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Big data, Genetics, Precision health, Research

Individuals’ medical histories predicted by non-coding DNA in Stanford study

Individuals' medical histories predicted by non-coding DNA in Stanford study

image.img.320.highAs whole-genome sequencing gains ground, researchers and clinicians are struggling with how best to interpret the results to improve patient care. After all, three billion base pairs are a lot to sift through, even with powerful computers. Now genomicist Gill Bejerano, PhD, and research associate Harendra Guturu, PhD, have published in PLoS Computational Biology the results of a study showing that computer algorithms and tools previously developed in the Bejerano lab (including one I’ve previously written about here called GREAT) can help researchers home in on important regulatory regions and predict which are likely to contribute to disease.

When they tried their technique on five people who agreed to publicly share their genome sequences and medical histories, they found it to be surprisingly prescient. From our release:

Using this approach to study the genomes of the five individuals, Guturu, Bejerano and their colleagues found that one of the individuals who had a family history of sudden cardiac death had a surprising accumulation of variants associated with “abnormal cardiac output”; another with hypertension had variants likely to affect genes involved in circulating sodium levels; and another with narcolepsy had variants affecting parasympathetic nervous system development. In all five cases, GREAT reported results that jibed with what was known about that individual’s self-reported medical history, and that were rarely seen in the more than 1,000 other genomes used as controls.

Bejerano and Guturu focused on a subset of regulatory regions that control gene expression. As I explained:

The researchers focused their analyses on a relatively small proportion of each person’s genome — the sequences of regulatory regions that have been faithfully conserved among many species over millions of years of evolution. Proteins called transcription factors bind to regulatory regions to control when, where and how genes are expressed. Some regulatory regions have evolved to generate species-specific differences — for example, mutating in a way that changes the expression of a gene involved in foot anatomy in humans — while other regions have stayed mostly the same for millennia. […]

All of us have some natural variation in our genome, accumulated through botched DNA replication, chemical mutation and simple errors that arise when each cell tries to successfully copy 3 billion nucleotides prior to each cell division. When these errors occur in our sperm or egg cells, they are passed to our children and perhaps grandchildren. These variations, called polymorphisms, are usually, but not always, harmless.

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Ethics, Genetics, In the News, Research

Cautious green light for CRISPR use in embryos in the U.K.; Stanford’s Hank Greely weighs in

Cautious green light for CRISPR use in embryos in the U.K.; Stanford's Hank Greely weighs in

balance-154516_1280Big news out of the United Kingdom today about the gene editing technology known as CRISPR/Cas9. Stanford law professor Hank Greely, JD, posted a brief take on his blog this morning applauding the move by the British Human Fertilisation and Embryology Authority to allow researcher Kathy Niakan, PhD, of the Francis Crick Institute to conduct gene editing experiments in early human embryos.

The BBC News and Nature each have good summaries of the science side of the ruling. Greely, who directs Stanford’s Center for Law and the Biosciences, breaks down the ethics. From his post:

This is important research that can only be done with human embryos, it is being done with surplus IVF embryos whose prospective parents agreed to this kind of use, and the researchers are forbidden to to try to produce human gene-edited babies.

Niakan’s experiments, tailored to increase our understanding of the very earliest stages of human development, will allow the modified embryos to develop for only 14 days, or until they consist of just a few hundred cells. She hopes that her findings will shed light on infertility and miscarriage.

Previously: Using CRISPR to investigate pancreatic cancer, CRISPR marches forward: Stanford scientists optimize use in human blood cells and CRISPR critters and CRISPR conundrums
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History, Research, Science, Stanford News, Stem Cells

The making of a scientist — Stanford’s Irv Weissman under the Big Sky

The making of a scientist — Stanford's Irv Weissman under the Big Sky

Some people just seem larger than life. That’s certainly the case with stem cell scientist Irving Weissman, MD. His presence fills a room whether he’s speaking to a crowd or conversing one-on-one with a fellow researcher. Some of that presence comes from his academic stature. After all, he’s director of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine and the Ludwig Center for Cancer Stem Cell Research and Medicine. But it’s immediately apparent that Weissman also has a natural ease and composure that’s hard to beat.

Recently, I had the opportunity to shadow Weissman during one of his regular visits to my home state of Montana. Like me, Weissman grew up in Montana and even cut his scientific teeth here at the McLaughlin Research Institute for Biomedical Sciences in Great Falls. My profile of his career is published today in our medical school newspaper, Inside Stanford Medicine.

From the article:

In school, Weissman was a good, but not exceptional, student. He struggled with memorization, and didn’t particularly enjoy reading. His mother was a classically trained pianist, and Weissman played the piccolo and flute.

When he was about 15 years old, a friend of his mentioned a man named Ernst Eichwald, MD, who had been recruited in 1953 from the University of Utah to work as a pathologist at Montana Deaconess Hospital in Great Falls. Eichwald had made the move on the condition that he be allowed to spend part of his time as a one-man research program, studying the biology of skin transplantation in laboratory mice.

“Instead of working at the scrapyard for my father’s hardware store, I went to see Ernst, because my friend said it was fun to be around mice and rats,” Weissman said. “But the difficulty was that he was very hard of hearing, and he spoke in a thick German accent. So I couldn’t understand anything that he was saying, and I was pretty sure he couldn’t understand what I was saying. Finally, in a moment of desperation, I said, ‘I’ll work for nothing!’ Suddenly he understood and could talk to me. So I started to work with him in the summer as mouse caretaker, autopsy assistant and lab researcher.”

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Big data, Cancer, Genetics, Precision health, Research, Stanford News, Stem Cells

Stem-cell knowledge may help outcomes for colon-cancer patients, says Stanford study

Stem-cell knowledge may help outcomes for colon-cancer patients, says Stanford study

Pinpointing which colon cancer patients need chemotherapy in addition to surgery can be difficult. Studies have suggested that those with stage-2 disease aren’t likely to benefit from chemotherapy, so doctors may chose to bypass the treatment and its toxic side effects.

Now cancer biologist Michael Clarke, MD, working with former postdoctoral scholars Piero Dalerba, MD, and Debashis Sahoo, PhD, have found a way to identify a small but significant minority of stage-2 patients who differ from their peers: They have a poorer overall prognosis, but they are also more likely than other stage-2 patients to benefit from additional chemotherapy. The research was published today in the New England Journal of Medicine.

This research is one of the first examples of how we can use our growing knowledge of stem cell biology to improve patient outcomes

From our press release:

Clarke and his colleagues have been studying the connection between stem cells and cancer for several years. For this study, Dalerba and Sahoo sought to devise a way to identify colon cancers that were more stem-cell-like, and thus likely to be more aggressive. They looked for a gene that was expressed in more mature cells but not in stem or progenitor cells. They did this by using a novel bioinformatics approach that drew on their knowledge of stem cell biology to identify developmentally regulated genes important in colon tissue maturation.

Because they knew from previous research by Dalerba in the Clarke laboratory that stem and immature colon cells express a protein called ALCAM, Dalerba and Sahoo looked for genes whose protein product was negatively correlated with ALCAM expression. “We reasoned that those proteins would likely be involved in the maturation of colon tissue and might not be found in more aggressive, immature cancers,” Sahoo said.

Finally, to ensure their results would be useful to doctors, the researchers added another criterion: The gene had to make a protein that was easily detectable by an existing, clinical-grade test.

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Addiction, Cancer, Genetics, Public Health, Research, Stanford News

For some African Americans, light smokers may not have lower lung cancer risk than heavy ones

For some African Americans, light smokers may not have lower lung cancer risk than heavy ones

CigaretteAlthough the relationship between smoking and lung cancer has been established beyond any doubt, it’s still difficult to know how a patient’s ethnicity might play into risk assessment. But it’s clear that it has a role. Lung cancer is the leading cause of cancer death in this country, and it disproportionately affects African Americans. Doctors are struggling to understand the interactions between genes and environment that contribute to lung cancer risk in all populations.

Physician scientist Sean David, MD, DPhil, and a multidisciplinary team of colleagues recently published in EBioMedicine the results of a study suggesting that African Americans who carry a panel of risky genetic sequences may be at higher risk for the disease, even if they are light smokers.

The study involved analyses of more than 7,000 Women’s Health Initiative participants and nearly 2,000 participants in a lung cancer case-control study with collaborators from multiple institutions in the United States.

As David explained to me in an email:

All smokers are at heightened risk for lung cancer, particularly those possessing high-risk genotypes. Our study suggests that African American light smokers are not at lower risk than heavy smokers if they possess certain genotypes, but that smoking more cigarettes does markedly increase lung cancer risk in individuals without these high-risk genotypes. These conclusions reinforce the message that light or heavy smoking is a risky proposition for African Americans, who can benefit from smoking cessation and evidence-based lung cancer screening services.

The researchers identified six nucleotide changes that appeared to affect the relationship between cigarettes smoked per day and lung cancer risk in African American smokers – all on chromosome 15. Although the nucleotide changes, called single nucleotide polymorphisms, or SNPs, had been associated with lung cancer risk in previous studies, this is the first time the risk has been tied to daily cigarette exposure in African Americans.

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Evolution, Genetics, Orthopedics, Research, Science, Stanford News

From whence the big toe? Stanford researchers investigate the genetics of upright walking

From whence the big toe? Stanford researchers investigate the genetics of upright walking

A tiny armored fish may seem like an unlikely experimental animal to someone interested in understanding how humans may have evolved to walk on two legs.

But developmental biologist David Kingsley, PhD, has made a career out of studying how changes in gene regulation in the aquatic threespine stickleback broadly affect the fish’s skeletal structure. His recent research, published today in Cell, pinpoints a stretch of DNA that controls the size of the protective bone plates sported by marine sticklebacks.

As I explained in our release:

The threespine stickleback is remarkable in that it has evolved to have many different body structures to equip it for life in different parts of the world. It sports an exterior of bony plates and spines that act as armor to protect it from predators. In marine environments, the plates are large and thick; in freshwater, the fish have evolved to have smaller, lighter-weight plates, perhaps to enhance buoyancy, increase body flexibility and better slip out of the grasp of large, hungry insects. Kingsley and his colleagues wanted to identify the regions of the fish’s genome responsible for the skeletal differences that have evolved in natural populations.

“So what?” might ask the more jaded, fish haters among us. (Don’t count me among them — I recently blogged here about my undying love for the silvery, colorful killifish that’s made an undeniable splash in the field of aging research.)

Well, it turns out that this bit of regulatory DNA controls the expression of an important protein involved in bone formation during development. What’s more, this regulatory region is shared among animals separated by millions of years of evolution, from mice to chimpanzees.

But you know who doesn’t have it? Humans. Further experiments in the Kingsley laboratory suggest that the region specifically drives expression of the protein, called GDF6, in the hind limbs of our nearest evolutionary relatives, the chimpanzee.

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Cancer, Immunology, Research, Science, Stanford News, Stem Cells, Transplants

One (blood stem) cell to rule them all? Perhaps not, say Stanford researchers

One (blood stem) cell to rule them all? Perhaps not, say Stanford researchers

4294019174_3f269b3f38_oThe blood stem cell, or hematopoietic stem cell, is a cell that’s believed to give rise to all the components of the blood and immune system. Nestled in our bone marrow, it springs into action as necessary and is a key component of bone marrow transplantation procedures (more accurately called hematopoietic stem cell transplantation) conducted to save patients with blood diseases or whose immune systems have been wiped out by large doses of chemotherapy or radiation.

But new research published today in Stem Cell Reports by research associate Eliver Ghosn, PhD, and colleagues in the laboratory of geneticist Leonore Herzenberg suggests that, at least in laboratory mice, this stem cell may not be as omnipotent as previously thought. In particular, it seems unable to give rise to an important subpopulation of B cells, a type of immune cell. As Ghosn explained to me in an email:

Briefly, our findings challenge the idea that a single blood, or hematopoietic, stem cell (HSC) can fully regenerate all components of the immune system. We’ve shown that transplantation with highly purified HSCs fails to fully regenerate the B lymphocyte compartment, which is needed to protect against infections such as influenza, pneumonia and other infectious diseases, and also to respond to vaccinations.

Further studies conducted by the researchers suggest that these B cells may arise from an alternative fetal progenitor cell distinct from the HSC — perhaps as an evolutionary effort to separate what’s known as innate immunity from adaptive immunity. They urge further research into the clinical outcomes of the transplantation of purified HSC in humans. As Ghosn said:

From a clinical standpoint, these findings raise the key question of whether human HSC transplantation, widely used in human regenerative therapies to restore immunity in immune-compromised patients, is sufficient to regenerate human tissue B cells that help protect transplanted patients from subsequent infectious diseases. This is specially relevant today considering that the field is moving toward using highly purified human HSCs in clinical settings. 
More research is needed to confirm the findings in humans, however. If you’re interested in learning more about this, Ghosn expanded upon the idea earlier this month with a review in the Annals of the New York Academy of Sciences.

Genetics, Immunology, Microbiology, Research, Science, Stanford News

Stanley Falkow awarded National Medal of Science, White House announces today

Stanley Falkow awarded National Medal of Science, White House announces today

Falkow picExciting news today: Stanley Falkow, PhD, has been awarded the 2015 National Medal of Science. The honor was announced today by the White House. Falkow is being recognized for his pioneering work in studying how bacteria can cause human disease and how antibiotic resistance is transmitted.

Dean Lloyd Minor, MD, commented in our release:

Dr. Falkow is deeply deserving of this award. He has made invaluable contributions to the field of microbiology and the effect of bacteria on human health. We at Stanford Medicine are extremely proud and honored that he has been recognized by his peers in this way.

Falkow, 81, is an emeritus professor of microbiology and immunology and a member of the Stanford Cancer Institute. The award will be presented in a ceremony at the White House in January 2016.

Falkow is well known for his work on extrachromosomal elements called plasmids and their role in antibiotic resistance and pathogenicity in humans and animals. As a graduate student in the 1960s, he discovered that bacteria gained their resistance to antibiotics by sharing their genes much more promiscuously then had been thought possible. When Falkow arrived at Stanford in 1981, he set aside his study of plasmids to concentrate on how organisms as diverse as cholera, plague and whooping cough cause disease in humans. Along the way he’s mentored countless students and spoken out about the growing threat of antibiotic resistance due to the routine use of antibiotic in animal feed.

As Falkow, who learned of the award on Dec. 19 in an email from John Holdren, PhD, the president’s chief science advisor, said in our announcement:

It was a total surprise. I always say, ‘In science, it’s not ‘I,’ it’s ‘we.’ And it’s so true. There are hundreds of students and colleagues around the world with whom I’d like to share this honor.

I had the honor of writing about Falkow’s work in 2008, when he was awarded the Lasker-Koshland Award for Special Achievement in Medical Science. I thoroughly enjoyed my conversation with him and I’m so happy for today’s announcement.

Previously: National Medal of Science winner Lucy Shapiro: “It’s the most exciting thing in the world to be a scientist”Stanford’s Lucy Shapiro receives National Medal of Science and FDA changes regulation for antibiotic use in animals
Photo by Krista Conger

Aging, Big data, Genetics, Research, Science, Stanford News

Genetic links to healthy aging explored by Stanford researchers

Genetic links to healthy aging explored by Stanford researchers

Old man with babyIs the secret to a long life written in your genes? Or will your annual merry-go-rides around the sun be cut short by disease or poor health? The question is intriguing, but difficult to answer. But that hasn’t stopped researchers from looking for genes or biological traits that may explain why some people live to be very old while others sicken and die at relatively young ages.

Today, developmental biologist Stuart Kim, PhD, published some very interesting research in PLoS Genetics about regions of the human genome that appear to be associated with extreme longevity  (think upper 90s to over 100 years old).

One, a gene called APOE, is associated with the development of Alzheimer’s disease. It’s been previously been implicated in longevity. However, the other four regions identified by the study are new. They are involved in biological processes such as cellular senescence or aging, autoimmune disease and signaling among cells.

As explained in the journal’s press release:

Previous work indicated that centenarians have health and diet habits similar to normal people, suggesting that factors in their genetic make-up could contribute to successful aging. However, prior genetic studies had identified only a single gene (APOE, known to be involved in Alzheimer’s disease) that was different in centenarians versus normal agers.

As we’ve explained here before, studying the very old is difficult, in part because there are so few of them. That makes it hard to come up with statistically significant results when comparing them to others. For this study, Kim and his colleagues devised a new technique to identify regions of the genome associated with longevity by linking it to the likelihood of developing other common diseases or disease-related traits, including type 2 diabetes, bone density, blood pressure and coronary artery disease.

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Cancer, Neuroscience, Research, Science, Stanford News

“Chemobrain” studied by researchers at Stanford, MD Anderson

"Chemobrain" studied by researchers at Stanford, MD Anderson

5490361039_7af0ae216b_zIt’s an unfortunate fact that even successful cancer treatment can leave lasting scars. Surgeries are sometimes needed to remove tumors, skin can be permanently damaged from radiation therapy and powerful chemotherapy drugs can wreak havoc throughout the body.

One of the least understood lasting effects, however, is a cognitive deficit that some survivors describe as “chemobrain.” The difficulties they experience in focusing and remembering are attributed to the neurotoxic effects of chemotherapy. But it’s not been clear whether some drugs are worse than others in this regard.

Now Stanford oncologist Douglas Blayney, MD, and former Stanford faculty member Shelli Kesler, PhD, have published a study in JAMA Oncology assessing cognitive defects in a group of 62 breast cancer patients treated between 2008 and 2014. About one-third of the patients had received a class of chemotherapy drugs that are anthracycline-based, like doxorubicin; one-third received other chemotherapy drugs that were non-anthracycline-based; and the remainder received no chemotherapy at all.

As Blayney explained in an email to me:

Chemotherapy for breast cancer is often associated with cognitive problems in patients. However, it is unclear whether certain treatment regimens are associated with greater cognitive difficulties than others. In a small study, we showed that women treated with anthracycline-based chemotherapy had lower verbal memory, including immediate recall and delayed recall, compared with non-anthracycline chemotherapy treated breast cancer patients, and breast cancer patients not treated with chemotherapy.

Kesler, who has published before on chemobrain in breast cancer patients, is now at MD Anderson Cancer Center in Texas.

Although their results are intriguing, Blayney cautions that the study was relatively small and it’s too soon to start ruling out one type of chemotherapy over another. But it’s important to begin these types of analyses. He writes:

Patient-reported outcomes of cognitive dysfunction and psychological distress were elevated in both groups of women treated with chemotherapy compared with patients treated without chemotherapy.  Our study is hypothesis generating, involves small numbers of patients, there is no dose-response information available, and it is way too soon to abandon doxorubicin adjuvant treatment, which remains a valuable chemotherapeutic agent.  We are currently enrolling in a larger, longitudinal study of women measuring cognitive functioning before any treatment, after completion of systemic treatment, and one year later.

Previously: Wellness after cancer: Stanford opens clinic to address survivors’ needs,  A look at stem cells and “chemobrain” and Stanford study shows effects of chemotherapy and breast cancer on brain function
Image by Steve Snodgrass

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