Hope vs. hype in stem cell research

A few weeks ago CIRM grantee at UC Davis Paul Knoepfler wrote a blog entry distinguishing hype from hope in the stem cell research field. This is no small task. The hype in this field is incredible (as evidence, see all too many headlines on the topic). But then, so is the hope. CIRM was voted into existence by the 59% of Californians who had high hopes for therapies coming out of stem cell research.

When I talk to patient advocates who come to our board meetings, or who speak at our spotlights on disease or who we interview for our video series they are filled with hope for the field (see Roman Reed, for example, who is filled with hope). What’s hard in writing or speaking about stem cell research is describing that hope without veering into hype. Those new therapies will come — but they’ll take a while. Anyone who says differently is on the hype side of the equation.

My personal favorite of Knoepfler’s Hope vs Hype statements is this one:

Many stem cell therapies that really work are available now. Verdict = HYPE

Unless you are talking about bone marrow transplants, which are a form of stem cell transplant and have a long history of treating a wide range of blood diseases, other so-called “stem cell therapies” are hype. No other type of stem cell has gone through all three phases of clinical trials to prove that those approaches are safe and effective. Several cell types — adult and embryonic — are in clinical trials right now, and some portion of those will likely end up being effective. But the majority of those early clinical trials that you read about will likely need refining and rethinking before they eventually work.

Knoepfler wrote his blog entry right around the time that Tim Caulfield wrote a piece for the Canadian journal The Walrus about a talk he gave deriding stem cell tourism. Caulfield is Canada Research Chair in health law and policy at the University of Alberta. Turns out, you shouldn’t insult stem cell tourism — in which people travel to foreign countries where therapies aren’t well regulated — while in front of a room full of people who run those clinics. Ooops.

He relates stem cell tourism to former heath claims for magnetism and radioactivity. He says:

Research on magnetism resulted in the sale of products promising magical restorative properties, curing everything from gout to constipation to paralysis. According to one advertisement from the late nineteenth century, “There need not be a sick person in America… if our Magneto-Conservative Underwear would become a part of the wardrobe of every lady and gentleman, as also of infants and children.” More dangerous was the excitement over atomic physics in the early 1900s. The work of scientists such as Marie Curie in the field of radiology garnered considerable public interest, which led to an array of radioactive products, including skin creams, toothpaste, bath salts, and pills.

Skin creams? That sound familiar to anyone following the stem cell field today? Obviously, radioactivity has turned out to be extremely useful as a form of cancer therapy, so there was some real hope in that hype. The trouble is telling the difference, and explaining that difference to people who might be swayed to hope when presented with hype.

Here’s something to be hopeful about: 44 CIRM research projects are in various stages of making their way to the clinic. Many of these are in cancer, heart disease, and other diseases that directly affect my family members. That gives me hope.


Progress toward stem cell clinical trials?

The CIRM governing board meeting yesterday, held on the Stanford campus, included a number of important agenda items — planning awards worth $1.8 million and changes to the grants review process to name a few — and one seeming sleeper item titled “Presentation and discussion of CIRM Translational Grant Portfolio.”

Yawn, right? But that’s the item that generated the most excitement among board members, particularly the patient advocate members who are often asked to talk about progress CIRM is making in generating new therapies in their disease areas.

Many who read a major newspaper in California have probably read assertions about CIRM’s apparent lack of progress. No new therapies in five years of funding? Must be a failure! (This, despite the twelve or more years it generally takes to go from a good idea in the lab to a new therapy in the clinic.)

The grant portfolio presentation by Patricia Olson, executive director of scientific activities, and Ellen Feigal, VP of research and development, should answer those complaints. The document was attached to the agenda and is available here. It looks about as dull as it sounds, and in its current state has more acronyms than complete words. However, the message is an exciting one: CIRM has 44 awards that are all in the late stages of therapy development, many with the goal of beginning clinical trials in the next few years. These include teams working on cancer, blindness, spinal cord injury, osteoarthritis, diabetes, and neurodegenerative disorders like Parkinson’s disease, Alzheimer’s disease and Huntington’s disease.

We’ll be putting this information online in a more digestible form over the next few weeks.

In addition to support from board members, the presentation prompted a humorous plea from new board chair Jonathan Thomas to members of the press to please, next time, look at this analysis before writing that we haven’t accomplished much. All that research closing in on clinical trials likely wouldn’t have occurred without us. That’s pretty phenomenal.

We’ve written previously about the reasons for funding the full pipeline of research (Where are the cures?). Out of hundreds of basic science projects only a few even get to clinical trial, and of all clinical trials only a small number result in a new therapy. If we do want to see new therapies one day (and we do) then we need a lot of good ideas that will feed into these translational awards and eventual come out the end of the research pipeline as new therapies. With these 44 awards we should be seeing a number of new clinical trials over the next few years, and one day some of those are going to be therapies in a clinic near you.


Guest blogger Alan Trounson: What A Mouse’s Toe Tells Us about CIRM’s Investment

Guest blogger Alan Trounson is President of CIRM

Yesterday, my colleague Uta Grieshammer used this space to describe a Nature paper out of Irv Weissman’s Stanford lab that sought to pin down which cells are responsible for the regrowth of the tip of a mouse’s toe after amputation.

Salamanders and many lower organisms have the ability to regenerate whole limbs and most of their organs. However, while mice and men have the capacity to regrow parts of certain organs, notably the liver, they have lost the ability to replace any part of our limbs other than the very tip of digits—fingers and toes.

How does this relate to CIRM’s research investments? Some critics of our model, notably one writer at the New York Times, have suggested that we would have better spent our taxpayer investment entirely trying to figure out how salamanders accomplish their more robust regeneration. Specifically, the recommendation was that CIRM should be directing researchers to investigate the salamander cells responsible for this feat – called the blastema.

A long-held theory suggested that in salamanders, adult cells at the site of injury can be dedifferentiated into a stem-like state called a blastema that can then go on to produce all the cell types—bones, skin, tendon, vessels and nerves—needed to regrow the digit tip. The Stanford work very clearly showed no evidence of such a blastema cell in mice. They labeled the adult cells of each tissue type with a different color florescent marker and after regrowth they saw very clear demarcations of color between the various tissue types. The skin cells formed skin and the bone cells formed bone.

CIRM funded this work in keeping with our philosophy of funding the full spectrum of stem cell research, across all cell types, and in basic research funding work that looks at all aspects of stem cell growth and maturation. By funding stem cell research broadly, we believe we have had more successes than if we had concentrated our funding on any one aspect of stem cell research.

Of salamanders, mice and men – digit regeneration mechanisms revealed

Regenerated mouse digit tip/Yuval Rinkevich

 Guest blogger Uta Grieshammer is a science officer at CIRM

A form of regeneration that has captured the imagination of scientists and the general public for many decades occurs in certain salamanders, as they have the remarkable ability to regrow a severed leg. Leg regeneration is unusual not only because it is so rare among vertebrates, but also because the underlying mechanism is thought to be quite different from that operating during the regeneration of organs in mammals.

Although mammalian legs do not regenerate, the very tips of our fingers and toes, and those of mice, do sometimes regrow. A new study published August 24 in Nature from Irv Weissman’s lab at Stanford University, and partially funded by CIRM, now comes to the surprising conclusion that the mechanism at work during mouse digit tip regeneration more resembles that of our other organs rather than the way that salamanders’ legs have been thought to regrow.

Although it may not be obvious, many of the organs in a healthy person regenerate themselves throughout life, some more than others. Our whole blood forming system and our gut, for instance, turn over relatively rapidly, whereas only about half of our heart cells are replaced in our entire life. Some organs, such as our skin, muscles, and bones, also have a reasonable capacity for repair after injury, if the damage was relatively small, while much of our liver will be faithfully replaced after a large portion has been removed. Other organs, though, replace cells lost to insult or disease only poorly or not at all, such as the heart following a heart attack. The hope is, if we figure out how the regeneration superstars of our body, or those of salamanders, accomplish their remarkable feats, we can use that knowledge to coax their less talented brethren into action.

Scientists have three basic models for how regeneration occurs: 1) tissue-specific stem cells within the organ divide and mature into the additional tissue, 2) mature cells divide to produce more of themselves without contributing to other cell types, or 3) mature cells lose their specificity, become more like embryonic cells and form a blastema with the ability to divide and form the original cell type and also other cell types in the regenerating tissue.

Weissman’s work with postdoctoral scholar Yuval Rinkevich, who was first author on the paper, shows that during digit regeneration in mice, the third model is not the right one. Remaining skin cells only make new skin cells, bone cells only make new bone. This comes a bit as a surprise, as this appears to be very different from the blastema mechanism thought to be used by salamanders to regrow their limbs. However, recent experiments from Elly Tanaka’s group in Dresden have challenged that long held model, showing that blastema cells in regrowing salamander legs do not typically adopt fates different from those of the cells they’re derived from. These studies then suggest that regeneration of limbs and digits in salamanders and mice, respectively, does occur through related mechanisms, just not the one originally thought. In both cases, repopulating cells do not switch cell fate, but whether regenerated digit or limb cells are derived from tissue-specific stem cells or from mature cells remains an open question for both species, although the Weissman paper makes a cogent argument that their data are consistent with the stem cell model, at least for some of the cell types involved in mouse digit regeneration.

Concerted efforts by scientists studying animals such as salamanders and mice will likely lead to an ever more accurate picture of limb and digit regeneration, thereby laying the groundwork for translating these findings to human cells, and eventually to human treatments.

CIRM funding: Irv Weissman (RC1-00354)
Nature, August 24, 2011

New journal focuses on developing stem cell therapies

In March 2011 CIRM began working with AlphaMed press to develop a new peer-reviewed journal to publish research that is translating basic stem cell science into new therapies. The idea was simple. AlphaMed had been publishing the elite journal Stem Cells for 30 years and recognized that the time had come to form a new journal focusing on the next phase of the science. The phase where all that early science published in Stem Cells started turning into therapies. At the same time, CIRM leaders were realizing that the scientists they were funding didn’t necessarily have an elite journal focused on their work.

Turns out great minds were thinking alike, and before long CIRM and AlphaMed press had plans in place for their new collaboration. At the time, CIRM President Alan Trouson said:

“Science moves forward through publications in outstanding, peer-reviewed journals,. This new publication will provide a venue for studies that move stem cell research closer toward clinical trials. In addition to publishing new discoveries that help all scientists in their goals the journal will also take the unusual step of publishing studies considered negative, with results that did not back up the original hypothesis or that did not show a new path to therapies, which will save other scientists the time of carrying out those experiments.”

CIRM is supporting the journal for the first three years, then the journal is expected to be self-funded.

We had a chance to meet with AlphaMed president and vice president Ann and Marty Murphy today to talk about how things are coming along. The first issue is due out in January and they already have a pipeline of outstanding papers. Scientists interested in publishing in the journal can get information about submissions on the website www.stemcellstm.com.

They’ve also put a few interesting videos on the site, including journal editor Anthony Atala’s short speech introducing the rational for the new journal. In the video he says:

“The mission of the journal is to bring together the best scientific papers in the field that will chart the course for the future not only for our investigations but also for the benefit of our patients and their healthcare.”


GMP grade embryonic stem cell lines approved by NIH

The NIH has approved four new human embryonic stem cell lines for federally funded research. The lines, from CIRM-funded BioTime, have one thing going for them that many other lines don’t. They were developed in compliance with Good Manufacturing Practice requirements, which is a critical step for developing a transplantation therapy. The FDA will only allow clinical trials involving cells and materials that were developed according to GMP guidelines, which carefully control the quality and consistency of a product. Working with cells that are already GMP-compliant removes that time-consuming step from the process of submitting a new clinical trial to the FDA.

Medical News Today quotes BioTime President and CEO, Michael West:

“This approval is key to our strategy of making our bank of GMP-compliant hES cell lines the industry standard for the development of a wide array of new human therapeutic products. We believe our ESI hES cell lines are the best characterized and documented lines available today. Our clinical grade hES cell lines were derived using procedures and documentation that are in compliance with current Good Tissue Practices (cGTP) and cGMP, which we believe will facilitate the transition of therapeutic products derived by researchers from these cell lines from laboratory to clinical use. We’re grateful the NIH has approved the use of ESI-014 and ESI-017 and we look forward to working with researchers to translate the science into commercially successful therapeutic products.”

In December 2010 BioTime agreed to make research grade versions of their embryonic stem cell lines available to CIRM researchers. According to a BioTime press release those have been supplied to dozens of researchers throughout California.


Stem cell therapy gives dog a new leash on life

Here’s a happy stem cell story for the dog days of summer: A veterinarian in Pennsylvania used an experimental stem cell therapy to help a dog regrow severely burned foot pats. The dog, named Bernie, had been left on a scorching rooftop for 10 hours.

According to the Reading Eagle:

When the dog was brought to the shelter, an examination found he also had burn marks on his spine and his nipples. Officials believe the dog received those burns by lying down on the hot roof, trying to take weight off his painful paws.

“I don’t think I’ve seen anything that bad in 25 years,” said Dr. Boyd Wagner, veterinarian and owner of the Wyomissing Animal Hospital. “They were severe, third-degree burns.”

Wagner worked with California-based Celevet, which is developing stem cell therapies for horses and dogs. There’s not much information available about the type of cells Wagner used — “stem cells” is a pretty loose term — or how they were used to repair the foot pads. According to the story it’s also not yet clear whether the therapy worked.

Still, as a dog owner it’s nice to read about stem cells — whatever kind they used — helping give Bernie a chance at a better life. 


Cells derived from embryonic stem cells, iPS cells appear immature

A trend over the past few years has been comparing embryonic stem cells, adult stem cells and reprogrammed adult cells (also known as iPS cells) to each other and to other cell types. The goal is to understand what the cells are, exactly, and and how they differ from each other. Eventually this information could help researchers learn which type of cell will be most effective for developing therapies, understanding diseases or drug screening.

A group of CIRM grantees at UCLA has published the latest in the unfolding story of stem cell comparisons. In their case, they didn’t compare the stem cells themselves. Instead, they matured embryonic stem cells and iPS cells into the cells that eventually form neurons, cells that eventually form skin, and cells that eventually form liver. These so-called progenitor cells also exist in adult humans, where they lurk in tissues waiting to be needed to repair damage.

The scientists compared the progenitor cells to each other and to equivalent cells taken from adult tissue as well as to developing tissues. What they found is that the progenitors for nerves, skin and liver that came from embryonic or iPS cells had a lot in common with each other and with developing tissues. However, they had much less in common with their counterparts taken from adult tissues.

A press release from UCLA quotes William Lowry, who was senior author on the paper, which appeared in Cell Research.

“What we found, looking at gene expression, was that the cells we derived were similar to cells found in early fetal development and were functionally much more immature than cells taken from human tissue. This finding may lead to exciting new ways to study early human development, but it also may present a challenge for transplantation, because the cells you end up with are not something that’s indicative of a cell you’d find in an adult or even in a newborn baby.”

The release goes on to quote first author Michaela Patterson:

“One important reason to do this is to ensure that the cells we are creating in the Petri dish and potentially using for transplantation are truly analogous to the cells originally found in humans,” said Michaela Patterson, first author of the study and a graduate student researcher. “Ideally, they should be a similar as possible.”

“The roles these cells play in the fetus and the adult are inherently different,” she said. “It may be that the progeny, if transplanted into a human, would mature to the same levels as those found in the adult liver. We don’t know.”

This is the first paper we’ve seen comparing progenitor cells to adult or developing tissues. As with all first steps, we’ll likely see more papers over the next few years refining and expanding on this team’s findings and clarifying what these findings mean in terms of transplantation.

CIRM Funding: William Lowry (RS1-00259-1), Michaela Patterson (T1-00005)
Cell Research, August 16, 2011


Weeding out the tumor-forming cells from potential stem cell therapies

CIRM grantees at Stanford University have removed some of the risk of therapies based on human embryonic stem cells or reprogrammed adult cells, known as iPS cells.

Both of these cells types are known as pluripotent, which means that the cells can go on to form all the mature cells of the human body. The problem is that those cells also form tumors called teratomas. In the process of developing new therapies, scientists first prod the stem cells into a more mature cell type, such as a neural progenitor for spinal cord injury, an insulin-producing pancreatic cell for diabetes or retinal cell for forms of blindness. Then, they go through a laborious process to show that no tumor-forming cells still remain in that batch of cells that they hope to use in therapies.

The new technique, published August 14 in Nature Biotechnology, provides a novel way of identifying cells that are potentially tumorigenic and removing them from a batch of cells. Krista Conger at Stanford wrote about this paper:

“The ability to do regenerative medicine requires the complete removal of tumor-forming cells from any culture that began with pluripotent cells,” said Irving Weissman, MD, director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine. “We’ve used a combination of antibodies to weed out the few undifferentiated cells that could be left in the 10 or 100 million differentiated cells that make up a therapeutic dose.”

Weissman pointed out that the production of therapeutic cells from pluripotent stem cells for regenerative medicine was a major goal of Proposition 71, the ballot measure that established the California Institute for Regenerative Medicine to allocate $3 billion to advance stem cell science. CIRM funded this research.

“Commonly used differentiation protocols for embryonic stem and iPS cells often give rise to mixed cultures of cells,” said research associate Micha Drukker, PhD. “Because even a single undifferentiated cell harbors the ability to become a teratoma, we sought to develop a way to remove these cells before transplantation.”

If other research groups repeat these findings, the technique could reduce some of the risk of therapies based on pluripotent cells.

Nature Biotechnology, August 14, 2011


High school students get stem cell experience in California labs

UC Davis interns Rex Reyes, Jaskaran Dhillon, Thomas Gepts and Kalani Ratnasiri

Last week CIRM gathered together the Creativity Award interns to learn about their summer projects. These high school students came from UC Davis, UC San Francisco, UC Santa Barbara and Stanford to congregate at the Children’s Hospital Oakland, home of CIRM board member Bert Lubin.

The goal of the awards was to give high school students experience in research labs, and to encourage those students to think broadly about science with the idea that novel therapies will come from creative thinking. The students all carried out additional projects in humanities or other areas of science. (We blogged about the program here.)

The students I met were incredible, and I’m apparently not the only person to think so. Charlie Casey at UC Davis did a story about the program quoting Jan Nolta, who directs the school’s Institute for Regenerative Cures.

“These students truly exceeded our expectations,” said Jan Nolta, director of the UCD Institute for Regenerative Cures and a mentor for several of the students. “One of our other interns was so determined to learn about stem cell science that he traveled two hours from Vallejo and back each day to work in our Sacramento lab.

“All of these young people performed fabulously, and they represent a very bright future for science, particularly, I hope, in stem cell research.”

The Sacramento Bee wrote about the four UC Davis interns.

Program directors selected the students based on their award-winning presentations of biotechnology concepts on websites they designed for UCD’s 2011 Teen Biotech Challenge.

The four took a course in the procedures and techniques of stem cell production with master’s-degree students from California State University, Sacramento, and worked on individual projects with scientist mentors.

When I talked to Gerhard Bauer, who taught that master’s-level course, he said the high school students held their own among those more senior students. It’ll be a while before we know where these students end up. For now, it’s exciting to see high school students—many from lower socioeconomic homes—get excited about college and about the potential for stem cell research.