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Big data, Cancer, Genetics, NIH, Precision health, Research, Stanford News

Cancer’s mutational sweet spot identified by Stanford researchers

Cancer's mutational sweet spot identified by Stanford researchers

dots-1002903_1280I’m constantly fascinated by the fact that the cells that make up a cancerous tumor are each undergoing their own private evolution every time they divide. Unlike most normal cells, cancer cells are so wacky that even a small batch can morph into a highly variable mass within a few generations. As I wrote in a story last week:

In many ways, cancer cells represent biology’s wild west. These cells divide rampantly in the absence of normal biological checkpoints, and, as a result, they mutate or even lose genes at much higher rate than normal. As errors accumulate in the genome, things go ever more haywire.

Recently, oncologist Hanlee Ji, MD, the senior associate director of the Stanford Genome Technology Center, and postdoctoral scholar Noemi Andor, PhD, devised a way to measure the extent of these differences among individual cancer cells and to associate their effect with the virulence of the disease as a whole. They published their results today in Nature Medicine.

As Ji, who is also a member of the Stanford Cancer Institute, explained in an email to me:

Until recently the scientific community believed that a typical tumor was composed of malignant cells with very similar genomes. The advent of next-generation sequencing technologies has revealed that this is not the case, and that most tumors are a heterogeneous product of ongoing evolution. This genetic heterogeneity also explains why therapeutic interventions in advanced cancers are often unsuccessful: some cells within a tumor develop resistance to therapies. Understanding the extent of tumor heterogeneity and how it leads to drug resistance is a major challenge in cancer biology research.

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Clinical Trials, Ethics, Patient Care, Research

When medical knowledge is at a crossroads, how research can take patient preferences into account

When medical knowledge is at a crossroads, how research can take patient preferences into account

4000195795_6841659fc6_z (1)Let’s say you have high blood pressure that can be treated with one of two medications.

Neither drug is experimental; both are within the standard of care. Your doctor doesn’t have any medical reason to recommend one or the other. But she’d like to help the medical community figure out which one works best, and she’s wondering if you would, too. If so, you can enroll in a randomized study, effective immediately.

The question is, what steps are necessary to ensure you understand and consent to the research?

One possibility is that your doctor informs you about the purpose of the research, its risks and benefits, and your alternatives to participating; she then documents the conversation and your decision in your medical record. A patient-friendly consent process is essential to the success of this type of research on clinical practices, say researchers at the Stanford Center for Biomedical Ethics (SCBE), and most patients are comfortable skipping a written consent form when the form might prove so cumbersome that the research couldn’t go forward. Patients also prefer to talk about participating in these studies with their own doctors, not with researchers.

But draft guidance from the federal Office for Human Research Protections (OHRP), if finalized, would require formal written consent in any study that is designed to assess a risk, even if the same risk exists in ordinary clinical care. In other words, whether you get Hypertension Medication A vs. Hypertension Medication B is characterized as a research risk, even though the risk is inherent in the doctor visit whether you participate in the study or not.

“They make it seem really risky,” said Stephanie Alessi Kraft, an SCBE clinical ethics fellow and the lead author of a paper in the American Medical Association Journal of Ethics that argues for reconsideration of the draft guidance. “We’re talking about cases of genuine uncertainty and equipoise. In our research, we use the example of a gumball machine. You know you’re going to get a gumball. You know you’re going to get a medication that works. You just don’t know what color.”

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Behavioral Science, Neuroscience, Research, Stanford News

Like or dislike? Brain scans reveal source of initial preferences

Like or dislike? Brain scans reveal source of initial preferences

3228273137_020ba1b3c1_oJust seconds into an interview with a potential babysitter, I had already formed a slightly unfavorable opinion. She had excellent reviews — five stars across the board. She was polite and paid attention to my baby. Why didn’t I like her?

Well, I may not consciously know, but perhaps the answer lies deep in my brain, new research from Stanford’s Department of Psychology suggests.

A team led by Jeanne Tsai, PhD, associate professor of psychology, showed volunteers faces that varied by gender, ethnicity and emotion and monitored their reactions using functional magnetic resonance imaging (fMRI), a recent Stanford News article details:

In the study, Tsai and her colleagues examined whether cultural values could drive neural responses and preferences for different positive facial expressions – like excited versus calm faces…

“Within cultures, European Americans responded similarly to excited and calm faces, but Chinese showed greater activity in the ventral striatum in response to calm versus excited expressions,” Tsai said.

The ventral striatum is part of the brain involved in emotional responses, particularly those related to the anticipation of pleasure. “This pattern held regardless of the ethnicity or gender of the face,” Tsai added.

This finding reflects the cultural preference in China for calm expressions, Tsai said, and it could have implications for employment decisions as well as mate selection.

Previously: Hidden memories: A bit of coaching allows subjects to cloak memories from fMRI detector, Thinking about “culture” as part of global well-being and From phrenology to neuroimaging: New finding bolsters theory about how brain operates
Photo by Dar’ya Sip

Big data, Clinical Trials, Events, Research

At TEDMED 2015: Benign drugs? Not under the lens of big data

At TEDMED 2015: Benign drugs? Not under the lens of big data

This year’s TEDMED was held Nov. 18-20 in Palm Springs, Calif. Stanford Medicine is a medical research institution partner of TEDMED, and a group of MD and PhD students who represented Stanford at the conference will be sharing their experiences here.

xCUEHR0MrJlqiC9phSMFFEjCxjrDDo54Bv0Hc18sYdkPicture this: you go to the doctor and find out that your cholesterol is high. Your doctor prescribes you a medication taken by millions of Americans for lowering cholesterol – Pravastatin. A few months later, you see your doctor again because of persistent depression, and again, you are given a commonly prescribed medication – Paxil.

Russ Altman, MD, PhD, opened his 2015 TEDMED talk with this seemingly innocuous scenario. But through the course of his talk, Altman demonstrated how his lab leveraged big data to reveal the adverse side effects of supposedly benign pharmacological interventions.

When choosing medications for my patients during my clinical rotations, I would often cite evidence from randomized controlled trials about the clinical benefits versus the risks of that particular drug. However, this evidence-based medicine has one major limitation: In clinical studies, patients are usually only on one drug.

My patients, on the other hand, would often come in with bags full of prescription bottles in order to show me which drugs they took, since there were too many medication names to memorize. Often, I found myself wondering quietly, “Is there any way to know if combining these drugs could lead to an adverse event?”

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Big data, Cancer, Genetics, NIH, Precision health, Research, Stanford News

“Housekeeping” RNAs have important, and unsuspected, role in cancer prevention, study shows

"Housekeeping" RNAs have important, and unsuspected, role in cancer prevention, study shows

BroomsNot every character in a novel is a princess, a knight or a king. It’s the same for our cellular cast of characters. Most molecules spend their time completing the thousands of mundane tasks necessary to keep our cells humming smoothly. Many of these are referred to as “housekeeping” genes or proteins, and biologists tend to focus their attentions on other, more flashy players.

Now dermatologists Paul Khavari, MD, PhD, and Zurab Siprashvili, PhD, have found that a pair of housekeeping RNA molecules play an important role in cancer prevention. They published their findings yesterday in Nature Genetics.

As I explain in our release:

[The researchers] compared 5,473 tumor genomes with the genomes obtained from surrounding normal tissue in 21 different types of cancer. In many ways, cancer cells represent biology’s wild west. These cells divide rampantly in the absence of normal biological checkpoints, and, as a result, they mutate or even lose genes at much higher rate than normal. As errors accumulate in the genome, things go ever more haywire.

The researchers found that a pair of snoRNAs called SNORD50A/B had been deleted in 10 to 40 percent of tumors in 12 common human cancers, including skin, breast, ovarian, liver and lung. They also noted that breast cancer patients whose tumors had deleted SNORD50A/B, and skin cancer patients whose tumors made lower levels of the RNAs than normal tissue, were less likely than other similar patients to survive their disease.

The researchers used data from the National Institutes of Health’s The Cancer Genome Atlas to find that the RNAs are frequently deleted in tumor tissue. They further went on to show that the RNAs bind an important cancer-associated protein called KRAS and keep it from associating with an activating molecule.

“This is really last thing we would have expected,” said Khavari. “It was particularly surprising because my lab has been studying KRAS intensively for more than a decade, so it was quite a coincidence.”

The researchers believe that understanding more about how the RNAs inhibit KRAS activation could point to possible new therapies for many types of human cancers.

Previously: Listening in on the Ras pathway identifies new target for cancer therapySmoking gun or hit-and-run? How oncogenes make good cells go bad  and Linking cancer gene expression with survival rates, Stanford researchers bring “big data” into the clinic 
Photo by Rob Shenk

Events, Research, Science, Technology

At TEDMED 2015: Thinking about “breaking through” the valley of death in science

At TEDMED 2015: Thinking about "breaking through" the valley of death in science

This year’s TEDMED was held Nov. 18-20 in Palm Springs, Calif. Stanford Medicine is a medical research institution partner of TEDMED, and a group of MD and PhD students who represented Stanford at the conference will be sharing their experiences here. 

“I am #BreakingThrough the ‘valley of death.’”

That’s what I wore on my nametag last week at TEDMED. The theme of this year’s conference was “Breaking Through,” and every delegate was asked to write a brief statement that illustrates an area of health care that they’re most passionate about.

The “valley of death” refers to the vast gap in the landscape of biomedical therapeutic development between academia and industry. Traditionally, an academic institution and industry have played two separate but equally important roles in the lengthy and expensive process of bringing new medical innovations to the patient. Academic researchers investigate new mechanisms, pathways and methods, making discoveries that yield promise. Industry then takes these experimental innovations and conducts product development, safety profiling, clinical trials, and manufacturing and distribution, ensuring that extensively tested, safe and efficacious products are widely made available.

However, this transition between academia and industry is not always a smooth one. The pharmaceutical industry is notorious for its extreme risk aversion with new products – and with an average cost of $1B, a 10-year path to FDA approval, and a failure rate north of 95 percent, who can blame them? Meanwhile, most academic labs are neither equipped to nor interested in spending the resources to conduct important yet labor-intensive preclinical work (which, quite frankly, won’t help a scientist graduate, secure tenure, or win a Nobel Prize). And so, because of this, potentially beneficial therapeutics are liable to languish in the valley of death between discovery and human trials.

On Thursday, Stanford professor Daria Mochly-Rosen, PhD, took the TEDMED stage to describe her own experience crossing that valley on the TED stage. In the early 2000s her lab had discovered a novel class of compounds for reducing cardiac injury after heart attack. After receiving universal rejections from pharma companies that they hoped would license the compounds, Mochly-Rosen and one of her graduate students reluctantly took matters into their own hands, left the university, and started KAI Therapeutics to bring their compounds into clinical trials. Long story short, they were eventually wildly successful and acquired by Amgen after demonstrating efficacy in Phase II clinical trials. The experience drove Mochly-Rosen to start the Stanford’s SPARK program, which offers a variety of resources – including classes, industry mentors and grants – to help scientists here survive their own journeys through the valley of death.

As a scientist developing new potential tools for diagnosis and therapy, and as someone who works frequently with early-stage life science companies, I spend a disturbing amount of time thinking about the valley of death. But to me, the valley is much deeper and wider than what it means for pharmaceutical development. It spans similar challenges in medical devices, diagnostics, and even digital health solutions.

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Events, Genetics, Research, Science

At TEDMED 2015: How microbiome studies could improve the future of humanity

At TEDMED 2015:  How microbiome studies could improve the future of humanity

This year’s TEDMED was held Nov. 18-20 in Palm Springs, Calif. Stanford Medicine is a medical research institution partner of TEDMED, and a group of MD and PhD students who represented Stanford at the conference will be sharing their experiences here. 

TEDMED scholarsOne of the highlights at TEDMED for me was meeting and hearing from Chris Mason, PhD, a Weill Cornell Medical College researcher in epigenetics. This is my field of study, so I was excited to talk to someone deeply involved in the world of genomics. Mason was an engaging and fast talking speaker, with a great sense of humor. And I soon discovered that, while he was doing the same sort of work and analysis that I was doing, his samples are incredibly unique.

While I work on primary cell types across the human body, Mason has interesting questions about the microbiome surrounding our body. The cells that make up the microbiome actually outnumber human cells ten times over – and scientists are increasingly gaining an understanding of how the microbiome, individual and personal to each and every person, can have a unique impact on human health and wellness. Mason, knowing this, began to look for interesting and unique ones that could tell us about how these microbiomes could be enhanced and utilized for improving our human lives.

Mason sequenced microbial cells that were gathered from subway riders around the world, and he discovered that about half of the cells discovered were not known microbial species. Literally under our feet, as Mason puts it, there is a world of diversity to explore and the possibility of discovering new antibiotics and cures to disease. But then Mason also went in the other direction – up! – and collected samples from astronauts in space. Now he has access to more than 8,000 samples of astronaut samples (let your imagination wander on what they saved) for a study of the human body in extreme environments.

During Mason’s talk on the last day of the conference, provocatively described by TEDMED organizers as a discussion of how his work is being done “in the interest of humanity’s interplanetary survival,” he touched on the subway experiments as well as the astronaut work, and then tied it all together by talking about the future of humanity. For Mason, an understanding of biology, both microbial and human, is the natural next step in humans’ progress to the stars and beyond. Genetic engineering is already here and will continue to grow as a technology, and he suggested we use it to extend our reach to the moon and beyond. The microbiome could be altered to protect us from UV radiation in space or to help us adapt to new planets, for example. Think of it as an astronaut suit, but biological, he suggested.

Mason’s thoughts may be controversial, depending on what you think about genetics, but he has clearly thought very hard about what new biological technologies mean for humanity’s future. It’s unknown whether the future will develop as Mason has envisioned it, but his work will likely be influential nonetheless.

Daniel Kim is a fifth-year MD/PhD student at Stanford. He studies biomedical informatics and genomics and is interested in all things data-related.

Photo of the author (second from left) and three other TEDMED scholars, from Lichy Han

Evolution, Fertility, Pregnancy, Research, Science, Stanford News, Stem Cells, Videos

Viral RNA essential for human development, say Stanford researchers

Viral RNA essential for human development, say Stanford researchers

Viruses are tricky, but we humans may be trickier still. Stanford stem cell biologists Vittorio Sebastiano, PhD, and Jens Durruthy-Durruthy, PhD, published a study today in Nature Genetics indicating that the genetic remnants of ancient viral infections that still linger in our genome are essential to early human embryonic development.

As Sebastiano explained in our release:

We’re starting to accumulate evidence that these viral sequences, which originally may have threatened the survival of our species, were co-opted by our genomes for their own benefit. In this manner, they may even have contributed species-specific characteristics and fundamental cell processes, even in humans.

The researchers, who talk about their work in the video above, relied on a new RNA sequencing technique to investigate the expression of what are called long-intergenic noncoding, or lincRNAs. These molecules don’t contain protein-making instructions, but instead affect the expression of other genes. They’ve been implicated in many important biological processes, including the acquisition of a developmental state called pluripotency that is necessary for a fertilized egg to develop into the cells and tissues of a growing fetus.

More from our release:

They identified more than 2,000 previously unknown RNA sequences, and found that 146 are specifically expressed in embryonic stem cells. They homed in on the 23 most highly expressed sequences, which they termed HPAT1-23, for further study. Thirteen of these, they found, were made up almost entirely of genetic material left behind after an eons-ago infection by a virus called HERV-H.

[…] After identifying HPAT1-23 in embryonic stem cells, Sebastiano and his colleagues studied their expression in human blastocysts — the hollow clump of cells that arises from the egg in the first days after fertilization. They found that HPAT2, HPAT3 and HPAT5 were expressed only in the inner cell mass of the blastocyst, which becomes the developing fetus. Blocking their expression in one cell of a two-celled embryo stopped the affected cell from contributing to the embryo’s inner cell mass. Further studies showed that the expression of the three genes is also required for efficient reprogramming of adult cells into induced pluripotent stem cells.

I can’t stop marveling at the close ties we have with viruses. It makes me think of the words of Michael Corleone in The Godfather: “Keep your friends close, and your enemies closer.” As Durruthy-Durruthy told me, “It’s fascinating to imagine how, during the course of evolution, primates began to recycle these viral leftovers into something that’s beneficial and necessary to our development.”

Previously: My baby, my… virus? Stanford researchers find viral proteins in human embryonic cellsMastermind or freeloader? Viral proteins in early human embryos leave researchers puzzled  and Species-specific differences among placentas due to long-ago viral infection, say Stanford researchers
Video by Christopher Vaughan/Stanford Institute for Stem Cell Biology and Regenerative Medicine

Cancer, Complementary Medicine, In the News, Research

“We need a breakthrough”: Cancer researchers call for more effective, lower cost therapies

"We need a breakthrough": Cancer researchers call for more effective, lower cost therapies

1024px-Tripterygium_regelii_1Cancer is wily. Although drug developers are continually crafting hard-hitting drugs, a variety of factors, such as a tumor’s genetic heterogeneity, mean that cancer usually comes out on top.

Something else is needed.

And that something, writes a panel of 180 researchers in a special issue of Seminars in Cancer Biology, is an array of treatments that bombard a series of targets. These treatments can be based on substances found in nature that are lower in cost and toxicity than many current treatments, the researchers write. Some of these compounds stem from plants, such as the Chinese herb Tripterygium wilfordii (although that herb, like many treatments is not without a downside: it also suppresses the immune system).

The team identified 74 molecular targets deserving of investigation and set up a framework for researchers to pitch in. And the time is now, researchers Anupam Bishayee, PhD, and Keith Block, MD, write in the introductory paper: “We have a long way to go before oncology can offer true comfort to most patients.”

Stanford oncologist Dean Felsher, MD, PhD, was part of the project. “This is an area that merits considerable attention and where interdisciplinary and international collaboration is needed,” he said in a statement.  “Our approaches to therapy are improving, but we need a breakthrough that can helps us address the problem of relapse.”

Previously: Researchers develop molecular target for brain cancer, Kidney cancer secrets revealed by Stanford researchers and Tool to identify the origin of certain types of cancer could be a “boon to doctors prescribing therapies”
Photo by Qwert1234

Cancer, Pediatrics, Research, Stanford News

A cure is not enough for young cancer survivors

flower-887443_1920I survived Hodgkin’s lymphoma as a young adult about twenty years ago, thanks to the chemotherapy and radiotherapy that I received at Stanford Hospital as part of a clinical trial.

Even back then, the focus of the research was on fine-tuning my cancer treatment to maintain an excellent likelihood of survival, while minimizing the long-term health problems due to therapy. I knew Hodgkin’s was unlikely to kill me, so I had to worry instead about future health issues caused by my radiation and chemotherapy.

People that survive cancer at a young age are expected to live many decades after diagnosis and treatment, so they are the most vulnerable population to long-term damaging effects from cancer therapy. Stanford’s Karen Effinger, MD, MS, and Michael Link, MD, explore this issue in an editorial published today in JAMA Oncology.

The editorial explains that it is critical to directly study the late effects in young adult cancer survivors, rather than the common practice of extrapolating from studies of children and middle-aged adults.

In particular, they discuss a new study by Katherine Rugbjerg, PhD, and Jorgen Olsen, MD, DMSc, from the Danish Cancer Society Research Center, which used the national Danish registries to compare the long-term risk of hospitalization in almost 34,000 5-year survivors of adolescent and young adult cancers with that of more than 228,000 age- and sex-matched population controls. Reported in the latest issue of JAMA Oncology, Rugbjerg and Olsen found that adolescent and young adult cancer survivors had significant health issues due to their treatment; however, these treatment effects were different than survivors of childhood cancers.

The editorial also discusses the late effects of pediatric cancer treatment on survivors’ neurocognitive development, which impacts education, employment and quality of life. Effinger and Link specifically describe a new study reported in JAMA Oncology by Kevin Krull, PhD, and colleagues from the St. Jude Children’s Research Hospital, which compared the neurocognitive outcomes in 80 adult 25-year survivors of a pediatric cancer with 39 controls. Krull concluded that the risk of neurocognitive impairment from cancer treatment was related to the development of chronic health conditions — rather than directly from exposure to high-doses of chemotherapy, as expected — but longitudinal studies are needed to sort out possible modifying factors.

The editorial authors conclude:

Going forward, we must apply our knowledge of late effects to improve monitoring and interventions for patients. While the progress made in the management of cancer in children and young adults has been gratifying, we must remember the words of Giulio D’Angio, who reminds us that “cure is not enough.”

Jennifer Huber, PhD, is a science writer with extensive technical communications experience as an academic research scientist, freelance science journalist, and writing instructor.

Previously: Study highlights childhood cancer survivors’ increased risk of future health problems, Questioning whether physicians are equipped to care for childhood cancer survivors and A cancer survivor discusses the importance of considering fertility preservation prior to treatment
Photo by klimkin

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