origin of a disease.

A criteria used for classifying different types of myelodysplastic syndromes (MDS). The FAB (French, American, British) Classification System was developed by a group of French, American and British scientists. This system is based on 2 main factors: the percentage of blast cells in bone marrow, and the percentage of blast cells in the bloodstream. The FAB system is somewhat outdated, but is still used by some doctors today. The World Health Organization (WHO) Classification System has largely replaced the FAB Classification System.

A rare inherited disorder that happens when the bone marrow does not make enough blood cells: red cells, white cells, and platelets. Fanconi anemia is diagnosed early in life. People with Fanconi anemia have a high likelihood of developing cancer. Genetic testing is used to diagnose Fanconi anemia.

(FER-i-tin) A protein inside of cells that stores iron for later use by your body. Sometimes ferritin is released into the blood. The ferritin level in the blood is called serum ferritin.

(FER-i-tin) A blood test used to monitor how much iron the body is storing for later use.

(fie-BRO-suss) Scarring of tissue. Fibrosis of the bone marrow is an feature seen in some types of unclassified myeldysplastic syndrome (MDS).

See fluorescence in situ hybridization.

(sy-TOM-uh-tree) A laboratory test that gives information about cells, such as size, shape, and percentage of live cells. Flow cytometry is the test doctors use to see if there are any proteins missing from the surface of blood cells. It is the standard test for confirming a diagnosis of paroxysmal nocturnal hemoglobinuria (PNH).

(flor-EH-sense in SIT-tyoo hy-bru-duh-ZAY-shun) An important laboratory test used to help doctors look for chromosomal abnormalities and other genetic mutations. Fluorescence in situ hybridization, also called FISH, directs colored light under a microscope at parts of chromosomes or genes. Missing or rearranged chromosomes are identified using FISH.

(FOE-late) A B-vitamin that is found in fresh or lightly cooked green vegetables. It helps the bone marrow make normal blood cells. Most people get enough folate in their diet. Doctors may have people with paroxysmal nocturnal hemaglobinuria (PNH) take a man-made form of folate called folic acid.

See folate.

A laboratory test that looks at the whether red blood cells break apart too easily when they are placed in mild acid. This test has been used in the past to diagnose paroxysmal nocturnal hemoglobinuria (PNH). Most doctors now use flow cytometry, a more accurate method of testing for PNH. Ham Test is also called acid hemolysin test.

(hi-MA-tuh-crit) A blood test that measures the percentage of the blood made up of red blood cells. This measurement depends on the number of red blood cells and their size. Hematocrit is part of a complete blood count. Also called HCT, packed cell volume, PCV.

(hee-muh-TOL-uh-jist) A doctor who specializes in treating blood diseases and disorders of blood producing organs.

(hi-mat-uh-poy-EE-suss) The process of making blood cells in the bone marrow.

A condition that occurs when the body absorbs and stores too much iron. This leads to a condition called iron overload. In the United States, hemochromatosis is usually caused by a genetic disorder. Organ damage can occur if iron overload is not treated.

A protein in the red blood cells. Hemoglobin picks up oxygen in the lungs and brings it to cells in all parts of the body.

(hee-muh-gloe-buh-NYOOR-ee-uh) The presence of hemoglobin in the urine.

(hi-MOL-uh-suss) The destruction of red blood cells.

See human leukocyte antigen.

A part of the endocrine system that serves as the body's chemical messengers. Hormones move through the bloodstream to transfer information and instruction from one set of cells to another.

(LEW-kuh-site ANT-i-jun) One of a group of proteins found on the surface of white blood cells and other cells. These antigens differ from person to person. A human leukocyte antigen test is done before a stem cell transplant to closely match a donor and a recipient. Also called HLA.

A condition in which there are too many cells, for example, within the bone marrow. Patients with leukemia have hypercellular bone marrow filled with to many immature white blood cells.

A condition in which there are too few cells, for example, within the bone marrow. Patients with aplastic anemia have hypocellular bone marrow.

Usually refers to any condition with no known cause.

(i-myoo-no-KOM-pruh-mized) Occurs when the immune system is not functioning properly, leaving the patient open to infection. A person can be immunocompromised due to low white blood cell count or due to some medicines. Also called immune compromised.

(i-myoo-no-suh-PREH-siv) Drugs that lower the body's immune response and allow the bone marrow stem cells to grow and make new blood cells. ATG (antithymocyte globulin) or ALG (antilymphocyte globulin) with cyclosporine are used to treat bone marrow failure in aplastic anemia. Immunosuppressive drugs may help some patients with myelodysplastic syndromes (MDS) and paroxysmal nocturnal hemoglobinuria (PNH).

A committee that makes sure a clinical trial is safe for patients in the study. Each medical center, hospital, or research facility doing clinical trials must have an active Institutional Review Board (IRB). Each IRB is made up of a diverse group of doctors, faculty, staff and students at a specific institution.

A system that turns patient data into a score. The score tells how quickly a myelodysplastic syndrome (MDS) case is progressing and helps predict what may happen with the patient's MDS in the future. Also called IPSS.

A method of getting fluids or medicines directly into the bloodstream over a period of time. Also called IV infusion.

A new drug, antibiotic drug, or biological drug that is used in a clinical trial. It also includes a biological product used in the laboratory for diagnostic purposes. Also called IND.

(kee-LAY-shun) A drug therapy to remove extra iron from the body. Patients with high blood iron (ferritin) levels may receive iron chelation therapy. The U.S. Food and Drug Administratin (FDA) has approved two iron chelators to treat iron overload in the U.S.: deferasirox, an oral iron chelator, and deferoxamine, a liquid given by injection.

A condition that occurs when too much iron accumulates in the body. Bone marrow failure disease patients who need regular red blood cell transfusions are at risk for iron overload. Organ damage can occur if iron overload is not treated.

(iss-KEE-mee-uh) Occurs when the blood supply to specific organ or part of the body is cut off, causing a localized lack of oxygen.

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Stem Cell-Based Therapy for Cartilage Regeneration and …

Our initial application established the goals of our project and the reasons for our study. Arthritis is the result of degeneration of cartilage (the tissue lining the joints) and leads to pain and limitation of function. Arthritis and other rheumatic diseases are among the most common of all health conditions and are the number one cause of disability in the United States. The annual economic impact of arthritis in the U.S. is estimated at over $120 billion, representing more than 2% of the gross domestic product. The prevalence of arthritic conditions is also expected to increase as the population increases and ages in the coming decades. Current treatment options for osteoarthritis are limited to pain reduction and joint replacement surgery. Stem cells have tremendous potential for treating disease and replacing or regenerating the diseased tissue. In this project our objective is to use cells derived from stems cells to treat arthritis. We have completed our experiments as per our proposed timeline and have met milestones outlined in our grant submission. We have established conditions for converting stem cells into cartilage tissue cells that can repair bone and cartilage defects in laboratory models. We have identified several cell lines with the highest potential for tissue repair. We optimized culture conditions to generate the highest quality of tissue. In our initial experiments we found no evidence of cell rejection response in vivo. We have testing efficacy of the most promising cell lines in regenerating healthy repair tissue in cartilage defects and have selected a preclinical candidate.The next step is to plan safety and efficacy studies for the preclinical phase, identify collaborators with the facilities to obtain, process, and provide cell-based therapies, and identify clinical collaborators in anticipation of clinical trials. If necessary we will also identify commercialization partners. We also anticipate that stem cells implanted in arthritic cartilage will treat the arthritis in addition to producing tissue to heal the defect in the cartilage. An approach that heals cartilage defects as well as treats the underlying arthritis would be very valuable. If our research is successful, this could lead to first treatment of osteoarthritis that alters the progression of the disease. This treatment would have a huge impact on the large numbers of patients who suffer from arthritis as well as in reducing the significant economic burden created by arthritis.

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Medical genetics – Wikipedia

Medical genetics is the branch of medicine that involves the diagnosis and management of hereditary disorders. Medical genetics differs from human genetics in that human genetics is a field of scientific research that may or may not apply to medicine, while medical genetics refers to the application of genetics to medical care. For example, research on the causes and inheritance of genetic disorders would be considered within both human genetics and medical genetics, while the diagnosis, management, and counselling people with genetic disorders would be considered part of medical genetics.

In contrast, the study of typically non-medical phenotypes such as the genetics of eye color would be considered part of human genetics, but not necessarily relevant to medical genetics (except in situations such as albinism). Genetic medicine is a newer term for medical genetics and incorporates areas such as gene therapy, personalized medicine, and the rapidly emerging new medical specialty, predictive medicine.

Medical genetics encompasses many different areas, including clinical practice of physicians, genetic counselors, and nutritionists, clinical diagnostic laboratory activities, and research into the causes and inheritance of genetic disorders. Examples of conditions that fall within the scope of medical genetics include birth defects and dysmorphology, mental retardation, autism, and mitochondrial disorders, skeletal dysplasia, connective tissue disorders, cancer genetics, teratogens, and prenatal diagnosis. Medical genetics is increasingly becoming relevant to many common diseases. Overlaps with other medical specialties are beginning to emerge, as recent advances in genetics are revealing etiologies for neurologic, endocrine, cardiovascular, pulmonary, ophthalmologic, renal, psychiatric, and dermatologic conditions.

In some ways, many of the individual fields within medical genetics are hybrids between clinical care and research. This is due in part to recent advances in science and technology (for example, see the Human genome project) that have enabled an unprecedented understanding of genetic disorders.

Clinical genetics is the practice of clinical medicine with particular attention to hereditary disorders. Referrals are made to genetics clinics for a variety of reasons, including birth defects, developmental delay, autism, epilepsy, short stature, and many others. Examples of genetic syndromes that are commonly seen in the genetics clinic include chromosomal rearrangements, Down syndrome, DiGeorge syndrome (22q11.2 Deletion Syndrome), Fragile X syndrome, Marfan syndrome, Neurofibromatosis, Turner syndrome, and Williams syndrome.

In the United States, physicians who practice clinical genetics are accredited by the American Board of Medical Genetics and Genomics (ABMGG).[1] In order to become a board-certified practitioner of Clinical Genetics, a physician must complete a minimum of 24 months of training in a program accredited by the ABMGG. Individuals seeking acceptance into clinical genetics training programs must hold an M.D. or D.O. degree (or their equivalent) and have completed a minimum of 24 months of training in an ACGME-accredited residency program in internal medicine, pediatrics, obstetrics and gynecology, or other medical specialty.[2]

Metabolic (or biochemical) genetics involves the diagnosis and management of inborn errors of metabolism in which patients have enzymatic deficiencies that perturb biochemical pathways involved in metabolism of carbohydrates, amino acids, and lipids. Examples of metabolic disorders include galactosemia, glycogen storage disease, lysosomal storage disorders, metabolic acidosis, peroxisomal disorders, phenylketonuria, and urea cycle disorders.

Cytogenetics is the study of chromosomes and chromosome abnormalities. While cytogenetics historically relied on microscopy to analyze chromosomes, new molecular technologies such as array comparative genomic hybridization are now becoming widely used. Examples of chromosome abnormalities include aneuploidy, chromosomal rearrangements, and genomic deletion/duplication disorders.

Molecular genetics involves the discovery of and laboratory testing for DNA mutations that underlie many single gene disorders. Examples of single gene disorders include achondroplasia, cystic fibrosis, Duchenne muscular dystrophy, hereditary breast cancer (BRCA1/2), Huntington disease, Marfan syndrome, Noonan syndrome, and Rett syndrome. Molecular tests are also used in the diagnosis of syndromes involving epigenetic abnormalities, such as Angelman syndrome, Beckwith-Wiedemann syndrome, Prader-willi syndrome, and uniparental disomy.

Mitochondrial genetics concerns the diagnosis and management of mitochondrial disorders, which have a molecular basis but often result in biochemical abnormalities due to deficient energy production.

There exists some overlap between medical genetic diagnostic laboratories and molecular pathology.

Genetic counseling is the process of providing information about genetic conditions, diagnostic testing, and risks in other family members, within the framework of nondirective counseling. Genetic counselors are non-physician members of the medical genetics team who specialize in family risk assessment and counseling of patients regarding genetic disorders. The precise role of the genetic counselor varies somewhat depending on the disorder.

Although genetics has its roots back in the 19th century with the work of the Bohemian monk Gregor Mendel and other pioneering scientists, human genetics emerged later. It started to develop, albeit slowly, during the first half of the 20th century. Mendelian (single-gene) inheritance was studied in a number of important disorders such as albinism, brachydactyly (short fingers and toes), and hemophilia. Mathematical approaches were also devised and applied to human genetics. Population genetics was created.

Medical genetics was a late developer, emerging largely after the close of World War II (1945) when the eugenics movement had fallen into disrepute. The Nazi misuse of eugenics sounded its death knell. Shorn of eugenics, a scientific approach could be used and was applied to human and medical genetics. Medical genetics saw an increasingly rapid rise in the second half of the 20th century and continues in the 21st century.

The clinical setting in which patients are evaluated determines the scope of practice, diagnostic, and therapeutic interventions. For the purposes of general discussion, the typical encounters between patients and genetic practitioners may involve:

Each patient will undergo a diagnostic evaluation tailored to their own particular presenting signs and symptoms. The geneticist will establish a differential diagnosis and recommend appropriate testing. Increasingly, clinicians use SimulConsult, paired with the National Library of Medicine Gene Review articles, to narrow the list of hypotheses (known as the differential diagnosis) and identify the tests that are relevant for a particular patient. These tests might evaluate for chromosomal disorders, inborn errors of metabolism, or single gene disorders.

Chromosome studies are used in the general genetics clinic to determine a cause for developmental delay/mental retardation, birth defects, dysmorphic features, and/or autism. Chromosome analysis is also performed in the prenatal setting to determine whether a fetus is affected with aneuploidy or other chromosome rearrangements. Finally, chromosome abnormalities are often detected in cancer samples. A large number of different methods have been developed for chromosome analysis:

Biochemical studies are performed to screen for imbalances of metabolites in the bodily fluid, usually the blood (plasma/serum) or urine, but also in cerebrospinal fluid (CSF). Specific tests of enzyme function (either in leukocytes, skin fibroblasts, liver, or muscle) are also employed under certain circumstances. In the US, the newborn screen incorporates biochemical tests to screen for treatable conditions such as galactosemia and phenylketonuria (PKU). Patients suspected to have a metabolic condition might undergo the following tests:

Each cell of the body contains the hereditary information (DNA) wrapped up in structures called chromosomes. Since genetic syndromes are typically the result of alterations of the chromosomes or genes, there is no treatment currently available that can correct the genetic alterations in every cell of the body. Therefore, there is currently no "cure" for genetic disorders. However, for many genetic syndromes there is treatment available to manage the symptoms. In some cases, particularly inborn errors of metabolism, the mechanism of disease is well understood and offers the potential for dietary and medical management to prevent or reduce the long-term complications. In other cases, infusion therapy is used to replace the missing enzyme. Current research is actively seeking to use gene therapy or other new medications to treat specific genetic disorders.

In general, metabolic disorders arise from enzyme deficiencies that disrupt normal metabolic pathways. For instance, in the hypothetical example:

Compound "A" is metabolized to "B" by enzyme "X", compound "B" is metabolized to "C" by enzyme "Y", and compound "C" is metabolized to "D" by enzyme "Z". If enzyme "Z" is missing, compound "D" will be missing, while compounds "A", "B", and "C" will build up. The pathogenesis of this particular condition could result from lack of compound "D", if it is critical for some cellular function, or from toxicity due to excess "A", "B", and/or "C". Treatment of the metabolic disorder could be achieved through dietary supplementation of compound "D" and dietary restriction of compounds "A", "B", and/or "C" or by treatment with a medication that promoted disposal of excess "A", "B", or "C". Another approach that can be taken is enzyme replacement therapy, in which a patient is given an infusion of the missing enzyme.

Dietary restriction and supplementation are key measures taken in several well-known metabolic disorders, including galactosemia, phenylketonuria (PKU), maple syrup urine disease, organic acidurias and urea cycle disorders. Such restrictive diets can be difficult for the patient and family to maintain, and require close consultation with a nutritionist who has special experience in metabolic disorders. The composition of the diet will change depending on the caloric needs of the growing child and special attention is needed during a pregnancy if a woman is affected with one of these disorders.

Medical approaches include enhancement of residual enzyme activity (in cases where the enzyme is made but is not functioning properly), inhibition of other enzymes in the biochemical pathway to prevent buildup of a toxic compound, or diversion of a toxic compound to another form that can be excreted. Examples include the use of high doses of pyridoxine (vitamin B6) in some patients with homocystinuria to boost the activity of the residual cystathione synthase enzyme, administration of biotin to restore activity of several enzymes affected by deficiency of biotinidase, treatment with NTBC in Tyrosinemia to inhibit the production of succinylacetone which causes liver toxicity, and the use of sodium benzoate to decrease ammonia build-up in urea cycle disorders.

Certain lysosomal storage diseases are treated with infusions of a recombinant enzyme (produced in a laboratory), which can reduce the accumulation of the compounds in various tissues. Examples include Gaucher disease, Fabry disease, Mucopolysaccharidoses and Glycogen storage disease type II. Such treatments are limited by the ability of the enzyme to reach the affected areas (the blood brain barrier prevents enzyme from reaching the brain, for example), and can sometimes be associated with allergic reactions. The long-term clinical effectiveness of enzyme replacement therapies vary widely among different disorders.

There are a variety of career paths within the field of medical genetics, and naturally the training required for each area differs considerably. It should be noted that the information included in this section applies to the typical pathways in the United States and there may be differences in other countries. US Practitioners in clinical, counseling, or diagnostic subspecialties generally obtain board certification through the American Board of Medical Genetics.

Genetic information provides a unique type of knowledge about an individual and his/her family, fundamentally different from a typically laboratory test that provides a "snapshot" of an individual's health status. The unique status of genetic information and inherited disease has a number of ramifications with regard to ethical, legal, and societal concerns.

On 19 March 2015, scientists urged a worldwide ban on clinical use of methods, particularly the use of CRISPR and zinc finger, to edit the human genome in a way that can be inherited.[3][4][5][6] In April 2015 and April 2016, Chinese researchers reported results of basic research to edit the DNA of non-viable human embryos using CRISPR.[7][8][9] In February 2016, British scientists were given permission by regulators to genetically modify human embryos by using CRISPR and related techniques on condition that the embryos were destroyed within seven days.[10] In June 2016 the Dutch government was reported to be planning to follow suit with similar regulations which would specify a 14-day limit.[11]

The more empirical approach to human and medical genetics was formalized by the founding in 1948 of the American Society of Human Genetics. The Society first began annual meetings that year (1948) and its international counterpart, the International Congress of Human Genetics, has met every 5 years since its inception in 1956. The Society publishes the American Journal of Human Genetics on a monthly basis.

Medical genetics is now recognized as a distinct medical specialty in the U.S. with its own approved board (the American Board of Medical Genetics) and clinical specialty college (the American College of Medical Genetics). The College holds an annual scientific meeting, publishes a monthly journal, Genetics in Medicine, and issues position papers and clinical practice guidelines on a variety of topics relevant to human genetics.

The broad range of research in medical genetics reflects the overall scope of this field, including basic research on genetic inheritance and the human genome, mechanisms of genetic and metabolic disorders, translational research on new treatment modalities, and the impact of genetic testing

Basic research geneticists usually undertake research in universities, biotechnology firms and research institutes.

Sometimes the link between a disease and an unusual gene variant is more subtle. The genetic architecture of common diseases is an important factor in determining the extent to which patterns of genetic variation influence group differences in health outcomes.[12][13][14] According to the common disease/common variant hypothesis, common variants present in the ancestral population before the dispersal of modern humans from Africa play an important role in human diseases.[15] Genetic variants associated with Alzheimer disease, deep venous thrombosis, Crohn disease, and type 2 diabetes appear to adhere to this model.[16] However, the generality of the model has not yet been established and, in some cases, is in doubt.[13][17][18] Some diseases, such as many common cancers, appear not to be well described by the common disease/common variant model.[19]

Another possibility is that common diseases arise in part through the action of combinations of variants that are individually rare.[20][21] Most of the disease-associated alleles discovered to date have been rare, and rare variants are more likely than common variants to be differentially distributed among groups distinguished by ancestry.[19][22] However, groups could harbor different, though perhaps overlapping, sets of rare variants, which would reduce contrasts between groups in the incidence of the disease.

The number of variants contributing to a disease and the interactions among those variants also could influence the distribution of diseases among groups. The difficulty that has been encountered in finding contributory alleles for complex diseases and in replicating positive associations suggests that many complex diseases involve numerous variants rather than a moderate number of alleles, and the influence of any given variant may depend in critical ways on the genetic and environmental background.[17][23][24][25] If many alleles are required to increase susceptibility to a disease, the odds are low that the necessary combination of alleles would become concentrated in a particular group purely through drift.[26]

One area in which population categories can be important considerations in genetics research is in controlling for confounding between population substructure, environmental exposures, and health outcomes. Association studies can produce spurious results if cases and controls have differing allele frequencies for genes that are not related to the disease being studied,[27] although the magnitude of this problem in genetic association studies is subject to debate.[28][29] Various methods have been developed to detect and account for population substructure,[30][31] but these methods can be difficult to apply in practice.[32]

Population substructure also can be used to advantage in genetic association studies. For example, populations that represent recent mixtures of geographically separated ancestral groups can exhibit longer-range linkage disequilibrium between susceptibility alleles and genetic markers than is the case for other populations.[33][34][35][36] Genetic studies can use this admixture linkage disequilibrium to search for disease alleles with fewer markers than would be needed otherwise. Association studies also can take advantage of the contrasting experiences of racial or ethnic groups, including migrant groups, to search for interactions between particular alleles and environmental factors that might influence health.[37][38]

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Medical genetics - Wikipedia

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