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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, 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

Biomed Bites, Neuroscience, Research, Science, Videos

Circuit breaker: One Stanford scientist and his quest to control epileptic seizures

Circuit breaker: One Stanford scientist and his quest to control epileptic seizures

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

John Huguenard, PhD, was wooed by the magic of anti-epileptic drugs when he was in graduate school at Duke University.  “I was fascinated by the idea that a drug that you could take would block the seizure without affecting normal brain function,” Huguenard says in the video above.

Now a professor of neurology and neurological sciences at Stanford, Huguenard and his colleagues have taken a deep dive into the brain’s circuits, trying to figure out exactly how and why the circuits “go haywire” during an epileptic seizure and what can be done to prevent that from happening.

He has discovered that those broad-based anti-epileptic drugs that once fascinated him might not be the best approach to treat epilepsy. “We’re learning that if we can focus our therapies on very small portions of the brain, we can reduce the chances of side  effects even more,” Huguenard says.

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

Previously: Brain’s wiring more dynamic than originally thought, The brain makes its own Valium: Built-in seizure brake? and Light-switch seizure control? In a bright new study, researchers show how

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

Aging, Applied Biotechnology, Biomed Bites, Research, Science, Videos

Are your cells stressed out? One Stanford researcher is helping them relax

Are your cells stressed out? One Stanford researcher is helping them relax

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

In her family, Daria Mochly-Rosen, PhD, is the odd woman out: One parent and four of her siblings are architects.

But as the George D. Smith Professor in Translational Medicine at Stanford, Mochly-Rosen brings her family’s focus on space and design to her work as a biomedical researcher. “I’m looking at the cell as a physical space as a room or a building where things need to touch each other in certain ways,” Mochly-Rosen says in the video above.

She applies this lens of the world to address several basic research questions, including learning about how cells deal with stress. For a cell, stress isn’t a bad day at work or a rough commute home. Instead, its prolonged exposure to chemicals or physical forces that build up and impair cellular function.

In healthy cells, there are “lots of little machines” that reduce the stress, Mochly-Rosen said. In her lab, researchers work to enhance the efficacy of these built-in destressors and to capitalize on the cell’s existing machinery. She says:

We are really interested in finding ways to boost them up and to increase their activity so we can deal better with stresses that are associated with disease or even with simple aging.

And what we do there is we try to find small molecules — in other words, drugs — that will boost the system.

For example, Mochly-Rosen and her team have discovered a molecule that helps with the negative effects of alcohol and alcohol-related cancers.

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

Previously: Why drug development is time consuming and expensive (hint: it’s hard), New painkiller could tackle pain, without risk of addiction and Stanford researchers show how hijacking an enzyme could help reduce cancer risk

Research, Science, Stanford News

Celebrating 25 years of biomedical innovation at Stanford’s Beckman Center

Celebrating 25 years of biomedical innovation at Stanford's Beckman Center

Beckman dinner - smallInnovation in the Biosphere,” a recent symposium organized to celebrate the 25th anniversary of the Beckman Center for Molecular and Genetic Medicine, attracted a standing-room-only crowd eager to listen to leading researchers in the biosciences. The February 23 gathering was so packed at the Li Ka Shing Center for Learning and Knowledge that live streaming had to be set up to accommodate the many faculty, PhDs and guests that arrived to hear from the impressive list of multidisciplinary presenters.

The symposium was designed to celebrate the concept of information transfer, while acknowledging the many innovations and breakthroughs in immunology, stem cell science, chemical biology, and imaging technology through the years.

The event was conceived by National Medal of Science winner Lucy Shapiro, PhD, the Virginia and D.K. Ludwig Professor of Cancer Research and director of the Beckman Center. “I cannot believe 25 years have gone by,” said Shapiro. “We thought we knew so much.”

Shapiro, the co-organizer of the event, credited Paul Berg, PhD, Nobel Prize-winning professor emeritus in biochemistry, and others with starting the center. The Beckman Center was founded in 1989 “at a time of great expectation” to promote the exchange of ideas across diverse scientific disciplines, based on the notion that innovation transcends traditional academic boundaries. Here’s Shapiro:

What has changed so dramatically is our understanding of how the biological world codes, decodes, and uses information in time and space to create and maintain life on this planet. And almost everything we do comes down to mining information and dealing with not only vast amounts of data but very small molecules and small circuitry.

The bedrock of what it means to be a living entity is an understanding of how a cell or tissue functions as an integrated system. No longer is it enough to study the biochemistry of specific reactions. Or a specific event. Or an overall function that happens when a tissue turns into something else. We now have to understand all these parts as an integrated, logical process.

Investigators from Stanford, UC-Berkeley, UCSF, and other institutions shared their research on the design principles of cellular networks, the manipulation of genetic circuitry to re-engineer life, and the genetic circuitry that establishes the blueprint of a living cell. They explored the deep reading of the genome to mine the information in living things and in creating life from scratch.

Continue Reading »

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

Biomed Bites, Microbiology, Research, Science, Videos

By investigating cells, researchers can “stumble” on the next big thing in medicine

By investigating cells, researchers can "stumble" on the next big thing in medicine

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

Tobias Meyer, PhD, was hooked on biology when he learned humans are made out of cells — 10 trillion distinct little entities, joining together to make a human. (“The way to remember this number is that it is approximately the same as the number of dollars in the American debt,” Meyer suggests in the video above.) He goes on to say:

What fascinated me is that each of these individual cells is really something like a small computer that senses the environment — for example hormones it senses but also pathogens like bacteria or even stress.

Then it processes that information, which makes it do things like secrete, divide, or move. So my lab is particularly interested in this question of how cells integrate all these important signals.

Now chair of the Department of Chemical and Systems Biology at Stanford, Meyer and his team try to decipher how the cells that make up the human body work together:

For example, we recently found a receptor that senses calcium in cells that has not been found before. We were able to show this is important in many different systems like immunology and now many drugs companies are using it to develop drugs they didn’t have before.

For Meyer, the takeaway from his experience in biomedical research is clear: “By doing fundamental research, we often stumble accidentally on a big thing that can have a big impact later in human health.”

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

Research, Science, Stanford News

Stanford researchers show how hijacking an enzyme could help reduce cancer risk

Stanford researchers show how hijacking an enzyme could help reduce cancer risk

Mochly-RosenFor the first time, Stanford researchers figured out a sneaky way to make an enzyme do something it wouldn’t normally do — imitate another enzyme and digest alcohol properly. Their work suggests a possible preventative mechanism for alcohol-related cancers in an at-risk population and is a promising new route for drug discovery.

Daria Mochly-Rosen, PhD, professor in chemical and systems biology, and Che-Hong Chen, PhD, senior research scientist, conducted the study, which was published online yesterday in Proceedings of the National Academy of Sciences.

Enzymes are notoriously choosy, selectively responding to certain molecules that bind precisely in their active site, but the researchers were able to change the selectivity of an enzyme’s active site by “hijacking” it with a small molecule.

Making an enzyme act like another enzyme isn’t just cool. It can have important health consequences for people who have broken enzymes because of genetic mutations.

I wrote about this enzyme deficiency in a press release on the study:

When most people and animals consume alcohol, the body digests it rapidly, within a few hours. One of the byproducts of alcohol metabolism is a chemical called acetylaldehyde. According to the World Health Organization, acetylaldehyde is a Group-1 carcinogen, which means there is a direct link between exposure and cancer.

For most people, acetylaldehyde is not a major health risk — though it can contribute to hangover symptoms — because an enzyme called ALDH2 quickly converts it to a harmless acid. But for some, acetylaldehyde is a big problem.

These people lack a working version of ALDH2 because of a genetic mutation. ALDH2 deficiency is the most common genetic mutation in humans, affecting about 40 percent of East Asians — some 560 million people, or nearly 8 percent of the world’s population. Without a working enzyme, the body cannot clear the toxic acetylaldehyde quickly.

Continue Reading »

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