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Evolution, Fertility, Pregnancy, Research, Science, Stanford News, Stem Cells, Videos

Viral RNA essential for human development, say Stanford researchers

Viral RNA essential for human development, say Stanford researchers

Viruses are tricky, but we humans may be trickier still. Stanford stem cell biologists Vittorio Sebastiano, PhD, and Jens Durruthy-Durruthy, PhD, published a study today in Nature Genetics indicating that the genetic remnants of ancient viral infections that still linger in our genome are essential to early human embryonic development.

As Sebastiano explained in our release:

We’re starting to accumulate evidence that these viral sequences, which originally may have threatened the survival of our species, were co-opted by our genomes for their own benefit. In this manner, they may even have contributed species-specific characteristics and fundamental cell processes, even in humans.

The researchers, who talk about their work in the video above, relied on a new RNA sequencing technique to investigate the expression of what are called long-intergenic noncoding, or lincRNAs. These molecules don’t contain protein-making instructions, but instead affect the expression of other genes. They’ve been implicated in many important biological processes, including the acquisition of a developmental state called pluripotency that is necessary for a fertilized egg to develop into the cells and tissues of a growing fetus.

More from our release:

They identified more than 2,000 previously unknown RNA sequences, and found that 146 are specifically expressed in embryonic stem cells. They homed in on the 23 most highly expressed sequences, which they termed HPAT1-23, for further study. Thirteen of these, they found, were made up almost entirely of genetic material left behind after an eons-ago infection by a virus called HERV-H.

[…] After identifying HPAT1-23 in embryonic stem cells, Sebastiano and his colleagues studied their expression in human blastocysts — the hollow clump of cells that arises from the egg in the first days after fertilization. They found that HPAT2, HPAT3 and HPAT5 were expressed only in the inner cell mass of the blastocyst, which becomes the developing fetus. Blocking their expression in one cell of a two-celled embryo stopped the affected cell from contributing to the embryo’s inner cell mass. Further studies showed that the expression of the three genes is also required for efficient reprogramming of adult cells into induced pluripotent stem cells.

I can’t stop marveling at the close ties we have with viruses. It makes me think of the words of Michael Corleone in The Godfather: “Keep your friends close, and your enemies closer.” As Durruthy-Durruthy told me, “It’s fascinating to imagine how, during the course of evolution, primates began to recycle these viral leftovers into something that’s beneficial and necessary to our development.”

Previously: My baby, my… virus? Stanford researchers find viral proteins in human embryonic cellsMastermind or freeloader? Viral proteins in early human embryos leave researchers puzzled  and Species-specific differences among placentas due to long-ago viral infection, say Stanford researchers
Video by Christopher Vaughan/Stanford Institute for Stem Cell Biology and Regenerative Medicine

Ethics, In the News, NIH, Research, Science, Science Policy, Stanford News, Stem Cells

Stanford researchers protest NIH funding restrictions

penSeven Stanford researchers, including Irving Weissman, MD, who directs Stanford’s Institute for Stem Cell Biology and Regenerative Medicine, and David Magnus, PhD, director of Stanford’s Center for Biomedical Ethics, have joined with four other prominent scientists to urge the lifting of a recent and unexpected ban on funding by the National Institutes of Health for research that involves placing human stem cells into early-stage, non-human embryos. Their comments will be published tomorrow in a letter to Science.

As I describe in our release:

At issue is the growing field of research that seeks to understand how human pluripotent stem cells, which can become any cell type, may integrate and contribute to the development of a nonhuman animal, such as a laboratory mouse. Pluripotent stem cells can be isolated from human embryos or created in a lab from adult human cells, in which case they’re known as induced pluripotent stem cells. Once obtained, these versatile cells can be injected into an early-stage animal embryo and studied as the embryo develops into an adult animal.

Tracking where these cells go and how they function in the growing embryo and the adult animal can help researchers understand early stages of human development that can’t be studied any other way. (Although researchers can and do study the development of fertilized human eggs, the study period is restricted to only a few days after fertilization for ethical reasons.)

In addition to investigating human development, the research is expected to lead to significant advances in disease modeling, drug testing and even transplantation. As cardiologist and one of the co-senior authors of the letter, Sean Wu, MD, PhD, explains:

By eliminating federal funding for all aspects of this research, the NIH casts a shadow of negativity toward all experiments involving chimera studies regardless of whether human cells are involved. The current NIH restriction serves as a significant impediment to major scientific progress in the fields of stem cell and developmental biology and regenerative medicine and should be lifted as soon as possible.

Science recently published a great background article describing the ban, and its effect on researchers like Sean Wu and geneticist and stem cell researcher Hiromitsu Nakauchi, MD, PhD, who also signed the letter. Other signees include Joseph Wu, MD, PhD, professor of medicine and director of Stanford Cardiovascular Institute; Christopher Scott, PhD, director of Stanford’s Program on Stem Cells and Society; and Vittorio Sebastiano, PhD, assistant professor of obstetrics and gynecology and director of Stanford’s Human Pluripotent Stem Cells Core Facility.

Previously: NIH intramural human embryonic stem cell research haltedSupreme Court decision on human embryonic stem cell case ends research uncertaintyUsing organic chemistry to decipher embryogenesis and The best toxicology lab: a mouse with a human liver
Photo by Fimb

Cancer, Research, Sleep, Stanford News, Stem Cells, Transplants

Sleep deprivation affects stem cell function, say Stanford scientists

Sleep deprivation affects stem cell function, say Stanford scientists

sleepy mouseWe all know that sleep is important for many biological functions. But I’m still surprised at the breadth of its influence. Today, a former postdoctoral scholar at Stanford, Asya Rolls, PhD, published a fascinating study in Nature Communications showing that blood-forming stem cells from drowsy mice perform more poorly when transplanted into recipient animals. In particular, they are less able to home to the bone marrow, and they generate a smaller proportion of a type of immune cell called a myeloid cell than do stem cells from well-rested mice.

Although the researchers studied only laboratory mice, the possible implications for human transplant recipients (in humans, these procedures are called hematopoietic stem cell transplants, or sometimes bone marrow transplants) are intriguing. As Rolls, who is now an assistant professor at the Israel Institute of Technology, said in our release, “Considering how little attention we typically pay to sleep in the hospital setting, this finding is troubling. We go to all this trouble to find a matching donor, but this research suggests that if the donor is not well-rested it can impact the outcome of the transplantation.”

At Stanford, Rolls worked in the laboratory of psychiatrist and sleep medicine specialist Luis de Lecea, PhD, and she collaborated with Wendy Pang, MD, PhD, and Irving Weissman, MD, director of the Stanford Institute of Stem Cell Biology and Regenerative Medicine, to conduct the research.

Despite the fact that sleep deprivation in the donor reduced the efficacy of their stem cells by about 50 percent, all is not lost. From our release:

Although the effect of sleep deprivation was stark in this study, Rolls and her colleagues found that it could be reversed by letting the drowsy mice catch up on their ZZZs. Even just two hours of recovery sleep restored the ability of the animals’ stem cells to function normally in the transplantation tests.

“Everyone has these stem cells, and they continuously replenish our blood and immune system,” said Rolls. “We still don’t know how sleep deprivation affects us all, not just bone marrow donors. The fact that recovery sleep is so helpful only emphasizes how important it is to pay attention to sleep.”

Previously: In mice, at least, uninterrupted sleep is critical for memory and Bone marrow transplantation: The ultimate exercise in matchmaking
Photo by Eddy Van 3000

Events, Neuroscience, Science, Stanford News, Stem Cells

Stanford Neuroscience Institute’s annual symposium captured on Storify

Stanford Neuroscience Institute's annual symposium captured on Storify

IMG_0246When I talked to William Newsome, MD, PhD, director of the Stanford Neurosciences Institute, about its annual symposium last week, he told me one of the pleasures of directing the institute is getting to pick speakers whose science he really likes.

We captured tweets, images and videos from those speakers on our Storify page, and they make it clear that Newsome has very diverse tastes. Topics ranged from aging and mental health policy to virtual reality for mice.

From Stanford, geneticist Anne Brunet, PhD, discussed her work on aging, particularly how stem cells in the brain change with age. Engineer Krishna Shenoy, PhD, described how his lab was reading signals from the brains of paralyzed people and using those to drive computer cursors or prosthetic limbs. Others discussed machine learning, new technologies for imaging the brain, the genetics of mental health disorders, and insights into how smells illicit behaviors in flies.

It’s worth a look at the Storify page to get a sense of the breadth of work encompassed under the banner of neuroscience.

Previously: “Are we there yet?” Exploring the promise, and the hype, of longevity researchMy funny Valentine – or, how a tiny fish will change the world of aging research and Stanford researchers provide insights into how human neurons control muscle movement
Photo of Krishna Shenoy by Matt Beardsley

Cardiovascular Medicine, Research, Stanford News, Stem Cells

Tension helps heart cells develop normally, Stanford study shows

Tension helps heart cells develop normally, Stanford study shows

heart_newsTension might not be fun for us, but it looks like it’s critical for our hearts. So much so that without a little tension heart cells in the lab fail to develop normally.

This is a finding that took a mechanical engineer looking at a biological problem to solve. For many years now scientists have been able to mature stem cells into beating clumps of cells in the lab. But although those cells could beat, they didn’t do it very well. They don’t produce much force, can’t maintain a steady rhythm and would be a failure at pumping actual blood.

Beth Pruitt, PhD, a Stanford mechanical engineer, realized that in our bodies heart cells are under considerable tension, and thought that might be critical to how the cells develop.

She and postdoctoral scholar Alexandre Ribeiro started investigating how heart cells matured in different shapes and under different amounts of tension. They found a combination that produces normal looking cells with strong contractions.
The work could be useful for scientists hoping to replace animal heart cells as the gold standard for identifying heart-related side effects of drugs. Those cells are quite different from our own and often fail to detect side effects that could damage hearts in people taking the drug.

In my story about the work, I quote Ribeiro saying, “We hope this can be a drop-in replacement for animal cells, and potentially instead of having to do individual recordings from each cell we could use video analysis.”

Previously: A new era for stem cells in cardiac medicine? A simple, effective way to generate patient-specific heart muscle cells and “Clinical trial in a dish” may make common medicines safer, say Stanford scientists
Photo by Alexandre Ribeiro

Cardiovascular Medicine, Chronic Disease, Science, Stanford News, Stem Cells

Patching broken hearts: Stanford researchers regrow lost cells

Patching broken hearts: Stanford researchers regrow lost cells

Design 1_2Most heart attack survivors face a long and progressive course of heart failure due to damage done to the heart muscle. Now, in a study published in the journal Nature, researchers are reporting a method of delivering a missing protein to the lining of the damaged heart that regenerates heart muscle cells — cardiomyocytes — killed off during a heart attack.

The study, which was conducted in animal models, offers hope for future treatments in humans, according to the senior author of the study. “This finding opens the door to a completely revolutionary treatment,” Pilar Ruiz-Lozano, PhD, told me. “There is currently no effective [way] to reverse the scarring in the heart after heart attacks.”

The delivery system that researchers used in this study is a biodesigned tissue-like patch that gets stitched directly onto the damaged portion of the heart. The protein Fstl1 is mixed into the ingredients of the patch, and the patch, made of an acellular collagen, eventually gets absorbed into the heart leaving the protein behind. Our press release explains how the patch came to be:

The researchers discovered that a particular protein, Fstl1, plays a key role in regenerating cardiomyocytes. The protein is normally found in the epicardium — the outermost layer of cells surrounding the heart — but it disappears from there after a heart attack. They next asked what would happen if they were to add Fstl1 back to the heart. To do this, they sutured a collagen patch that mimicked the epicardium to the damaged muscle. When the patch was loaded with Fstl1, it caused new cardiomyocytes to regenerate in the damaged tissue.

In reading over the study, I was particularly interested in what an engineered tissue-like patch applied to a living heart looked like – and how exactly the patch got made. I called one of the study’s first authors and went to see him in his lab.

Vahid Serpooshan, PhD, a postdoctoral scholar in cardiology at Stanford, told me he can make a patch in about 20 minutes. It’s a bit like making Jell-O, he said; collagen and other ingredients get mixed together then poured into a mold. Serpooshan uses molds of various sizes depending on what kind of a heart the patch will be surgically stitched onto.

“The damaged heart tissue has no mechanical integrity,” Serpooshan said. “Adding the patch is like fixing a tire… Once the patch is stitched onto the heart tissue, the cardiac cells start migrating to the patch. They just love the patch area…”

Previously: Stanford physician provides insight on use of aspirin to help keep heart attacks and cancer away, Collagen patch speeds healing after heart attacks in mice and Big data approach identifies new stent drug that could help prevent heart attacks
Image, of a patch stitched to the right side of the heart, by Vahid Serpooshan

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

Chimps and humans face-off in Stanford study on inter-species variation

Chimps and humans face-off in Stanford study on inter-species variation

wysocka_illustration (6)Our nearest primate relative, the chimpanzee, shares much of its genome with us. And yet, despite the astounding similarities in our DNA sequences, it’s not difficult to discern the face of one species from the other.

Developmental biologist Joanna Wysocka, PhD, researches, among other things, how human faces are formed during early embryonic development. She and graduate student Sara Prescott compared gene expression patterns between humans and chimpanzees in the hopes of identifying not just what makes us recognizably human, but also how human faces also differ among themselves.

They describe their work, which was published today in Cell, as a kind of “cellular anthropology” that can illuminate important genomic tweaks in our recent evolutionary past. In particular, they found that the critical differences between the two species lie not in the DNA sequence of the genes themselves, but in when and where (and to what levels) the genes are made into proteins during development. These changes have led to important, human-specific adaptations. As Wysocka explained in our release:

We are trying to understand the regulatory changes in our DNA that occurred during recent evolution and make us different from the great apes. In particular, we are interested in craniofacial structures, which have undergone a number of adaptations in head shape, eye placement and facial structure that allow us to house larger brains, walk upright and even use our larynx for complex speech.

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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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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

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.”


(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


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