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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

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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