Stem Cells

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.

On the heels of news that a fourth patient – this one at Stanford – has participated in Geron’s human embryonic stem cell trial, Massachusetts-based Advanced Cell Technology has announced its plans to conduct the first ESC cell trial outside the United States. Spoonful of Medicine reports:

The trial will essentially be a repeat performance of one of ACT’s ongoing trials in the US, but this time conducted at the Moorfields Eye Hospital in London. Led by Moorfields ophthalmologist James Bainbridge, the trial, which is scheduled to begin before the end of the year, will use retinal cells derived from ESCs to treat 12 people suffering from Stargardt’s macular dystrophy, a progressive juvenile vision loss disorder that affects about one in every 10,000 children.

According to [Robert Lanza, MD, ACT’s chief scientific officer] in the near future ACT also expects to gain UK approval to use the same cell therapy to treat people with age-related macular degeneration, a common cause of blindness in the elderly and the other disease currently under investigation by the company in US trials. Meanwhile, ACT is also in late-stage talks with regulators and clinicians in France, China and elsewhere to launch further global trials.

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

On Saturday, Stanford and Santa Clara Valley Medical Center (SCVMC) treated the fourth of ten patients in Geron’s trial of cells derived from human embryonic stem cells. The patient is the first on the West Coast to receive the treatment, which is intended to test the safety of the procedure in paralysis patients before moving into larger trials. Stanford neurosurgeon Gary Steinberg, MD, PhD, implanted the cells.

From our release:

“We are extremely excited to participate in this landmark clinical trial,” said Steinberg, who is the Bernard and Ronni Lacroute-William Randolph Hearst Professor in Neurosurgery and Neurosciences at Stanford and the principal investigator of the Stanford/SCVMC portion of the trial. “It signifies a major advance in translating an innovative research discovery into clinical therapy. I believe it is critically important to encourage and take part in stem cell trials like this, which represent a new era in the effort to restore function for patients with stroke, brain injury, Parkinson’s disease and other devastating neurologic disorders.”

Those sentiments were echoed by Stephen McKenna, MD, chief of the Rehabilitation Trauma Center at SCVMC. “It has been an extraordinarily collaborative process at every step, from developing the screening process and identifying possible patients to evaluating these patients for surgery,” McKenna said. “Although it’s been an intensive commitment of resources, we understand the importance of advancing new therapies for patients.”

The trial is being run by Geron Corp. of Menlo Park, Calif., which developed and manufactures the cells being tested. In May, Geron received a $25 million grant from the California Institute for Regenerative Medicine to continue and extend the trial to include a greater proportion of spinal cord injuries.

The patient entered an intensive inpatient rehabilitation program at SCVMC and will be monitored for any adverse events to confirm that the cells are safe for use in humans.

Previously: Stanford joins first human embryonic stem cell trial
Photo of Steinberg by Mark Tuschman

There’s a Q&A with Mahendra Rao, MD, PhD, the first director of the NIH Intramural Center for Regenerative Medicine,  over at Spoonful of Medicine today. Rao took the reins of the new, $52-million, seven-year center last month, and he had some something interesting things to say about his new place of employment:

Are you worried that the new center’s efforts could be derailed given the recent litigation surrounding the NIH’s stem cell policy?

I have to admit that was one of concerns when I took the job. The problem is that there’s no way to predict the future. But there’s a commitment from the NIH that this [new center] will be at least a five- to seven-year experiment. Maybe in two years’ time policies will change or the Supreme Court will rule differently, but we will still have a path to get things done.

What sets the regenerative medicine center apart from other academic institutes dedicated to stem cell technologies?

Neither in size nor in scientific quality could one say that this center is any different from some of the other more established centers. However, there are two crucial differences. One, this is a government center, and the government’s mandate is different than that at any other center. So, that’s a really important distinction. The second thing is that the center doesn’t function in isolation. It’s what’s around it that makes it very useful, and what’s around it is a whole lot of infrastructure and investment that’s gone in to building up a way to take things from the bench to the bedside. There are two really important pieces to that in the NIH Chemical Genomics Center and the NIH Clinical Center. Both of them are widely recognized, state of the art, best in class type of centers.

Previously: After the lawsuit, what’s next for stem cell research?

Neuroscientist Tony Wyss-Coray, PhD, and his anything-goes grad student, Saul Villeda (now a PhD) decided to ignore the traffic light called the blood-brain barrier and charge full-speed ahead into a study, now published in Nature, of naturally occurring blood-borne substances that – however they do it – manage to make young brains act older. These substances, whose levels unfortunately rise with increasing age, appear to inhibit the brain’s ability to produce new nerve cells critical to memory and learning.

Wyss-Coray, Villeda, and their Stanford peers not only identified a half-dozen such substances in a mouse study but confirmed that they all rose in an age-related fashion in humans, too. One of the blood-borne chemicals, eotaxin, is well known as a signaling molecule that attracts immune cells called eosinophils to areas where it’s being secreted. Eosinophils, in turn, have been implicated in allergy and asthma — which is a whole other story, except for the consequence that drugs that block eotaxin’s action are already in clinical trials for asthma.

One wonders – and you can be sure Wyss-Coray and Villeda are wondering, too – what would happen if one were to block four or five of these age-related substances’ activity. Would we be able to produce more new brain cells in our 80s and 90s? Would we remember where we left the car keys?

Tom Rando, MD, PhD, one of the study’s co-authors, had gotten the ball rolling five or six years ago when he demonstrated, using a technique later adopted by Wyss-Coray’s group, that muscle stem cells are more robust if bathed in young blood. Another study, which I wrote about a year and a half ago, got similar results when looking at the effects of young versus old blood on the relative pep of blood-forming stem cells.

The possibilities are huge. As I wrote in a news release on this study:

The findings raise the question of whether it might be possible to shield the brain from aging by eliminating or mitigating the effects of these apparently detrimental blood-borne substances, or perhaps by identifying other blood-borne substances that exert rejuvenating effects on the brain but whose levels decline with age.

Wyss-Coray’s group also learned that something in young mice’s blood makes old brains act (or at least look) younger. They’re now trying to identify some of these “rejuvenating factors” for further experiments directed at keeping our brains young. Stay tuned.

Previously: Freshen up those stem cells with young blood.
Photo by  Marxchivist

Although you may not know it, mammals (even humans!) can regrow small portions of amputated digits like fingers and toes. This remarkable ability has perplexed scientists for some time, as they pondered whether it was due to the presence of already-existing adult stem cells in each of the various tissues that make up the end of a finger (blood vessels, bone, skin and tendons, for example), or if specialized cells near the site of injury were somehow able to regress developmentally and gain the capacity to become many different tissue types. As described in our release today:

[The researchers...] have shown that damage to a digit tip is repaired by specialized adult stem cells that spend their lives quietly nestled in each tissue type. Like master craftsmen, these cells spring into action at the first sign of damage, working independently yet side-by-side to regenerate bone, skin, tendon, vessels and nerves. But just as you wouldn’t ask a mason to wire your house, or an electrician to put on a new roof, the division of labor among these stem cells is strict. Each is responsible solely for its own tissue type.

In contrast, the blastema theory invokes a new pluripotent cell type formed out of urgency from previously specialized cells. This jack-of-all-trades cell discards its former profession and instead jumps in to indiscriminately regenerate all the tissue types of the limb.

The work was performed by postdoctoral scholar Yuval Rinkevich, PhD, in the laboratory of Irving Weissman, MD. Weissman had this to say about the findings:

We’ve shown conclusively that what was thought to be a blastema is instead simply resident stem cells that are already committed to become specific tissue types. The controversy about limb regeneration in mammals should be over.

According to Weissman, the study is particularly important because, in the past, some scientists and national media reports have championed the idea that money allotted by the California Institute for Regenerative Medicine for stem cell studies would have been better funneled to blastema research.

Photo by Yuval Rinkevich

In a rather nice Technology Review piece, David Ewing Duncan takes an in-depth look at cardiomyocytes grown from induced pluripotent stem cells that were created by “reprograming” his blood cells – all in an effort to understand his risk for disease. The piece also mentions Stanford cardiologist Euan Ashley, MD, who looks at Duncan’s cells and:

. . .verified my persistent normalcy – and confirmed that the cells in question were what they were supposed to be. “These tests prove that the cells are cardiomyocytes,” [Ashley] said, “which at this early stage in this science is important.”

The rest of Duncan’s inquiry is quite interesting and worth reading.

Previously: Genomics gets personal

This year, the California Institute for Regenerative Medicine launched a pilot program during which high-school students intern in university labs and work on projects combining stem cell research and other disciplines, such as engineering, chemistry, social sciences and ethics. Titled the CIRM Creativity Awards, the program placed 18 students in labs at Stanford and University of California campuses in San Francisco, Davis and Santa Barbara.

In the above video, Samantha Guhan, who completed her internship at Stanford, and other students talk about the types of projects they worked on and how the program increased their awareness about the potential of stem cell research.

Previously: Stanford’s med school training programs in full swing, A look at the Stanford Medical Youth Science Program and A prescription for improving science education

UPDATE: A transcript of the talk is now available. (Scroll down to “The Future of Stem Cell Research” box.)

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Ever since U.S. district court judge Royce Lamberth dismissed a case that threatened to ban federal funding for all human embryonic stem cell research, scientists and others in the biomedical community have wondered what’s next for the field. Today, Stanford law professor Hank Greely, JD, joins a live online chat hosted by Science to discuss the ups and downs of stem cell policy over the past decade and the latest legal ruling.

For a quick primer on the issue, read Greely’s informative blog post on Lamberth’s decision and then tune into the ScienceLive chat at 12 p.m. Pacific Time.

Previously: Stem cell funding injunction overturned by federal court , Judge Lamberth’s stem cell opinion is disappointingly bad, More concern over US judge’s stem cell ruling and Stanford stem cell expert weighs in on district court ruling
Photo by California Institute for Regenerative Medicine

One week ago, a federal judge threw out a lawsuit against government funding for human embryonic stem cell research. But, as Nature’s Meredith Wadman is reporting, the field remains vulnerable:

…[R. Alta Charo, JD] who studies law and bio­ethics at the University of Wisconsin–Madison] notes that the current US Congress is so politically divided it is unlikely to enact a law either explicitly permitting or explicitly prohibiting government funding for the research. But, she says, “nothing in this decision and nothing in the Dickey–Wicker amendment” stops a new president from quashing research simply by refusing to fund it. [Stanford's Hank Greely, JD] says that the best way to protect the research “is to get some real medical progress with stem cells” to prove the worth of the field.

This may prove difficult in the short-term though, as the field took a hit from the funding threat:

Although NIH approval of new stem-cell lines has resumed, and even accelerated (see ‘Bouncing back’), some say that it will take years to recover from the impact of the shutdown. Scientists who left the field in the interim might never return.

“Things have changed permanently. It’s not just going to go back to the way it was — not immediately,” says Meri Firpo, who researches stem-cell therapies at the University of Minnesota Stem Cell Institute in Minneapolis.

Previously: Stanford law professor on embryonic stem cell ruling, Judge Lamberth dismisses stem cell lawsuit, Stem cell funding injunction overturned by federal court and NIH intramural human embryonic stem cell research halted