Category Archives: Gene Medicine

Raleigh, N.C. Many people spend years searching for a diagnosis of a debilitating medical problem, paying for treatments or surgery that don't help. Now, researchers at UNC say that, for some, recent advances in genetic testing could fix their problems once and for all.

Elizabeth Davis, a local genes study participant, does not take walking for granted. For 30 years, she could barely walk at all. "When I was 6, I started walking on my toes," she said. "I started going to different doctors, trying to find out what it was."

The muscles in Davis' foot had tightened up, causing her pain. She needed crutches and, sometimes, a wheelchair. For years, the cause of her condition remained a mystery.

According to Dr. James Evans, a researcher at UNC's Center for Genetic Medicine, about 30 percent of patients find an answer to their problems when they participate in a genes study. Participants' blood samples are analyzed with the latest advances in DNA sequencing.

"The patients themselves typically seek us out because they've been looking for answers for a long time," said Evans. "There might not be a known treatment, so sometimes that answer doesn't really change their life significantly."

Davis saw positive results after participating in the study, and Dr. Jonathan Berg, an Assistant Professor of Genetics at UNC, was happy with the results. "Her case is an unusual one in that it just happened to be a condition that is exquisitely treatable -- with just a pill," said Berg.

The genes study discovered that Davis had a muscle rigidity problem similar to that of many people with Parkinson's Disease. Doctors learned that it was Dopa, a drug used by millions of Americans with the disease, could help Davis walk again.

"The relief was fast and just by taking a quarter of a pill," said Davis. "I overheard my oldest son telling his friend that 'his mom is not on crutches anymore.' I'll never forget him saying that."

The study, funded by the National Institutes of Health, has even bigger plans for the future. UNC researchers say they're planning a randomized controlled trial to see if these types of genetic tests can benefit patients in the long run and prove to be a cost-effective diagnostic test.

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In pain? For some, gene studies could provide a quick cure - WRAL.com

The first step consisted of genetically modifying a laboratory cell line in which the researchers could monitor the levels of fluorescent MeCP2 as they inhibited molecules that might be involved in its regulation. First author Dr. Laura Lombardi, a postdoctoral researcher in the Zoghbi lab at the Howard Hughes Medical Institute, developed this cell line and then used it to systematically inhibit one by one the nearly 900 kinase and phosphatase genes whose activity could be potentially inhibited with drugs.

We wanted to determine which ones of those hundreds of genes would reduce the level of MeCP2 when inhibited, Lombardi said. If we found one whose inhibition would result in a reduction of MeCP2 levels, then we would look for a drug that we could use.

The researchers identified four genes than when inhibited lowered MeCP2 level. Then, Lombardi and her colleagues moved on to the next step, testing how reduction of one or more of these genes would affect MeCP2 levels in mice. They showed that mice lacking the gene for the kinase HIPK2 or having reduced phosphatase PP2A had decreased levels of MeCP2 in the brain.

These results gave us the proof of principle that it is possible to go from screening in a cell line to find something that would work in the brain, Lombardi said.

Most interestingly, treating animal models of MECP2 duplication syndrome with drugs that inhibit phosphatase PP2A was sufficient to partially rescue some of the motor abnormalities in the mouse model of the disease.

This strategy would allow us to find more regulators of MeCP2, Zoghbi said. We cannot rely on just one. If we have several to choose from, we can select the best and safest ones to move to the clinic.

Beyond MeCP2, there are many other genes that cause a medical condition because they are either duplicated or decreased. The strategy Zoghbi and her colleagues used here also can be applied to these other conditions to try to restore the normal levels of the affected proteins and possibly reduce or eliminate the symptoms.

Other contributors to this work include Manar Zaghlula, Yehezkel Sztainberg, Steven A. Baker, Tiemo J. Klisch, Amy A. Tang and Eric J. Huang.

This project was funded by the National Institutes of Health (5R01NS057819), the Rett Syndrome Research Trust and 401K Project from MECP2 duplication syndrome families, and the Howard Hughes Medical Institute. This work also was made possible by the following Baylor College of Medicine core facilities: Cell-Based Assay Screening Service (NIH, P30 CA125123), Cytometry and Cell Sorting Core (National Institute of Allergy and Infectious Diseases, P30AI036211; National Cancer Institute P30CA125123; and National Center for Research Resources, S10RR024574), Pathway Discovery Proteomics Core, the DNA Sequencing and Gene Vector Core (Diabetes and Endocrinology Research Center, DK079638), and the mouse behavioral core of the Intellectual and Developmental Disabilities Research Center (NIH, U54 HD083092 from the National Institute of Child Health and Human Development).

The full study can be found inScience Translational Medicine.

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Test reveals possible treatments for disorders involving MeCP2 - Baylor College of Medicine News (press release)

Once difficult and expensive even for the most technologically advanced labs, genetic testing is fast becoming a cheap and easy consumer product. With a little spit and 200 dollars, you can find out your risk for everything from cystic fibrosis to lactose intolerance.

But its important to remember that not all genetic tests are created equal. And even the best clinical genetic test, carried out in a medical lab under a doctor's supervision, isn't perfectgenes are important, but they don't seal your fate.

Genetic tests are diagnostic, so anyone who is curious about their health can get one done. But they're more informative if you think you might be at risk for a genetic disorder.

Heavy-duty genetic tests have been used as a clinical tool for almost half a centurylong before 23andMe and Ancestry.com began offering direct-to-consumer tests. Lets say that many women in your family have had breast cancer. You can get a genetic test to see if you may have inherited an abnormal version of the BRCA gene, known to increase your risk for breast cancer.

Heidi Rehm, associate professor of pathology at Harvard Medical School, is the director of the Laboratory for Molecular Medicine, where patients get tested for diseases that can be traced to specific genetic roots. She says it is most common for people to get tested when they either suspect or know that they have a genetic disease; it may have affected multiple people in their family or they could show symptoms of something widely known to be genetic, like sickle cell anemia. For these people, genetic tests can provide a much-needed explanation for an illness and help doctors determine the best course of treatment. Babies are often tested for genetic diseases, either while they are still fetuses or shortly after birth.

Others get genetic tests if they and their partner both have family histories of an inherited diseaseeven if they dont have the disease themselves. For example, cystic fibrosis is linked to one particular gene, but you have to inherit the abnormal version of the gene from both your parents to get the disease. If you only inherit one copy, you may never knowyou wont display any of the symptoms. But if you and your partner both carry one copy of the faulty gene, your child could still inherit two copies. Genetic tests can forewarn you of that possibility.

But Rehm says there has been a recent trend of healthy people getting tested to predict whether theyll get certain diseases. I do think there are settings where predictive genetic testing is incredibly important and useful, Rehm says; for example, knowing that youre at risk for breast cancer gives you the opportunity for early intervention (remember when Angelina Jolie got a double mastectomy upon finding out she had a mutated BRCA gene?)

But Rehm also points out that genetic tests may not be as straightforward as they seem. For example, some genes are thought to increase risk of getting a certain disease, but it might only happen if you have specific family history, or you might be able to reduce your risk with lifestyle changes. So remember that a genetic test isnt the final verdictthere are other factors at play too.

Not entirelyits scope is limited. For starters, not all diseases are caused by genes. Plenty of conditions stem from environmental and lifestyle factors; they may interact with your genes, but the external factors are the real trigger.

But even if a disease is caused solely by faulty instructions written in your genes, you wont necessarily be able to test for it. Thats because genetic tests are mainly used for diseases that are penetrant, a term that scientists use to describe a strong connection between having a certain gene (or multiple genes) and getting a disease.

Genetic tests are surprisingly simple on the surface. All thats required of you is a small sample of cells, like a blood sample or saliva (which doesnt have DNA itself, but picks up cheek cells during its journey out of your mouth). It get sent to a lab where sequencing machines match up small pieces of synthetic DNA with your DNA to figure out the overall sequence.

Once they have your sequence, geneticists can compare it with "normal" or disease-causing sequences. In the end, they might give you a yes or no answer, or sometimes youll get a probabilitya measure of how much your genes increase your risk of developing the disease. Then, its up to your doctor to figure out what these genes (in combination with your lifestyle, family history and other risk factors) mean for your health.

With penetrant diseases, theres a very, very high ability to explain the disease, Rehm says. For example, the breast cancer-related gene BRCA1 can give you a 60 percent chance of getting breast cancer (in Jolies case, with her family history, the risk was 87 percent.)

This makes genetic tests better at detecting so-called rare diseases, says Steven Schrodi, associate research scientist at the Marshfield Clinic Research Institutes Center for Human Genetics, but theyre less useful when it comes to more common diseases, like heart disease or diabetes. Genetics can increase your likelihood of getting these disease, but scientists still dont know quite how much. Part of the problem is that there may be dozens or hundreds of genes responsible for these diseases, Schrodi says.

We have an incomplete understanding of why people get diseases, Schrodi says. A large part of it hinges on how we define diseases. Perhaps physicians have inadvertently combined multiple diseases together into a single entity.

Consumer genetic teststhe ones where you send in samples from homesometimes claim to test for these more complex traits, but be careful: Their results might not be very medically relevant, Rehm says. If they tell you that your genes make you twice as likely to develop diabetes, for example, that's a marginal increase that doesn't significantly affect your risk, especially when you take into account lifestyle factors.

Genes do seem to play a role in determining lifespan. After all, some family reunions stretch from great-great-grandparents all the way down to infants. Scientists have studied centenarianspeople who lived to be 100 years oldand found that people with certain versions of genes involved in repairing DNA tend to live longer.

This makes sense because aging leaves its mark on your DNA. Environmental factors can damage DNA, and even the routine chore of replicating cells can introduce errors as the three billion units of your DNA are copied over and over. Long-lived individuals have different sequences that seem to make their cells better at keeping DNA in mint condition.

But figuring out your expiration date is more complex than just testing for a few genes, says Jan Vijg, professor of genetics at Albert Einstein College of Medicine. In theory, you could design a test that looks at specific genes that might measure your risk for developing Alzheimers Disease or other age-related diseases, or your risk for aging quickly. To some extent, yes: Biomarkers will tell you something about your chances of living a long life, Vijg says. Still, that will only work if you live a careful life. And that means no accidents, infections, or cancers.

Aging also affects the exposed ends of your DNA, called "telomeres." DNA is stored as chromosomes, those X-like structures that you may have seen in biology textbooks. The most vulnerable parts of the chromosome are the chromosomes tips, which get shorter as you age because they arent properly replicated. But while telomere length might let you compare your DNA now with your DNA from a decade ago, you cant compare your own telomeres with other peoples telomeres. Theres a lot of variation between individuals, Vijg says. Some of us are just old souls (on the genomic level, that is.)

The methylation test, which looks at how the presence of small chemical groups attached to your DNA changes as you age, might be a better bet. A study at UCLA showed that changes were slower in longer-lived people. But Vijg is hesitant: I would not put my hopes on that as a marker to predict when exactly youre going to die.

For now, just enjoy your life, because you cant predict death. And if you decide to unlock the secrets of your DNA with an at-home test, don't take those results for more than their worth.

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What can genetic testing really tell you? - Popular Science

On July 12, an FDA panel recommended approval of the first genetically engineered T cell for commercial sale to treat childhood leukemia, a blood cancer. The biologic could cost $300,000 per patient, leaving questions of whether some insurance companies will pay for it. Such cancer therapies can run into sizable costs for patient follow-ups. But, in the coming years, engineered T cells will be in high demand, even more so if they can be applied to solid tumors.

The Trump administration keeps threatening to repeal the Affordable Care Act, which suggests new inequalities to health care access. This will only be made worse by expensive new drugs, which test the limits of insurance reimbursement. However, even a single-payer system is unlikely to help to ensure access to such staggeringly expensive biologics. For instance, the National Health Services in Britain will be hard pressed to reimburse for six-figure biologics. If so, the only ethical action would be to use the power of the state to force down the cost of such cancer drugs.

A conservative argument against socialized medicine is based on the tragic vision of human nature, which suggests that people are guided by innate self-interests, and that societyand, by implication, biotechrequires constraint through moral and legal checks. The reality is that many of us do harbor a genetic variant that predicts a rare genetic disorder, or cancer, and we certainly cant afford to correct every anomaly in nature. However, a counter-position is that we are already participating in socialized medicine through funding the National Institutes of Health, which subsidizes the risk and cost of investigating drug targets and tools, not to mention results in generous salaries for many scientists.

In 2004, Noam Chomsky noted that Eisenhowers military-industrial complex was a misnomer, arguing that the actual purpose of taxpayer support is to boost economic prospects for investors, including those at life science companies. If you walk around MIT today, around Kendall Square, you see small biotech companies, spin-offs of government-sponsored research in what will be the cutting edge of the economy, namely, biology-based industries.

If you looked around 40 years ago (then to the newly developing Route 128 corridor), you would have seen small electronics firms, spin-offs of what was then the cutting edge of the economy, electronics, under military cover. So Eisenhowers military-industrial complex is not quite what is generally interpreted. In part, yes, its military. But a main function of the military, or the National Institutes of Health, or the rest of the federal system, is to provide some device to socialize costs, get the public to pay the costs, to take the risks. Ultimately, if anything comes out, you put it into private pockets.

That cancer patients should be criticized for depending on socialized medicine on the consumer end conceals the fact that scientists depend on taxpayers to subsidize their careers, while developing many of the technologies in academic settings and then profiteering them out. The high profile patent battle over CRISPR gene editing system was one of these situations, which resulted in a mix of philanthropic and public money paying for the invention of a technology that is now enrapt in a web of financial dealings not to mention bitter rivalries. Editas Medicine, a spinout of Harvard and MITs Broad Institute, which claims exclusive rights to medical applications of CRISPR-Cas9, signed a highly profitable $737 million deal with cancer T-cell company Juno Therapeutics.

If we are already participating in socialized medicine, the only tragedy will be if the socialism stops on the consumer side. One suggestion I have made previously is to no longer fund academic scientists and their partners who have established a strong foothold in the economy. Novartis (the company with the cancer biologic expected to price up to $300,000, compared with the $25,000 cost to actually manufacture it) recently completed a$600 million campus in Cambridge. The Broad Institute is seeded with $1.4 billion in wealth. The state of the union of life science is strong. If cutting taxpayer subsidies to scientists is too sensitive an idea, then we can use the power of the state to contain the costs of biologics, which we effectively subsidize.

A drug price fairness initiative is on the ballot in Ohio, and would enable public payers such as Medicaid to pay 20 percent under market price; transparency laws, established in Vermont make the costs of drugs clear; indeed, we may even cap the cost of biologics by executive order.

Entrepreneurial scientists are moving ahead with some exciting work on making use of CRISPR to disable genes in our T cells, which could prevent cancer cells from shutting down an immune response, and by adding bits of code to our immune cells to enable them to attach to abnormal protein fragments on solid tumors. If we take a tragic view of nature, these drugs will be priced as high as the market will allow. We can use the power of the state to change that.

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We've Already Got Socialized Medicine - Scientific American (blog)

The first reportof gene editing in viable human embryos performed in the United Stateshas beenpublished. The landmark study demonstrates that gene editing technology can successfully repair faulty genes in the human germline a scientific term that refers to sperm or egg cells, zygotes, and embryos.

Correcting gene mutations in the germline is powerful because any such modifications are inherited by subsequent generations in a fixed, self-perpetuating configuration. To many, this represents the Holy Grail of modern medicine.

Germline editing contrasts gene therapy and other methods that target somatic cells all of the body's non-reproductive, differentiated cells. An individual whose somatic cells have been corrected at a specific gene cannot produce offspring that carry the correction.

The ability to edit genes at the germline level brings immense prospects for human health and welfare. Clinical applications that have only ever existed in science fiction are now within the realm of reality. Scientists have developed basic tools that may soon be used to prevent a myriad of debilitating and fatal genetic diseases including Cystic Fibrosis, Tay-Sachs, certain types of cancer, and hereditary forms of Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), and Alzheimer's Disease.

Despite the vast potential for good, gene editing for clinical purposes is controversial. Jennifer Doudna, a gene editing pioneer, stated she is "uncomfortable" with the clinical applications of the technology. She and others have previously argued for a moratorium on germline editing citing unknown risks, safety, and efficacy concerns.

However, the latest germline editing report suggests that many of the concerns against future use of gene editing technologies for gene repair in human embryos may be premature and overstated. The study sought to correct a mutated version of the MYBPC3 gene, which causes hypertrophic cardiomyopathy, a heritable disease that leads to sudden cardiac failure, often in young athletes.

The study revealed that co-injecting the CRISPRCas9 system and sperm carrying the faulty MYBPC3 into healthy donor eggs corrected the pathogenic mutation. Importantly, the researchers overcame many of the problems associated with editing of human embryos that Chinese teams have experienced since 2015.

By injecting the gene editing system before the first cell division, the researchers discovered that mosaicism a characteristic of embryos that have a mix of edited and unedited cells could be avoided. This strategy led to highly precise and accurate editing, as evidenced by the lack of unintended off-target mutations in the embryos' genomes.

Progress aside, germline editing is not yet ready for primetime. Further research and considerable technology optimization are essential prerequisites for clinical use. Laws that prohibit clinical trials may be reconsidered, in due course, as the technology develops. That all takes time.

Researchers know this. Unfortunately, scientific progress is frequently susceptible to sensationalism.

Unjustified debates concerning germline editing often conjure up eugenics. Alluring and frivolous claims that reproductive technologies will inevitably be used to create tall, beautiful, superhuman geniuses with superb athletic abilities circulate ad nauseam. The myth of "designer babies" has become an emblem of misinformation.

Never mind that the quest to uncover specific intelligence gene(s) has proven to be an exercise in futility. Research shows that, while heritable, highly polygenic traits those determined by multiple genesare often determined by the collective contribution of hundreds of genes. For instance, hundreds of genetic variants in at least 180 genetic loci have been reported to influence height in humans.

Knowledge concerning the genetics of complex polygenic traits is vastly incomplete. The notion that scientists can tinker with a few genes let alone hundreds of them simultaneously, and know precisely how such manipulation will affect an individual is simply preposterous at this time. And it will likely remain so during our lifetimes.

That scientific fact favors gradual and thoughtful measures including legislation and policymakingto address actual concerns raised by germline editing. Entertaining dubious hypotheticals is a dangerous endeavor. And seeking to ban a technology over far-fetched contingencies is bad policy.

So be skeptical when encountering views that aver humans are entering a Brave New World. Be skeptical when scientific progress is reduced to a Frankenstein-like fable engineered to pollute thoughtful debate. The designer baby canard must be confronted.

We are indeed entering a new exciting world. One in which human ingenuity can and will be used to eradicate disease and suffering by pushing the boundaries of knowledge.

We should all embrace this momentous time in human history.

Paul Enrquez is a lawyer and scientist. His work focuses on the intersection of science and law and has been featured in legal and scientific journals. He explores gene editing as it relates to eugenics and the genetics of human intelligence in his recently published article "Genome Editing and the Jurisprudence of Scientific Empiricism."

The views expressed by contributors are their own and not the views of The Hill.

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Why we should all embrace gene editing in human embryos - The Hill (blog)

Jennifer Doudna, Ph.D. , professor, Molecular and Cell Biology and Chemistry, University of California, Berkeley. (UC-Berkeley)

Jennifer Doudna, Ph.D. , professor, Molecular and Cell Biology and Chemistry, University of California, Berkeley. (UC-Berkeley)

Luciano Marraffini, Ph.D., associate professor, Laboratory of Bacteriology, The Rockefeller University, New York City. (Mario Morgado)

Luciano Marraffini, Ph.D., associate professor, Laboratory of Bacteriology, The Rockefeller University, New York City. (Mario Morgado)

Gene-editing scientists to share $500K Albany Med prize

Albany

Five scientists whose work on the revolutionary gene-editing technology CRISPR will share the 2017 Albany Medical Center Prize in Medicine and Biomedical Research.

The decision by the Albany Prize National Selection Committee to award the $500,000 prize to these researchers stands out from recent announcements of the prestigious award, which have acknowledged scientists for groundbreaking work leading to current medical advances. While developments using CRISPR have exploded this year, its use in humans remains a promise, but one with far-reaching effects.

"The committee saw this technology as having huge potential for eradicating human disease," said Dr. Vincent Verdile, dean of Albany Medical College and chair of the prize committee.

CRISPR (pronounced "crisper") stands for "clustered regularly interspaced short palindromic repeats." It is a DNA sequence that simple bacteria use to defend themselves against viruses by snipping out part of the virus DNA so it can be recognized by the bacteria's own immune systems. The technology based on it lets scientists "edit" genes at specific locations by removing, adding or altering parts of the DNA sequence.

In the last year, CRISPR technology has been used to remove a gene linked to heart disease from human embryos and to create a cancer-killing gene that shrinks tumors in mice. Last week, scientists revealed in the journal Science that they had created piglets stripped of viruses that could cause disease in humans; the technique could open the door for eventual transplantation of livers, hearts and other organs from pigs to people.

The scientists who will share the Albany Prize are:

Emmanuelle Charpentier of the Max Planck Institute for Infection Biology in Germany. Charpentier is co-inventor and co-owner of the intellectual property comprising the CRISPR gene-editing system, and co-founder of two companies developing the technology for biotech and biomedical applications.

Jennifer Doudna of the University of California, Berkeley. Five years ago, Doudna described a simple way of editing the DNA of any organism using an RNA-guided protein founded in bacteria.

Luciano Marraffini of Rockefeller University in New York City. Marraffini discovered that CRISPR works by severing DNA and was the first to propose that it could be used to edit genes in organisms other than bacteria. With Feng Zhang, he performed the first successful CRISPR gene-editing experiment in human cells.

Francisco J.M. Mojica of the University of Alicante in Spain. Mojica's work has led to the development of tools used in the genetic manipulation of any living being, including humans.

Feng Zhang of the Broad Institute of Massachusetts Institute of Technology and Harvard University. Zhang pioneered the development of gene editing tools for use in human cells from bacterial CRISPR systems.

The Albany Prize Committee's selection of five scientists to share the award this year reflects an increasing trend in science toward collaboration, where information is shared and groups of researchers move knowledge forward in ways that no one of them could do alone, Verdile said. It's a major change since the days when a single scientist would be credited with, say, the discovery of a vaccine.

"That's more of where the future of biomedical research is going what's good for the good of mankind, not me personally," Verdile said.

News reports in recent years have focused on the ethical aspects of CRISPR technology, which in addition to its potential to prevent devastating diseases, could also be used for cosmetic purposes or have unintended consequences that affect the descendants of the person whose genes are edited. The Albany Prize Committee did not consider such "what if" scenarios, Verdile said, leaving those conversations for future ethicists and policymakers as specific medical techniques are developed.

The Albany Prize, one of the nation's largest for science and medicine, was established in 2000 by the late Morris "Marty" Silverman, a New York City businessman and philanthropist who grew up in Troy. A commitment of $50 million from the Marty and Dorothy Silverman Foundation allows for the prize to be awarded annually for 100 years.

Albany Med released the 2017 award recipients' names Tuesday morning. The recipients will formally receive their awards at a Sept. 27 ceremony in Albany.

chughes@timesunion.com 518-454-5417 @hughesclaire

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Gene-editing scientists to share $500K Albany Med prize - Albany Times Union