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Addiction, Behavioral Science, Genetics, Research

Alcohol-use disorder can be inherited: But why?

Alcohol-use disorder can be inherited: But why?

man-69287_1280Drop into any support group meeting, and you’ll likely find that many of the addicts there had a parent who was also an addict. It’s estimated that alcoholism (now sometimes called alcohol-use disorder) is 50 percent heritable, although researchers have struggled to identify genes specifically associated with the condition.

The hunt continues for alcohol-use disorder related genes, and a new frontier in the field is the study of the epigenome, a term that refers to inherited changes that affect gene expression, rather than the genes themselves. A new review by a team based at the University of Pittsburgh School of Medicine in the journal Alcohol compiles all that is known about the effects of the epigenome on alcohol inheritance.

“Only recently, with improvements in technology to identify epigenetic modifications in germ cells, has it been possible to identify mechanisms by which paternal ethanol (alcohol) exposure alters offspring behavior,” the researchers wrote.

The basic mechanism is that traits can be passed on through modification of the proteins associated with DNA; these proteins control how genes are expressed. Several studies have examined the role of a father’s alcohol use in the time period surrounding conception, finding their children more likely to suffer from some psychiatric disorders; in research on mice, some effects of paternal alcohol use include low birth weight and decreased grooming. These effects are likely attributed to the alteration of the development of sperm, the researchers write.

Many mysteries remain, leaving plenty of opportunities for additional research. Now, the team is starting to examine how paternal exposure affects offspring’s alcohol consumption.

Previously: Alcoholism: Not just a man’s problem, Could better alcohol screening during doctor visits reduce underage drinking? and Are some teens’ brains pre-wired for drug and alcohol experimentation?
Image by geralt

Big data, Cancer, Genetics, Immunology, Research, Science, Stanford News

Linking cancer gene expression with survival rates, Stanford researchers bring “big data” into the clinic

Linking cancer gene expression with survival rates, Stanford researchers bring "big data" into the clinic

Magic 8 ball“What’s my prognosis?” is a question that’s likely on the mind, and lips, of nearly every person newly diagnosed with any form of cancer. But, with a few exceptions, there’s still not a good way for clinicians to answer. Every tumor is highly individual, and it’s difficult to identify anything more than general trends with regard to the type and stage of the tumor.

Now, hematologist and oncologist Ash Alizadeh, MD, PhD; radiologist Sylvia Plevritis, PhD; postdoctoral scholar Aaron Newman, PhD; and senior research scientist Andrew Gentles, PhD, have created a database that links the gene-expression patterns of individual cancers of 39 types with the survival data of the more than 18,000 patients from whom they were isolated. The researchers hope that the resource, which they’ve termed PRECOG, for “prediction of cancer outcomes from genomic profiles” will provide a better understanding of why some cancer patients do well, and some do poorly. Their research was published today in Nature Medicine.

As I describe in our release:

Researchers have tried for years to identify specific patterns of gene expression in cancerous tumors that differ from those in normal tissue. By doing so, it may be possible to learn what has gone wrong in the cancer cells, and give ideas as to how best to block the cells’ destructive growth. But the extreme variability among individual patients and tumors has made the process difficult, even when focused on particular cancer types.

Instead, the researchers pulled back and sought patterns that might become clear only when many types of cancers, and thousands of patients were lumped together for study:

Gentles and Alizadeh first collected publicly available data on gene expression patterns of many types of cancers. They then painstakingly matched the gene expression profiles with clinical information about the patients, including their age, disease status and how long they survived after diagnosis. Together with Newman, they combined the studies into a final database.

“We wanted to be able to connect gene expression data with patient outcome for thousands of people at once,” said Alizadeh. “Then we could ask what we could learn more broadly.”

The researchers found that they were able to identify key molecular pathways that could stratify survival across many cancer types:

In particular, [they] found that high expression of a gene called FOXM1, which is involved in cell growth, was associated with a poor prognosis across multiple cancers, while the expression of the KLRB1 gene, which modulates the body’s immune response to cancer, seemed to confer a protective effect.

Alizadeh and Plevritis are both members of the Stanford Cancer Institute.

Previously: What is big data?Identifying relapse in lymphoma patients with circulating tumor DNA,  Smoking gun or hit-and-run? How oncogenes make good cells go bad and Big data = big finds: Clinical trial for deadly lung cancer launched by Stanford study
Photo by CRASH:candy

Applied Biotechnology, Big data, Cancer, Genetics, Research, Science, Stanford News

Peeking into the genome of a deadly cancer pinpoints possible new treatment

Peeking into the genome of a deadly cancer pinpoints possible new treatment

small cell lung cancerSmall cell lung cancer is one of the most deadly kinds of cancers. Typically this aggressive disease is diagnosed fairly late in its course, and the survival rates are so dismal that doctors are reluctant to even subject the patient to surgery to remove the tumor for study. As a result, little is known about the molecular causes of this type of cancer, and no new treatments have been approved by the Food and Drug Administration since 1995.

Now a massive collaboration among researchers around the world, including the University of Cologne in Germany and Stanford, has resulted in the collection of more than 100 human small cell lung cancer tumors. Researchers sequenced the genomes of the tumors and identified some key steps in their development. They also found a potential new weak link for treatment.

The findings were published today in Nature, and Stanford cancer researcher Julien Sage, PhD, one of three co-senior authors of the paper, provided some details in an email:

With this larger number of specimens analyzed, a more detailed picture of the mutations that contribute to the development of small cell lung cancer now emerges. These studies confirmed what was suspected before, that loss of function of the two tumor suppressor genes, Rb and p53, is required for tumor initiation. Importantly, these analyses also identified new therapeutic targets.

The researchers also saw that, in about 25 percent of cases, the Notch protein receptor was also mutated. This protein sits on the surface of a cell; when Notch binds, it initiates a cascade of signaling events within the cell to control its development and growth. As Sage explained:

The mutations in the Notch recepetor were indicative of loss of function, suggesting that Notch normally suppresses small cell lung cancer development. Indeed, when graduate student Jing Lim in my lab activated Notch in mice genetically engineered to develop small cell lung cancer, we found a potent suppression of tumor development. These data identify the Notch signaling pathway as a novel therapeutic target in a cancer type for which new therapies are critically needed.

This is not Sage’s first foray into fighting small cell lung cancer. In 2013, he collaborated with other researchers at Stanford, including oncologist Joel Neal, MD, PhD, to identify a class of antidepressants as a possible therapy for the disease.

Previously: Gene-sequencing rare tumors – and what it means for cancer research and treatment, Listening in on the Ras pathway identifies new target for cancer therapy and Big data = big finds: Clinical trial for deadly lung cancer launched by Stanford study
Image by Yale Rosen

Cancer, Clinical Trials, Dermatology, Genetics, Pain, Pediatrics, Research, Stanford News

The worst disease you’ve never heard of: Stanford researchers and patients battle EB

The worst disease you've never heard of: Stanford researchers and patients battle EB

EB patient and docsI’m often humbled by my job. Well, not the job, exactly, but the physicians, researchers, and especially patients who take the time to speak with me about their goals and passions, their triumphs and fears. Their insight helps me as I struggle to interpret what goes on here at the Stanford University School of Medicine for others across the university and even around the world.

But every once in a while, an article comes along that brings me to my (emotional) knees. My article “The Butterfly Effect” in the latest issue of Stanford Medicine magazine describes the toll of a devastating skin disease called epidermoloysis bullosa on two young men and their families, as well as the determined efforts of a dedicated team of doctors and scientists to find a treatment. As a result, Stanford recently launched the world’s first stem-cell based trial aimed at correcting the faulty gene in the skin cells of patients with a severe form of the condition, which is often called EB.

I trace the path of one family as they learn, mere hours after his birth, that their son, Garrett Spaulding, has EB, which compromises the ability of the outer layers of the to stick together during friction or pressure. Patients develop large blisters and open wounds over much of their bodies. It’s incurable, fatal, and nearly indescribably painful. Paul Khavari, MD, PhD, now the chair of Stanford’s Department of Dermatology, was a young doctor at the time newborn Garrett was admitted to Lucile Packard Children’s Hospital Stanford in 1997.

“His whole body, his skin was blistered and falling off everywhere someone had touched him,” Khavari recalls in the article. “His parents were devastated, of course, at a time that was supposed to be one of the most joyful of their lives.”

Garrett’s now 18 years old, but the disease is taking its toll.

You’ll also meet Paul Martinez, one of the first participants in Stanford’s new clinical trial. He’s 32, which makes him an old man in the EB community. Unlike many EB patients, he has finished high school and completed a college degree in business marketing with a dogged determination that makes me ashamed of my petty complaints about my minor life trials. And he’s done it without relying on the pain medications essential for most EB patients. As he explains in the article:

We don’t know what it is like to not be in pain. It’s just normal for us. […] I have a very high tolerance, and don’t take any pain medication. I cherish my mind a lot. Rather than feel like a zombie, I prefer to feel the pain and feel alive.

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Aging, Cancer, Dermatology, Genetics, Research, Stanford News

Genetic secrets of youthful skin

Genetic secrets of youthful skin

new hatEvery year, upwards of $140 billion a year gets spent on cosmetics. In the United States alone, says an authoritative report, a recent year saw upwards of 5.6 million Botox procedures, 1.1 million chemical peels, almost a half-million laser skin procedures, 196,286 eyelid surgeries and a whole bunch of face lifts.

If you’ve got the courage to compare your present-tense face with the one you were wearing 20 or even 10 years ago, you’ll see why. As I wrote in a just-published Stanford Medicine article, “Wither youth?”:

The terrain of aging skin grows all too familiar with the passing years: bags under the eyes, crow’s feet, jowls, tiny tangles of blood vessels, ever more pronounced pores and pits and pigmentation irregularities. Then there are wrinkles — long, deep “frown lines” radiating upward from the inside edges of the eyebrows and “laugh lines” that trace a furrow from our nostrils to the edges of our lips in our 40s, and finer lines that start crisscrossing our faces in our 50s. Sagging skin gets more prominent in our later years as we lose bone and fat.

“And,” I added wistfully, “it’s all right there on the very outside of us, where everyone else can see it.”

Stanford dermatologist Anne Chang, MD, who sees a whole lot of skin, got to wondering: Why does skin grow old? Armed with a sophisticated understanding of genetics, she went beyond lamenting lost youth and resolved to address the question scientifically, asking: “Can you turn back time? Can aging effects be reversed? Can you rejuvenate skin, make it young again?”

The answers she’s come up with so far – from hereditary factors to a possible underlying genetic basis for how some treatments now in common commercial cosmetic use (such as broadband light therapy) could potentially slow or even reverse the aging of skin – are described in my magazine article.

Previously: This summer’s Stanford Medicine magazine shows some skinResearchers identify genetic basis for rosacea, New study: Genes may affect skin youthfulness and Aging research comes of age
Photo by thepeachpeddler

Big data, BigDataMed15, Chronic Disease, Genetics, Videos

Parents turn to data after son is diagnosed with ultra-rare disease

Parents turn to data after son is diagnosed with ultra-rare disease

Keynote talks and presentations from the 2015 Big Data in Biomedicine conference at Stanford are now available on the Stanford YouTube channel. To continue the discussion of how big data can be harnessed to improve the practice of medicine and enhance human health, we’re featuring a selection of the videos on Scope.

Four years ago, Matthew Might, PhD, and his wife, Christina, learned that their son Bertrand was the first person to be diagnosed with ultra-rare genetic disorder called N-Glycanase Disorder. At the 2015 Big Data in Biomedicine conference at Stanford, Might recounted the story of his son’s medical odyssey and explained how a team of Duke University researchers used whole-exome sequencing, which is a protein-focused variant of whole-genome sequencing, on himself, his wife and Bertrand to arrive at his son’s diagnosis.

Watch the video above to find out how Might and his family, who turned a deaf ear to doctors’ advice that nothing could be done for their son, harnessed the power of the Internet to identify 35 more patients with the same disorder and are now leading the charge in helping scientists better understand the disorder.

Previously: Nobel Laureate Michael Levitt explains why “biology is information rich” at Big Data in Biomedicine, At Big Data in Biomedicine, Stanford’s Lloyd Minor focuses on precision health, Experts at Big Data in Biomedicine: Bigger, better datasets and technology will benefit patients, On the move: Big Data in Biomedicine goes mobile with discussion on mHealth and Big Data in Biomedicine panelists: Genomics’ future is bright

Genetics, In the News, Research, Science, Stanford News, Stem Cells, Technology

CRISPR marches forward: Stanford scientists optimize use in human blood cells

CRISPR marches forward: Stanford scientists optimize use in human blood cells

The CRISPR news just keeps coming. As we’ve described here before, CRISPR is a breakthrough way of editing the genome of many organisms, including humans — a kind of biological cut-and-paste function that is already transforming scientific and clinical research. However, there are still some significant scientific hurdles that exist when attempting to use the technique in cells directly isolated from human patients (these are called primary cells) rather than human cell lines grown for long periods of time in the laboratory setting.

Now pediatric stem cell biologist Matthew Porteus, MD, PhD, and postdoctoral scholars Ayal Hendel, PhD, and Rasmus Bak, PhD, have collaborated with researchers at Santa Clara-based Agilent Research Laboratories to show that chemically modifying the guide RNAs tasked with directing the site of genome snipping significantly enhances the efficiency of editing in human primary blood cells — an advance that brings therapies for human patients closer. The research was published yesterday in Nature Biotechnology.

As Porteus, who hopes to one day use the technique to help children with genetic blood diseases like sickle cell anemia, explained to me in an email:

We have now achieved the highest rates of editing in primary human blood cells. These frequencies are now high enough to compete with the other genome editing platforms for therapeutic editing in these cell types.

Porteus and Hendel previously developed a way to identify how frequently the CRISPR system does (or does not) modify the DNA where scientists tell it. Hendel characterizes the new research as something that will allow industrial-scale manufacturing of pharmaceutical-grade CRISPR reagents. As he told me:

Our research shows that scientists can now modify the CRISPR technology to improve its activity and specificity, as well as to open new doors for its use it for imaging, biochemistry, epigenetic, and gene activation or repression studies.

Rasmus agrees, saying, “Our findings will not only benefit researchers working with primary cells, but it will also accelerate the translation of CRISPR gene editing into new therapies for patients.”

Onward!

(Those of you wanting a thorough primer on CRISPR —how it works and what could be done with it — should check out Carl Zimmer’s comprehensive article in Quanta magazine. If you prefer to learn by listening (perhaps, as I sometimes do, while on the treadmill), I found this podcast from Radiolab light, but interesting.)

Previously: Policing the editor: Stanford scientists devise way to monitor CRISPR effectiveness and “It’s not just science fiction anymore”: Childx speakers talk stem cell and gene therapy

 

Chronic Disease, Genetics, Health Disparities, Pediatrics, Research, Stanford News

Cystic fibrosis is deadlier for Hispanic patients, Stanford study finds

Cystic fibrosis is deadlier for Hispanic patients, Stanford study finds

Lungs-embroideryHow do physician-scientists select research projects? Sometimes, they’re prompted by the niggling feeling that something is not right.

That’s what happened to cystic fibrosis doctor MyMy Buu, MD, the lead author on a new paper that uncovers an important health disparity, a higher mortality rate for CF patients of Hispanic ethnicity. Buu, a pediatric pulmonologist who takes care of CF kids at Lucile Packard Children’s Hospital Stanford, launched the research because she noticed something worrying: It seemed to her that a lot of Hispanic children with CF were not doing well.

“…I didn’t know if this was just because we have more Hispanic patients in California, or if they were actually, really, sicker,” Buu said. CF is a genetic disease that causes serious breathing and digestive problems; Buu’s job is a mixture of trying to help her patients stay relatively healthy and dealing with complications of the disease.

“Because I’m interested in health disparities, I wanted to see if there were any differences in outcomes in the Hispanic group,” she said.

She turned to the Cystic Fibrosis Foundation‘s patient registry, focusing on 20 years of data that encompass every California child diagnosed with CF from the beginning of 1991 to the end of 2010. Of the children studied, Hispanic CF patients were almost three times as likely to die as their non-Hispanic counterparts.

Buu and her colleagues were able to use the data to eliminate several possible explanations for the disparity. Hispanic children were not being diagnosed later than non-Hispanic kids and did not have less access to health care, for instance. Our press release about the study describes the factors that may contribute to the disparity:

However, the researchers did find important clinical and social differences between the groups. At age 6, the earliest that lung function is routinely and reliably measured for patients with CF, Hispanic children with CF had worse lung function than non-Hispanic kids with the disease. The gap in lung function persisted as the children aged, although it did not widen. And although the same proportion of patients in both groups eventually developed CF complications, the complications struck Hispanic patients earlier in life. Hispanic patients lived in poorer neighborhoods and were more likely to be covered by public health insurance than their non-Hispanic counterparts.

The research also showed that, between the two groups, different mutations prevailed in the disease-causing gene, which is called the CF transmembrane conductance regulator gene. Hispanic patients tended to have rare and poorly characterized mutations in their CFTR gene, whereas non-Hispanic patients had more common mutations that have been more extensively researched.

The next steps, Buu said, are to make others aware of the increased risk for Hispanic CF patients and to figure out how the risk can be reduced.

Previously: Cystic fibrosis patient on her 20+ years of care, New Stanford-developed sweat test may aid in development of cystic fibrosis treatments and Film about twin sisters’ double lung transplants and battle against cystic fibrosis available online
Image by Hey Paul Studios

Evolution, Genetics, Research, Science, Stanford News

Kennewick Man’s origins revealed by genetic study

Kennewick Man's origins revealed by genetic study

K man - 560

One day in 1996, on the banks of the Columbia River near Kennewick, Washington, two men found a human skull about ten feet from shore. Eventually, the nearly complete skeleton of an adult man was unearthed and found to be nearly 9,000 years old.

Since that find, controversy has swirled as to whether the man was an ancestor of Native American tribes living in the area, or was more closely related to other population groups around the Pacific Rim. A study published in 2014, based in part on anatomical measurements, concluded that the skeleton, known as the Kennewick Man, was more likely related to indigenous Japanese or Polynesian peoples.

Now Stanford geneticists Morten Rasmussen, PhD, and Carlos Bustamante, PhD, working with Eske Willerslev, PhD, and others at the University of Copenhagen’s Centre for GeoGenetics have studied tiny snippets of ancient DNA isolated from a hand bone. They’ve compared these DNA sequences with those of modern humans and concluded that the Kennewick Man (known to many Native Americans as the Ancient One) is more closely related to Native American groups than to any other population in the world.

The findings are published today online in Nature, and they’re likely to reignite an ongoing controversy as to the skeleton’s origins and to whom the remains belong.

As Rasmussen said in our press release:

Due to the massive controversy surrounding the origins of this sample, the ability to address this will be of interest to both scientists and tribal members. […]

Although the exterior preservation of the skeleton was pristine, the DNA in the sample was highly degraded and dominated by DNA from soil bacteria and other environmental sources. With the little material we had available, we applied the newest methods to squeeze every piece of information out of the bone.

Increasingly, such methods of isolating and sequencing ancient DNA are being used to solve millennia-old mysteries, including those surrounding Otzi the Iceman and a young child known as the Anzick boy buried more than 12,000 years ago in Montana.

Bustamante explained in the release:

Advances in DNA sequencing technology have given us important new tools for studying the great human diasporas and the history of indigenous populations. Now we are seeing its adoption in new areas, including forensics and archeology. The case of Kennewick Man is particularly interesting given the debates surrounding the origins of Native American populations. Morten’s work aligns beautifully with the oral history of native peoples and lends strong support for their claims. I believe that ancient DNA analysis could become standard practice in these types of cases since it can provide objective means of assessing both genetic ancestry and relatedness to living individuals and present-day populations.

Previously: Caribbean skeletons hold slave trade secrets,  Melting pot or mosaic? International collaboration studies genomic diversity in Mexico and  On the hunt for ancient DNA, Stanford researchers improve the odds
Photo, of bust showing how Kennewick Man may have looked, by Brittany Tatchell/Smithsonian (bust by StudioEIS; forensic facial reconstruction by sculptor Amanda Danning)

Biomed Bites, Evolution, Genetics, Research, Science, Videos

One mutation, two people and two (or more) outcomes: What gives?

One mutation, two people and two (or more) outcomes: What gives?

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

Tweak a piano string and you’ve created a different note. Tweak a gene and no one knows exactly what might happen. Perhaps the resultant protein is completely defective. Perhaps the same change does nothing in me but turns your world upside down. Who knows?

One Stanford researcher is working to demystify some of that variability, an endeavor that could lead to big changes in the development of therapies for diseases such as cancer. Daniel Jarosz, PhD, assistant professor of chemical and systems biology and of developmental biology, describes his work in the video above:

We all know there are many mutations associated with disease, for example, that give rise to that disease in some patients, yet there are other patients that have the same mutations and don’t have any effects. We’d really like to understand that…

The clinical benefits of this work are potentially very large.

For example, Jarosz said he and his team study why some tumor genes are able to evolve rapidly to evade chemotherapy. With a greater understanding of what conditions cause rapid evolution — and drug resistance — they can more easily evaluate new therapies.

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

Previously: From finches to cancer: A Stanford researcher explores the role of evolution in disease, Computing our evolution and Whole genome sequencing: The known knowns and the unknown unknowns

Stanford Medicine Resources: