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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, 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

Big data, Genetics, In the News, Precision health, Research

Personal proteins: Assembling a “‘complete parts list’ of the human body”

3597686581_389d7b3df2_zGeneticist Michael Snyder, PhD, is on the forefront of a global effort to catalog — and investigate — the presence and activities of proteins in the human body. The worker bees of cells, proteins are responsible for the actions — such as germ fighting, digestion, reproduction and more — that keep us alive.

The task of tallying proteins is daunting, as a recent Nature article lays out:

Proteins… vary over time, changing during exercise, disease and menstrual cycles, for example. Another complication is that the most abundant protein can be about 10 billion times as common as the least.

Snyder started with himself and watched how his protein expression changed when he became ill with an infection. He also discovered his unexpected predisposition for diabetes. “I had no idea I’d turn out to be so interesting,” Snyder told Nature.

The piece outlines the multiple global efforts to “create a ‘complete parts list’ of the human body,'” as described by Gilbert Omenn, MD, PhD, head of the Human Proteome Project. Those endeavors, including the HPP, are using a variety of methods and tackling different tasks. For example, one is looking at proteins involved in disease, while another is systematically probing proteins produced by each chromosome.

Ultimately, Snyder said he hopes he and others can assemble protein inventories on as many as a million people. A key challenge of this work is what to do with, and how to analyze, the enormous amounts of data generated.

Previously: Gene regulation controls identity — and health, You say “protein interactions,” I say “mosh pit:” New insights on the dynamics of gene expression and ‘Omics’ profiling coming soon to a doctor’s office near you?
Image by Jer Thorp

Big data, Genetics, Research, Stanford News

Locking the door on big-data risks to privacy

Locking the door on big-data risks to privacy

Back doorUntil this week, you could have hacked into your rich Uncle Al’s account at a popular family tree website, downloaded his genome and then gotten your geneticist cousin, Todd, to help you find out if Al had a disease that could hopefully lead to an early and lucrative death. Thanks to a pair of researchers here, you won’t be able to do that.

Suyash Shringarpure, PhD, a postdoctoral scholar in genetics, and Carlos Bustamante, PhD, a professor of genetics, realized that an unnoticed back door to a network of genomic data sets was capable of revealing more about a person’s health than anyone would like. But thanks to the two men’s work, that back door will soon be locked tight.

In a new paper, published yesterday in The American Journal of Human Genetics, the researchers demonstrate both how someone might extract personal information from a major network of disease databases and how to prevent that from happening. As I explain in my story:

The Beacon Project has the potential to be enormously valuable to future genetic research… In their paper, the Stanford researchers suggest various approaches for making the information more secure, including banning anonymous researchers from querying the beacons; merging data sets to make it harder to identify the exact source of the data; requiring that users be approved; and limiting access in a beacon to a smaller region of the genome.

Their paper also bears importantly on the larger question of how to analyze mixtures of genomes, such as those from different people at a crime scene or the many different species of microbes in a person’s microbiome.

Previously: A conversation about the benefits and limitations of direct-to-consumer genetic tests
Image – of Back Door, Cliff Cottage watercolor painting – by Artistically

Dermatology, Genetics, Infectious Disease, Microbiology, Research, Stanford News

Inside job: Staphyloccus aureus gets critical assist from host-cell protein accomplice

Inside job: Staphyloccus aureus gets critical assist from host-cell protein accomplice

bank heistStaphylococcus aureus is a bacterium that colonizes the skin (and, often, the noses) of about one in three people, mostly just hanging out without causing symptoms. But when it breaches the skin barrier, it becomes a formidable pathogen.

S. aureus not only accounts for the majority of skin and soft-tissue infections in the U.S. and Europe, but can spread to deeper tissues leading to dangerous invasive infections in virtually every organ including the lungs, heart valves, and bones. These complications cause an estimated 11,000 deaths in the U.S. annually.

Making matters worse, antibiotic-resistant strains of S. aureus are becoming increasingly prevalent and even more difficult and costly to treat. All of which makes it crucial to understand the factors that control the bug’s virulence: What turns a common colonizer into a pathogen?

The answers that typically spring to mind involve molecules the pathogen produces that enable damage to cells of the host organism. Certainly S. aureus is no slouch in that arena. Prominent among the many virulence factors it produces, one called α-toxin aggregates on host cell surfaces to form pores that injure the cells’ outer membranes, often killing the cells.

But it turns out that forming pores appears not to be enough, by itself, for lethal host-cell injury. In a study published in Proceedings of the National Academy of Sciences, a team directed by Stanford microbe sleuths Manuel Amieva, MD, PhD, and Jan Carette, PhD, identified several hitherto-unsuspected molecules produced within host cells themselves that determine whether the cells live or die after α-toxin-induced pore formation.

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Cancer, Genetics, Pediatrics, Research

California collaboration focuses on analyzing pediatric cancers

California collaboration focuses on analyzing pediatric cancers

Breakthroughs in medical research can take a frustratingly long time to reach doctors and the patients they treat. But a newly funded collaboration between computational biologists at UC Santa Cruz and researchers conducting pediatric cancer clinical trials at three California institutions, including one led by Stanford’s Alejandro Sweet-Cordero, MD, may set the stage to bring the power of cancer genomic research into the hands of clinicians and their patients.

The California Initiative to Advance Precision Medicine is funding the UC Santa Cruz Genomics Institute’s California Kids Cancer Comparison project. The project will develop technology to use a cancer’s genetic mutations, its DNA signature, to match it to similar cancers regardless of the tissues the cancers originated from. So, if a lung cancer’s DNA signature more closely resembles a certain kind of brain cancer’s signature, then doctors may pursue treatments that have proven effective against that brain cancer. This technique is especially beneficial for pediatric cancers, which are rarer than adult cancers and less likely to have been included in clinical drug trials.

The project builds on the UC Santa Cruz Genomic Institute’s Treehouse Childhood Cancer Project, led by bioinformatics researcher and UCSC postdoctoral scholar Olena Morozova, PhD, which showed how the academic investigations could have real world consequences.

“Treehouse was started as a research project – we weren’t thinking we could go clinical with it,” Morozova told me. That changed when she and colleagues analyzed the genes of an aggressive sarcoma from an 8-year-old boy enrolled in a cancer genomic clinical trial six months ago.

The child’s cancer had originated in his brain and had gone into remission after a standard treatment of chemotherapy, radiation and a bone marrow transplant. But two years later doctors found tumor growths in his lungs.

Morozova and her colleagues found that genes turned on in the boy’s cancer cells matched those turned on in a rare neuron tumor called a neuroblastoma that is found almost exclusively in children.

Neuroblastomas happened to be the cancer Morozova researched for her PhD, and she knew of a molecular signaling pathway that could be active in the boy’s cancer. Two drugs that target this pathway had been shown to be effective in clinical trials and had received Food and Drug Administration approval for adult patients. The UCSC researcher’s passed on their data supporting that the pathway was active in the tumor to the boy’s physician, who chose to administrate the drugs.

By partnering with researchers like Sweet-Cordero, who’s conducting a trial on difficult-to-treat cancers in children and young adults, the California Kids Cancer Comparison project will be able to compare the cancer DNA sequences to a collected database of both adult and pediatric cancers. And they hope to automate parts of the analysis to make this technology accessible to doctors without degrees in bioinformatics.

“If it is successful, we hope to offer it to every child with cancer in California and elsewhere,” said Morozova.

Kim Smuga-Otto is a student in UC Santa Cruz’s science communication program and a former writing intern in the medical school’s Office of Communication and Public Affairs. 

Previously: Gene-sequencing rare tumors – and what it means for cancer research and treatment

Cardiovascular Medicine, Genetics, Research, Stanford News

Close-up look at mutinous mutant molecule implicated in hypertrophic cardiomyopathy

Close-up look at mutinous mutant molecule implicated in hypertrophic cardiomyopathy

heart failureThe healthy human heart is a hard-working muscle: Beating just over 100,000 beats per day,  it pumps five quarts of blood per minute – enough to fill three supertankers worth of blood over the course of an average person’s lifetime.

Like any other mechanical pump, the heart is made up of various components, including different kinds of proteins. One of those proteins, a “molecular motor” called cardiac myosin (there are several varieties of myosin), plays a crucial role. A myosin molecule can oscillate lengthwise, contracting and relaxing by turns. It’s the coordinated oscillations of myriad cardiac myosin molecules that are, in the aggregate, responsible for the heartbeat.

Defective cardiac myosin exacts a severe medical price. Hypertrophic cardiomyopathy, caused by mutations in a gene encoding cardiac myosin, occurs in at least one in 500 people and is a leading cause of heart failure in the United States and worldwide. It’s also the primary cause of sudden deaths due to heart attack in people under age 30.

A mutation known as R403Q, identified a couple of decades ago, ranks among the nastiest and most widely studied of literally hundreds of cardiac-myosin mutations.  The general thinking has been that the mutation results in a “gain of function,” meaning stronger-than-normal myosin contractility.

Now, researchers under the direction of Stanford biochemist Jim Spudich, PhD, have for the first time been able to look at the effects of this mutation in human cardiac myosin as opposed to animal models. Spudich, whom I wrote up in 2012 as the winner of that year’s prestigious Lasker Award for Basic Medical Research, is a pioneer in the analysis of myosin and its associated motility-related proteins. Integrating approaches drawn from cell physiology, physics, biochemistry, structural biology and genetics, Spudich and his colleagues have developed methods of  measuring the exact amount of energy consumed in each contraction of a single molecule of myosin. (In my 2012 Lasker Award write-up, I explained myosin’s critical involvement not only in heartbeat but also in all muscular movement and, indeed, all transport of molecular materiel within every living plant or animal cell.)

In a study published in Science Advances, Spudich’s team measured the effects of the R403Q mutation at the single-molecule level and was able to demonstrate tiny, but relevant changes in the power of the mutant myosin molecule.The next step is to, in an even more sophisticated way, measure these effects in a microenvironment more closely approximating that of a living human heart.

R403Q is just the first of several hypertrophic-cardiomyopathy-inducing mutations the team is analyzing, one by one, with their state-of-the-art techniques.

Previously: Stanford molecular-motor maven Jim Spudich wins Lasker Award, Sudden cardiac death has cellular cause, say Stanford researchers and Stanford patient on having her genome sequenced: “This is the right thing to do for our family”
Photo by Sharon Sinclair

Addiction, Behavioral Science, Genetics, Neuroscience, Research, Stanford News

Found: a novel assembly line in brain whose product may prevent alcoholism

Found: a novel assembly line in brain whose product may prevent alcoholism

alcohol silhouette

High-functioning binge drinkers can seem charming and stylish. The ultimate case in point: Nick and Nora of the famed Thirties/Forties “Thin Man” film series (you can skip the ad after the first few seconds).

But alcoholism’s terrific toll is better sighted on city streets than in celluloid skyscraper scenarios. At least half of all homeless people suffer from dependence on one or another addictive drug. (My Stanford Medicine article “The Neuroscience of Need” explores the physiology of addiction.) Alcohol, the most commonly abused of them all (not counting nicotine), has proved to be a particularly hard one to shake.

Alcoholism is an immense national and international health problem,” I wrote the other day in a news release explaining an exciting step toward a possible cure:

More than 200 million people globally, including 18 million Americans, suffer from it. Binge drinking [roughly four drinks in a single session for a man, five for a woman] substantially increases the likelihood of developing alcoholism. As many as one in four American adults report having engaged in binge drinking in the past month.

While there are a few approved drugs that induce great discomfort when a person uses them drinks alcohol, reduce its pleasant effects, or alleviate some of its unpleasant ones, there’s as of yet no “magic bullet” medication that eliminates the powerful cravings driving the addictive behavior to begin with.

But a study, just published in Science, by Stanford neuroscientist Jun Ding, PhD, and his associates, may be holding the ticket to such a medication. In the study, Ding’s team identified a previously unknown biochemical assembly line, in a network of nerve cells strongly tied to addiction, that produces a substance whose effect appears to prevent pleasurable activity from becoming addictive. The substance, known as GABA, acts as a brake on downstream nerve-cell transmission.

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Genetics, In the News, Mental Health, Neuroscience, Research, Stanford News

Bright Young Mind: Stanford postdoc featured as a top young scientist

Bright Young Mind: Stanford postdoc featured as a top young scientist
100315_nobels_rajasethupathy_resizedYoung researchers don’t always get the accolades they deserve, so I was delighted to see a recent story that’s bucking this trend. This week Science News released its list of “10 scientists who are making their mark,” and Stanford neuroscientist Priya Rajasethupathy, MD, PhD, a postdoctoral research fellow in the lab of Karl Deisseroth, MD, PhD, was featured among them.

Rajasethupathy was nominated for this honor by another group of outstanding scientists: Science News polled 30 Nobel Prize winners to learn which young researchers are doing work that’s worth watching.

Rajasethupathy’s research on how memories are made and stored caught their eye because she’s found that long-term memories may leave lasting marks on DNA. (Her work “has been called groundbreaking, compelling and beautifully executed,” according to the piece.) By studying sea slugs, she and her colleagues have also identified a tiny molecule that may be involved in memory.

Now Rajasethypathy is expanding on this early work and investigating the neural circuits involved in memory recall. To do this, she’s exploring specific genetic mutations to see if they result in abnormal memory behavior. This work may offer insights into neurological disorders, she explains.

Previously: Exploring the role of prion-like proteins in memory disordersNo long-term cognitive effects seen in younger post-menopausal women on hormone therapy and Individuals’ extraordinary talent to never forget could offer insights into memory
Photo by Connie Lee; courtesy of Pryia Rajasethupathy

Cancer, Genetics, Research, Science, Stanford News

Combination therapy could fight pancreatic cancer, say Stanford researchers

Combination therapy could fight pancreatic cancer, say Stanford researchers

I’ve mentioned here before my personal connection to pancreatic cancer, which claimed the life of my grandmother. So I was excited to hear from Stanford cancer researcher Julien Sage, PhD, about some developments on the research front. Sage and postdoctoral scholar Pawal Mazur, PhD, collaborated with Alexander Herner, MD and Jens Svieke, MD, at the Technical University Munich to conduct the work, which was published today in Nature Medicine.

In our release on the study, which was done in animal models, Sage explained:

Pancreatic cancer is one of the most deadly of all human cancers, and its incidence is increasing. Nearly always the cause of the disease seems to be a mutation in a gene called KRAS, which makes a protein that is essential for many cellular functions. Although this protein, and others that work with it in the Ras pathway, would appear to be a perfect target for therapy, drugs that block their effect often have severe side effects that limit their effectiveness. So we decided to investigate drugs that affect the DNA rather than the proteins.

Mazur and Herner worked together to test whether drugs that affect the epigenetic status of a cancer cell (that is, the dynamic arrangement of chemical tags on the DNA and its associated proteins that control how and when genes are expressed) could rein in its growth without serious side effects. Many of these tags are what’s called acetyl groups, and they are added to protein complexes called histones that keep the DNA tightly wound in the cell’s nucleus. As I explained in our release:

They started by investigating the effect of a small molecule they called JQ1 on the growth of human pancreatic tumor cells in a laboratory dish. JQ1 inhibits a family of proteins responsible for sensing acetyl groups on histones. The researchers found that the cells treated with JQ1 grew more slowly and displayed fewer cancerous traits. The molecule was also able to significantly shrink established pancreatic tumors in mice with the disease. However, it did not significantly affect the animals’ overall likelihood of survival.

Mazur, who began the work in Siveke’s lab and continued it when he moved to Sage’s lab, next tested whether using JQ1 in combination with any other medications could be more effective:

“It happened that the drug that worked best was another epigenetic drug called vorinostat,” said Sage. “On its own, vorinostat didn’t work very well, but when combined with JQ1 it showed a very strong synergistic effect in both the laboratory mice with pancreatic cancer and in pancreatic cancer cells from people with the disease.”

Vorinostat works by inhibiting a family of proteins that remove the acetyl groups from histones. It has been approved by the FDA for use in people with recurrent or difficult-to-treat cutaneous T cell lymphoma. When human pancreatic cancer cells were treated simultaneously with JQ1 and vorinostat, the cells grew more slowly and were more likely to die.

Mice with established pancreatic cancers treated with both of the drugs showed a marked reduction in tumor size and a significant increase in overall survival time. Their tumors showed no signs of developing a resistance to the treatment, and the mice did not develop any noticeable side effects.

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