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Cancer, Research, Science, Stanford News, Stem Cells

A stem cell “kill switch” may make therapies safer, say Stanford researchers

A stem cell "kill switch" may make therapies safer, say Stanford researchers

3225255407_596aa5bdff_zStem cell biologist Hiromitsu Nakauchi, MD, PhD, and his colleagues published an interesting article today about how to use stem cell technology to boost our body’s own immune cells to fight cancer or chronic viral infections like HIV or Epstein Barr virus. Because there’s a possible cancer risk with the use of induced pluripotent stem cells, or iPS cells, in humans, he and his colleagues have devised an innovative way to specifically eliminate these cells within the body if they start to cause problems. Their research appears today in Stem Cell Reports.

As Nakauchi explained to me in an email:

The discovery of induced pluripotent stem cells created promising new avenues for therapies. However, the tumorigenic potential of undifferentiated iPSCs is a major safety concern that must be addressed before iPS cell-based therapies can be routinely used in the clinic.

The researchers studied a type of immune cell called a cytotoxic T cell. These cells recognize specific sequences, or antigens, on the surface of other cells. Some antigens indicate that the cell is infected with a virus; others are found on cells that have become cancerous. When a cytotoxic T cells sees these antigens, it moves in to kill the cell and remove the threat.

In order to ensure that our immune systems recognize the widest variety of antigens, developing T cells randomly shuffle their genes to create unique antigen receptors. Researchers have found that it’s possible to identify, and isolate, T cell populations that specifically recognize cancer cells. By growing those cells in the laboratory, and then injecting them back into a patient, clinicians can give a boost to the immune response that can help kill tumor cells. The technique is known as adoptive immunotherapy, and it’s shown promise in treating melanoma. However, these cytotoxic T cells can become exhausted as they fight the cancer and become less effective over time.

Recently researchers in Nakauchi’s lab showed that it’s possible to create induced pluripotent stem cells from cytotoxic T cells. These iPS cells are then induced to again become cytotoxic T cells. These rejuvenated T cells, or rejT cells, recognize the same antigen they did before their brief dip in the pluripotency pool, but they are far more sprightly than the cells from which they were derived – they can divide many more times and have longer telomeres (an indicator of youthfulness).

So far, so good. But, as Nakauchi mentioned above, iPS cells carry their own set of risks. Because they are by definition pluripotent (they can become any cell in the body), they can easily grow out of control. In fact, one way of proving a cell’s pluripotency is to inject it into an animal and see if it forms a type of tumor called a teratoma, which is made up of multiple cell types.

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Research, Science

Short and sweet: Research papers with succinct titles cited more often

Short and sweet: Research papers with succinct titles cited more often

As a burgeoning journalist, I was often coached to cut unnecessary words. College professors mandated that story ledes be short and snappy and never exceed 35 words in length. When I began working at a daily newspaper, my editors were constantly condensing paragraphs and reminding me that “it takes more skill to write short than it does to write long.”

So I was interested to read a Nature article about new research showing that scientific studies with shorter titles receive more citations. Boer Deng writes:

Adrian Letchford and his colleagues at the University of Warwick in Coventry, UK, analysed the titles of 140,000 of the most highly cited peer-reviewed papers published between 2007 and 2013 as listed on Scopus, a research-paper database. They compared the lengths of the papers’ titles with the number of times each paper was cited by other peer-reviewed papers— a statistic sometimes used as a crude measure of importance.

As they report in Royal Society Open Science, “journals which publish papers with shorter titles receive more citations per paper”.

The impetus for the current study came from a desire to pen better papers, says Letchford, and to see whether good writing is rewarded in research. “As scientists, we’re all cursed,” when it comes to writing, Letchford says, as researchers hone their specialised knowledge but often cannot explain themselves to readers outside their own field.

While some quoted in the article agreed that concise titles can offer advantages, including increasing appeal to outside audiences, John Ioannidis, MD, DSc, director of the Meta-Research Innovation Center at Stanford, questioned whether the findings were conclusive. He said, “I will continue to struggle finding appropriate titles for my papers without worrying about whether the title length may affect their citations.”

Previously: A conversation with John Ioannidis, “the superhero poised to save” medical research, Shake up research rewards to improve accuracy, says Stanford’s John Ioannidis and John Ioannidis discusses the popularity of his paper examining the reliability of scientific research

Genetics, Microbiology, Neuroscience, Research, Science, Stanford News

Quest for molecular cause of ALS points fingers at protein transport, say Stanford researchers

Quest for molecular cause of ALS points fingers at protein transport, say Stanford researchers

Amyotrophic lateral sclerosis, or ALS, is a progressive, fatal neurodegenerative disease made famous by Lou Gehrig, who was diagnosed with the disorder in 1939. Although it can be inherited among families, ALS more often occurs sporadically. Researchers have tried for years to identify genetic mutations associated with the disease, as well as the molecular underpinnings of the loss of functioning neurons that gradually leaves sufferers unable to move, speak or even breathe.

We hope that our research may one day lead to new potential therapies for these devastating, progressive conditions

Now Stanford geneticist Aaron Gitler, PhD, and postdoctoral scholar Ana Jovicic, PhD, have investigated how a recently identified mutation in a gene called C9orf72  may cause neurons to degenerate. In particular, a repeated sequence of six nucleotides in C9orf72 is associated with the development of ALS and another, similar disorder called frontotemporal dementia. They published their results today in Nature Neuroscience.

As Gitler explained in our release:

Healthy people have two to five repeats of this six-nucleotide pattern. But in some people, this region is expanded into hundreds or thousands of copies. This mutation is found in about 40 to 60 percent of ALS inherited within families and in about 10 percent of all ALS cases. This is by far the most common cause of ALS, so everyone has been trying to figure out how this expansion of the repeat contributes to the disease.

Gitler and Jovicic turned to a slightly unusual, but uncommonly useful, model organism to study the effect of this expanded repeat:

Previous research has shown that proteins made from the expanded section of nucleotides are toxic to fruit fly and mammalian cells and trigger neurodegeneration in animal models. However, it’s not been clear why. Gitler and Jovicic used a yeast-based system to understand what happens in these cells. Although yeast are a single-celled organism without nerves, Gitler has shown that, because they share many molecular pathways with more-complex organisms, they can be used to model some aspects of neuronal disease.

Using a variety of yeast-biology techniques, Jovicic was able to identify several genes that modulated the toxicity of the proteins. Many of those are known to be involved in some way in shepherding proteins in and out of a cell’s nucleus. They then created neurons from skin samples from people with and without the expanded repeat. Those with the expanded repeat, they found, often had a protein normally found in the nucleus hanging out instead in the cell’s cytoplasm.

Jovicic and Gitler’s findings are reinforced by those of two other research groups, who will publish their results in Nature tomorrow. Those groups used different model organisms, but came to the same conclusions, suggesting that the researchers may be close to cracking the molecular code for this devastating disease.

As Jovicic told me, “Neurodegenerative diseases are very complicated. They likely occur as a result of a defect or defects in basic biology, which is conserved among many distantly related species. We hope that our research may one day lead to new potential therapies for these devastating, progressive conditions.”

Previously: Stanford researchers provide insights into how human neurons control muscle movement, Researchers pinpoint genetic suspects in ALS and In Stanford/Gladstone study, yeast genetics further ALS research

In the News, Media, Medicine and Society, Public Health, Research, Science

Science for popular audiences is not just “adding to the noise”

Science for popular audiences is not just "adding to the noise"

4787885058_d174638233_zIf you’re reading this blog, chances are you’re a fan of popular science – i.e. scientific research made accessible to people who aren’t professional academics. Many academics, myself included, are also in favor of taking cutting-edge knowledge and sharing it broadly with the public.

But some scientists hesitate to share their work on forums like blogs and other social media. According to a recent SciLogs post, they worry that their knowledge might be wrong or incomplete, be misinterpreted, or just add more static to the internet’s noise. But, as the post lays out, those who think about such things are precisely those who should be publishing for broader audiences. Those who publish misinformation are not stopping to question the quality of the knowledge they broadcast; doubt and the recognition of ignorance are the hallmarks of true scientists. Adding even a small amount of high-quality research to the “science media ecosystem” helps.

Moreover, much of the public seems to have little trust in media, much trust in scientists, and is more receptive to information that acknowledges uncertainty. So bring on the science blogs!

Previously: Can science journals have beautiful prose?, The disturbing trend of science by press release, Science rapper “busts a move” to explain Nobel discovery, Science writer Deborah Blum on blogging: “There were so many smaller stories I wanted to tell” and Veteran blogger offers tips for starting a science blog
Photo by Robin Bray-Hurren

Genetics, In the News, NIH, Science, Technology

The quest to unravel complex DNA structures gets a boost from new technology and NIH funding

The quest to unravel complex DNA structures gets a boost from new technology and NIH funding

5232013153_7808b471a2_zIf you’ve ever tried folding a map, packing an overnight bag or coiling a string of holiday lights, you know that the way you arrange an object affects how much space it takes up and how easy it is to use in the future. This same principle is true of DNA.

As a recent article in Science News explains, the way a DNA double helix is folded, packed and coiled is known to have a big effect on how much space it requires and how easy it is to access the information stored within. But, until recently, researchers lacked the technology to fully explore these four-dimensional DNA structures.

Now, new technology and last year’s launch of the National Institutes of Health‘s five-year, $120 million, 4D Nucleome project is helping researchers reveal the complex architecture of DNA. William Greenleaf, PhD, assistant professor of genetics at Stanford, discusses the significance of a genome‘s arrangement in the Science News article:

Like the genetic text within it, the genome’s shape holds specific instructions. “The way it’s compacted forms this sort of physical memory of what the cell should be doing,” Greenleaf says.

Loops of DNA that aren’t needed by a particular cell are tucked away from the biological machinery that reads genetic blueprints, leaving only relevant genes accessible to produce proteins. Studies have shown that sections of the genome that are shoved toward the edges of a nucleus are often read less than centrally located DNA. Such specialized arrangements allow cells as diverse as brain cells, skin cells and immune cells to perform different jobs, even though each contains the same genome. “In different cell types, there are very large changes to the regions that are being used,” Greenleaf says.

Much more remains to be understood about how a genome’s shape directs its activity. Future maps might zero in on functionally interesting regions of the genome, Greenleaf says. But he cautions there is also a benefit to unbiased, general exploration. Focusing on one location in the nucleome might lead researchers to miss important structural information elsewhere, he says.

Previously: DNA origami: How our genomes foldPacked and ready to go: The link between DNA folding and disease and DNA architecture fascinates Stanford researcher – and dictates biological outcomes
Photo by: Kate Ter Haar

Cardiovascular Medicine, Evolution, Genetics, Research, Science

Ethiopian gene offers potential help for hypoxia

Ethiopian gene offers potential help for hypoxia

8494671414_5bc71743c8_zGene therapies have been developed for color blindness, Parkinson’s, SCID, and muscular dystrophy, among others. Now there soon could be another to add to the list: hypoxia, or oxygen deprivation.

In a study published in PNAS, researchers investigated how mice with lower levels of the endothelin receptor type B (EDNRB) gene – a gene that is present among Ethiopians, who evolved to live at high elevations where oxygen levels are low – fare in hypoxic conditions. It found that even with five percent oxygen, lower than you’d find atop Mount Everest, the mice with the gene alteration survived. They managed to get oxygen to their vital organs with the help of several “downstream” genes that are regulated by EDNRB.

According to a press release, these three heart-specific genes “help heart cells perform crucial functions such as transport calcium and contract. The finding provides a direct molecular link between EDNRB levels and cardiovascular performance.”

The implications of this work are described in the release by senior author Gabriel Haddad, MD, professor and chair of pediatrics at UC San Diego School of Medicine: “In addition to improving the health of the more than 140 million people living above 8,000 feet, information on how Ethiopians have adapted to high altitude life might help us develop new and better therapies for low oxygen-related diseases at sea level — heart attack and stroke, for example.” Haddad and his team are now testing therapeutic drugs that inhibit ENDRB.

Previously: Near approval: A stem cell gene therapy developed by Stanford researcher, Using genetics to answer fundamental questions in biology, medicine, and anthropology and “It’s not just science fiction anymore”: ChildX researchers talk stem cell and gene therapy
Photo by mariusz klozniak

Cancer, Research, Science, Stanford News, Stem Cells

Liver stem cell identified in mice

Liver stem cell identified in mice

Image of liver stem cellsAn elusive quarry has finally been chased to ground. Or, more accurately, to the central vein of one of our most important organs: the liver. Developmental biologist Roel Nusse, PhD, and visiting scholar and gastroenterologist Bruce Wang, MD, announced the identification of the liver stem cell in mice today in Nature. The finding will help researchers better understand liver biology and disease. It may also aid in the decades-long quest to find a reliable and efficient way to grow liver cells, called hepatocytes, in the laboratory for study and to test the effect of drugs.

Until now, researchers had assumed that all hepatocytes were created equal. And none of them seemed to have stem-cell-like traits. As Nusse described in our release:

There’s always been a question as to how the liver replaces dying hepatocytes. Most other tissues have a dedicated population of cells that can divide to make a copy of themselves, which we call self-renewal, and can also give rise to the more-specialized cells that make up that tissue. But there never was any evidence for a stem cell in the liver.

Wang and Nusse took a different approach. They looked in the liver to see which cells, if any, were expressing a gene called Axin2. Axin2 is expressed when a cell encounters a member of the Wnt protein family. Years of previous work in the Nusse lab have shown that Wnt family members are critical regulators of embryonic development and stem cell maintenance.

They found a small population of Axin2-expressing hepatocytes with just two copies of each chromosome surrounding the central vein of the liver. These cells can both self-renew and divide to create new hepatocytes that migrate outward from the vein. As they migrate, these cells become polyploid and begin to express hepatocyte-specific genes. Eventually much of the animals’ livers were made up of these stem-cell descendents. As Wang described:

People in the field have always thought of hepatocytes as a single cell type. And yet the cell we identified is clearly different from others in the liver. Maybe we should accept that there may be several subtypes of hepatocytes, potentially with different functions.

If this result in mice is also found to be true in humans, it’s possible that the liver stem cells may be easier to grow in the laboratory that normal hepatocytes. This would enable researchers to test the effect of drugs under development on human liver cells before they are tested in people (my colleague Bruce Goldman wrote about another potential solution to this problem last year). As Wang explained:

The most common reason that promising new drugs for any type of condition fail is that they are found to be toxic to liver. Researchers have been trying for decades to find a way to maintain hepatocytes in the laboratory on which to test the effects of potential medications before trying them in humans. Perhaps we haven’t been culturing the right subtype. These stem cells might be more likely to fare well in culture.

The finding opens the doors to answering other important questions as well, said Wang: “Does liver cancer arise from a specific subtype of cells? This model also gives us a way to understand how chromosome number is controlled. Does the presence of the Wnt proteins keep the stem cells in a diploid state? These are fundamental biological questions we can now begin to address.”

Previously: Which way is up? Stem cells take cues from localized signals, say Stanford scientists and The best toxicology lab: a mouse with a human liver
Photo of liver stem cells (red) and their progeny (green) by Bruce Wang

Behavioral Science, In the News, Research, Science

“Benign masochism” motivates common strange behaviors

"Benign masochism" motivates common strange behaviors

14674431439_be72558bd3_zI can recall many times I’ve offered something to a friend saying, “Smell this, it’s disgusting!” And more than once, the friend obliged. According to a National Geographic blog piece, the psychological motivation behind the appeal of stinky things is the same as the appeal of roller coasters, painfully spicy foods, and deep tissue massage. Likewise with reading sad novels or watching scary movies (though this last one is not something I personally enjoy). So what’s the common thread?

“Benign masochism,” a term coined by Paul Rozin, PhD, professor emeritus of psychology at the University of Pennsylvania, describes how humans enjoy negative sensations and emotions when they’re reassured that no harm will come to them. A “safe threat,” in other words.

The blog post is centered on our enjoyment of disgust, inspired by the massive audience at a recent blooming of a corpse flower at UC Berkeley’s Botanical Gardens. Valerie Curtis, PhD, a research director at the London School of Hygiene and Tropical Medicine and Psychology Today’sDisgustologist“, is quoted as saying the phenomenon is not dissimilar from kids playing war games in which they can “practice” their reactions to unpleasant situations.

“The ‘play’ motive leads humans (and most mammals, especially young ones) to try out experiences in relative safety, so as to be better equipped to deal with them when they meet them for real,” she says. “We are motivated to find out what a corpse smells like and see how we’d react if we met one.” Gross!

Previously: Looks of fear and disgust help us see threats, study shows
Photo by Dave Pape

Health Disparities, Medical Education, Medicine and Society, Public Health, Science

Stanford Medical Youth Science Program for underrepresented students expands and deepens

Stanford Medical Youth Science Program for underrepresented students expands and deepens

unnamedThe Stanford Medical Youth Science Program (SMYSP) is a 5-week summer residential program for rising high school juniors and seniors interested in science and medicine. The students, who come from underrepresented and low-income backgrounds, have an opportunity to experience the medical profession from the inside out. This year’s program concluded late last month with a graduation ceremony in which the students presented their scientific research projects on health disparities and advocacy to an audience of their parents and supporters.

A few weeks ago, I had the chance to speak with the program’s longtime director, Judith T. Ned, EdD, who told me SMYSP has come a long way since it was co-founded 28 years ago by Stanford epidemiologist Marilyn Winkleby, PhD, MPH. This is Ned’s 14th year running the show. She has made lot of beneficial changes and expansions, many of which happened since we last featured SMYSP in 2010, without losing sight of the program’s purpose: to expose these kids to the fields of science and medicine while increasing workforce diversity in the health professions.

Each year, 12 boys and 12 girls are selected for the program, all of whom come from 20 counties surrounding Stanford. “The goal is to really provide services and opportunities to students who are in our backyard, if you will,” Ned told me. The students have a well-rounded curriculum – not only do they attend lectures by leading academics and industry professionals, anatomy lectures and labs (with cadavers!), and twice-weekly clinical internships, but they have non-clinical days where they investigate departments like hospital food service, security, and art therapy. “We want to show them that it takes multiple people in multiple areas to really make the hospital function. Most of the time, many of my students serve as translators for their parents when they go into the hospital. This is the flip side: the provider’s perspective, not the patient’s. It’s been an interesting experience to see them switch mindsets.”

Programming includes SAT prep, “game shows” to improve knowledge retention, and evening workshops that include leadership development and performing arts. Ned wants the students to know that “you can take a well-rounded liberal arts education, get into medical school, and still practice your craft, embracing both sides of your identity.” Community service is also a key feature of the program, such as the beautification project they did at the East Palo Alto YMCA the Saturday before our interview.

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Autoimmune Disease, Genetics, Immunology, Science, Stanford News, Technology

Women and men’s immune system genes operate differently, Stanford study shows

Women and men's immune system genes operate differently, Stanford study shows

A new technology for studying the human body’s vast system for toggling genes on and off reveals that genes connected with the immune system switch on and off more frequently than other genes, and those same genes operate differently in women and men. What’s more, the differences in gene activity are mostly not genetic.

A couple of years ago, geneticists Howard Chang, MD, PhD; Will Greenleaf, PhD, and others at Stanford invented a way to map the epigenome – essentially the real time on/off status of each of the 22,000 genes in our cells, along with the switches that control whether each gene is on or off.

Imagine a fancy office vending machine that can dispense 22,000 different drinks and other food items. Some selections are forever pumping out product; other choices are semi permanently unavailable. Still others dispense espresso, a double espresso or hot tea depending on which buttons you push. The activity of the 22,000 genes that make up our genomes are regulated in much the same way.

That’s a lot to keep track of. But Chang and Greenleaf’s technology, called ATAC-seq, makes it almost easy to map all that gene activity in living people as they go about their lives. Their latest study, published in Cell Systems, showed that the genes that switch on and off differently from person to person are more likely to be associated with autoimmune diseases, and also that men and women use different switches for many immune system genes. That sex-based difference in activity might explain the much higher incidence of autoimmune diseases in women — diseases like multiple sclerosis, lupus and rheumatoid arthritis.

The team took ordinary blood samples from 12 healthy volunteers and extracted immune cells called T cells. T cells are easy to isolate from a standard blood test and an important component of the immune system. With T cells in hand, the team looked at how certain genes are switched on and off, and how that pattern varied from individual to individual. Chang’s team also looked at how much change occurred from one blood draw to the next in each volunteer.

Chang told me, “We were interested in exploring the landscape of gene regulation directly from live people and look at differences. We asked, ‘How different or similar are people?’ This is different from asking if they have the same genes.”

Even in identical twins, he said, one twin could have an autoimmune disease and the other could be perfectly well. And, indeed, the team reported that over a third of the variation in gene activity was not connected to a genetic difference, suggesting a strong role for the environment. “I would say the majority of the difference is likely from a nongenetic source,” he said.

Previously: Caught in the act! Fast, cheap, high-resolution, easy way to tell which genes a cell is using
Photo by Baraka Office Support Services

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