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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

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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

Genetics, HIV/AIDS, Infectious Disease, Research, Stanford News

Study shows toothed whales have persisted millions of years without two common antiviral proteins

Study shows toothed whales have persisted millions of years without two common antiviral proteins

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Our ability to fend off the flu, HIV and other viruses is enhanced when proteins are produced by two “immune genes,” called MX1 and MX2. Other mammals also have these genes, but little is known about the role they play in the immune responses of these animals.

Now a study comparing the genomes and Mx genes of 60 mammal species has revealed a surprising finding: Every species in the study has functioning Mx1 and Mx2 genes except for dolphins, whales and orcas — species from a lineage of toothed whales that’s persisted for roughly 33 million years.

Gill Bejerano, PhD, a geneticist and developmental biologist, graduate student Benjamin Braun and their team wanted to know more about the status and function of Mx genes in non-human mammals. To do this, they examined and compared the part of the genome that contains the Mx genes in 60 different species including humans, cows, whales, dolphins and orcas.

I think this will open up very exciting research avenues, either to better protect the compromised whales, or to study their different viral defenses, and someday add them to our own arsenal.

The study, published this week in the Proceedings of National Sciences, showed that the Mx1 and Mx2 genes in the toothed whales (bottlenose dolphin, orca, Yangtze river dolphin and sperm whale) they tested were non-functional, and couldn’t produce the proteins that help fight viral infections. Bejerano explained the significance of this finding in our press release:

Given how important the Mx genes seem to be in fighting off disease in humans and other mammals, it’s striking to see a species lose them both and go about its business for millions of years.

To find out when in evolutionary history these genes became inactive the researchers compared the genomes of toothed whales to that of their closest ancestors, the baleen whales and hoofed mammals (ungulates). They found that the Mx genes function in baleen whales and hoofed mammals, but not in toothed whales. This means that some — perhaps all — toothed whales likely lost use of their Mx genes when this lineage split off from these ancestors about 33 million years ago (see Fig. 1).

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Genetics, Imaging, Neuroscience, Research, Stanford News

From phrenology to neuroimaging: New finding bolsters theory about how brain operates

From phrenology to neuroimaging: New finding bolsters theory about how brain operates

phrenologyNeuroscience has come a long way since the days of phrenology, when lumps on the outside of the skull were believed to denote enhanced size and strength of the particular brain region responsible for particular individual functions. Today’s far more advanced neuroimaging technologies allow scientists to peer deep into the living brain, revealing not only its anatomical structures and the tracts connecting them but, in recent years, physiological descriptions of the brain at work.

Visualized this way, the brain appears to contain numerous “functional networks:” clusters of remote brain regions that are connected directly via white-matter tracts or indirectly through connections with mediating regions. These networks’ tightly coupled brain regions not only are wired together, but fire together. Their pulses, purrs and pauses, so to speak, are closely coordinated in phase and frequency.

Well over a dozen functional networks, responsible for brain operations such as memory, language processing, vision and emotion, have been identified via a technique called resting-state functional magnetic resonance imaging. In a resting-state fMRI scan, the individual is asked to simply lie still, eyes closed, for several minutes and relax. These scans indicate that even at rest, the brain’s functional networks continue to hum along — albeit at lower volumes — at distinguishable frequencies and phases, like so many different radio stations playing simultaneously on the same radio.

But whether the images obtained via resting-state fMRI truly reflect neuronal activity or are some kind of artifact has been controversial. Now, a new study led by neuroscientist Michael Greicius, MD, and just published in Science, has found genetic evidence that convincingly bolsters neuroimaging-based depictions of these brain-activity patterns.

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Biomed Bites, Genetics, Infectious Disease, Research, Videos

Why are viruses so wily? One researcher thinks she knows — and is working to thwart them

Why are viruses so wily? One researcher thinks she knows — and is working to thwart them

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

Some of the world’s best known viruses use RNA, rather than DNA, to code for proteins, including polio, measles and hepatitis C. There are a few differences:  RNA uses a component not used in DNA, and RNA is usually single-stranded, rather than the familiar double helix of DNA.

RNA viruses change rapidly, evading efforts to develop vaccines and therapies. But the change is uneven — some genes evolve with nearly every replication, others stay the same for generations. Molecular biologist Karla Kirkegaard, PhD, wondered why. The chair of Stanford’s Department of Microbiology and Immunology explains her discovery in the video above:

The answer was unusual. It turns out that there are different kinds of selective pressures on these regions, and it is very hard for new variants to arise in certain regions because their family members around them poison their advantage.

Alone, for example, a mutated gene might perform better than one that is unaltered. But when it is mixed with other genes, it might make the resultant virus less competitive.

That offers valuable insight for drug development, she said. Consider the interaction of genes and viruses together, rather than aiming to disable a single player, Kirkegaard advises:

My quest right now is to convince people who target antivirals for the common cold, West Nile virus and SARS to think about those processes the viruses have to cooperate on so we won’t have such a big problem with drug resistance.

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

Previously: Ending enablers: Stanford researcher examines genes to find virus helpers, A conversation on West Nile virus and its recent California surge and Exploring the role of extracellular RNA communication in human disease

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

Stanford researchers suss out cancer mutations in genome’s dark spots

Stanford researchers suss out cancer mutations in genome's dark spots

lighted pathOnly a small proportion of our DNA contains nucleotide sequences used to make proteins. Much of the remainder is devoted to specifying how, when and where those proteins are made. These rules are encoded in our DNA as regulatory elements, and they’re what makes one cell type different from another, and keep them from running wild like children in an unattended classroom. When things go awry, the consequences (like rampant growth and cancers) can be severe.

Geneticist Michael Snyder, PhD, and postdoctoral scholar Collin Melton, PhD, recently combined information from The Cancer Genome Atlas, a national effort to sequence and identify mutations in the genomes of many different types of cancers, with data from the national ENCODE Project, which serves as an encyclopedia of DNA functional regions, or elements. Their aim was to better understand the roles that mutations in regulatory regions may play in cancer development.

Snyder and Melton found that fewer than one of every thousand mutations in each cancer type occurs in the coding region of a gene. In contrast, more than 30 percent of the mutations occur in regulatory regions. The study was published this morning in Nature Genetics.

As Snyder explained to me:

Until recently, many mutations outside the coding regions of genes have been mostly invisible to us. Cancer researchers largely focused on identifying changes within coding regions. Using ENCODE data, we’ve been able to define some important regions of the genome and found that certain regulatory regions are often enriched for mutations. This opens up a whole new window for this type of research.

Snyder, who leads Stanford’s genetics department and directs the Stanford Center for Genomics and Personalized Medicine, likens looking for cancer-causing mutations only in coding regions as “looking under the lamppost” for keys lost at night. Until recently, the coding regions of genes were the most well-studied, and unexpected mutations stood out like a sore thumb. We’ve known there’s a lot more of the genome outside the coding regions, but until the ENCODE project was largely completed in 2012, researchers were often in the dark as to where, or even how, they should look.

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