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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

Cancer, Global Health, Patient Care, Stanford News

New global cancer map aims to improve care in developing countries

New global cancer map aims to improve care in developing countries

cancer map2

Most people don’t associate cancer with the developing world, yet 60 percent of new cancer cases and 70 percent of cancer deaths occur in less developed parts of the world, according to the World Health Organization. Now, the nonprofit Global Oncology, Inc. has launched a Global Cancer Project Map, a first-of-its-kind resource that will connect cancer experts around the world in an effort to advance cancer research and care in low-resource areas.

The interactive map includes more than 800 projects on six continents. With a few simple clicks, users can search for cancer experts and research projects and then contact the investigators and program managers. The goal is to spur collaboration among people in the field and enable experts to share their collective knowledge.

“Before it was difficult or often impossible to find information about cancer projects or experts, especially in limited-resource settings,” said Ami S. Bhatt, MD, PhD, an assistant professor of medicine and genetics at Stanford and co-founder of Global Oncology, Inc. “The map now makes it possible to connect colleagues in the global cancer community with a maximum of six clicks of a computer mouse.”

Bhatt, who directs global oncology for Stanford’s Center for Innovation in Global Health, and GO co-founder Franklin Huang, MD, PhD, have been working with the National Cancer Institute on ways to bring multidisciplinary teams together to solve complex problems in cancer. While there are many dedicated scientists and caregivers doing innovative work in cancer in the developing world, there’s been no single place where they could share knowledge or reference the work of their colleagues, she said. The cancer map is a first step in this process.

“We have the ambitious goal of providing access to every cancer research, care and outreach program in the world through the map,” said Huang, who is an instructor at the Dana-Farber Cancer Institute.

A collaboration with the NCI, the map was developed by GO volunteers, who are scientists, policymakers, public health experts, lawyers and other highly skilled individuals. It covers a wide range of projects, from prevention and screening to clinical programs and palliative care. For instance, it includes a project in Turkey to improve diagnostic accuracy of mammograms to detect breast cancer; development of an early screening test for gastric cancer in Mexico; and use of supplements to prevent arsenic-induced skin cancer in Bangladesh.

“The map is an important and innovative step forward in our effort to reduce health disparities and strengthen human capital in underserved areas of the world,” said Michele Barry, MD, director of Stanford’s Center for Innovation in Global Health. “With cancer rates rapidly increasing in low-resource settings, the map creates a place where the global cancer community can share and access information that is critical to providing better treatment and care.”

Bhatt and Huang unveiled the new map today at the Symposium on Global Cancer Research, being held in Boston. The symposium is co-sponsored by the NCI, the Consortium of Universities for Global Health and the Dana-Farber Cancer Institute.

Image from Global Oncology, Inc.

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

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

Cancer, Stanford News

Stanford neurosurgeon Paul Kalanithi, who touched countless lives with his writing, dies at 37

Stanford neurosurgeon Paul Kalanithi, who touched countless lives with his writing, dies at 37

Paul K and daughter - fixedNeurosurgeon and writer Paul Kalanithi, MD, passed away on Monday. A death is almost always sad, but for me this one is indescribably so – though if he were alive he might convince me of a positive angle.

Kalanithi died at 37 of lung cancer less than a year after finishing his neurosurgery residency at Stanford. During the roughly two years between his diagnosis and death, he spent time as a surgeon saving lives and passing his skills and insights to neurosurgery trainees. But I came to meet him through my work as editor of Stanford Medicine magazine, which published an essay he crafted. His words changed how I think about my life – and, based on the many letters and emails I’ve received, changed how many people looked at theirs as well.

After his diagnosis he wrote essays for The New York Times and Stanford Medicine about his changing perception of mortality and time and the joy he continued to find in life. I interviewed him for a video produced for our magazine, talking with him at his apartment and meeting his wife and baby girl. My colleagues also got to know him by working on stories about his life and illness; just a few days ago, Paul Costello shared on Scope a 45-minute conversation the two had last fall.

Kalanithi’s message, to appreciate every moment, sounds corny when I write it, but in his eloquent words it hits home. In the obituary I wrote today, I shared this excerpt from his Stanford Medicine essay – words he wrote for his infant daughter:

When you come to one of the many moments in life when you must give an account of yourself, provide a ledger of what you have been, and done, and meant to the world, do not, I pray, discount that you filled a dying man’s days with a sated joy, a joy unknown to me in all my prior years, a joy that does not hunger for more and more, but rests, satisfied. In this time, right now, that is an enormous thing.

Previously: Stanford neurosurgeon/cancer patient Paul Kalanithi: “I can’t go on. I will go on.”For this doctor couple, the Super Bowl was about way more than football, A neurosurgeon’s journey from doctor to cancer patient, Stop skipping dessert:” A Stanford neurosurgeon and cancer patient discusses facing terminal illness and No one wants to talk about dying but we all need to
Image – a screenshot from a Stanford Medicine video – from Mark Hanlon

Cancer, Medicine and Society, Patient Care, Public Health, Videos

March marks National Colon Cancer Awareness Month: The takeaway? It’s preventable

March marks National Colon Cancer Awareness Month: The takeaway? It's preventable

What is the leading, preventable cause of death in the United States? I suppose the headline gave away my punchline, but remembering that colon cancer is both deadly and preventable is a timely exercise during March, which is National Colon Cancer Awareness Month.

Here’s what you need to know: Don’t wait until your colon hurts to come to the doctor. That won’t work. “Polyps and early tumors are often not symptomatic,” said gastroenterologist Uri Ladabaum, MD, in the above Stanford Health Care video.

It’s best to catch cancer 10 years before it appears, making 50 a key age to spot a cancer that often appears in the 60s,  said endoscopy director Subhas Banerjee, MD.

And a prime screening procedure, colonoscopy, “is no big deal,” said oncologist Mark Welton, MD. “They give you a little sedation and the next thing you know is you’re saying, ‘Are we done?'”

If physicians do spot the cancer early — or even later — they can often remove it, the physicians agreed. Chemotherapy and surgery are continuing to improve, making it more likely that patients can continue to live long, healthy lives.

Family history and race can leave you more vulnerable to colon cancer — African Americans are more likely to get, and die from, the disease — but in general, a fruit-and-vegetable packed diet, avoiding smoking and getting regular exercise can help stave off colon cancer.

Previously: The Big Bang model of human colon cancer, Stanford researchers explore new ways of identifying colon cancer and Study shows evidence-based care eliminates racial disparity in colon-cancer survival rates 

Cancer, Podcasts, Stanford News

Stanford neurosurgeon/cancer patient Paul Kalanithi: “I can’t go on. I will go on.”

Stanford neurosurgeon/cancer patient Paul Kalanithi: "I can't go on. I will go on."

Kalanthi and childEditor’s note: Paul Kalanithi passed away on March 9, after this post was published.

Frankly, I didn’t quite know how to begin my conversation with Paul Kalanithi, MD. How do you talk to a 37–year-old man about his terminal illness and facing death? A conversation with someone so young who’s the father of a small child is supposed to be ebullient, not dark.

Kalanithi, a Stanford Medicine neurosurgeon and fellow with Stanford Neurosciences Institute, was diagnosed with advanced stage lung cancer in 2013. His illness is terminal. While he’s hopeful that a treatment may extend his life, there is no cure. He faces big questions and small ones. And he wonders: “How do I talk about myself – in the present, past or future tense? When someone says, ‘See you next year,’ will I?”

It all began with back pain, night sweats, weight loss and fever. His neurosurgical training prepared him for what he reviewed on his CT scan. Metastatic cancer. He responded well to his initial treatment plan, but a second round of chemotherapy last spring led to a number of complications and setbacks. Though he finished his residency he’s now taking time off to recover and regain his strength. He remains hopeful about a return to neurosurgery, yet he has to prepare for an end. He’s spoken with a palliative-care expert. He’s mulling the existential questions and trying to grapple with moving on while not giving up. He takes comfort in the words of the Irish novelist and playwright, Samuel Beckett: “I can’t go on. I can go on.” They’ve become sort of his mantra.

Still, he knows he faces the inevitable and whether it’s a year, two years or five, terminal is the diagnosis. He’s trying to find a way to leave a trail of bread crumbs to his life so his child will know she was loved deeply when his presence is all but a shadow.

I spoke with him last November for a 1:2:1 podcast while he was in the throes of writing a book proposal. It was hard for me at points in our conversation to keep it together as our talk pried open my own grief over my brother’s death to cancer at age 48.

Kalanithi also wrote a beautiful piece for Stanford Medicine magazine. It’s magical. It’s lyrical. It touches the heart. And it’s clear, no matter what his health status, no matter what the outcome, he will live on.

Previously: Stanford Medicine magazine reports on time’s intersection with health, For this doctor couple, the Super Bowl was about way more than football, A neurosurgeon’s journey from doctor to cancer patient, Stop skipping dessert:” A Stanford neurosurgeon and cancer patient discusses facing terminal illness and No one wants to talk about dying but we all need to
Photo by Gregg Segal

Cancer, Stanford News, Stem Cells, Videos

A look at stem cells and “chemobrain”

A look at stem cells and "chemobrain"

As many as 75 percent of cancer patients experience memory and attention problems during or after their treatment, and up to 3.9 million are afflicted by long-term cognitive dysfunction. This foggy mental state, often referred to as “chemobrain,” can also affect cancer survivors’ fine motor skills, information processing speed, concentration and ability to calculate.

In this recently posted California Institute for Regenerative Medicine video, Stanford physician-scientist Michelle Monje, MD, PhD, explains the role that damage to stem cells in the brain plays in the condition, outlines some of the interventions that can mitigate patients’ symptoms, and highlights efforts to develop effective regenerative therapies.

Previously: Stanford brain tumor research featured on “Bay Area Proud”, Emmy nod for film about Stanford brain tumor research – and the little boy who made it possible and Stanford study shows effects of chemotherapy and breast cancer on brain function

Applied Biotechnology, Cancer, Evolution, Immunology, Research, Stanford News

Corrective braces adjust cell-surface molecules’ positions, fix defective activities within cells

Corrective braces adjust cell-surface molecules' positions, fix defective activities within cells

bracesStanford molecular and cellular physiologist and structural biologist Chris Garcia, PhD, and his fellow scientists have tweaked together a set of molecular tools that work like braces of varying lengths and torque to fix things several orders of magnitude too small to see with the naked eye.

Like faulty cell-surface receptors, for instance, whose aberrant signaling can cause all kinds of medical problems, including cancer.

Cell-surface receptors transmit naturally occurring signals from outside cells to the insides of cells. Molecular messengers circulating in the blood stumble on receptors for which they’re a good fit, bind to them, and accelerate or diminish particular internal activities of cells, allowing the body to adjust to the needs of the minute.

Things sometimes go wrong. One or another of the body’s various circulating molecular messengers (for example, regulatory proteins called cytokines) may be too abundant or scarce. Alternatively, a genetic mutation may render a particular receptor type overly sluggish, or too efficient. One such mutation causes receptors for erythropoietin – a cytokine that stimulates production of certain blood-cell types – to be in constant overdrive, resulting in myeloproliferative disorders. Existing drugs for this condition sometimes overshoot, bringing the generation of needed blood-cell types to a screeching halt.

Garcia’s team took advantage of the fact that many receptors – erythropoietin receptors, for example – don’t perform solo, but instead work in pairs. In a proof-of-principle study in Cell, Garcia and his colleagues made brace-like molecular tools composed of stitched-together antibody fragments (known in the trade as diabodies). They then showed that these “two-headed beasts” can selectively grab on to two members of a mutated receptor pair and force the amped-up erythropoietin receptors into positions just far enough apart from, and at just the right angles to, one another to slow down their hyperactive signaling and act like normal ones.

That’s a whole new kind of therapeutic approach. Call it “cellular orthopedics.”

Previously: Souped-up super-version of IL-2 offers promise in cancer treatment and Minuscule DNA ring tricks tumors into revealing their presence
Photo by Zoe

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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