Published by
Stanford Medicine

Author

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

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

Cancer, Dermatology, Research, Science

Common skin cancer evades treatment via specific mutations

Common skin cancer evades treatment via specific mutations

Anthony OroBasal cell carcinoma is the most common type of skin cancer. It is also one of the most treatable. But people with advanced cases of the disease often experience only a temporary response to the drug vismodegib, and their tumors recur within a few months as the cancer becomes resistant to the drug.

Now dermatologists Anthony Oro, MD, PhD; Jean Tang, MD, PhD; and Anne Chang, MD, have identified the specific mutations involved in the development of vismodegib resistance, and identified another treatment that may be successful even on vismodegib resistant tumors. They’ve recently published their findings in Cancer Cell (with an accompanying companion paper and commentary).

From our release:

Approximately 2 million new cases of basal cell carcinoma are diagnosed each year in the United States, making it the most common cancer in the country. About half of patients with advanced basal cell carcinomas will respond to vismodegib, which belongs to a class of drug compounds called Smoothened inhibitors. About 20 percent of these responders will go on to quickly develop resistance to the drug.

Basal cell carcinomas are uniquely dependent on the inappropriate activation of a cellular signaling cascade called the Hedgehog pathway. Blocking signaling along this pathway will stop the growth and spread of the cancer cells. The Hedgehog pathway plays a critical role in normal development. It’s also been found to be abnormally active in many other cancers, including pancreatic, colon, lung and breast cancers, as well as in a type of brain cancer called medulloblastoma.

The researchers found two classes of mutations in the Smoothened gene that inhibit vismodegib’s effectiveness by keeping the Smoothened protein active. Treating the cells with inhibitors that target a portion of the pathway downstream of Smoothened blocked the activation of the pathway even in cells with the mutations. These inhibitors, called Gli antagonists, could be an effective way to treat vismodegib-resistant tumors, the researchers said.

As Oro told me, “This research sheds new light on mechanisms of how tumors evolve to develop drug resistance, and has already helped us with personalized cancer genetics and therapy for our patients. It is now possible for us to identify those people who may benefit from a combination therapy even before they begin treatment.”

Previously: Studies show new drug may treat and prevent basal cell carcinoma, New skin cancer target identified by Stanford researchers and Another blow to the Hedgehog pathway? New hope for patients with drug-resistant cancers
Photo of Anthony Oro by Steve Fisch

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

Microbiology, Research, Science, Stanford News

Tiny balloon-like vesicles carry cellular chatter with remarkable specificity, say Stanford researchers

Tiny balloon-like vesicles carry cellular chatter with remarkable specificity, say Stanford researchers

6292985963_bbc06df590_z“BRUSH YOUR TEETH,” I bellowed up the stairs last night at my (seemingly deaf and clueless) children for what seemed like the one-millionth time since their birth. “Surely there has to be a better way,” I pondered, as I trudged up the stairs to deliver my threatening message in person.

The cells in our bodies don’t have the option to, however reluctantly, leave their metaphorical couch and wag their fingers under the noses of their intended recipients. And yet, without a fail-safe method of communication among distant participants, the orderly workings of our bodies would screech to a halt.

Now biologists Masamitsu Kanada, PhD, and Christopher Contag, PhD, have published in the Proceedings of the National Academy of Sciences an interesting and revealing glimpse into one tool cells can use to do the job: tiny balloon-like vesicles capable of delivering a payload of protein or genetic information from one cell to another. As Contag and Kanada explained to me in an email:

Extracellular vesicles are nanosized little containers of information that are produced by most, if not all, cells in the bodies of plants, animals and humans. From many studies it is apparent that adding vesicles from one cell type to another can affect the behavior of the recipient cells, both in a culture dish and in the living body, even across species from plants to animals and presumably humans.

We wanted to assess, under controlled sets of conditions, which biomolecules within vesicles transfer the most information most efficiently. We learned that the process is complex, and that a biomolecule in one type of vesicle is transferred in a way that affects other cells, but the same molecule in another type of vesicle may not affect cell function.

In other words, Contag, who co-directs Stanford’s Molecular Imaging Program, and his colleagues found that not all these vesicles are created equal. Some, whose outer layer was derived from the cell’s external plasma membrane (these are known as micro-vesicles), handily delivered both protein and DNA to recipient cells. Others, with outer layers derived from internal membranes in the cell (known as exosomes), were less capable and didn’t deliver any functional DNA. Interestingly, neither kind was able to deliver RNA, which was instead swiftly degraded.

The distinction between vesicle type and function is important as researchers increasingly rely on them to eavesdrop on cellular conversations or even to deliver particular biomolecules to be used for therapy or imaging. Understanding more about how they work will allow researchers to both better pick the right type for the job at hand and to learn more about how cells talk with one another. As Contag and Kanada said:

How cells communicate across distances is relevant to mobilization of immune cells to attack pathogens, depression of immune responses by tumor cells, signaling of cancer cells to metastasize, modulation of physiological processes in intestinal cells in response to plant-derived diets and to many other biological process. Understanding this form of cell-to-cell communication will bring us closer to controlling how cells talk to one another inside the body.

Now if only I could find the right kind of vesicle to communicate with my recalcitrant children. Perhaps a helium-filled balloon with a pointed message inside could float up the stairs and pop next to their ears? On second thought, that might not be the best choice.

Previously: Researchers develop imaging technologies to detect cancer earlier, faster
Photo by Matthew Faltz

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.

Continue Reading »

Genetics, NIH, Research, Science, Stanford News

Project Roadmap: Mysteries of the epigenome revealed

Project Roadmap: Mysteries of the epigenome revealed

Let’s hear it for large, international collaborations! Hot on the heels of the ENCODE Project (well, in research time anyway) comes the National Institutes of Health’s Roadmap Epigenomics Project, which is geared toward understanding how chemical tags on DNA and its associated proteins determine how each cell uses the information in the genome to develop its own identity. One of the leaders of the massive project was geneticist Anshul Kundaje, PhD, who helped to analyze the huge amounts of data generated by labs around the world as they studied more than 100 adult and fetal human tissues.

The work is published today in Nature in the form of a large package of papers. Kundaje is the first author of the main paper; Nature has also published a nice summary of all the papers in the issue and produced a musical video to explain the project.

From our release:

The problem [of picking and choosing from a genome’s worth of information] is somewhat like being handed a list of all the ingredients available in a well-stocked kitchen without any idea of how to combine them. Tossing a few of them together, willy-nilly, into a baking dish and popping it into the oven isn’t likely to yield anything edible. But with a well-written recipe telling you how much and when to mix together flour, sugar, eggs and butter, you can turn out a perfect cake or fantastic waffles.

The completion of the Human Genome Project gave biologists the list of ingredients to which every cell has access. The Roadmap Epigenomics Project outlines the recipes and shows how cells use these ingredients to generate their own special sauce. By comparing and contrasting these cellular recipes, researchers can begin to draw parallels among cell types and even predict which cells might be involved in specific traits and diseases.

As a proof of principle, Kundaje and others showed in one of the companion papers that, based on the epigenomic maps shared among cells, the immune system is likely to play a larger role in the development of Alzheimer’s disease than previously thought.

Previously: Scientists announce the completion of the ENCODE project, a massive genome encyclopedia , Red light, green light: Simultaneous stop and go signals on stem cells’ genes may enable fast activation, provide “aging clock” and Caught in the act! Fast, cheap, high-resolution, easy way to tell which genes a cell is using

Aging, Genetics, Research, Science, Stanford News

My funny Valentine – or, how a tiny fish will change the world of aging research

My funny Valentine - or, how a tiny fish will change the world of aging research

YoungFishI admit it. I have crush on a fish. The object of my affection is the African turquoise killifish – a tiny, colorful fish that lives in seasonal ponds and puddles under the hot sun of Mozambique and Zimbabwe. Because the pools dry out regularly, the fish have evolved to have a normal lifespan of only a few months. In fact, it’s one of the shortest-lived vertebrates known. It’s also zippy, territorial and (maybe it’s just me?) seemingly possessing a degree of chutzpah noticeably absent in your average goldfish.

The killifish’s compressed lifespan, plus the ease and speed with which it can be housed and bred, make it an ideal model for genetic studies of aging and longevity. But in the absence of a fully sequenced genome and little information about gene expression patterns or a way to introduce selective mutations, it’s been difficult for researchers to get a scientific handle on the slippery creature.

Today, geneticists Anne Brunet, PhD, and Itamar Harel, PhD, published a comprehensive genetic toolbox for use by researchers around the world wanting to draw parallels between humans and my tiny, finned crush. The article appears online in Cell; a charming video abstract describing their work is also available.

As I describe in our release:

Although the similarities between fish and humans may not be immediately evident, people have much more in common with the tiny, minnowlike creature than with other short-lived laboratory animals.

“This fish gives us the best of both worlds,” said postdoctoral scholar Itamar Harel, PhD. “As a vertebrate, it shares many critical attributes with humans, including an adaptive immune system, real blood and similar stem cell biology.

At the same time, its very short life span mimics those of the laboratory worms, yeast and fruit flies that until now have served as the traditional models of aging research.”

A short life span allows researchers to quickly assess the effect of genetic variations among different strains of fish. It also allows them to breed and raise hundreds of progeny for study within the span of months, rather than the many years required to conduct similar experiments in other vertebrates.

“The life span of a mouse can be as long as three to four years,” said Anne Brunet, PhD, professor of genetics. “This is close to the average length of a postdoctoral or graduate student position. This means that it would be very difficult for a researcher to conduct a meaningful analysis of aging in the mouse within a reasonable time period.”

Continue Reading »

Aging, Ethics, Medicine and Society, Research, Science, Stanford News

Golden years? Researcher explores longevity research and the companies banking on its success

Golden years? Researcher explores longevity research and the companies banking on its success

Elderly Japanese woman for Scott blog postAlthough I haven’t had a birthday yet this year, the transition to writing 2015 on all my checks (whoops, did I just date myself there? ahem) has made me feel older. Coincidentally, I’ve also been working on an article for an upcoming issue of Stanford Medicine magazine about aging and longevity. So, yeah. I’ve been thinking a lot about the passage of time.

That’s why I was really interested to learn that Stanford bioethicist Christopher Scott, PhD, teamed up with Nature Biotechnology senior editor Laura DeFrancesco to c0-author a feature article examining the commercialization of longevity research. The article layers research advances with the rise and fall (and rise again) of companies and organizations that have tossed their hats into the anti-aging ring since the 1990s. With it, Scott and DeFrancesco paint a picture of a dynamic field on the brink of something big. As Scott explained in an email to me:

Aging research, as we knew it in the 1990s and 2000’s, is being abandoned in favor of something much more ambitious. The central features of longevity research include an embrace of big data, a pivot away from studies hoping to find aging genes, a recognition that aging is best thought of a collection of diseases, not just one disease.

I’m fascinated by how quickly this new direction has taken off, especially since classic aging research yielded so little, and became saddled with hype. Longevity research has that same feel to it, and from an ethics and policy perspective one question is whether the promise of healthy lifespans will outrun the reality of the science.

And there’s the rub. As Scott points out, it’s not enough to just live long. No one wants a prolonged, but unhealthy, old age. We need to live long and well. The concept that gained ground is “healthspan” rather than “lifespan.” And from Google’s Calico to Craig Venter’s Human Longevity, Inc , there are a lot of bright minds (and plenty of $) focused on this problem. But there’s a lot at stake.

As Scott explained:

These are highly consequential decisions (funding research, creating new companies, establishing new scientific disciplines), technological inventions, and social changes that are being pursued on the tacit assumption that such decisions, inventions, and changes do lead to a healthier, longer life and the promise of a better future. In ethics, I think these assumptions are largely unexplored and unacknowledged.

The article is a fascinating cross-section of a rapidly growing field, but, as Scott points out, there are still many questions that scientists haven’t addressed. It’s well worth the time to read, whether you’re a writer on a deadline or just a person trying to figure out how to gracefully change that “4” into a “5” on …all your paperwork.

Previously: Exploring the value of longevity with bioethicist Ezekiel Emanuel , Tick tock goes the clock – is aging the biggest illness of all? and Researchers aim to extend how long – and how well – we live
Photo by Maya Stone

Stanford Medicine Resources: