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Evolution, Genetics, Microbiology, Pregnancy, Research, Science, Stanford News, Stem Cells

My baby, my… virus? Stanford researchers find viral proteins in human embryonic cells

My baby, my... virus? Stanford researchers find viral proteins in human embryonic cells

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One thing I really enjoy about my job is the opportunity to constantly be learning something new. For example, I hadn’t realized that about eight percent of human DNA is actually left-behind detritus from ancient viral infections. I knew they were there, but eight percent? That’s a lot of genetic baggage.

These sequences are often inactive in mature cells, but recent research has shown they can become activated in some tumor cells or in human embryonic stem cells. Now developmental biologist Joanna Wysocka, PhD, and graduate student Edward Grow, have shown that some of these viral bits and pieces spring back to life in early human embryos and may even affect their development.

Their research was published today in Nature. As I describe in our press release:

Retroviruses are a class of virus that insert their DNA into the genome of the host cell for later reactivation. In this stealth mode, the virus bides its time, taking advantage of cellular DNA replication to spread to each of an infected cell’s progeny every time the cell divides. HIV is one well-known example of a retrovirus that infects humans.

When a retrovirus infects a germ cell, which makes sperm and eggs, or infects a very early-stage embryo before the germ cells have arisen, the viral DNA is passed along to future generations. Over evolutionary time, however, these viral genomes often become mutated and inactivated. About 8 percent of the human genome is made up of viral sequences left behind during past infections. One retrovirus, HERVK, however, infected humans repeatedly relatively recently — within about 200,000 years. Much of HERVK’s genome is still snuggled, intact, in each of our cells.

Wysocka and Grow found that human embryonic cells begin making viral proteins from these HERVK sequences within just a few days after conception. What’s more, the non-human proteins have a noticeable effect on the cells, increasing the expression of a cell surface protein that makes them less susceptible to subsequent viral infection and also modulating human gene expression.

More from our release:

But it’s not clear whether this sequence of events is the result of thousands of years of co-existence, a kind of evolutionary symbiosis, or if it represents an ongoing battle between humans and viruses.

“Does the virus selfishly benefit by switching itself on in these early embryonic cells?” said Grow. “Or is the embryo instead commandeering the viral proteins to protect itself? Can they both benefit? That’s possible, but we don’t really know.”

Wysocka describes the findings as “fascinating, but a little creepy.” I agree. But I can’t wait to hear what they discover next.

Previously: Viruses can cause warts on your DNA, Stanford researcher wins Vilcek Prize for Creative Promise in Biomedical Science and Species-specific differences among placentas due to long-ago viral infection, say Stanford researchers
Photo of Joanna Wysocka by Steve Fisch

Cancer, Genetics, Patient Care, Research, Science, Stanford News

Identifying relapse in lymphoma patients with circulating tumor DNA

Identifying relapse in lymphoma patients with circulating tumor DNA

3505577004_6fc17ba8c2_zCancer patients in remission often live on a knife’s edge, wondering if their disease will recur. This possibility is more likely in some types of cancers than in others. One of these is diffuse large B-cell lymphoma, which is the most common blood cancer in this country. It’s often successfully treated, but a significant minority of patients will relapse. Detecting these relapses early is critical, but difficult.

Hematologist and oncologists Ash Alizadeh, MD, PhD, and David Kurtz, MD, and former postdoctoral scholar Michael Green, PhD, wanted to find a better way to track disease progression in these patients. They’ve developed a new technique, published Friday in the journal Blood, that is more accurate and can detect relapses earlier than conventional methods.

“As a clinician, I care for many of these patients,” Alizadeh explained to me. “Detecting relapse can be very difficult. It would be a major step forward to develop a way to identify these patients before they become sick again.”

Detecting relapse can be very difficult. It would be a major step forward to develop a way to identify these patients before they become sick again.

The researchers turned to what’s known as circulating tumor DNA in the blood. The approach, which was pioneered by Stanford bioengineer Stephen Quake, PhD, relies on the idea that when the cells in our body die, they rupture and release their contents, including their DNA, into our bloodstream. Tracking the rise and fall of the levels of these tiny snippets of genetic information can give insight into what is happening throughout the body.

When a B cell becomes cancerous, it begins to divide uncontrollably. Each of these cancer cells shares the DNA sequence of the original cell; as the cells multiply, so does the overall amount of that DNA sequence in the body. Alizadeh and his colleagues wondered whether tracking the levels of cancer-specific DNA in a patient’s blood could help them identify those patients in the early stages of relapse.

Currently patients in remission are monitored for relapse with regular physical exams and blood tests. Imaging techniques such as PET or CT scans can be used to look for residual disease, but they don’t detect every case, and often deliver false positive results. They are also costly and expose the patient to DNA-damaging radiation that could potentially cause secondary cancers years later.

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Big data, Events, Genetics, Stanford News, Videos

Using genetics to answer fundamental questions in biology, medicine and anthropology

Using genetics to answer fundamental questions in biology, medicine and anthropology

At last year’s Big Data in Biomedicine conference, Stanford geneticist Carlos Bustamante, PhD, spoke about the potential of using genetic information to answer fundamental questions in biology, medicine and anthropology. In this video from the 2014 event, Bustamante explains his lab’s efforts to better understand the structure of human genome, how genetic variations are portioned among different human populations and the significance of this information for designing medical genetic studies.

Bustamante will return to the Big Data in Biomedicine conference in May to moderate the genomics session. Speakers for the session are Christina Curtis, PhD, assistant professor of medicine and genetics at Stanford; Yaniv Erlich, PhD, assistant professor of computer science at Columbia University and a core member at the New York Genome Center; David Glazer, director of Engineering at Google and founder of the Google Genomics team; and Heidi Rehm, PhD, director of the Partners Laboratory for Molecular Medicine and associate professor of pathology at Harvard Medical School.

The conference will be held May 20-22 at the Li Ka Shing Center for Learning and Knowledge at Stanford; registration details can be found on the event website.

Previously: Big data used to help identify patients at risk of deadly high-cholesterol disorder, Examining the potential of big data to transform health care and Registration for Big Data in Biomedicine conference now open

Events, Genetics, Patient Care, Pediatrics, Research, Stanford News, Stem Cells

“It’s not just science fiction anymore”: Childx speakers talk stem cell and gene therapy

“It’s not just science fiction anymore": Childx speakers talk stem cell and gene therapy

childx PorteusAt the Childx conference last week there was a great deal of optimism that stem cell and genetic therapies are about to have a huge impact on many childhood disease. “It’s not just science fiction anymore,” Matthew Porteus, MD, PhD, told the audience. “We can correct mutations that cause childhood diseases.”

The session was hosted by Stanford professor Maria Grazia Roncarolo, MD, who until recently was head of the Italy’s Telethon Institute for Cell and Gene Therapy at the San Raffaele Scientific Institute in Milan. Roncarolo pointed out that there are more than 10,000 human diseases that are caused by a single gene defect. “Stem cell and gene therapies can be used to treat cancer and other diseases,” Roncarolo said.

Two such diseases are sickle cell disease and severe combined immune deficiency. In both cases, a single nucleotide change in DNA becomes a deadly defect for children with the bad luck to have them. Porteus is working on very new genome editing technologies that allow clinicians to go in and fix those DNA typos and cure diseases.

Stanford dermatology researcher Anthony Oro, MD, PhD is working to do something similar with skin cells for a painful blistering disease called epidermolysis bullosa. Children with EB lack a functional gene for one of the proteins that anchors the layers of skin together. Oro and Stanford Institute for Stem Cell Biology and Regenerative Medicine scientist Marius Wernig, MD, PhD, are taking defective skin cells from patients, transforming them into embryonic-like stem cells, fixing the gene defect, and then growing them back into skin stem cells and then layers of skin ready for transplantation. Oro says that they have shown that they can do this in a scalable way in mice, and they hope to start a clinical trial in humans soon.

One of the challenges to genetic therapy is that it often requires putting the gene into blood stem cells to deliver it to the body, but the high dose chemotherapy or radiation that is necessary to remove the bodies own blood stem cells and make way for the transplanted cells is very dangerous in itself. Researchers like Stanford researcher Hiromitsu Nakuchi, MD, PhD, are exploring gentler ways to make space in the body for the transplanted cells. He has discovered that simply by feeding mice a diet deficient in a particular amino acid, blood stem cells begin to die. Other cells in the body don’t seem to be as strongly affected. A dietary solution may eventually allow clinicians to avoid using the highly toxic treatments that have traditionally been used for blood stem cell transplant.

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Ebola, Events, Genetics, Global Health, Patient Care, Pediatrics, Stanford News

Global health and precision medicine: Highlights from day two of Stanford’s Childx conference

Global health and precision medicine: Highlights from day two of Stanford's Childx conference

Childx Shah“I do think it’s possible to end preventable child death.” Those were the powerful words spoken by Rajiv Shah, MD, the former administrator of USAID, during his keynote address at the start of the second day of Stanford’s recent Childx conference. More than 6 million children die each year before age 5, mostly of easily preventible diseases, Shah told the audience.

Shah went on to describe some of the more daunting health and humanitarian crises he faced during his 5-year tenure at the helm of United States Agency for International Development, including the recent Ebola outbreak in West Africa, and the Somali famine that he helped to address with the U.S. government’s Feed the Future program. Speaking about visiting a severely overcrowded Somali refugee camp, he said, “If you looked closely, you saw signs of hope and innovation.” For instance, children were receiving the pentavalent vaccine that protects against five serious childhood diseases and that was, until quite recently, considered too expensive to distribute in this type of setting.

Shah also described how a rapid redesign of protective gear for health-care workers fighting Ebola was essential to helping get the highly contagious illness under control: The old gear was much too hot and cumbersome, as well as being difficult to remove safely, and may have been a factor in the high rates of infection among health care workers early in the Ebola outbreak. Several partners, including NASA, the Department of Defense, Kimberly-Clark and Motorola, worked together to make new protective equipment that was easier to use and better suited to intense heat.

Our capacity to innovate is essential for solving global health problems, Shah concluded. “…Saving children’s lives in resource-poor settings is not just… great and morally important,” he said. “It actually creates more stability in communities.” Families have fewer children and invest more in the education of those kids, including the girls, and the surrounding society begins to look more stable and prosperous, he said. Innovation and technology in the arena of child health are important “not just for health purposes but for shaping the kind of world that keeps us safe, secure and prosperous over many decades.”

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Chronic Disease, Clinical Trials, Genetics, Patient Care, Pediatrics, Stanford News

Cystic fibrosis patient on her 20+ years of care

Cystic fibrosis patient on her 20+ years of care

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When Lauren Catron was first diagnosed with a severe form cystic fibrosis, an inherited disease that makes mucous and sweat glands go haywire, her doctors were unsure that she’d live to be a teenager. That was nearly 23 years ago. Now, 26-year-old Catron is a full-time college student at Mission College in Santa Clara, Calif. with enough energy to work a job in her spare time.

Catron credits her sustained health to the more than two decades of care she’s received at the Pulmonary and Cystic Fibrosis Center at Lucile Packard Children’s Hospital. Catron shares her story on the Happier, Healthier Lives Blog:

“When I was first diagnosed in 1992, the doctors told my parents that I may not make it to my teens,” said Catron, who has the genotype associated with a shorter lifespan and the most severe symptoms of cystic fibrosis, including a constant buildup of mucus in her lungs that interferes with breathing. “But a whole team of people at Stanford has dedicated themselves to keeping me healthy. They have given me absolute unconditional support, amazing treatment and care, and have become my second family.”

Carol Conrad, MD, director of the pediatric pulmonary function lab, explains that the center’s expert care stems from the many clinical trials and studies they do to advance the treatment of cystic fibrosis. “No other CF center in California is doing these kinds of clinical trials,” Conrad said.

This research, which ranges from dietary-supplement studies by Conrad to gene therapy work done by Richard Moss, MD, shows promise. Moss and his colleagues were the first to discover that gene therapy could improve pulmonary function in cystic fibrosis patients – an important finding that may lead to a treatment for the disease in the future. “As depressing as the disease can be, there’s a lot of hope. That’s what keeps us motivated,” said Conrad.

Previously: New Stanford-developed sweat test may aid in development of cystic fibrosis treatmentsFilm about twin sisters’ double lung transplants and battle against cystic fibrosis available onlineDiverse microbes discovered in healthy lungs shed new light on cystic fibrosis and Living – and thriving – with cystic fibrosis
Photo of Conrad (left) and Catron courtesy of Lucile Packard Children’s Hospital

Genetics, Research, Science, Stanford News

When X+X = X: Stanford scientists shed light on X-inactivation

When X+X = X: Stanford scientists shed light on X-inactivation

2189014070_339cb830f9_z-1With apologies to some of my colleagues (cough, Margarita Gallardo, cough), I’ve never really enjoyed the Garfield comic strip. The rotund cartoon cat and his insatiable lasagna cravings has always seemed odd to me. Plus, most orange and black cats are female, due to a curious biological phenomenon called X inactivation.

The inactivation of one X chromosome in female animals (and humans) is necessary to ensure that both sexes end up with roughly the same dosage of X-chromosome associated genes. In most species, the chromosome to be inactivated is selected randomly in each cell early in development, and the selected chromosome remains inactive in all of the cell’s subsequent progeny. Researchers believe that X inactivation might explain at least in part why some diseases are more prevalent or severe in one gender than the other.

Now dermatologist Howard Chang, MD, PhD, and former graduate student Ci Chu, PhD, have shed some light on the process, which occurs through the action of a regulatory RNA molecule called Xist. Their research was published today in Cell.

From our release:

[The researchers] have outlined the molecular steps of inactivation, showing that it occurs in an orderly and directed fashion as early embryonic cells begin to differentiate into more specialized tissues. They’ve identified more than 80 proteins in mouse cells that bind to Xist to help it do its job. They hope their findings will shed light on conditions in humans that are typically more severe in one gender than the other.

“We see some very interesting phenomena with X-linked diseases in humans,” said [Chang]. “Often, when the faulty gene is on the X chromosome, the condition is more severe in boys. This happens in hemophilia, for example. In contrast, women are far more likely than men to suffer from autoimmune diseases, for reasons we don’t yet understand. This research opens the door to possibly understanding the biological basis for these differences.”

The researchers were able to pinpoint the protein partners of Xist only after Chu developed an entirely new technique. More from our release:

Chu’s technique, which the researchers call CHIRP-MS for “comprehensive identification of RNA-binding proteins by mass spectrometry,” allowed the researchers to identify the sequential interaction of over 80 proteins with Xist during X inactivation. Many of these proteins have never before been associated with that process. It’s thought that they may help target and anchor Xist to active genes along the length of the X chromosome like burrs on a shoelace after a hike in the woods.

“If you lay all the copies of Xist in a cell end to end, they are not long enough to coat the entire X chromosome,” said Chang. “Instead, Xist spreads judiciously, finding active genes and shutting them down. It also must stay anchored to the chromosome and not float over to any other chromosomes in the nucleus. This requires an elaborate set of machinery that we believe acts in a sequential fashion.”

Specifically, the researchers suspect that some proteins help Xist locate and silence active genes, while others work to maintain that silencing once it has been established.

Clearly X inactivation is a complex process. But are you still wondering about Garfield? Because the genes for “orange” or “black” fur occur on the X chromosome, female cats that carry one of each version can be a patchwork of the two colors, depending on which chromosome is inactivated. Blobs of orange fur indicate an ancestor cell in which the chromosome with the black fur gene was inactivated, and vice versa. But a male cat, with only one X chromosome can only be orange or black, but not both.

An exception would be a male cat who had inherited two X chromosomes and one Y (in humans, this is called Klinefelter syndrome). This genetic anomaly, which is found in about one of every 3,000 calico cats, would likely have other oddities, however. Perhaps even a craving for pasta, cheese and tomato sauce?

Previously: Tomayto, tomahto: Separate genes exert control over differential male and female behaviors, Does it matter which parent your “brain genes” came from? and Stanford professor encourages researchers to take gender into account
Photo by Jerry Knight

Biomed Bites, Cancer, Genetics, Research, Science, Videos

From finches to cancer: A Stanford researcher explores the role of evolution in disease

From finches to cancer: A Stanford researcher explores the role of evolution in disease

Welcome to Biomed Bites, a feature that appears each Thursday and introduces readers to some of Stanford’s most innovative researchers.

My parents just returned from the trip of a lifetime to the Galapagos. I would have loved to go along — I really dig tortoises, which abound on the islands; my parents even saw a pair mating! And, ever since I took an introductory class on evolution as an undergrad, I’ve longed to visit the spot that was central in Darwin’s postulation of the theory of evolution and natural selection.

No famous finches for me though — I just toiled away behind my computer in northern California. But that doesn’t mean evolution is only happening in another hemisphere. Far from it: Just down the street in the lab of Gavin Sherlock, PhD, experiments are ongoing to elucidate evolution’s fundamental processes.

Sherlock shares his views role of evolution in disease in the video above:

The evolutionary process underlies many disease mechanisms. One such example is cancer, which recapitulates the evolutionary process as mutation occur and then get selected within the tumor. In addition, treatments with chemotherapy may select particular mutations within the tumor itself.

Resistance to antibiotics is also driven by evolution, Sherlock points out. With a deeper understanding, researchers will be better able to combat cancer and craft more effective antibiotics — no international travel required.

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

Previously: Bubble, bubble, toil and trouble — yeast dynasties give up their secrets, Get sloshed, have sex? Wine-making has promoted a frenzy of indiscriminate mating in baker’s yeast, according to Stanford researchers and Computing our evolution

Aging, Genetics, Research, Science, Stanford News

“Are we there yet?” Exploring the promise, and the hype, of longevity research

"Are we there yet?" Exploring the promise, and the hype, of longevity research

Brunet photoThe days are getting longer, and it’s no longer dark outside when I drop my teenager at school for her early-bird class. I appreciate the light, of course, and there’s something soothing about the rhythmic change of seasons.

If only we could extend our lifespan in a similar gentle, reliable manner.

The idea of living longer, and healthier, is the theme of my story for the new issue of Stanford Medicine magazine. It’s my favorite kind of article – a dash of juicy science history, a panoply of dedicated scientists and a brand-new animal model (and my newest crush) that may open all kinds of research doors. Best of all, there’s a sense of real progress in the field. From my article:

“Ways of prolonging human life span are now within the realm of possibility,” says professor of genetics and newbie fish keeper Anne Brunet, PhD. Brunet, who is an associate director of Stanford’s Paul F. Glenn Center for the Biology of Aging, focuses her research on genes that control the aging process in animals such as the minnowlike African killifish I’d watched fiercely guarding his territory.

The killifish is especially important to researchers like Brunet because it has an extremely variable, albeit short, life span. One strain from eastern Zimbabwe completes its entire life cycle — birth, maturity, reproduction and death — within about three to four months. Another strain can live up to nine months.

It’s also a vertebrate, meaning it belongs to the same branch of the evolutionary tree as humans. This gives it a backbone up over more squishy models of aging like fruit flies or roundworms — translucent, 1-millimeter-long earth dwellers you could probably find in your compost pile if you felt like digging.

I hope you’ll read the rest of my piece to learn more.

Previously: My funny Valentine – or, how a tiny fish will change the world of aging research, Stanford Medicine magazine reports on time’s intersection with health and Living loooooooonger: A conversation on longevity
Photo of Anne Brunet by Gregg Segal

Cancer, Genetics, In the News, Women's Health

Angelina Jolie Pitt’s New York Times essay praised by Stanford cancer expert

Angelina Jolie Pitt's New York Times essay praised by Stanford cancer expert

4294641229_c78b406658_zYou’ve likely heard today about Angelina Jolie Pitt’s New York Times essay regarding her decision to have her ovaries and fallopian tubes removed. Women who carry mutations in the BRCA1 or BRCA2 genes have a significantly increased risk for breast and ovarian cancer; Jolie carries such a mutation, and in 2013 she shared publicly her decision to have her breasts removed to reduce her risk of cancer.

Jolie Pitt shares her decision-making process and notes that though she won’t be able to have any more children and though she still remains prone to cancer, she feels “at ease with whatever will come.” She closes her latest essay by writing, “It is not easy to make these decisions. But it is possible to take control and tackle head-on any health issue. You can seek advice, learn about the options and make choices that are right for you.”

After reading the piece I reached out to Stanford cancer geneticist Allison Kurian, MD, who told me:

Angelina Jolie made a very courageous decision to share her experience publicly.  The surgery she chose is strongly recommended for all women with BRCA1/2 mutations by age 40, since it’s the only way to prevent an ovarian cancer in these high-risk women, and early detection doesn’t work. This is a life-saving intervention for high-risk women.

Kurian is associate director of the Stanford Program in Clinical Cancer Genetics and a member of the Stanford Cancer Institute. In 2012 she published on online tool to help women with BRCA mutations understand their treatment options.

Previously: Helping inform tough cancer-related decisions, NIH Director highlights Stanford research on breast cancer surgery choices and Breast cancer patients are getting more bilateral mastectomies – but not any survival benefit
Photo by Marco Musso

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