Stem Cells

Think of it as the “Rocky” RNA. Researchers here at the School of Medicine have found that a small piece of RNA, called a microRNA, plays a key role in determining when muscle stem cells in mice start to divide. It’s the first time a microRNA has been implicated in the maintenance of the adult stem cell resting state.

According to our news story:

“Although on the surface the quiescent state seems to be relatively static, it’s quite actively maintained,” said Thomas Rando, MD, PhD, professor of neurology and neurological sciences. “We’ve found that changing the levels of just one specific microRNA in resting muscle stem cells, however, causes them to spring into action.”

The findings are potentially important because:

Unlike stem cells in the blood or skin, muscle stem cells spend most of their lives nestled in the surrounding tissue. “They don’t do much most of the time,” said Rando. “They remain in a quiescent state for most of a person’s life. When you injure your muscle, however, they begin dividing to repair the damage.” Like all adult stem cells, each muscle stem cell becomes two daughter cells: one with stem cell properties, and the other that continues dividing to become mature muscle cells and fibers to replenish those that are damaged. Without such “asymmetric” division, the stem cells would quickly be depleted after injury.

Pinpointing exactly what calls the stem cells to begin dividing is an important first step to using them in human therapies. It’s also a key to understanding how muscles age and why they become less able over time to repair normal wear and tear.

Rando and his collaborators have published their findings in Nature.

When Stanford neurosurgeon Gary Steinberg, MD, PhD, injected human stem cells this fall into the damaged spinal cord tissue of specially-selected patients, it was considered a major step forward in moving research discoveries toward clinical application. In November, however, the Menlo Park-based Geron Corp. announced it was ending the trial and its research into stem cells to concentrate on cancer drugs. Steinberg was disappointed, as many were. But, as he explained in a new Q&A on the Stanford Hospital & Clinics website:

We should remember that five of the anticipated eight total patients were successfully transplanted with no adverse effects noted to date. Since this was designed as a safety study, the outcomes are very encouraging. These patients will be followed for 15 years to assess continued safety as well as any signs of neurologic improvement. I don’t believe the early termination of enrollment in this study will significantly set back the stem cell therapy field.

And when asked about his personal motivation to pursue and study embryonic stem cell treatment, he told me:

I was inspired by what I see every day: Patients devastated by neurological disorders and psychiatric disease with no hope or little hope for recovery of function. And it’s been like that for hundreds of years for many neurological diseases or injuries, including stroke, degenerative disorders like Parkinson’s, brain tumors, Alzheimer’s. These patients are disabled and we have no treatment once the injury has occurred to restore or regenerate function. Stem cell therapy offers great hope to change that status for a large number of patients.

Previously: First California patient treated in Geron’s human embryonic stem cell trial and Stanford joins first human embryonic stem cell trial

Eight years ago I wrote an article about particles. More precisely, I wrote about how, when it comes to lipoprotein particles like the notorious LDL and the vaunted HDL, the bigger and fluffier the better from a health standpoint. In the course of researching the article I telephoned Nir Barzilai, MD, of Yeshiva University’s Albert Einstein College of Medicine.

Barzilai has assembled a collection of over 500 Ashkenazi Jews 95 years old or older, leveraging this relatively homogeneous group to tease out gene variants that distinguish long-lived from shorter-lived but otherwise similar people. Among the interesting longevity-associated gene variants he’s fished out is one whose presence renders HDL and LDL particles larger and more bouyant. (Think of this as the biochemical equivalent of dotting I’s with big round circles, which connotes an optimistic outlook.)

I finally got to meet Barzilai in person at a symposium (read about it here) hosted by the Glenn Laboratories for the Biology of Aging. Directed by Tom Rando, MD, PhD, this Stanford-based center focuses on how changes in stem cells in various tissues that occur as we get older contribute to the development of age-related disorders.

The Jan. 30 event was the kickoff for an ongoing series of Monday-afternoon seminars that will highlight advances in our understanding, at a fundamental level, of the aging process.

A key point that Barzilai, Rando and other symposium speakers broadly agreed on: Like tots engaged in parallel play in a sandbox, investigators have tended to focus narrowly on one or another of numerous aging-related diseases from cancer to arthritis to Alzheimer’s, without necessarily talking to one another very much. But slowing the aging process, the speakers emphasized, will delay or prevent all those diseases.

Sign me up for that plan.

February is American Heart Month, and to mark the occasion I sat down with Robert Robbins, MD, chair of the Department of Cardiothoracic Surgery (and director of the Stanford Cardiovascular Institute), to ask him about innovations in cardiac care and what the future holds. My Q&A was recently posted on the Stanford Hospital & Clinics website, and I’ve included a few highlights below.

Robbins on minimally-invasive aortic valve replacement:

As part of a clinical trial, we’re doing some valve replacements transfemorally — that is, using a catheter to maneuver the new valve through blood vessels to the heart. Only one small incision to the femoral artery is needed, and the procedure generally takes little more than an hour. Recovery time is a few days.

On heart health and the human genome:

Much of the work in this area is being done at Stanford, where we have a lot of strength not only in mapping DNA but also interpreting the massive amount of data it produces. Our researchers will be able to create algorithms and ways to manage and interpret this data. One day you’ll probably be able to walk into your doctor’s office and say, “Here’s my genetic code. What does it mean?”

Another great hope is to customize drug therapy to specific cardiovascular diseases, such as hypertension, based on your genetic profile. If your genes make certain proteins or enzymes that metabolize a certain class of drugs better than another class, then doctors could use this so-called pharmacogenomic approach to customize treatments.

On stem cells:

I think they hold huge promise, but we’re not ready yet to employ stem-cell therapies to treat end-stage heart failure. But I do believe our group here at Stanford, one of the world’s leaders in this area, will be the first to put embryonic stem cells into the human heart.

Previously: Either you’re a woman or you know one: Help spread the message of women’s heart health, A focus on women’s heart health and At new Stanford center, revealing dangerous secrets of the heart
Photo by epSos.de

California stem-cell research aficionados are of course familiar with the California Institute for Regenerative Medicine, or CIRM. The state stem-cell agency has handed out over a billion dollars of funding to build new facilities, recruit promising faculty members and otherwise encourage and support stem cell research in California (Stanford has received the lion’s share of grants, to the tune of nearly 200 million dollars). But, as noted in today’s Nature News:

Halfway through its initial ten-year mandate, the California Institute for Regenerative Medicine (CIRM) in San Francisco is confronting a topic familiar to anyone at middle age: its own mortality.

The publicly funded institute, one of the world’s largest supporters of stem-cell research, was born from a state referendum in 2004. Endorsements from celebrities such as then-state governor Arnold Schwarzenegger and the late actor Christopher Reeve, who had been paralysed by a spinal injury, helped to garner voter support for a public bond to underwrite the institute. But with half of the US$3 billion that it received from the state now spent and the rest expected to run out by 2021, CIRM is now actively planning for a future that may not include any further state support.

The article quotes Stanford dermatologist and stem cell researcher Howard Chang, MD, PhD:

“It would be a very different landscape if CIRM were not around,” says Howard Chang, a dermatologist and genome scientist at Stanford University in California. Chang has a CIRM grant to examine epigenetics in human embryonic stem cells, and is part of another CIRM-funded team that is preparing a developmental regulatory protein for use as a regenerative therapy. Both projects would be difficult to continue without the agency, he says. Federal funding for research using human embryonic stem cells remains controversial, and could dry up altogether after the next presidential election (see Nature 481, 421–423; 2012). And neither of Chang’s other funders — the US National Institutes of Health (NIH) and the Howard Hughes Medical Institute in Chevy Chase, Maryland — supports his interdisciplinary translational work.

You can read more about Chang’s research here and here. The news article is brief, but it’s interesting to hear directly from researchers how CIRM grants have affected their work, and what it might be like if the agency is unable to find new sources of funding.

Previously New job description for RNA, oldest professional biomolecule and Stanford researcher finds new marker to identify severe breast cancer cases.

I was excited last week to learn about the recent work of stem cell scientist Marius Wernig, MD, published today (direct link to come) in the Proceedings of the National Academy of Sciences. Wernig directly converted mouse skin cells to neural precursor cells – an extension of previous work in which he created functional neurons from the same types of cells. Although functional neurons might sound more exciting, neural precursor cells promise to be research workhorses. That’s because these cells can become any of three main components of the nervous system: neurons, oligodendrocytes and astrocytes. They can also be grown to large numbers in the laboratory – a critical factor when carrying out drug screening or considering future transplantation into animals or perhaps even one day even into humans. As Wernig explained in our release:

We are thrilled about the prospects for potential medical use of these cells. We’ve shown the cells can integrate into a mouse brain and produce a missing protein important for the conduction of electrical signal by the neurons. This is important because the mouse model we used mimics that of a human genetic brain disease. However, more work needs to be done to generate similar cells from human skin cells and assess their safety and efficacy.

The release also advances what, for some researchers, may be an even more intriguing idea:

The multiple successes of the direct conversion method could refute the idea that pluripotency (a term that describes the ability of stem cells to become nearly any cell in the body) is necessary for a cell to transform from one cell type to another. Together, the results raise the possibility that embryonic stem cell research and another technique called “induced pluripotency” could be supplanted by a more direct way of generating specific types of cells for therapy or research.

As always, however, more research is needed to determine how cell types generated by the various techniques differ or resemble one another at a molecular level. Right now, there’s no clear winner and it appears there are still several horses in the race.

Previously: Human neurons from skin cells without pluripotency?

Yesterday, my colleague and others reported on early results of two studies involving human embryonic stem cell therapy for macular degeneration-caused blindness; the report (.pdf) in The Lancet represents “the first description of hESC-derived cells transplanted into human patients.” Now, on the Law and  Biosciences Blog, Stanford law professor Hank Greely, JD, weighs in on the significance of the findings:

…This clearly is some good news for those hoping for treatments from human embryonic stem cells. Granted, it is only a little good news. A report on four months of treatment in two patients, with two related but different diseases, cannot bear heavy reliance. That’s too few patients for too little time to be too exciting. But it is, at least, a little exciting – and in a field that saw its first approved clinical trial stopped two months ago, even a little exciting news is very welcome.

When California passed Proposition 71 in November 2004, I was quoted saying that I would be disappointed if there were not some human clinical trials within 5 years and would be further disappointed if there were not some treatments emerging within 10 years. I did not count on the three year delay in funding from that Proposition caused by frivolous litigation (and courts unwilling to act promptly to dismiss those claims). Given that CIRM funding did not really start until 2007, I’m going to take (some, little) heart from this report.

Previously: First results of human embryonic stem cell trials for blindness, Two new human embryonic stem cell trials launched and After the lawsuit, what’s next for stem cell research?

Exciting news! Researchers at UCLA and Advanced Cell Technology have published the first report (.pdf) of the use of human embryonic stem cell therapy for blindness caused by a condition called macular degeneration. The preliminary report indicates that the cells are well-tolerated and appear safe. Although the two trials were not designed to test whether the cells can improve vision, the investigators were encouraged by the fact that the two trial participants did not show any further vision loss during the first four months of the trial and the vision of one participant seemed to improve. In an article published in The Lancet today, the authors wrote:

We noted clear functional visual improvement in the study eye of the patient with Stargardt’s macular dystrophy corresponding subjectively to the transplanted region of the posterior pole. At baseline the central vision was hand motions. By week 2, best corrected visual acuity was improved to counting fingers (one ETDRS letter). We recorded continued improvement during the study period (five ETDRS letters [best corrected visual acuity 20/800] at 1, 2, and 3 months; table). The patient is very reliable and worked for years as a graphic artist. She reports subjectively improved colour vision and improved contrast and dark adaptation from the operated eye.

Before implantation, the stem cells were coaxed to become cells that form the retinal pigment epithelium – the tissue that is compromised in both dry age-related macular degeneration and Stargardt’s macular dystrophy. The newly derived epithelial cells were then transplanted into two patients, where they integrated and survived over time. They appeared to grow normally after transplantation.

Much more work needs to be done, of course, before any conclusions can be made about the potential usefulness of these cells as therapy. But I imagine that proponents of human embryonic stem cell research are breathing a cautious sigh of relief this morning. After Geron abruptly dropped their hESC trial for spinal cord injury last November, researchers and media people alike wondered aloud whether the move would set the field back irreversibly. This news, however preliminary, must be welcome indeed.

(If you’d like to learn more about Advanced Cell Technology and their chief scientific officer, Robert Lanza, MD, check out this fascinating history of the company published in Nature earlier this month.)

Previously: Two new human embryonic stem cell trials launched

A few years ago, Tom Rando, MD, PhD, found that if the circulatory systems of a young and an old mouse were connected, something in the blood of the young mouse seemed to rejuvenate the old mouse’s liver and muscle. And something in the old mouse’s blood seemed to age the young mouse’s equivalent organs and tissues. Rando taught Tony Wyss-Coray, PhD, the mouse-hookup technique, and last year the latter showed that factors in blood can similarly influence the robustness of stem cells in the brain, too. (This was the subject of a recent Stanford Medicine article.)

Meanwhile, Howard Chang, MD, PhD, and one or two other investigators in the research-osphere were showing the world that a whole lot of the DNA in each of our cells codes for not proteins but RNA molecules whose job it is to fire up or shut down the genes that do code for protein production. (For more, see this.)

In a just-out review article in the journal Cell, Rando and Chang raise the possibility of getting old cells to act younger. And not just any old cells, but the “adult” stem cells that reside in most if not all of our various tissues.

Most of us are more familiar with these cells’ more publicized relatives, embryonic stem cells (eSCs). These superstars are famous for being able to perform two tricks. They can multiply indefinitely in a dish, and they can differentiate into any of the 200-odd cell types in our body. That’s good and it’s bad. Good, because they offer the promise of regenerative medicine: essentially, differentiating eSCs into the needed cell types and infusing them to rejuvenate worn-out or defective tissue. Bad, because on their way to becoming the right kind of cells, they could go wrong instead, and become tumors.

Unlike eSCs, tissue-resident cells already know what they want to be when they grow up: They want to be whatever type of cell within that particular tissue that happens to be in short supply. In other words, these adult stem cells are already committed to a given lineage. A nerve stem cell’s not going to surprise you by turning into a fat stem cell.

Rando and Chang’s review, and this Q-and-A session I conducted with Rando the other day, explore the prospects for restoring aging tissues’ tiring stem cells to more-youthful activity levels. It might be possible to kickstart them with bloodborne factors isolated through experiments of the type I mentioned above – or, better, with pharmaceutical compounds that mimic the actions of those factors.

I feel younger already.

Previously:Old blood + young brain = old brain, Old blood makes young brains act older, and vice versa, New job description for RNA, oldest professional biomolecule
Photo by jikatu

This “60 Minutes” segment tells the heart-breaking story of one family’s experience at a Mexican clinic, where they sought treatment for their three-year-old son’s cerebral palsy. The piece cautions others about the dangers than can arise when international clinics offer unverified stem cell therapies. In a post today on the California Institute of Regenerative Medicine’s blog, Amy Adams discusses the segment and further describes why such treatments are unsafe and ineffective. Adams offers the following advice for anyone thinking about visiting another country to receive a stem cell treatment:

If people are considering clinics outside the U.S., please do read the ISSCR web page. They have a good list of qualifications to look for in identifying clinics that are being truthful about what they offer rather than simply peddling hope. Included in what they suggest people look for is oversight of investigational treatments to be sure the physicians are qualified, the investigational treatment is prepared appropriately, and that the risks and potential benefits are accurately and clearly explained. People should also look for published records showing results from clinical trials. CIRM also has a page about stem cell tourism and what we are doing to try to speed the timeline to new therapies.

Previously: Stem cell researchers challenge clinics’ questionable practices, Beware: Stem cell clinics offering “miracle” cures, International Cellular Medicine Society evaluates overseas stem cell clinics and The cruelty of fraudulent stem cell therapies

This eye-catching image from the California Institute of Regenerative Medicine (CIRM) Flickr photostream looks like a piece of abstract art but is actually a depiction of human embryonic stem cells differentiating into precursors cells of the retina. According to the CIRM photo caption:

Nuclei are in blue. Pink indicates the presence of Pax6, a protein found in retinal tissue. The retinal pigment epithelium is the tissue responsible for macular degeneration, the most common cause of blindness.

The image was taken by David Buchholz, PhD, in the lab of Dennis Clegg, PhD, at UC Santa Barbara where researchers are working to determine if stem cells be applied in novel therapies to treat retinal diseases including age-related macular degeneration.

Seizing on the serendipitous finding of a human embryo carrying a genetic condition known as Marfan syndrome, an all-star team of Stanford scientists led by Mike Longaker, MD, pitted induced pluripotent stem cells (iPS cells for short) against embryonic stem cells and showed that the former mirror Marfan at the cellular level every bit as well as the latter do. This bodes well for the use of iPS cells for personalized medicine.

Breakthrough – a term that should not be tossed around lightly – is the right word choice for iPS cells’ discovery by Shinya Yamanaka, MD, PhD, in 2006. Derived in a dish from fully differentiated tissues such as skin (which is one hell of a lot easier to get hold of and work with than embryos), these cells closely mimic embryonic stem cells (ESCs) in their ability to differentiate into every one of the 200-odd cell types occurring in our bodies, or alternatively to rest content, replicating placidly in the petri plate where they were produced, until duty calls.

The proliferative potential and protean plasticity of ESCs and iPS cells alike render them promising prospects for regenerative medicine: differentiation of such cells into one or another tissue of choice, then popping this new material into place as a substitute for the spent, injured or defective tissue of an ailing patient. That’s going to be a long, long way off.

But because iPS cells can be derived from essentially anyone through relatively noninvasive means, they offer a much more near-term, low-cost kicker: The tissues into which they differentiate carry precisely the same genetic background as those of the person they came from. You wouldn’t want to go drilling into a person’s heart or brain for a tissue sample; you’d even think twice before probing the liver, pancreas, or other internal organs for a biopsy. But with iPS cells, you don’t have to. They can be coaxed in vitro into becoming cell types that, in the patient/donor, are malfunctioning. Then they can be studied with all the analytical tools of modern bioscience. In principle, they can also be used for in vitro assays screening thousands or tens of thousands of drugs, to see which drugs best rectify or at least mitigate that particular patient’s problem.

But are iPS cells the sparkling surrogates for their more problematic and technically finicky counterparts, the hESCs, that many experts believe them to be? Or are they instead dubious doppelgangers, doomed to deliver a distorted reflection of natural tissues and whatever disease they may be packing? Does iPS cells’ sorcery-like summoning (via a witches’ brew of transcription factors to coax initially differentiated cells back to an ESC-like state) leave them too artifact-ridden to accurately mirror those maladies?

The new study suggests that the answer is no. The iPS cells made from the skin of Marfan patients matched ESCs derived from a Marfan-syndrome-carrying embryo in their ability to mirror Marfan’s defining features: a pronounced proclivity to form cartilage at the expense of bone.

Maybe Ponce de Leon should have considered becoming a vampire. My just-out magazine article, “Old Blood, New Tricks: What Blood’s Got to Do with It,” highlights the work of a couple of wild and crazy guys named Tony Wyss-Coray, PhD, and his erstwhile graduate student, Saul Villeda, now a full-blown PhD himself. Against all odds, the intrepid duo (with help from many others in the Wyss-Coray lab and beyond) showed that old blood can gum up a young brain.

Okay, well, so that’s a bummer. But the real intrigue of Wyss-Coray, Villeda et al.‘s research lies in tantalizing hints that the inverse – “young blood can soup up an old brain” - quite possibly may be true as well. Or, as the article puts it:

Aging takes a toll on all tissues, but its wrath is reserved especially for tissues with low regenerative potential — for instance, the brain. What Villeda and Wyss-Coray found - in mice, to be sure - was that old blood has a detrimental effect on the brain. The hope: We humans might someday be able to rejuvenate our own aging brains with as-yet-unidentified factors circulating in young blood.

Now, don’t go dancing on down to your local blood bank looking for young blood just yet. Blood products, like pharmaceutical drugs, are regulated by the FDA, which demands evidence of efficacy in humans — something that’s still a long way down the road.

Previously : Old Blood Makes Young Brains Act Older, and Vice Versa and Freshen Up Those Stem Cells with Young Blood
Photo by El Bibliomata

At the risk of being overly depressing, we’re all getting older. And there’s more to bemoan than just the gray hairs and wrinkles that might be popping up. Every cell in our body is aging, including the hematopoietic stem cells that generate our blood cells and immune system. According to our release:

Specifically, the researchers found that hematopoietic stem cells from healthy people over age 65 make fewer lymphocytes — cells responsible for mounting an immune response to viruses and bacteria — than stem cells from healthy people between ages 20 and 35. (The cells were isolated from bone marrow samples.) Instead, elderly hematopoietic stem cells, or HSCs, have a tendency to be biased in their production of another type of white blood cell called a myeloid cell. This bias may explain why older people are more likely than younger people to develop myeloid malignancies.

It could also be why elderly people find it hard to shake off colds, flu and other viruses, say graduate student Wendy Pang, MD and stem cell biologist Irving Weissman, MD, who co-authored the study in today’s Proceedings of the National Academy of Sciences.

“In both mice and humans, the puzzle has been how the system ages,” said Weissman, who is also the Virginia & D.K. Ludwig Professor for Clinical Investigation in Cancer Research and a member of Stanford’s Cancer Institute. “Because HSCs in old mice and humans are derived from the HSCs they had in their youth, there are two possibilities to describe how these differences occur. Either individual, young HSCs change their gene expression patterns as they age, undergoing heritable adaptations that favor the myeloid lineage, or each young HSC already has a specific lineage bias and is battling for precious niches through the natural selection of aging, which favors those biased toward myeloid cells.” Understanding which possibility is true could help clinicians of the future encourage the survival of HSCs with more-appropriate properties in patients with age-related diseases, Weissman believes.

Previously Freshen up those stem cells with young blood

Happy International Stem Cell Awareness Day! Researchers from the New York Stem Cell Foundation are celebrating by publishing (subscription required) the first reports of human stem cell lines created through a technique called somatic cell nuclear transfer, or SCNT. Although the technique is similar to that used to clone Dolly the sheep in 1996, the resulting human embryonic stem cell lines have three copies of each gene, rather than the normal two. As a result, they can not be used for therapies. But the research is an important proof of principle that will set the stage for future work, said study co-author Scott Noggle, PhD, in a press briefing yesterday:

The goal of this research was to create patient-specific embryonic stem cells. We have shown for the first time that the human oocyte has the capacity to reprogram somatic nuclei to a pluripotent state.

To conduct the research, Noggle and Dieter Egli, PhD, used donated human eggs. They first tried removing the eggs’ own haploid genomes (as reproductive cells, eggs and sperm each have one half the normal complement of genetic material) and replacing it with the nuclei of a somatic, or specialized adult, cell. They found that the resulting cell underwent only a few cell divisions before halting. When they simply added the somatic nuclei to the eggs, they had much better luck: the cell went on to form a multi-cellular structure called a blastocyst, from which Noggle and Egli successfully prepared human embryonic stem cell lines with three, rather than two, copies of each gene. Says Egli:

We are now trying a number of approaches to remove the egg genome. Although the long-term goal is to generate cells for use in therapies, we can use these cells now for several important studies, including comparing them to human iPS cells.

iPS cells are pluripotent cells created from somatic cells by using viruses or other genetic manipulation. While they, like cells derived from SCNT, can be generated from the patient they are meant to treat (and thus should not generate an immune response), researchers agree that they are not genetically identical to true embryonic stem cells and more research is needed to determine their therapeutic usefulness.

The full study requires a subscription to access. But you can read a nice review of the work in today’s Nature News.