Monthly Archives: August 2017

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