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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

Biomed Bites, Genetics, Research, Stanford News, Videos

Repairing DNA: A researcher strives to understand the root of DNA damage

Repairing DNA: A researcher strives to understand the root of DNA damage

Welcome to Biomed Bites, a weekly feature that introduces readers to some of Stanford’s most innovative researchers.

How’s your DNA? Is it in tip-top shape, a lovely helix of perfectly matched pairs? Or does it look like something the cat brought in, a chemical log-jam with gaps and mismatches? Granted, I’m taking a bit of liberty — no one is really going to inspect your genome, but someday, discoveries made by Karlene Cimprich, PhD, professor of chemical and systems biology, might make it possible to spot those flaws — and fix them — years before they lead to cancer or neurodegeneration.

Cimprich didn’t intend to become a doctor of DNA. As a graduate student at Harvard, she discovered a molecule that helps cells detect and repair DNA damage, and she was hooked.

“What I’ve found in the last 10 to 15 years is that our understanding of that molecule has been translated into research in companies that are now targeting that molecule and other proteins with which it interacts for treatment for cancer,” Cimprich says in the video above.

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

Previously: Clues about kidney disease from an unexpected direction, Spotting broken DNA — in the DNA fix-it shop and Door dings and DNA — connecting behavior and the environment to your health

Genetics, Pediatrics, Podcasts, Research, Stem Cells

Countdown to Childx: Stanford expert highlights future of stem cell and gene therapies

Countdown to Childx: Stanford expert highlights future of stem cell and gene therapies

RoncaroloNext month’s inaugural Childx conference will bring a diverse group of experts to Stanford to discuss big challenges in infant, child and maternal health. Today, in a new 1:2:1 podcast interview, stem cell and gene therapy expert Maria Grazia Roncarolo, MD, provides an interesting preview of a once-controversial area of research that will be featured at the conference.

Roncarolo talks about the history and future of stem cell and gene therapy treatments, which have recovered from tragic setbacks such as the 1999 death of 18-year-old Jesse Gelsinger in an early gene therapy trial. The early problems forced researchers to reevaluate what they were doing, with the result that the entire field has reemerged stronger, she explains:

I would say that there were major problems, that we underestimated the complexity that it takes to manipulate the genome, and to introduce a healthy gene to fix a genetic disease. However, from these mistakes and from these tragedies, we learned a lot. We were really forced as doctors, and more importantly, as scientists, to go back to the bench and develop better technologies and to understand more of what was required. … [Today] we use better vectors — which are the carriers to introduce the healthy gene — we know much more about what we have to do to prepare the patient to receive the gene therapy, and we also learned that we need to do a very careful monitoring of the patients to really understand where the gene lands in the genome.

At the Childx conference, Roncarolo will moderate a panel on “Definitive Stem Cell and Gene Therapy for Child Health,” hosting such guests as GlaxoSmithKline’s senior vice president of rare diseases, Martin Andrews, and Nadia Rosenthal, PhD, founding director of the Australian Regenerative Medicine Institute.

Information about registration for Childx, being held here April 2–3, is available on the conference website.

Previously: Stanford hosts inaugural Childx conference this spring and Stanford researchers receive $40 million from state stem cell agency
Photo by Norbert von der Groeben

Big data, Genetics, Research, Science, Stanford News

Caribbean skeletons hold slave trade secrets

Caribbean skeletons hold slave trade secrets

5598998640_3c9968b4ac_zI was excited yesterday to see the Los Angeles Times cover a really neat story out of the laboratory of geneticist Carlos Bustamante, PhD. He and his colleagues at the University of Copenhagen used genetic analysis to solve a 300-year-old mystery with origins in the city of Philipsburg on the island of Saint Martin.

Philipsburg is an idyllic retreat for thousands of tourists each year. Not so for three skeletons recently unearthed during a construction project in the city. The skeletons were those of African-born slaves who had been shipped from their homeland more than 300 years ago to the Caribbean island to serve as forced laborers. Like millions of other enslaved Africans, the two men and one woman likely led difficult lives and died young.

Now the researchers have identified the regions in Africa the individuals likely lived before their capture. To do so, they examined tiny, highly fragmented bits of ancient DNA that survived the hot, humid conditions of the tropics in the roots of the skeletons’ teeth.  The research was published this week in the Proceedings of the National Academy of Sciences.

As Bustamante explained in our release:

Through the barbarism of the middle passage, millions of people were forcibly removed from Africa and brought to the Americas. We have long sought to use DNA to understand who they were, where they came from, and who, today, shares DNA with those people taken aboard the ships. This project has taught us that we cannot only get ancient DNA from tropical samples, but that we can reliably identify their ancestry. This is incredibly exciting to us and opens the door to reclaiming history that is of such importance.

Bustamante is co-author of a paper describing the research.The study was led by Hannes Schroeder, PhD, a molecular anthropologist from the University of Copenhagen, and Stanford postdoctoral scholar Maria Avila-Arcos, PhD. The research was initiated in Denmark, and the senior author of the study is Thomas Gilbert, PhD, of the University of Copenhagen. More from our release:

Researchers could tell from the skeletons found in the Zoutsteeg area that the three people were between 25 and 40 years old when they died in the late 1600s. The skulls of each also bore teeth that had been filed down in patterns characteristic of certain African groups. But this alone wasn’t enough to pinpoint where the individuals originated on the African continent.

Schroeder and Avila-Arcos used a technique developed by study co-author Meredith Carpenter, PhD, a postdoctoral scholar in the Bustamante laboratory, to fish out snippets of ancient DNA from the material inside the teeth for sequencing. They then used a different technique called principal component analysis to identify the distinct ethnic groups from which each individual likely originated. The findings illuminate a tumultuous period of time in the Americas and may provide insight into subsequent population patterns and perceived ethnic identities. They also open doors to new advances in genealogy and historical research. As Bustamante told me:

Several years ago, we were part of the team that sequenced the genome of Otzi, the iceman, and we were able to show that the people alive today that most closely match him genetically are Sardinians. This incredible precision was possible because we, as a community, had invested lots of resources in understanding patterns of DNA variation in Europe. I started to talk about the ‘Otzi rule,’ or the idea that we should be able to do for all people alive today what we can do for a 5,000-year-old mummy.

Previously: Melting pot or mosaic? International collaboration studies genomic diversity in Mexico, Caribbean genetic diversity explored by Stanford/ University of Miami researchers and Recent shared ancestry between Southern Europe and North Africa identified by Stanford researchers
Photo by alljengi

Ask Stanford Med, Cardiovascular Medicine, Events, Genetics

A conversation about using genetics to advance cardiovascular medicine

A conversation about using genetics to advance cardiovascular medicine

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In recognition of American Heart Month, Stanford Health Care is hosting a heart fair on Saturday. The free community event includes a number of talks ranging in topic from the latest developments in treating atrial fibrillation to specific issues related to women’s heart health.

During the session on heart-disease prevention, Joshua Knowles, MD, PhD, will deliver a talk titled “How We Can (and Will) Use Genetics to Improve Cardiac Health.” Knowles’ research focuses on familial hypercholesterolemia, a genetic disease that causes a deadly buildup of cholesterol in the arteries. He and colleagues recently launched a project that uses a big-data approach to search electronic medical records and identify patients who may have the potentially fatal heart condition.

To kick off the conversation about preventing heart disease, I contacted Knowles to learn more about how the genomics revolution is changing the cardiovascular medicine landscape and what you can do to determine if you have a genetic heart disorder. Below he explains why heart disease is a “complex interplay between genetics and environment” and what the future may hold with respect to personalized treatments and pharmacogenetics.

Let’s start by talking about your work on familial hypercholesterolemia (FH). How has the understanding of the genetic basis of FH evolved over the last few years, and what key questions remain unanswered?

For FH, there has been a revolution in our understanding. FH causes very elevated cholesterol levels and risk of early onset heart disease. We used to think that it affected 1 in 500 individuals, but recent studies have pointed out that this is probably an underestimate and it may affect as many as 1 in 200 people. This means that there may be as many as 1 million people in the United States who are affected. We have also identified new genes that cause FH, and the identification of some of these genes has directly translated into the development of a new class of drugs (so called PCSK9 inhibitors) to treat this condition.

What steps can patients take to determine if they are at risk of, or may have, a genetic cardiovascular disorder like FH?

The easiest way is to know about your family history of medical conditions- to know what illnesses affected parents, grandparents, uncles, aunts and other relatives. Of course, genes aren’t the only things that are passed in families. Good and bad habits, such as exercise patterns, smoking and diet, are also passed down through the generations. But a family history of heart disease or certain forms of cancer is certainly a risk factor.

Past research suggests that patients with a genetic predisposition to heart disease can significantly reduce their chances of having a heart attack or stroke by making changes to their lifestyle, such as eating a diet rich in fruits and vegetables. Can lifestyle changes overcome genetics?

Heart disease is a result of the complex interplay between genetics and environment – lifestyle, for instance. For some people with specific genetic conditions, such as familial hypercholesterolemia or hypertrophic cardiomyopathy, the effect of genetics tends to dominate the effect of environment because the genetic effect is so large.

For the vast majority of people without these “Mendelian” forms of heart disease, which follow the laws of inheritance were derived by nineteenth-century Austrian monk Gregor Mendel, it’s difficult to determine at an individual level how much of the risk is due to genes and how much is due to environment (this is for things like high blood pressure, high cholesterol, coronary disease). One clue is certainly family history. However, for most of these diseases the genes are not “deterministic” – that is, people are not destined to have these diseases. Some are more at risk than others, but there are certainly ways to mitigate genetic risk through lifestyle choices. Choosing not to smoke and exercising regularly are two examples of ways you can help to greatly minimize genetic risk.

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Cancer, Evolution, Genetics, Infectious Disease, Microbiology, Research, Stanford News

Bubble, bubble, toil and trouble – yeast dynasties give up their secrets

Bubble, bubble, toil and trouble - yeast dynasties give up their secrets

yeasty brew

Apologies to Shakespeare for the misquote (I’ve just learned to my surprise that it’s actually “Double, double, toil and trouble“), but it’s a too-perfect lead-in to geneticist Gavin Sherlock’s recent study on yeast population dynamics for me to be bothered by facts.

Sherlock, PhD, and his colleagues devised a way to label and track the fate of individual yeast cells and their progeny in a population using heritable DNA “barcodes” inserted into their genomes. In this way, they could track the rise and fall of dynasties as the yeast battled for ever more scarce resources (in this case, the sugar glucose), much like what happens in the gentle bubbling of a sourdough starter or a new batch of beer.

Their research was published today in Nature.

From our release:

Dividing yeast naturally accumulate mutations as they repeatedly copy their DNA. Some of these mutations may allow cells to gobble up the sugar in the broth more quickly than others, or perhaps give them an extra push to squeeze in just one more cell division than their competitors.

Sherlock and his colleagues found that about one percent of all randomly acquired mutations conferred a fitness benefit that allowed the progeny of one cell to increase in numbers more rapidly than their peers. They also learned that the growth of the population is driven at first by many mutations of modest benefit. Later generations see the rise of the big guns – a few mutations that give carriers a substantial advantage.

This type of clonal evolution mirrors how a bacterium or virus spreads through the human body, or how a cancer cell develops mutations that allow it to evade treatment. It is also somewhat similar to a problem that kept some snooty 19th century English scientists up at night, worried that aristocratic surnames would die out because rich and socially successful families were having fewer children than the working poor. As a result, these scientists developed what’s known as the “science of branching theory.” They described the research in a paper in 1875 called “On the probability of extinction of families,” and Sherlock and his colleagues used some of the mathematical principles described in the paper to conduct their analysis.

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Genetics, In the News, LGBT, Medicine and Society, Research, Sexual Health

Sex biology redefined: Genes don’t indicate binary sexes

Sex biology redefined: Genes don't indicate binary sexes

14614853884_3d6d1d662a_zImagine being a forty-six-year-old woman pregnant with her third child, whose amniocentesis follow-up shows that half her cells carry male chromosomes. Or a seventy-year-old father of three who learns during a hernia repair that he has a uterus. A recent news feature in Nature mentioned these cases as it elaborated on the spectrum of sex biology. People can be sexed in a non-straightforward way and not even be aware of it; in fact, most probably aren’t. As many as 1 person in 100 has some form of “DSD,” a difference/disorder of sex development.

The simple scenario many of us learned in school is that two X chromosomes make someone female, and an X and a Y chromosome make someone male. These are simplistic ways of thinking about what is scientifically very complex. Anatomy, hormones, cells, and chromosomes (not to mention personal identity convictions) are actually not usually aligned with one binary classification.

The Nature feature collects research that has changed the way biologists understand sex. New technologies in DNA sequencing and cell biology are revealing that chromosomal sex is a process, not an assignation.

As quoted in the article, Eric Vilain, MD, PhD, director of the Center for Gender-Based Biology at UCLA, explains that sex determination is a contest between two opposing networks of gene activity. Changes in the activity or amounts of molecules in the networks can sway the embryo towards or away from the sex seemingly spelled out by the chromosomes. “It has been, in a sense, a philosophical change in our way of looking at sex; that it’s a balance.”

What’s more, studies in mice are showing that the balance of sex manifestation can be shifted even after birth; in fact, it is something actively maintained during the mouse’s whole life.

According to the Nature feature, true intersex disorders, such as those from divergent genes or the inability of cellular receptors to respond to hormones, yield conflicting chromosomal and anatomical sex. But these are rare, about 1 in 4,500. For the 1/100 figure, they used a more inclusive definition of DSDs. More than 25 genes that affect sex development have now been identified, and they have a wide range of variations that affect people in subtle ways. Many differences aren’t even noticed until incidental medical encounters, such as in the opening scenarios (the first was probably caused by twin embryos fusing in the woman’s mother’s womb; the second by a hormonal disorder).

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Applied Biotechnology, Bioengineering, Cancer, Genetics, Research, Stanford News

Minuscule DNA ring tricks tumors into revealing their presence

Minuscule DNA ring tricks tumors into revealing their presence

cool minicirclesAn animal study just published in Proceedings of the National Academy of Sciences shows how, in the not-distant future, doctors may be able to not only detect tumors early in humans, but also monitor the effectiveness of cancer drugs in real time, guide clinical trials of new drugs, and even screen entire populations of symptom-free people for nascent tumors that could have otherwise slipped under the radar.

The potential is huge. And the principal investigator, Sam Gambhir, MD, PhD, is credible: He chairs Stanford’s radiology department, directs the Canary Center at Stanford for Cancer Early Detection and has authored or co-authored nearly 600 peer-reviewed research publications.

From my news release about the study:

Imagine: You pop a pill into your mouth and swallow it. It dissolves, releasing tiny particles that are absorbed and cause only cancerous cells to secrete a specific protein into your bloodstream. Two days from now, a finger-prick blood sample will expose whether you’ve got cancer and even give a rough idea of its extent. That’s a highly futuristic concept. But its realization may be only years, not decades, away.

The key to early cancer detection lies in finding valid biomarkers: substances whose presence in a person’s blood or urine flags a probable tumor. (High blood levels of the molecule known as PSA, for example, can signify prostate cancer.) But although various tumor types indeed secrete characteristic substances into the blood, these same substances typically are made in healthy tissues, too, albeit usually in smaller amounts. So a positive test result for, say, PSA doesn’t necessarily mean the person has cancer. Contrariwise, a small tumor just may not secrete enough of the trademark substance to be detectable.

Gambhir’s team appears to have found a way to force any of numerous tumor types to produce a biomarker whose presence in the blood unambiguously signifies cancer, because no adult tissues – cancerous or otherwise – would normally be making it. This particular substance is a protein naturally present in human embryos as they’re forming and developing, but absent in adults.

The scientists designed a genetic construct, called a DNA minicircle, that contains a single gene coding for the telltale substance. DNA minicircles are tiny, artificial, single-stranded DNA rings about 4,000 nucleotides in circumference – roughly one-millionth as long as the strand that you’d get if you stretched the DNA in all 23 chromosomes of the human genome end to end.

Gambhir and his colleagues rigged their minicircles so that this sole gene would be “turned on” only inside cancer cells. (For more details on how to do this, please see my release.) They injected the minicircles into mice who had small tumors and mice who didn’t. Within 48 hours, a simple blood test indicated the presence of the biomarker in the blood of mice with tumors, but not in the blood of the tumor-free mice.The bigger the tumor volume, the more of the biomarker in the blood.

The technique will likely apply to a broad range of cancers, and can possibly be modified to help pinpoint budding tumors’ location in the body.

Previously: Nano-hitchhikers ride stem cells into heart, let researchers watch in real time and weeks later, Nanoparticles home in on human tumors growing in mice’s brains, increase accuracy of surgical removal and Nanomedicine moves one step closer to reality
Photo by Jim Strommer

Aging, Genetics, In the News, Mental Health, Neuroscience, Research, Women's Health

Are women at greater risk for Alzheimer’s? Stanford expert to discuss on today’s Science Friday

Are women at greater risk for Alzheimer’s? Stanford expert to discuss on today's Science Friday

2187905205_158290644d_zConfession: I named my parents’ cat (who died recently) Watson after listening to Ira Flatow interview James Watson, PhD, while driving cross country with my dad in 2000. Both before and after the all-critical cat-name-inspiring program, Science Friday has been a part of my Friday as often as I can squeeze it in.

So I was happy to hear that today’s program (which airs locally from 11 a.m. to 1 p.m. on KQED) will feature Stanford’s Michael Greicius, MD, MPH. He’ll be talking about Alzheimer’s disease and why the disease affects men and women differently.

Greicius, medical director of the Stanford Center for Memory Disorders, has worked with the gene variant known as ApoE4 – the largest single genetic risk factor for Alzheimer’s, particularly for women. Last spring, he published a study showing that healthy ApoE4-positive women were twice as likely to contract the disease as their ApoE4-negative counterparts.

Greicius is expected to be on in the second hour, from 12 to 1 p.m. Pacific time.

Previously: Blocking a receptor on brain’s immune cells counters Alzheimer’s in mice, Examining the potential of creating new synapses in old or damaged brains, The state of Alzheimer’s research: A conversation with Stanford neurologist Michael Greicius and Having a copy of ApoE4 gene variant doubles Alzheimer’s risk for women but not for men
Photo by *Ann Gordon

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