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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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Biomed Bites, Genetics, Research, Videos

RNA editing: Many mysteries remain

RNA editing: Many mysteries remain

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

DNA, RNA, protein, end of story, right? Well, no. Sometimes, RNA is edited after it is created. These new revised copies can perform different functions or contribute to the development of disease.

But for decades, no one had a great way to examine post-transcriptional changes to RNA, much less understand what role they play in cellular processes. Thanks to advances in technology, that is changing.

In the video above, Jin Billy Li, PhD, assistant professor of genetics, explains how his lab is working to unravel RNA’s remaining secrets. “In the future, we hope to associate this interesting phenomenon with human neurological conditions such as autism, epilepsy, depression and ALS,” he says.

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

Previously: Tissue-specific gene expression focus of Stanford research, grant, “Housekeeping” RNAs have important, and unsuspected, role in cancer prevention, study shows and Make it or break it — or both: New research reveals RNA’s dual role

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
Image by OpenClipartVectors

Genetics, Pediatrics, Precision health, Research

New cystic fibrosis screening test developed at Stanford

New cystic fibrosis screening test developed at Stanford

LungsStanford researchers have invented a new technique to detect cystic fibrosis in infants. The test, described in a paper published today in The Journal of Molecular Diagnostics, is more comprehensive, faster and cheaper than current newborn screening methods.

CF, which causes buildup of sticky mucus in the lungs and digestive organs, is the country’s most common fatal genetic disease. Newborn screening for the disease has been conducted in every U.S. state since 2010 and has mostly been a success story: Early diagnosis helps doctors start CF therapy more quickly, which can keep patients healthier longer. With good medical care, such as that provided by the CF experts at Lucile Packard Children’s Hospital Stanford, many people with CF now live into their 40s or beyond.

“Kids who are diagnosed early [with genetic screening tests] do not have a symptom-based diagnosis, so they don’t have to recover from any health insults,” study co-author Iris Schrijver, MD, told me when we discussed the research.

But there are limitations to the current screening tests. One big problem is that they can miss rare mutations in the CF gene, particularly those that prevail in nonwhite populations about whose CF changes scientists have limited knowledge. That’s especially an issue in California, where the 500,000 babies born each year have very diverse heritages. In fact, to help illuminate the problems of older CF tests, Schrijver recently published another study about the difficulty nonwhite CF patients face in receiving timely diagnosis.

In contrast to the current screening tests, the new test will detect virtually all CF-causing mutations in one step, which should make it far easier to find every affected newborn.

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Genetics, Immunology, Microbiology, Research, Stanford News

Special delivery: Discovery of viral receptor bodes better gene therapy

Special delivery: Discovery of viral receptor bodes better gene therapy

8565673108_28e017bf50_zGene therapy, whereby a patient’s disorder is treated by inserting a new gene, replacing a defective one, or disabling a harmful one, suffered a setback in 1999, when Jesse Gelsinger, an 18-year-old with a genetic liver disease, died from immense inflammatory complications four days after receiving gene therapy for his condition during a clinical trial. It was quite a while before clinical trials in gene therapy resumed.

But what Stanford virologist Jan Carette, PhD, describes as “intense interest” in the field is once again in full bloom. Gene therapies for several inherited genetic disorders have been approved in Europe, and a gene-therapy approach for countering congenital blindness is close to approval in the United States.

That a virologist would be paying such close attention to this topic isn’t odd, as the most well-worked-out method for introducing genetic material to human cells involves the use of a domesticated virus.

If there’s one thing viruses are really good at, it’s infecting cells. Another viral trick is transferring their genes into cellular DNA — it’s part of their modus operandi: hijacking cells’ replicative machinery and diverting it to production of numerous copies of themselves. Scientists have become increasingly adept at taming viruses, tweaking them so they retain their ability to infect cells and insert genes, but no longer contain factors that wreck tissues or taunt the infected victim’s immune system into a rage destructive to virus and victim alike.

Adenovirus-associated virus — ubiquitous in people and not associated with any disease – makes a great workhorse. Properly bioengineered, it can infect all kinds of cells without replicating itself inside of them or triggering much of an immune response, instead obediently depositing medically relevant genes into the infected cells to repair a patient’s defective metabolic, enzymatic, or synthetic pathways.

Figuring out how to tailor this viral servant so it will invade cells more efficiently, or invade some kinds of cells and tissues but not others, would broaden gene therapy’s utility and appeal. In a series of experiments described in a study in Nature, Carette’s group, with collaborators from Oregon Health & Science University and the Netherlands, used a sophisticated method pioneered by Carette to bring that capability a step closer.

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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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Big data, Genetics, Precision health, Research

Precision health in action — The hunt for families with a high-cholesterol disorder

Precision health in action — The hunt for families with a high-cholesterol disorder

3440634940_efbb70438d_zIf I don’t know I have a genetic disease, I’m not very likely to seek treatment or change my lifestyle. This lack of knowledge, obviously, leaves me medically vulnerable.

To find people who have one such disease — familial hypercholesterolemia (FH), a condition that causes high levels of LDL cholesterol — biomedical data specialist Nigam Shah, MBBS, PhD, and cardiologist Joshua Knowles, MD, PhD, are applying the powers of big data. Their work has been called a prime example of precision health.

A recent feature by FiveThirtyEight explains their work:

They started by identifying about 120 people known to have FH (true positives) from Stanford’s network of hospitals and doctors’ offices, and some people with high LDL who don’t have the genetic disorder (true negatives). Shah then began to train a computer to spot people with FH by letting it look through those patients’ files and to identify patterns in things like cholesterol levels, age, and the medicine patients were prescribed. The researchers then deployed this algorithm to look for undiagnosed FH within Stanford’s health records.

Using medical billing and lab data, the FH Foundation — Knowles is its chief medical officer — has developed a map to highlight the frequency of FH cases in the United States. Though imprecise, the map is intriguing, showing the condition is clustered on the East Coast, with a few notable exceptions such as a dense patch in eastern Oregon.

These efforts could improve current screening methods and allow affected families to obtain treatment and make life-extending changes in their diet and exercise patterns, the article states.

Previously: Big data used to help identify patients at risk of deadly high-cholesterol disorder, Could patients’ knowledge of their DNA lead to better outcomes? and Push-button personalized treatment guidance for patients not covered by clinical-trial results
Image by x6e38

Bioengineering, Ethics, Genetics, In the News, Research, Science

Are at-home gene splicing kits a good idea? Stanford researchers weigh in

Are at-home gene splicing kits a good idea? Stanford researchers weigh in

chemist_stick_figure_by_wrpigeekAs demonstrated by the Foldscope, the uber-affordable microscope developed by Stanford bioengineer Manu Prakash, PhD — there is real fervor for bringing easy, do-it-yourself science to the masses. But what if that at-home science allows novices to dabble in some serious stuff, like splicing genes?

One Bay Area scientist has done just that: He’s marketing a $130 gene-editing kit that could bring the popular technology CRISPR into kitchens, basements and garages nationwide.

This particular kit isn’t particularly dangerous, according to a recent article in the San Jose Mercury News:

The kit has limited applications. His altered bacteria and yeast, quite harmless, lead brief and fairly dull lives. They can’t do much except change color, fragrance or live in inhospitable places. Then they die.

But two Stanford experts — infectious disease researcher David Relman, MD, and bioethicist Hank Greely, JD — agree it could place powerful technology in the hands of people who might not use it responsibly.

“I do not think that we want an unregulated, non-overseen community of freelance practitioners of this technology,” Relman told the Mercury News.

Regulation, or control, might not be possible, though, Greely cautioned. “You’ve got guys with B.S. degrees, in a garage,” he said in the article.

Kit developer Josiah Zayner doesn’t have a garage. But one version of the kit has already sold out.

Previously: CRISPR critters and CRISPR conundrums, Foldscope inventor named one of the world’s top innovators under 35 by Technology Review and Manu under the microscope
Image by WRPIgeek

Genetics, Research, Stanford News

Epigenetics controls social dominance in African fish

Epigenetics controls social dominance in African fish

15995-fish_newsFor the few flashy, colorful male African cichlid fish, life is good. They control food, females and territory, and all the other fishies must follow their lead.

But 80 percent of the population is comprised of low-ranking males, dull-grey in color who must compete with the females to find food.

A team of Stanford researchers set out to see why some fish flourish, while the others flounder, discovering that changes in the expression of the cichlid’s genes, known as epigenetic changes, are responsible. In particular, a process called methylation adds methyl molecules to genes, controlling their expression. From the Stanford News release:

“Status differences exist in all social organisms,” said Russell Fernald, a biology professor at Stanford University and senior author of the study. “Our work reveals how social dominance status is possibly regulated through methylation, which is important because individuals higher in rank generally enjoy better health and quality of life.”

Fernald and his team manipulated the fish in his lab to directly test their hypothesis:

Several pairs of non-dominant males matched in size were each placed in an aquarium that could support only one territory. In each pair, one male was injected with a methylating agent while the other received a methylation suppressor, and the two fish fought for dominance.

“We could see the behavioral change in a matter of minutes, as one animal began to dominate the other,” Fernald said. “Videos of these confrontations showed that the fish injected with the methylating agent were much more likely to be the winners, while those receiving the methylation suppressor typically lost the fight for dominance.

“It was remarkable that we could determine which fish became dominant by changing the range of genes expressed in this context,” he said.

The release also explains the cichlids’ quirky mating process, which requires the male to fool the female by flashing a fin covered with egg-like spots. Thinking she dropped her eggs, the female tries to collect them, gathering sperm in the process.

For more, check out the study in PLoS ONE.

Previously: Using epigenetics to explain how Captain America and the Incredible Hulk gained their superpowers, A tiny fish helps solve how genes influence longevity and My funny Valentine — or, how a tiny fish will change the world of aging research
Photo by L.A. Cicero

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