Category Archives: Gene Medicine

In 2006, Shinya Yamanaka shook stem cell research with his discovery that mature cells can be converted into stem cells, relieving a longstanding political-ethical blockage and throwing open medical research on everything from curbing eye degeneration to organ printing.

But that process still has pitfalls, including in risk and scalability, and some researchers are exploring another way first hinted at years ago: new technology to convert mature cells directly into other mature cells without the complex and time-consuming process of first making them into stem cells.

One of those companies, Mogrify, just raised $16 million in Series A financing to bring its overall funding to over $20 million since its February launch. Led by CEO Darrin Disley, the funding will help expand their new base in Cambridge to a 60-strong staff and push forward their direct-conversion approach to cell therapy through research and licensing. Investors include Parkwalk Advisors and Ahren Innovation Capital.

They list potential applications as treatments for musculoskeletal and auto-immune disorders, cancer immunotherapy, and therapies for ocular and respiratory diseases. For example, you could use it regenerate cartilage in arthritis patients.

If you could take a cell from one part of the body and turn it into any other cell at any other stage of development for another part of the body, you effectively have the Holy Grail of regenerative medicine, Disley told Labiotech.eu in April.

Mogrifys advantage over the Yamanaka method called induced pluripotent stem cells (iPS), is that in theory it can be more scalable and avoid the problems associated with iPS. These include instabilities arising from the induced immature state and an increased risk of cancer if any pluripotent cells remain in the body.

The concept behind Mogrify actually predates, by nearly 19 years, Yamanakas discovery, which fast won him the 2012 Nobel Prize in Medicine. A 2017 Nature study on transdifferentiation, as the process is called, of fibroblasts into cardiac tissue traced the idea to a 1987 findingthat a master gene regulator could convert mice fibroblasts into skeletal muscle.

The problem though, according to Mogrify, is that most current efforts rely on an exhausting guess-and-check process. With hundreds of cell types and an even greater number of transcription factors the program that recodes the cell finding the right factor for the right cell can be like a custodian with a jangling, unmarked key ring trying to get into a building with thousands of locks.

Mogrifys key tech is a computer model they say can predict the right combination. The scientists behind the platform published a 2016 study in Nature applying the model to 173 human cell types and 134 tissues.

Before Mogrify, Disley led the Cambridge-based gene-editing company Horizon Discovery.

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Cell therapy startup raises $16 million to fund its quest for the Holy Grail in regenerative medicine - Endpoints News

The new Stanford Center for Definitive and Curative Medicine will fosterthe development ofstem cell and gene therapies for genetic diseases, including sickle cell anemia.

More than280 million people around the world have diseases with genetic causes, experts estimate. While research has identified the underlying causes of several, scientists have developed few therapies that can address the causes or cure the diseases.

Treatments have been developed thatsignificantly improve patients health, however. They include public health initiatives, targeted therapies and surgery.

Scientists believe stem cell and gene therapy can cure some genetic diseases. They would likely do this either by rewiring cells to fight a disease more efficiently or by correcting a genetic errorin a patients DNA.

Stanford not only does excellent research in disease mechanisms, cell and stem cell biology, but also promotes collaboration between its medical schools and hospitals.

The initiative is a joint venture of theStanford University School of Medicine,Stanford Health CareandStanford Childrens Health.

Dean Predicts Center Will Be Major Force in the Precision-health Revolution

The Center for Definitive and Curative Medicine is going to be a major force in theprecision-health revolution, Dr. Lloyd Minor, dean of the School of Medicine, said in a press release. Our hope is that stem cell and gene-based therapeutics will enable Stanford Medicine to not just manage illness but cure it decisively and keep people healthy over a lifetime.

We are entering a new era in medicine, one in which we will put healthy genes into stem cells and transplant them into patients,said Christopher Dawes, the president and CEO of Stanford Childrens Health. And with the Stanford Center for Definitive and Curative Medicine, we will be able to bring these therapies to patients more quickly than ever before.

The work of the center is not being done anywhere else in the country only at Stanford, said David Entwistle, president and CEO of Stanford Health Care. We have a pipeline of clinical translational therapies that the center is now driving forward, enabling us to translate basic science discoveries into state-of-the-art therapies for diseases which up until now have been considered incurable.

Dr. Maria Grazia Roncarolo will direct the center,which will be in the Department of Pediatrics.The renowned medical doctor and scientist is the George D. Smith Professor of Stem Cell and Regenerative Medicine.

It is a privilege to lead the center and to leverage my previous experience to build Stanfords preeminence in stem cell and gene therapies, said Roncarolo, who is also chief of pediatric stem cell transplantation and regenerative medicine, co-director of theBass Center for Childhood Cancer and Blood Diseases,and co-director of theStanford Institute for Stem Cell Biology and Regenerative Medicine.

Main Mission Will Be to Turn Scientific Discoveries Into Treatments

Stanford Medicines unique environment brings together scientific discovery, translational medicine and clinical treatment, Roncarolo added. We will accelerate Stanfords fundamental discoveries toward novel stem cell and gene therapies to transform the field and to bring cures to hundreds of diseases affecting millions of children worldwide.

The centers main mission will be to turn scientific discoveries into treatments. A world-classinterdisciplinary team of scientists should help it deliver on that promise.

Leaders of the team will include Dr. Matthew Porteus, an associate professor of pediatrics, and Dr. Anthony Oro, the Eugene and Gloria Bauer Professor of dermatology. Dr. Sandeep Soni will direct the centers stem cell clinical trial office.

The center will provide novel therapies that can prevent irreversible damage in children, and allow them to live normal, healthy lives, said Dr. Mary Leonard, chair of pediatrics at Stanford Childrens Health. The stem cell and gene therapy efforts within the center are aligned with the strategic vision of the Department of Pediatrics and Stanfordsprecision-healthvision, where we go beyond simply providing treatment for children to instead cure them definitively for their entire lives.

A unique feature of the center will be a close association with the Stanford Laboratory for Cell and Gene Medicine, which is working on new cell and gene therapies.

The lab has already developed genetically corrected bone marrow cells as a treatment for sickle cell anemia. Other genetically modified cells it has created include skin grafts for children with the genetic disease epidermolysis bullosa and lymphocytes for children with leukemia.

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Stanford Center Hopes to Take Stem Cell and Gene Therapies to a New Level - Sickle Cell Anemia News

Binding of steroid estrogen hormones to estrogen receptor (ER) in the cell nucleus triggers the sequential recruitment different coactivators to regulate gene transcription.

Estrogen hormones regulate gene expression. They achieve this by first binding to estrogen receptor in the cell nucleus, which triggers the recruitment of different molecules called coactivators in specific order. In a study published in Molecular Cell, a team of researchers at Baylor College of Medicine, the University of Texas MD Anderson Cancer Center and the University of Texas Health Science Center at Houston shows that the sequential recruitment of coactivators is not simply adding molecules to the complex, it results in dynamic specific structural and functional changes that are necessary for effective regulation of gene expression.

Estrogens are a group of hormones that are essential for normal female sexual development and for the healthy functioning of the reproductive system. They also are involved in certain conditions, such as breast cancer. Estrogen also plays a role in male sexual function. Estrogens carry out their functions by turning genes on and off via a multi-step process. After estrogen binds to its receptor, different coactivators bind to the complex in a sequential manner.

Experimental evidence suggests that different estrogen-receptor coactivators communicate and cooperate with each other to regulate gene expression, said corresponding author Dr. Bert OMalley, chair and professor of molecular and cellular biology and Thomas C. Thompson Chair in Cell Biology at Baylor College of Medicine. However, how this communication takes place and how it guides the sequence of events that regulate gene expression was not clear.

In this study, OMalley, Dr. Wah Chiu, Distinguished Service Professor and Alvin Romansky Professor of Biochemistry and Molecular Biology at Baylor during the development of this project, and their colleagues combined cryo-electron microscopy structure analysis and biochemical techniques and showed how the recruitment of a specific coactivator CARM1 into the complex guides the subsequent steps leading to gene activation.

For the estrogen receptor complex to be able to regulate gene expression, the coactivator CARM1 needs to be added after other coactivators have been incorporated into the complex, said first author Dr. Ping Yi, assistant professor of molecular and cellular biology at Baylor. We discovered that when CARM1 is added, it changes the complex both chemically and structurally, and these changes guide subsequent steps that lead to gene activation.

We now have a better understanding of how this molecular machine works and of what role each one of the components plays. We are better prepared to understand what might have gone wrong when the machine fails, OMalley said.

Other contributors to this work include Zhao Wang, Qin Feng, Chao-Kai Chou, Grigore D. Pintilie, Hong Shen, Charles E. Foulds, Guizhen Fan, Irina Serysheva, Steven J. Ludtke, Michael F. Schmid, Mien-Chie Hung and Wah Chiu.

Support for this study was provided by the Komen Foundation (5PG12221410), the Department of Defense (R038318-I and W81XWH-15-1-0536); National institutes of Health grants (HD8818, NIDDK59820, P41GM103832 and R01GM079429); CNIHR, R21AI122418 and R01GMGM072804; CPRIT grants (RP150648 and DP150052); and a National Cancer Institute Cancer Center Support grant (P30CA125123) to the BCM Monoclonal Antibody/recombinant Protein Expression Core Facility.

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Research reveals how estrogen regulates gene expression - Baylor College of Medicine News (press release)

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)

In 2007, DNA pioneer James Watson became the first person to have his entire genome sequencedmaking all of his 6 billion base pairs publicly available for research. Well, almost all of them. He left one spot blank, on the long arm of chromosome 19, where a gene called APOE lives. Certain variations in APOE increase your chances of developing Alzheimers, and Watson wanted to keep that information private.

Except it wasnt. Researchers quickly pointed out you could predict Watsons APOE variant based on signatures in the surrounding DNA. They didnt actually do it, but database managers wasted no time in redacting another two million base pairs surrounding the APOE gene.

This is the dilemma at the heart of precision medicine: It requires people to give up some of their privacy in service of the greater scientific good. To completely eliminate the risk of outing an individual based on their DNA records, youd have to strip it of the same identifying details that make it scientifically useful. But now, computer scientists and mathematicians are working toward an alternative solution. Instead of stripping genomic data, theyre encrypting it.

Gill Bejerano leads a developmental biology lab at Stanford that investigates the genetic roots of human disease. In 2013, when he realized he needed more genomic data, his lab joined Stanford Hospitals Pediatrics Departmentan arduous process that required extensive vetting and training of all his staff and equipment. This is how most institutions solve the privacy perils of data sharing. They limit who can access all the genomes in their possession to a trusted few, and only share obfuscated summary statistics more widely.

So when Bejerano found himself sitting in on a faculty talk given by Dan Boneh, head of the applied cryptography group at Stanford, he was struck with an idea. He scribbled down a mathematical formula for one of the genetic computations he uses often in his work. Afterward, he approached Boneh and showed it to him. Could you compute these outputs without knowing the inputs? he asked. Sure, said Boneh.

Last week, Bejerano and Boneh published a paper in Science that did just that. Using a cryptographic genome cloaking method, the scientists were able to do things like identify responsible mutations in groups of patients with rare diseases and compare groups of patients at two medical centers to find shared mutations associated with shared symptoms, all while keeping 97 percent of each participants unique genetic information completely hidden. They accomplished this by converting variations in each genome into a linear series of values. That allowed them to conduct any analyses they needed while only revealing genes relevant to that particular investigation.

Just like programs have bugs, people have bugs, says Bejerano. Finding disease-causing genetic traits is a lot like spotting flaws in computer code. You have to compare code that works to code that doesnt. But genetic data is much more sensitive, and people (rightly) worry that it might be used against them by insurers, or even stolen by hackers. If a patient held the cryptographic key to their data, they could get a valuable medical diagnosis while not exposing the rest of their genome to outside threats. You can make rules about not discriminating on the basis of genetics, or you can provide technology where you cant discriminate against people even if you wanted to, says Bejerano. Thats a much stronger statement.

The National Institutes of Health have been working toward such a technology since reidentification researchers first began connecting the dots in anonymous genomics data. In 2010, the agency founded a national center for Integrating Data for Analysis, Anonymization and Sharing housed on the campus of UC San Diego. And since 2015, iDash has been funding annual competitions to develop privacy-preserving genomics protocols. Another promising approach iDash has supported is something called fully homomorphic encryption, which allows users to run any computation they want on totally encrypted data without losing years of computing time.

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Kristen Lauter, head of cryptography research at Microsoft, focuses on this form of encryption, and her team has taken home the iDash prize two years running. Critically, the method encodes the data in such a way that scientists dont lose the flexibility to perform medically useful genetic tests. Unlike previous encryption schemes, Lauters tool preserves the underlying mathematical structure of the data. That allows computers to do the math that delivers genetic diagnoses, for example, on totally encrypted data. Scientists get a key to decode the final results, but they never see the source.

This is extra important as more and more genetic data moves off local servers and into the cloud. The NIH lets users download human genomic data from its repositories, and in 2014, the agency started letting people store and analyze that data in private or commercial cloud environments. But under NIHs policy, its the scientists using the datanot the cloud service providerresponsible with ensuring its security. Cloud providers can get hacked, or subpoenaed by law enforcement, something researchers have no control over. That is, unless theres a viable encryption for data stored in the cloud.

If we dont think about it now, in five to 10 years a lot peoples genomic information will be used in ways they did not intend, says Lauter. But encryption is a funny technology to work with, she says. One that requires building trust between researchers and consumers. You can propose any crazy encryption you want and say its secure. Why should anyone believe you?

Thats where federal review comes in. In July, Lauters group, along with researchers from IBM and academic institutions around the world launched a process to standardize homomorphic encryption protocols. The National Institute for Standards and Technology will now begin reviewing draft standards and collecting public comments. If all goes well, genomics researchers and privacy advocates might finally have something they can agree on.

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To Protect Genetic Privacy, Encrypt Your DNA - WIRED

In this photo provided by Oregon Health & Science University, taken through a microscope, human embryos grow in a laboratory for a few days after researchers used gene editing technology to successfully repair a heart disease-causing genetic mutation. The work, a scientific first led by researchers at Oregon Health & Science University, marks a step toward one day preventing babies from inheriting diseases that run in the family. ( Oregon Health & Science University via AP)

By Johnny Kung

Mon., Aug. 21, 2017

Recently, an international team of scientists successfully corrected a disease-causing gene in human embryos, using a gene editing technique called CRISPR. This has led to much excitement about the prospects of curing debilitating diseases in entire family lineages.

At the same time, the possibility of changing embryos genes has renewed fear about designer babies. The hype in both directions should be tempered by the fact that both these scenarios are some ways off a lot more work will need to be done to improve the techniques safety and efficacy before it can be applied in the clinic.

And because a lot of diseases, as well as other physical and behavioural characteristics, are controlled by the complex interaction of many genes with each other and with the environment, in many cases simple genetic fixes may never be possible.

But while the technology is still in early stages, now is the time to have frank, open and societywide conversations about how gene editing should be moving forward and genetic medicine more broadly, including the use of advanced genetic testing and sequencing to diagnose disease, personalize medical treatments, screening babies, etc.

We must raise broad awareness of the health benefits as well as the personal, social and ethical implications of genetics. This is important for individuals both to understand their options when making decisions about their own health care, and to participate as informed citizens in democratic deliberations about whether and how genetic technologies should be developed and applied.

In the U.S., affordability and insurance coverage strongly influence access to genetic medicine. In Canada, the reality of strapped budgets means access is far from equal either. But our public health-care system means it is at least conceivable that these technologies will eventually be available to a higher proportion of people who need them.

For example, OHIP currently pays for genetic testing and counselling for a number of diseases, such as http://www.mountsinai.on.ca/care/mkbc/medical-services/genetic-testingBRCA testingEND for breast and ovarian cancer, for patients who satisfy certain eligibility criteria. It also covers a kind of genetic screening tests called non-invasive prenatal testing (NIPT) for eligible pregnant women. Precisely because of this potential for widespread adoption, there is all the greater need for broad-based conversations about genetics.

Crucially, to ensure that the largest possible cross section of society will benefit from, and not be harmed by, advances in genetic technologies, these conversations must include the voices of all communities.

This is especially true for those who, for well-justified historical reasons, may harbour deep distrust of the biomedical establishment. In the U.S., for much of the 20th century, the eugenics movement had resulted in a range of sterilization programs, discriminatory policies and scientific abuses (such as the infamous Tuskegee syphilis trials) that disproportionately targeted the poor and, especially, racial minorities such as African Americans.

While the eugenics movement might have been less established in Canada, where it did occur (e.g., the sterilization program in Alberta or the Indian hospitals in B.C.) it had most heavily affected Indigenous communities. In both countries, this shameful history has led to lower trust and usage of the health-care system by the affected communities.

As genetic medicine advances, many scientists and health researchers are pointing out the importance of having the diversity of human populations represented in genetic studies in order to gain medical insights that can benefit everyone. If we fail to fully engage these under-represented communities and ensure that genetics is not just another way to exploit and discriminate against them, then we risk worsening this historical and ongoing injustice.

New genetic technologies, such as gene editing, also bring issues of disability rights into sharper focus. While designer babies may not be an immediate concern, even the possibility of selecting and changing our offsprings characteristics raises thorny questions.

For example, what conditions count as medically necessarily to treat how about deafness, dwarfism, autism, or intersex conditions? Ultimately, it is about what kinds of people get to live, and who gets to make those decisions. Many disability rights advocates (e.g., the Down syndrome community) are already voicing concerns about what these emerging technologies mean for how their communities are seen and valued today.

We must make sure that the conversations around genetics are not only about generalized notions of safety or effectiveness, or concerns of playing God. These conversations must also encompass questions of access and justice, and acknowledge that the benefits and harms of genetic technologies, like any new technologies, are not distributed equally.

And these conversations must involve all communities (be they of different racial or ethnic background, gender or sexuality, and physical or cognitive abilities) in a way that ensures their voices are respected and heard.

This is a task that will involve concerted efforts from scientists, funders and industry, to build trust with these communities and to genuinely listen and respond to their concerns. And it will need to be done in collaboration with many partners, including schools, community and faith groups, and the art/entertainment industry.

The ability to understand and, perhaps one day, change our genetics has huge potential to improve human well-being. Lets make sure that everyone will enjoy these benefits, and that no communities are left behind, or worse yet, harmed in the process.

Johnny Kung is the director of new initiatives for the Personal Genetics Education Project (www.pged.org ) at Harvard Medical Schools Department of Genetics.

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Designer babies the not most urgent concern of genetic medicine - Toronto Star

In 2013, University of Virginia researcher Michael McConnell published research that would forever change how scientists study brain cells.

McConnell and a team of nationwide collaborators discovered a genetic mosaic in the brains neurons, proving that brain cells are not exact replicas of each other, and that each individual neuron contains a slightly different genetic makeup.

McConnell, an assistant professor in the School of Medicines Department of Biochemistry and Molecular Genetics, has been using this new information to investigate how variations in individual neurons impact neuropsychiatric disorders like schizophrenia and epilepsy. With a recent $50,000 grant from the Bow Foundation, McConnell will expand his research to explore the cause of a rare genetic disorder known as GNAO1 so named for the faulty protein-coding gene that is its likely source.

GNAO1 causes seizures, movement disorders and developmental delays. Currently, only 50 people worldwide are known to have the disease. The Bow Foundation seeks to increase awareness so that other probable victims of the disorder can be properly diagnosed and to raise funds for further research and treatment.

UVA Today recently sat down with McConnell to find out more about how GNAO1 fits into his broader research and what his continued work means for all neuropsychiatric disorders.

Q. Can you explain the general goals of your lab?

A. My lab has two general directions. One is brain somatic mosaicism, which is a finding that different neurons in the brain have different genomes from one another. We usually think every cell in a single persons body has the same blueprint for how they develop and what they become. It turns out that blueprint changes a little bit in the neurons from neuron to neuron. So you have slightly different versions of the same blueprint and we want to know what that means.

The second area of our work focuses on a new technology called induced pluripotent stem cells, or iPSCs. The technology permits us to make stem cell from skin cells. We can do this with patients, and use the stem cells to make specific cell types with same genetic mutations that are in the patients. That lets us create and study the persons brain cells in a dish. So now, if that person has a neurological disease, we can in a dish study that persons disease and identify drugs that alter the disease. Its a very personalized medicine approach to that disease.

Q. Does cell-level genomic variety exist in other areas of the body outside the central nervous system?

A. Every cell in your body has mutations of one kind or another, but brain cells are there for your whole life, so the differences have a bigger impact there. A skin cell is gone in a month. An intestinal cell is gone in a week. Any changes in those cells will rarely have an opportunity to cause a problem unless they cause a tumor.

Q. How does your research intersect with the goals of the Bow Foundation?

A. Let me back up to a little bit of history on that. When I got to UVA four years ago, I started talking quite a lot with Howard Goodkin and Mark Beenhakker. Mark is an assistant professor in pharmacology. Howard is a pediatric neurologist and works with children with epilepsy. I had this interest in epilepsy and UVA has a historic and current strength in epilepsy research.

We started talking about how to use iPSCs the technology that we use to study mosaicism to help Howards patients. As we talked about it and I learned more about epilepsy, we quickly realized that there are a substantial number of patients with epilepsy or seizure disorders where we cant do a genetic test to figure out what drug to use on those patients.

Clinical guidance, like Howards expertise, allows him to make a pretty good diagnosis and know what drugs to try first and second and third. But around 30 percent of children that come in with epilepsy never find the drug that works, and theyre in for a lifetime of trial-and-error. We realized that we could use iPSC-derived neurons to test drugs in the dish instead of going through all of the trial-and-error with patients. Thats the bigger project that weve been moving toward.

The Bow Foundation was formed by patient advocates after this rare genetic mutation in GNAO1 was identified. GNAO1 is a subunit of a G protein-coupled receptor; some mutations in this receptor can lead to epilepsy while others lead to movement disorders.

Were still trying to learn about these patients, and the biggest thing the Bow Foundation is doing is trying to address that by creating a patient registry. At the same time, the foundation has provided funds for us to start making and testing iPSCs and launch this approach to personalized medicine for epilepsy.

In the GNAO1 patients, we expect to be able to study their neurons in a dish and understand why they behave differently, why the electrical activity in their brain is different or why they develop differently.

Q. What other more widespread disorders, in addition to schizophrenia and epilepsy, are likely to benefit from your research?

A. Im part of a broader project called the Brain Somatic Mosaicism Network that is conducting research on diseases that span the neuropsychiatric field. Our lab covers schizophrenia, but other nodes within that network are researching autism, bipolar disorder, Tourette syndrome and other psychiatric diseases where the genetic cause is difficult to identify. Thats the underlying theme.

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Researcher Seeks to Unravel the Brain's Genetic Tapestry to Tackle Rare Disorder - University of Virginia

August 22, 2017 A depiction of the double helical structure of DNA. Its four coding units (A, T, C, G) are color-coded in pink, orange, purple and yellow. Credit: NHGRI

A group of researchers from the National University of Singapore has found that CD38 and CD157 genes that regulate oxytocin, the supreme human social hormone, are associated with the sociality of young individuals. They found that young adults who have higher expression of the CD38 gene as well as differences in CD157 gene sequence are friendlier and more socially adept than others. They have more close friends and show greater social skills

Researchers found that CD38 and CD157 genes that regulate oxytocin, the supreme human social hormone, are associated with the sociality of young individuals

Why some individuals seek social engagement and friendship while others shy away may well be dependent on the expression and sequence of two genes in their bodies.

This novel study of gene expression (i.e. how much of a particular gene is produced in the body) supports the increasing importance of the oxytocin network and its impact on shaping social and communication skills that are important for building friendships. The findings were published in the scientific journal Psychoneuroendocrinology.

The study was conducted by Professor Richard Ebstein and recent NUS PhD graduate, Dr Anne Chong, from the Department of Psychology at NUS Faculty of Arts and Social Sciences, along with Professor Chew Soo Hong from the Faculty's Department of Economics and Professor Lai Poh San from the Department of Paediatrics at NUS Yong Loo Lin School of Medicine.

The team studied over 1,300 healthy young Chinese adults in Singapore in a non-clinical setting. They investigated the correlation between the expression of the CD38 gene and CD157 gene sequence, both of which have been implicated in autism studies, and an individual's social skills as captured by three different questionnaires. These questionnaires evaluated the participants' overall ability to engage in social relationships; their value on the importance of and interest in friendships as well as the number of close friends/confidants they have.

Link between CD38 and CD157 genes, oxytocin and social skills

"We believe that studying the expression of genes captures more information than simple structural studies of DNA sequence since it is the expression of genes that ultimately determine how a gene impacts our traits. Oxytocin plays an important role in these behaviours so it made good sense to our team to study the oxytocin network in relation to social skills important for friendships," said Prof Ebstein.

The results from the study showed that participants with higher expression of CD38 have more close friends, and this association was observed more prevalently among the male participants.

"Male participants with the higher gene expressions displayed greater sociality such as preferring activities involving other people over being alone, better communication and empathy-related skills compared to the other participants. Meanwhile, participants with lower CD38 expression reported less social skills such as difficulty in "reading between the lines" or engaging less in social chitchat, and tend to have fewer friends," said Dr Chong who is the first author of the study and worked under the supervision of Prof Ebstein.

Interestingly, the researchers found that a variation in the CD157 gene sequence that was more common in autism cases in a Japanese study, was also associated with the participants' innate interest in socialising and building relationships.

The evidence suggests that oxytocin, and the CD38 and CD157 genes that govern its release, contribute to individual differences in social skills from one extreme of intense social involvement (i.e. many good friendships and good relationships with peers) to the other extreme of avoiding social contacts with other people that is one of the characteristics of autism. There is no cause for worry however, as the researchers note that majority of people are in between the two extremes.

The researchers found that higher expression of the CD38 gene and differences in the CD157 gene sequence account for 14 per cent of the variance in social skills in the general population a remarkable finding, especially since typically less than two per cent of findings in behavioural genetic association studies rely on genetic variations alone.

"Moreover, while expressed genes can influence behaviours, our own experiences can influence the expression of genes in return. So, whether the genes are expressed to impact our behaviours or not, depend a lot on our social environments. For most people, being in healthy social environments such as having loving and supportive families, friends and colleagues would most likely lessen the effects from disadvantageous genes," said Dr Chong.

The findings from the study help deepen the understanding of the relationship between human sociability and oxytocin. By releasing the social hormone, the CD38 and CD157 genes not only regulate social life at a cellular level but also contribute to the development of human social skills important in establishing social bonds and friendship.

"In our study, we see that an individual's genetic makeup could only go so far as predicting one's social predisposition but does not necessarily trigger the trait since, in the end, it is the expression of gene that determines so. This knowledge would be helpful in coming up with future intervention therapies or targeted treatments to achieve desirable outcomes for individuals with special needs," said Prof Ebstein.

For instance, while there is already considerable research interest in using oxytocin therapy to improve the social skills of individuals with autism, the results so far have been mixed. The findings in this study point to an alternative research direction towards treatments based on new drugs that may mimic or enhance the functions of the CD38 and CD157 genes. The researchers noted however that this line of research has yet to be explored. If proven viable, future therapies may help those clinically determined to have extreme difficulty maintaining social and working relationships with others so that they too could live a better quality of life.

Next steps in research

Co-led by Prof Ebstein and Prof Chew, the Behavioural and Biological Economics and the Social Sciences (B2ESS) Group at the NUS Faculty of Arts and Social Sciences has been investigating the role of genes and hormones on human behaviours, decision making, and a variety of human attitudes including empathy, impulsivity, political attitudes, religiosity and risk attitudes.

The group is currently embarking on several behavioural economics and molecular genetics studies to investigate the impact of oxytocin on the human traits of creativity and openness to exposure, among others.

Explore further: Combination approach may boost social interactions in autism

More information: Anne Chong et al. ADP ribosyl-cyclases ( CD38 / CD157 ), social skills and friendship, Psychoneuroendocrinology (2017). DOI: 10.1016/j.psyneuen.2017.01.011

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Study finds that you may be as friendly as your genes - Medical Xpress

August 22, 2017 Dr. Alexandre R. Colas is an assistant professor at SBP. Credit: James Short

Researchers from Sanford Burnham Prebys Medical Discovery Institute (SBP), the Cardiovascular Institute at Stanford University and other institutions were surprised to discover that the four genes in the Id family play a crucial role in heart development, telling undifferentiated stem cells to form heart tubes and eventually muscle. While Id genes have long been known for their activity in neurons and blood cells, this is the first time they've been linked to heart development. These findings give scientists a new tool to create large numbers of cardiac cells to regenerate damaged heart tissue. The study was published in the journal Genes & Development.

"It has always been unclear what intra-cellular mechanism initiates cardiac cell fate from undifferentiated cells," says Alexandre Colas, Ph.D., assistant professor in the Development, Aging and Regeneration Program at SBP and corresponding author on the paper. "These genes are the earliest determinants of cardiac cell fate. This enables us to generate unlimited amounts of bona fide cardiac progenitors for regenerative purposes, disease modeling and drug discovery."

The international team, which included researchers from the International Centre for Genetic Engineering and Biotechnology in Italy, University Pierre and Marie Curie in France and the University of Coimbra in Portugal, combined CRISPR-Cas9 gene editing, high-throughput microRNA screening and other techniques to identify the role Id genes play in heart development.

In particular, CRISPR played a crucial role, allowing them to knock out all four Id genes. Previous studies had knocked out some of these genes, which led to damaged hearts. However, removing all four genes created mouse embryos with no hearts at all. This discovery comes after a decades-long effort to identify the genes responsible for heart development.

"This is a completely unanticipated pathway in making the heart," says co-author Mark Mercola, Ph.D., professor of Medicine at Stanford and adjunct professor at SBP. "People have been working for a hundred years to figure out how the heart is specified during development. Nobody in all that time had ever implicated the Id protein."

Further study showed Id genes enable heart formation by turning down the Tcf3 and Foxa2 proteins, which inhibit the process, and turning up Evx1, Grrp1 and Mesp1, which support the process.

In addition to contributing a new chapter in the understanding of heart development, this study illuminates a powerful technique to screen for protein function in complex phenotypical assays, which was previously co-developed by Colas and Mercola. This technology could have wide-spread impact throughout biology.

"On a technical level, this project succeeded because it combined high-throughput approaches with stem cells to functionally scan the entire proteome for individual proteins involved in making heart tissue," says Mercola. "It shows that we can effectively walk through the genome to find genes that control complex biology, like making heart cells or causing disease."

Understanding this pathway could ultimately jumpstart efforts to use stem cells to generate heart muscle and replace damaged tissue. In addition, because Id proteins are the earliest known mechanism to control cardiac cell fate, this work is an important milestone in understanding cardiovascular developmental biology.

"We've been influenced by the skeletal muscle development field, which found the regulator of myogenic lineage, or myoD," says Colas. "For decades, we have been trying to find the cardiac equivalent. The fact that Id genes are sufficient to direct stem cells to differentiate towards the cardiac lineage, and that you don't have a heart when you ablate them from the genome, suggests the Id family collectively is a candidate for cardioD."

Explore further: Discovery of a key regulatory gene in cardiac valve formation

More information: Thomas J. Cunningham et al, Id genes are essential for early heart formation, Genes & Development (2017). DOI: 10.1101/gad.300400.117

Scientists at the Gladstone Institutes identified two chemicals that improve their ability to transform scar tissue in a heart into healthy, beating heart muscle. The new discovery advances efforts to find new and effective ...

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Id genes play surprise role in cardiac development - Medical Xpress