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Big data, Events, Genetics, Stanford News, Videos

Using genetics to answer fundamental questions in biology, medicine and anthropology

Using genetics to answer fundamental questions in biology, medicine and anthropology

At last year’s Big Data in Biomedicine conference, Stanford geneticist Carlos Bustamante, PhD, spoke about the potential of using genetic information to answer fundamental questions in biology, medicine and anthropology. In this video from the 2014 event, Bustamante explains his lab’s efforts to better understand the structure of human genome, how genetic variations are portioned among different human populations and the significance of this information for designing medical genetic studies.

Bustamante will return to the Big Data in Biomedicine conference in May to moderate the genomics session. Speakers for the session are Christina Curtis, PhD, assistant professor of medicine and genetics at Stanford; Yaniv Erlich, PhD, assistant professor of computer science at Columbia University and a core member at the New York Genome Center; David Glazer, director of Engineering at Google and founder of the Google Genomics team; and Heidi Rehm, PhD, director of the Partners Laboratory for Molecular Medicine and associate professor of pathology at Harvard Medical School.

The conference will be held May 20-22 at the Li Ka Shing Center for Learning and Knowledge at Stanford; registration details can be found on the event website.

Previously: Big data used to help identify patients at risk of deadly high-cholesterol disorder, Examining the potential of big data to transform health care and Registration for Big Data in Biomedicine conference now open

Events, Genetics, Patient Care, Pediatrics, Research, Stanford News, Stem Cells

“It’s not just science fiction anymore”: Childx speakers talk stem cell and gene therapy

“It’s not just science fiction anymore": Childx speakers talk stem cell and gene therapy

childx PorteusAt the Childx conference last week there was a great deal of optimism that stem cell and genetic therapies are about to have a huge impact on many childhood diseases. “It’s not just science fiction anymore,” Matthew Porteus, MD, PhD, told the audience. “We can correct mutations that cause childhood disease.”

The session was hosted by Stanford professor Maria Grazia Roncarolo, MD, who until recently was head of the Italy’s Telethon Institute for Cell and Gene Therapy at the San Raffaele Scientific Institute in Milan. Roncarolo pointed out that there are more than 10,000 human diseases that are caused by a single gene defect. “Stem cell and gene therapies can be used to treat cancer and other diseases,” Roncarolo said.

Two such diseases are sickle cell disease and severe combined immune deficiency. In both cases, a single nucleotide change in DNA becomes a deadly defect for children with the bad luck to have them. Porteus is working on very new genome editing technologies that allow clinicians to go in and fix those DNA typos and cure diseases.

Stanford dermatology researcher Anthony Oro, MD, PhD is working to do something similar with skin cells for a painful blistering disease called epidermolysis bullosa. Children with EB lack a functional gene for one of the proteins that anchors the layers of skin together. Oro and Stanford Institute for Stem Cell Biology and Regenerative Medicine scientist Marius Wernig, MD, PhD, are taking defective skin cells from patients, transforming them into embryonic-like stem cells, fixing the gene defect, and then growing them back into skin stem cells and then layers of skin ready for transplantation. Oro says that they have shown that they can do this in a scalable way in mice, and they hope to start a clinical trial in humans soon.

One of the challenges to genetic therapy is that it often requires putting the gene into blood stem cells to deliver it to the body, but the high dose chemotherapy or radiation that is necessary to remove the bodies own blood stem cells and make way for the transplanted cells is very dangerous in itself. Researchers like Stanford researcher Hiromitsu Nakuchi, MD, PhD, are exploring gentler ways to make space in the body for the transplanted cells. He has discovered that simply by feeding mice a diet deficient in a particular amino acid, blood stem cells begin to die. Other cells in the body don’t seem to be as strongly affected. A dietary solution may eventually allow clinicians to avoid using the highly toxic treatments that have traditionally been used for blood stem cell transplant.

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Ebola, Events, Genetics, Global Health, Patient Care, Pediatrics, Stanford News

Global health and precision medicine: Highlights from day two of Stanford’s Childx conference

Global health and precision medicine: Highlights from day two of Stanford's Childx conference

Childx Shah“I do think it’s possible to end preventable child death.” Those were the powerful words spoken by Rajiv Shah, MD, the former administrator of USAID, during his keynote address at the start of the second day of Stanford’s recent Childx conference. More than 6 million children die each year before age 5, mostly of easily preventible diseases, Shah told the audience.

Shah went on to describe some of the more daunting health and humanitarian crises he faced during his 5-year tenure at the helm of United States Agency for International Development, including the recent Ebola outbreak in West Africa, and the Somali famine that he helped to address with the U.S. government’s Feed the Future program. Speaking about visiting a severely overcrowded Somali refugee camp, he said, “If you looked closely, you saw signs of hope and innovation.” For instance, children were receiving the pentavalent vaccine that protects against five serious childhood diseases and that was, until quite recently, considered too expensive to distribute in this type of setting.

Shah also described how a rapid redesign of protective gear for health-care workers fighting Ebola was essential to helping get the highly contagious illness under control: The old gear was much too hot and cumbersome, as well as being difficult to remove safely, and may have been a factor in the high rates of infection among health care workers early in the Ebola outbreak. Several partners, including NASA, the Department of Defense, Kimberly-Clark and Motorola, worked together to make new protective equipment that was easier to use and better suited to intense heat.

Our capacity to innovate is essential for solving global health problems, Shah concluded. “…Saving children’s lives in resource-poor settings is not just… great and morally important,” he said. “It actually creates more stability in communities.” Families have fewer children and invest more in the education of those kids, including the girls, and the surrounding society begins to look more stable and prosperous, he said. Innovation and technology in the arena of child health are important “not just for health purposes but for shaping the kind of world that keeps us safe, secure and prosperous over many decades.”

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Chronic Disease, Clinical Trials, Genetics, Patient Care, Pediatrics, Stanford News

Cystic fibrosis patient on her 20+ years of care

Cystic fibrosis patient on her 20+ years of care

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When Lauren Catron was first diagnosed with a severe form cystic fibrosis, an inherited disease that makes mucous and sweat glands go haywire, her doctors were unsure that she’d live to be a teenager. That was nearly 23 years ago. Now, 26-year-old Catron is a full-time college student at Mission College in Santa Clara, Calif. with enough energy to work a job in her spare time.

Catron credits her sustained health to the more than two decades of care she’s received at the Pulmonary and Cystic Fibrosis Center at Lucile Packard Children’s Hospital. Catron shares her story on the Happier, Healthier Lives Blog:

“When I was first diagnosed in 1992, the doctors told my parents that I may not make it to my teens,” said Catron, who has the genotype associated with a shorter lifespan and the most severe symptoms of cystic fibrosis, including a constant buildup of mucus in her lungs that interferes with breathing. “But a whole team of people at Stanford has dedicated themselves to keeping me healthy. They have given me absolute unconditional support, amazing treatment and care, and have become my second family.”

Carol Conrad, MD, director of the pediatric pulmonary function lab, explains that the center’s expert care stems from the many clinical trials and studies they do to advance the treatment of cystic fibrosis. “No other CF center in California is doing these kinds of clinical trials,” Conrad said.

This research, which ranges from dietary-supplement studies by Conrad to gene therapy work done by Richard Moss, MD, shows promise. Moss and his colleagues were the first to discover that gene therapy could improve pulmonary function in cystic fibrosis patients – an important finding that may lead to a treatment for the disease in the future. “As depressing as the disease can be, there’s a lot of hope. That’s what keeps us motivated,” said Conrad.

Previously: New Stanford-developed sweat test may aid in development of cystic fibrosis treatmentsFilm about twin sisters’ double lung transplants and battle against cystic fibrosis available onlineDiverse microbes discovered in healthy lungs shed new light on cystic fibrosis and Living – and thriving – with cystic fibrosis
Photo of Conrad (left) and Catron courtesy of Lucile Packard Children’s Hospital

Genetics, Research, Science, Stanford News

When X+X = X: Stanford scientists shed light on X-inactivation

When X+X = X: Stanford scientists shed light on X-inactivation

2189014070_339cb830f9_z-1With apologies to some of my colleagues (cough, Margarita Gallardo, cough), I’ve never really enjoyed the Garfield comic strip. The rotund cartoon cat and his insatiable lasagna cravings has always seemed odd to me. Plus, most orange and black cats are female, due to a curious biological phenomenon called X inactivation.

The inactivation of one X chromosome in female animals (and humans) is necessary to ensure that both sexes end up with roughly the same dosage of X-chromosome associated genes. In most species, the chromosome to be inactivated is selected randomly in each cell early in development, and the selected chromosome remains inactive in all of the cell’s subsequent progeny. Researchers believe that X inactivation might explain at least in part why some diseases are more prevalent or severe in one gender than the other.

Now dermatologist Howard Chang, MD, PhD, and former graduate student Ci Chu, PhD, have shed some light on the process, which occurs through the action of a regulatory RNA molecule called Xist. Their research was published today in Cell.

From our release:

[The researchers] have outlined the molecular steps of inactivation, showing that it occurs in an orderly and directed fashion as early embryonic cells begin to differentiate into more specialized tissues. They’ve identified more than 80 proteins in mouse cells that bind to Xist to help it do its job. They hope their findings will shed light on conditions in humans that are typically more severe in one gender than the other.

“We see some very interesting phenomena with X-linked diseases in humans,” said [Chang]. “Often, when the faulty gene is on the X chromosome, the condition is more severe in boys. This happens in hemophilia, for example. In contrast, women are far more likely than men to suffer from autoimmune diseases, for reasons we don’t yet understand. This research opens the door to possibly understanding the biological basis for these differences.”

The researchers were able to pinpoint the protein partners of Xist only after Chu developed an entirely new technique. More from our release:

Chu’s technique, which the researchers call CHIRP-MS for “comprehensive identification of RNA-binding proteins by mass spectrometry,” allowed the researchers to identify the sequential interaction of over 80 proteins with Xist during X inactivation. Many of these proteins have never before been associated with that process. It’s thought that they may help target and anchor Xist to active genes along the length of the X chromosome like burrs on a shoelace after a hike in the woods.

“If you lay all the copies of Xist in a cell end to end, they are not long enough to coat the entire X chromosome,” said Chang. “Instead, Xist spreads judiciously, finding active genes and shutting them down. It also must stay anchored to the chromosome and not float over to any other chromosomes in the nucleus. This requires an elaborate set of machinery that we believe acts in a sequential fashion.”

Specifically, the researchers suspect that some proteins help Xist locate and silence active genes, while others work to maintain that silencing once it has been established.

Clearly X inactivation is a complex process. But are you still wondering about Garfield? Because the genes for “orange” or “black” fur occur on the X chromosome, female cats that carry one of each version can be a patchwork of the two colors, depending on which chromosome is inactivated. Blobs of orange fur indicate an ancestor cell in which the chromosome with the black fur gene was inactivated, and vice versa. But a male cat, with only one X chromosome can only be orange or black, but not both.

An exception would be a male cat who had inherited two X chromosomes and one Y (in humans, this is called Klinefelter syndrome). This genetic anomaly, which is found in about one of every 3,000 calico cats, would likely have other oddities, however. Perhaps even a craving for pasta, cheese and tomato sauce?

Previously: Tomayto, tomahto: Separate genes exert control over differential male and female behaviors, Does it matter which parent your “brain genes” came from? and Stanford professor encourages researchers to take gender into account
Photo by Jerry Knight

Biomed Bites, Cancer, Genetics, Research, Science, Videos

From finches to cancer: A Stanford researcher explores the role of evolution in disease

From finches to cancer: A Stanford researcher explores the role of evolution in disease

Welcome to Biomed Bites, a feature that appears each Thursday and introduces readers to some of Stanford’s most innovative researchers.

My parents just returned from the trip of a lifetime to the Galapagos. I would have loved to go along — I really dig tortoises, which abound on the islands; my parents even saw a pair mating! And, ever since I took an introductory class on evolution as an undergrad, I’ve longed to visit the spot that was central in Darwin’s postulation of the theory of evolution and natural selection.

No famous finches for me though — I just toiled away behind my computer in northern California. But that doesn’t mean evolution is only happening in another hemisphere. Far from it: Just down the street in the lab of Gavin Sherlock, PhD, experiments are ongoing to elucidate evolution’s fundamental processes.

Sherlock shares his views role of evolution in disease in the video above:

The evolutionary process underlies many disease mechanisms. One such example is cancer, which recapitulates the evolutionary process as mutation occur and then get selected within the tumor. In addition, treatments with chemotherapy may select particular mutations within the tumor itself.

Resistance to antibiotics is also driven by evolution, Sherlock points out. With a deeper understanding, researchers will be better able to combat cancer and craft more effective antibiotics — no international travel required.

Learn more about Stanford Medicine’s Biomedical Innovation Initiative and about other faculty leaders who are driving biomedical innovation here.

Previously: Bubble, bubble, toil and trouble — yeast dynasties give up their secrets, Get sloshed, have sex? Wine-making has promoted a frenzy of indiscriminate mating in baker’s yeast, according to Stanford researchers and Computing our evolution

Aging, Genetics, Research, Science, Stanford News

“Are we there yet?” Exploring the promise, and the hype, of longevity research

"Are we there yet?" Exploring the promise, and the hype, of longevity research

Brunet photoThe days are getting longer, and it’s no longer dark outside when I drop my teenager at school for her early-bird class. I appreciate the light, of course, and there’s something soothing about the rhythmic change of seasons.

If only we could extend our lifespan in a similar gentle, reliable manner.

The idea of living longer, and healthier, is the theme of my story for the new issue of Stanford Medicine magazine. It’s my favorite kind of article – a dash of juicy science history, a panoply of dedicated scientists and a brand-new animal model (and my newest crush) that may open all kinds of research doors. Best of all, there’s a sense of real progress in the field. From my article:

“Ways of prolonging human life span are now within the realm of possibility,” says professor of genetics and newbie fish keeper Anne Brunet, PhD. Brunet, who is an associate director of Stanford’s Paul F. Glenn Center for the Biology of Aging, focuses her research on genes that control the aging process in animals such as the minnowlike African killifish I’d watched fiercely guarding his territory.

The killifish is especially important to researchers like Brunet because it has an extremely variable, albeit short, life span. One strain from eastern Zimbabwe completes its entire life cycle — birth, maturity, reproduction and death — within about three to four months. Another strain can live up to nine months.

It’s also a vertebrate, meaning it belongs to the same branch of the evolutionary tree as humans. This gives it a backbone up over more squishy models of aging like fruit flies or roundworms — translucent, 1-millimeter-long earth dwellers you could probably find in your compost pile if you felt like digging.

I hope you’ll read the rest of my piece to learn more.

Previously: My funny Valentine – or, how a tiny fish will change the world of aging research, Stanford Medicine magazine reports on time’s intersection with health and Living loooooooonger: A conversation on longevity
Photo of Anne Brunet by Gregg Segal

Cancer, Genetics, In the News, Women's Health

Angelina Jolie Pitt’s New York Times essay praised by Stanford cancer expert

Angelina Jolie Pitt's New York Times essay praised by Stanford cancer expert

4294641229_c78b406658_zYou’ve likely heard today about Angelina Jolie Pitt’s New York Times essay regarding her decision to have her ovaries and fallopian tubes removed. Women who carry mutations in the BRCA1 or BRCA2 genes have a significantly increased risk for breast and ovarian cancer; Jolie carries such a mutation, and in 2013 she shared publicly her decision to have her breasts removed to reduce her risk of cancer.

Jolie Pitt shares her decision-making process and notes that though she won’t be able to have any more children and though she still remains prone to cancer, she feels “at ease with whatever will come.” She closes her latest essay by writing, “It is not easy to make these decisions. But it is possible to take control and tackle head-on any health issue. You can seek advice, learn about the options and make choices that are right for you.”

After reading the piece I reached out to Stanford cancer geneticist Allison Kurian, MD, who told me:

Angelina Jolie made a very courageous decision to share her experience publicly.  The surgery she chose is strongly recommended for all women with BRCA1/2 mutations by age 40, since it’s the only way to prevent an ovarian cancer in these high-risk women, and early detection doesn’t work. This is a life-saving intervention for high-risk women.

Kurian is associate director of the Stanford Program in Clinical Cancer Genetics and a member of the Stanford Cancer Institute. In 2012 she published on online tool to help women with BRCA mutations understand their treatment options.

Previously: Helping inform tough cancer-related decisions, NIH Director highlights Stanford research on breast cancer surgery choices and Breast cancer patients are getting more bilateral mastectomies – but not any survival benefit
Photo by Marco Musso

Cardiovascular Medicine, Chronic Disease, Genetics, Public Health, Research

International team led by Stanford researchers identifies gene linked to insulin resistance

International team led by Stanford researchers identifies gene linked to insulin resistance

261445720_2f253a1336_zBack in the 1970s and 1980s, Stanford’s Gerald Reaven, MD, had the darndest time convincing others that type 2 diabetes wasn’t caused by a lack of insulin. No one would believe him that, as we now know, type 2 diabetics are insulin resistant — their cells no longer respond to insulin’s cue to take in glucose.

Fast-forward a few years. Insulin resistance has been implicated in a slew of symptoms such as high blood pressure and heart troubles known as metabolic syndrome — it isn’t just a problem for diabetes. Scientists knew that about half of insulin resistance was governed by weight, exercise and diet. But the heredity half was a mystery — until now.

Thanks to an international collaboration and many months of work, a team of researchers led by Joshua Knowles, MD, PhD, and Thomas Quertermous, MD, have found the first gene known to contribute to insulin resistance. It’s called NAT2, and when mutated, it leads to a greater chance for carriers to become insulin resistant.

From the release:

“It’s still early days,” Knowles said. “We’re just scratching the surface with the handful of variants that are related to insulin resistance that have been found.”

Researchers found NAT2 by compiling data from about 5,600 individuals for whom they had both genetic information and a direct test of insulin sensitivity. Measuring insulin sensitivity takes several hours and is usually done in research settings. No genes met the high standards demanded by genome-wide association studies. Yet NAT2 appeared promising, so researchers followed up with experiments using mice.

When they knocked out the analogous gene in mice, the mice’s cells took up less glucose in response to insulin. These mice also had higher fasting-glucose, insulin and triglyceride levels.

“Our goal was to try to get a better understanding of the foundation of insulin resistance,” Knowlessaid. “Ultimately, we hope this effort will lead to new drugs, new therapies and new diagnostic tests.”

Previously: New insulin-decreasing hormone discovered, named for goddess of starvation, Stanford researchers identify a new pathway governing growth of insulin-producing cells and Faulty fat cells may help explain how type 2 diabetes begins
Image by Andy Leppard

Ethics, Genetics, History, In the News, Medicine and Society, Microbiology, Stanford News

Stanford faculty lend voices to call for “genome editing” guidelines

Stanford faculty lend voices to call for "genome editing" guidelines

baby feetStanford law professor Hank Greely, JD, and biochemist Paul Berg, PhD, are two of 20 scientists who have signed a letter in today’s issue of Science Express discussing the need to develop guidelines to regulate genome editing tools like the recently discovered Crispr/Cas9. Researchers are particularly concerned that the technology could be used to alter human embryos. From the commentary:

The simplicity of the CRISPR-Cas9 system enables any researcher with knowledge of molecular biology to modify genomes, making feasible many experiments that were previously difficult or impossible to conduct. […]

We recommend taking immediate steps toward ensuring that the application of genome engineering technology is performed safely and ethically.

We’ve written a bit here before about the Crispr system, which essentially lets researchers swap one section of DNA for another with high specificity. The potential uses, for both research or therapy, are touted as nearly endless. But, as Greely pointed out in an email to me: “Making babies using genomic engineering right now would be reckless – it would be unknowably risky to the lives of those babies, none of whom consented to the procedure. For me, those safety issues are paramount in human germ line modification, but there are also other issues that have sparked social concern. It would be prudent for science to slow down while society as a whole discusses all the issues – safety and beyond.”

The list of others who signed the commentary reads like a veritable who’s who of biology and bioethics. It includes Caltech’s David Baltimore, PhD; U.C. Berkeley’s Michael Botchan, PhD; Harvard’s George Church, PhD; and George Q. Daley, MD, PhD; University of Wisconsin bioethicist R. Alta Charo, JD; and Crispr/Cas9 developer Jennifer Doudna, PhD. (Another group of scientists published a similar letter in Nature last Friday.)

The call to action echos one in the 1970s in response to the discovery of the DNA snipping ability of restriction endonucleases, which launched the era of DNA cloning. Berg, who shared the 1980 Nobel Prize in Chemistry for this discovery, organized a historic meeting at Asilomar in 1975 known as the International Congress on Recombinant DNA Molecules to discuss concerns and establish guidelines for the use of the powerful enzymes.

Berg was prescient in an article in Nature in 2008 discussing the Asilomar meeting:

That said, there is a lesson in Asilomar for all of science: the best way to respond to concerns created by emerging knowledge or early-stage technologies is for scientists from publicly-funded institutions to find common cause with the wider public about the best way to regulate — as early as possible. Once scientists from corporations begin to dominate the research enterprise, it will simply be too late.

Previously: Policing the editor: Stanford scientists devise way to monitor CRISPR effectiveness and The challenge – and opportunity – of regulating new ideas in science and technology
Photo by gabi manashe

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