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Genetics, Pregnancy, Research, Stanford News

Mouse placental cells contain dozens, even hundreds, of copies of genes key for pregnancy

Mouse placental cells contain dozens, even hundreds, of copies of genes key for pregnancy

19452628685_98cca6511f_zPeering inside a mouse placental cell is a bit like looking at a fun-house mirror. Rather than the standard two copies of each chromosome (mice have 20), there are as many as 900 copies of each genome segment.

What gives?

A team led by Julie Baker, PhD, associate professor of genetics, has found one clue: Genes that produce critical developmental proteins supporting the pregnancy are among the replicated regions. Baker, and first author Roberta Hannibal, PhD, published their results today in Current Biology.

“The placenta is a really fascinating organ,” Baker told me. “It’s a transient organ, so it doesn’t need to invest that much energy in conserving the genome. What it really needs is to get proteins and (placental) attachment molecules up and running really, really fast.”

And the best way to do that, rather than wasting energy cleaving the genome and producing a new cell with each division, may be to just jam many copies of the critical genes in one cell, Baker says.

This is the first time anyone has found genomic amplification of selective regions in mammals, the researchers write. That’s because no one has looked before, Baker said: “The placenta has been largely ignored.”

Next, she and her team are investigating the role of extra genome copies in human placentas. They’re also studying the particular mouse placental cells they examined, called trophoblast giant cells, in the lab, Baker said.

Previously: Species-specific differences among placentas due to long-ago viral infection, say Stanford researchers, Scientists create a placenta-on-a-chip to safely study process and pitfalls of pregnancy and NIH puts focus on the placenta, the “fascinating” and “least understood” organ
Photo by Michael Pardo

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

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

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

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

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

As I explained in our release:

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

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

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

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

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

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

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

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

Dean Lloyd Minor, MD, commented in our release:

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

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

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

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

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

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

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

Genetics, Research

A horse of a different color

A horse of a different color


Long before domesticated horses showed up with their striking chestnut, bay or spotted coats, wild horses stuck to the classic look of a dun coat — typically tan all over with a dark stripe down the back, and distinctive dark markings on the shoulders, face, and ankles. (Picture the horses in the Lascaux paleolithic cave paintings of southern France.)

Now, Gregory Barsh, MD, PhD, an emeritus professor of genetics and of pediatrics, and an international team of researchers have shown how simple mutations in a single gene can turn this coat pattern on or off.

The dun gene makes a protein that binds to DNA and controls other genes, a type of protein called a transcription factor. Barsh and his colleagues showed that the dun coat transcription factor — called T-box 3, or TBX3 — makes its presence known in the tiny hair follicles that make each hair of a horse’s fur. In humans, mutations in a similar gene cause serious birth defects.

But in horses with the dun transcription factor, the hair follicle puts pigments on only one-half of the shaft of each hair. As the hair grows out and flops over, the pigment side ends up underneath, next to the body. Meanwhile, the outer surfaces of all the hairs are unpigmented with just a hint of the pigment color coming through from underneath.

The exception are the hairs in the long stripe on the back, the dark face, stripes on the hocks and shoulders — places where the hair follicles make pigment on both sides of each hair. Why remains to be seen.

Two mutations in the gene for the dun transcription factor can override the light-colored body with a dark stripe. According to the authors of the paper, published today in Nature Genetics, one version is older than domesticated horses; the other evolved in domestic horses much more recently. In both cases, the altered dun gene no long suppresses pigment on one side of the hair, so horses carrying the mutated dun gene are dark all over.

In humans, mutations in the TBX3 transcription factor gene cause a collection of rare birth defects called “ulnar-mammary syndrome.” People with this syndrome may have scant to absent hair in the eyebrows and arm pits, but the most well-known effects are missing or deformed hands and feet and shortened arms and legs.

In horses, the dun transcription factor is all about pattern. The dun gene doesn’t determine if a horse is chestnut or bay, but only if it is lighter all over except for the distinctive dark marks.

Previously Dark-skinned mice lead researchers to protein linked to bone marrow failureHow the cheetah got its stripes: A genetic tale by Stanford researchers and Stanford researchers suss out cancer mutations in genome’s dark spots
Photo by Freyja Imsland

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

Genetic links to healthy aging explored by Stanford researchers

Genetic links to healthy aging explored by Stanford researchers

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

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

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

As explained in the journal’s press release:

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

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

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Biomed Bites, Genetics, Neuroscience, Research, Videos

A scientific metamorphosis: From butterflies to myelin

A scientific metamorphosis: From butterflies to myelin

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

William Talbot, PhD, started out studying how caterpillars become butterflies. Now a professor of developmental biology, his research focuses on the formation of myelin, that all-important sheath that protects nerve fibers and speeds the transmission of messages.

His aims are high: By understanding the genetic foundation of myelin development, he hopes to create treatments for conditions like multiple sclerosis, which affects myelin and myelin repair.

“We don’t know much about how [myelin] forms,” Talbot says in the video above. “We are taking a genetic approach to try to find mutations that disrupt myelin and use these to discover new genes that might allow us to repair myelin that is disrupted.”

The caterpillars were a crucial step in his own scientific development, Talbot says.

“The techniques that we use and the general logic we use to study these questions are basically the same, although the technology and specific research topics have evolved greatly,” Talbot says.

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

Previously: Face blindness stems form differences in neurocircuitry, Brain, heal thyself? Stanford research describes delayed onset of multiple sclerosis in mice and Video game accessory may help multiple sclerosis patients reduce falls, boost brain connections

Genetics, Immunology, Infectious Disease, Precision health, Research, Stanford News

Precision health: A blood test that signals need for antibiotics

Precision health: A blood test that signals need for antibiotics

antibioticsGo to your doctor with a sinus infection and the first thing she’ll likely ask you is how long you’ve been sick. If it’s been less than two weeks, chances are she’ll say you probably have a viral infection and won’t prescribe an antibiotic. If you say it’s been three or four weeks, she’ll probably give you a prescription, assuming viral infections typically resolve in two weeks. But this rule of thumb is more educated guess than science.

In a nice example of precision health, a new blood test being developed at Stanford could indicate whether you have a bacterial infection or a viral infection and tell you and your doctor whether an antibiotic would help.

So if you have a bacterial infection that an antibiotic could cure, you won’t have to wait days or weeks to get treatment. And if you don’t need a prescription, you won’t damage your body’s microbiome with a round of antibiotics you don’t need.

The test, developed by Purvesh Khatri, PhD, assistant professor of medicine, and a team of six other researchers at Stanford, is based on changes in the way human immune cells express their genes.

It seems almost like science fiction, but Khatri’s team has found that cells don’t just respond differently to bacterial infections and viral infections; they also respond differently to different kinds of viral infections, so it’s possible to tell whether someone has a cold versus the flu as much as 24 hours before they even show symptoms.

The same test could have other uses, including quickly showing whether a vaccine is working and, someday, telling if someone is infected with Ebola or other deadly and contagious viruses.

You can read more details in our press release and even more in the paper (subscription required), which was published online today in the journal Immunity.

Previously: Study means an early, accurate, life-saving sepsis diagnosis could be coming soon
Photo by Sheep purple

Genetics, Microbiology, Technology

The art of exploring the fecal-ome

The art of exploring the fecal-ome

Monet Cathé Monet La_Cathédrale_de_Rouen.yellowThe community of bacteria living inside our own guts is about as local an ecosystem as we’re likely to find. So you’d think navel-gazing biologists would already know all about it. But several barriers have made this ecosystem nearly as inaccessible as the forests of the Amazon River were for 18th century naturalists.

One problem has been that bacteria have traditionally been studied by growing them in glass or plastic dishes containing a “culture medium,” typically a sort of gelatin concoction containing mystery ingredients like calf serum. Lots of bacteria grow well on this stuff, but even more don’t. And most of what we know about bacteria comes from studies of the short of list bacteria that will grow in the lab.

Advances in genomics have revealed the presence of new species of bacteria everywhere biologists have looked. But, apparently, even that diversity is just the tip of the iceberg.

Computer scientists and geneticists at Stanford recently collaborated on a technique and uncovered an amazing amount of diversity in the gut contents of a human male, who volunteered a fecal sample. In the sample, the Stanford team found not just lots of species, but also lots of sub-strains — as many as five different strains of a single species. You can read more about the technique in the press release I wrote about the study, which appeared today in Nature Biotechnology.

The work’s similarity to an incredibly tough jigsaw puzzle captured my imagination.

Geneticist Michael Snyder, PhD, who is a senior author on the paper, explained to me that it’s now pretty easy to assemble the genome of a single person or bacterium from the short strands of DNA in a sample.

But when you have a mix of lots of different species, he said, it’s like assembling 100 jigsaw puzzles from a single pile of pieces from all those different jigsaw puzzles. Not only do you have to fit the pieces together, but you have to know which puzzle or species each piece came from.

If the jigsaw puzzles are as different as, say, a Van Gogh Sunflowers painting and Ansel Adams’ “Moonrise, Hernandez, New Mexico”, you wouldn’t have much trouble separating the pieces. But what if you’ve got several strains of the same bacterial species? That’s the equivalent of a mix of puzzles all depicting different versions of Monet’s paintings of Cathedral Rouen.

Previously: Microbiome explorations stoke researcher’s passionAt TEDMED 2015: How microbiome studies could improve the future of humanityInvestigating the human microbiome: “We’re only just beginning and there is so much more to explore
Monet image courtesy of KnightSerbia

Events, Genetics, Research, Science, Stanford News

Personalised Health Conference explores paradigm shift from treating disease to maintaining wellness

Personalised Health Conference explores paradigm shift from treating disease to maintaining wellness

Lars Steinmetz talkingWhat does it mean to be healthy? This is an important question for the numerous laboratories and hospitals worldwide who dedicate their livelihoods to defeating disease. Thanks to breakthroughs in biotechnology, researchers are starting to develop a more thorough profile of health – and to realize how different it can be from person to person. “We should all go get our ‘healthy’ profiles now before we get sick,” insists Michael Snyder, PhD, professor and chair of Stanford’s Department of Genetics.

Understanding what health means at an individual, molecular, and systematic level was the focus of the recent Personalised Health Conference at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany. Notably, the conference served as the kickoff event for the EMBL-Stanford Life Science Alliance and was the first of many anticipated joint conferences. In a preview of the interdisciplinary collaborations the alliance will enable, the four-day conference brought together international experts in genomics, healthcare, bioethics, bioinformatics, cancer, and more.

“The technologies now at our disposal are ushering in a change in the state of medicine, from reactive to proactive, from treating disease to maintaining health,” said Lars Steinmetz, PhD, the conference’s main organizer, in his opening remarks. Steinmetz is spearheading the EMBL-Stanford Life Science Alliance, inspired by his dual affiliation: At Stanford, he is co-director of the Stanford Genome Technology Center (SGTC); at EMBL, he is associate head of the Genome Biology Unit.

The conference was kicked off with a keynote lecture from Leroy Hood, MD, PhD, president and co-founder of the Institute for Systems Biology, who is widely known as the father of personalized medicine. In addition to his vision for systems medicine, Hood presented the 100K Wellness Project, a longitudinal, multiparametric study that generates “dynamical data clouds” for 100,000 healthy individuals.

“By studying the earliest wellness to disease transitions, we aim to enable the earliest reversal of disease back to wellness,” said Hood. “Understanding wellness will allow individuals to reach their full health potential. I predict that a major scientific wellness industry will emerge to play a dominant role in the democratization of health care.”

Hood’s vision was supported by several research efforts presented at the conference. Snyder’s integrative personal omics profiling (iPOP) protocol here at Stanford now measures billions of molecular parameters in several individuals over time, in efforts to develop predictive models of disease that integrate genomic, molecular, environmental, and physiological datasets. Genomics England’s Tim Hubbard, PhD, presented the United Kingdom’s 100,000 Genomes Project, which aims to leverage genome sequence data in the treatment of 100,000 people in the national healthcare system with unmet clinical needs. As the largest national project of its kind, it will help to establish principles and frameworks for incorporating genomics into standard clinical care.

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Genetics, Pain, Pediatrics, Precision health, Stanford News

Newly identified gene mutation explains why one family experiences unusual pain response to cold

Newly identified gene mutation explains why one family experiences unusual pain response to cold

snowy-handprintIf you’ve ever plunged your hand into a tub of ice water, you know about the overlap between cold and pain: that deep, biting ache makes you want to get your hand out of the water – fast. But while the protective value of that sensation is obvious, scientists have always been a bit mystified by how pain-sensing nerves register cold temperatures.

But now, research on a family with an extremely unusual gene mutation may help clarify what’s going on. The mutation, whose discovery was reported online this week in Nature, confers a heightened pain response to cold. The research was initiated by Stanford geneticists and expanded by scientists at three universities in Germany who specialize in hereditary pain syndromes.

The story began with a family who brought their young daughter to Lucile Packard Children’s Hospital Stanford to get help for her unusual episodes of pain. When cold, she experiences pain in her joints that radiates out to her arms and legs. The pain lasts 20 to 30 minutes at a time. The little girl’s father, paternal grandmother, paternal aunt and first cousin (the aunt’s daughter) also experience similar pain episodes, as the new paper explains in detail.

“When we saw her, we were really struck by the fact that the pain was going on in multiple generations of the family,” said one of the study’s authors, medical geneticist Jon Bernstein, MD, PhD. The pattern of inheritance made Bernstein suspect an autosomal dominant disease, in which only one bad copy of a gene causes symptoms. Although several hereditary pain syndromes are described in the medical literature, none matched the exact pattern of symptoms this family experienced, so the Stanford clinicians asked the German scientists to figure out what was going on.

The German team looked for rare mutations shared by the little girl and her cousin, finding one in a gene that codes for an electrical channel in nerve cell membranes. (Nerves transmit electrical signals via flow of charged ions through tiny protein tubes embedded in the cell membrane. There are several types of these channels.) The scientists’ experiments demonstrated that they had discovered a gain-of-function mutation – in which the encoded protein, instead of being rendered nonfunctional, instead alters what it does. In this case, there is a substitution of one amino acid for another in the structure of the affected electrical channel. That change causes pain-sensing nerves to fire at cool temperatures most people don’t find painful.

The same electrical channel, Nav1.9, was also identified as “a key determinant of cold pain sensation” in a paper published earlier this year that examined its activity in rats and mice. That study found that the channel was important to setting animals’ threshold for when cold begins to feel painful, and the new findings fit into that picture nicely.

The German team plans to continue studying the channel’s dynamics to help learn more about the normal threshold between cold and pain, Bernstein said. As for him? “I’m very much looking forward to working with the next family whose case is unsolved,” he told me.

Previously: One mutation, two people and two (or more) outcomes: What gives?, Crying without tears unlocks the mystery of a new genetic disease and Exploring the mystery of pain
Photo by Chris Geatch

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