Meeting of California's stem cell minds

Last week CIRM held our almost-yearly grantee meeting, which brought together our grantees from across California plus some international collaborators and world-renowned stem cell leaders who gave some riveting talks.

CIRM grantee Paul Knoepfler from UC Davis was blogging from the meeting. He had this to say:

Earlier I threw out there the idea that many different interested parties should come together to advance science. Something I called “big tent science” and “big tent team science”.

I think CIRM is an outstanding example of this idea in action and I could see that in evidence today at the CIRM Grantee Meeting here in San Francisco. It’s very inspirational.

He went on to share this from a talk by Craig Ventor:

The meeting was kicked off with a talk by Craig Venter, the amazing scientist who has pushed research forward in so many ways including sequencing the human genome and making the first synthetic life form.

Dr. Venter, who has been involved in some of the most cutting-edge, exciting science in the last century as well as founding or being involved in many scientific organizations, said this about CIRM:

"This is the greatest scientific organization founded in our era."

Being there what stood out was the wide range of diseases being studied by our grantees, all with the eventual hope of finding therapies. It's a real thrill to see signs of hope for the wonderful patient advocates I've gotten to know through CIRM, and for my friends and family, all of whom stand to benefit from this work.

We'll be posting more about the meeting, including videos of two talks (including Ventor's) and of a pre-meeting target product profile workshop,  and a video montage of our grantees talking about their work.

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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.

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Top questions in iPS cell research

Every once in a while CIRM grantee Paul Knoepfler at UC Davis posts an update on his blog about what he considers to be the big ticket question in research using reprogrammed adult cells, known as iPS cells. This time, he's posted five questions for the upcoming year.

1. Will any new methods for creating iPS cells be truly transformative in the coming year? On this one, he urges patience with the apparent lack of visible progress. We've blogged here about the glacial speed and incremental nature of research.


2. Will transdifferentiation make iPS cells obsolete? More and more papers are coming out about directly converting one type of cell into another, skipping the slow step of creating iPS cells. On this topic Knoepfler says, "I personally think transdifferentiation has enormous potential, but I’m betting that for some areas, for generating some types of differentiated cells, iPS cells are going to be needed."


3. Are the various differences between embryonic stem cells and iPS cells going to be a concern? Yes, he says, but, "It seems likely that at least some of the mutations and differences will have functional meaning, but a key area in the coming year will be mapping out the meaning of these differences."


4. What's the best way of making better cells, rather than more cells? In the past, new methods of generating iPS cells focused on making the cells in higher numbers. Knoepfler argues that making better cells—cells with fewer abnormalities—is more important than making more cells.


5. How tumorigenic are iPS cells? As a cancer survivor and tumor biologist, Knoepfler has a personal interest in this question. He argues that studying whether or not iPS cells themselves cause tumors is irrelevant, because nobody is ever going to inject iPS cells into a patient. What scientists hope to do is convert those iPS cells into a therapeutically useful cell type (insulin-producing cell, neuron progenitor, skin cell) and transplant THAT cell to a patient. So the question isn't whether the iPS cells forms tumors. The question is whether these more mature cell types can form tumors.

It'll be interesting to see where these questions stand a year from now.

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A welcome voice in stem cell communication - a new podcast launches

CIRM grantee Paul Knoepfler at UC Davis has been blogging about stem cell science for a while now. He recently expanded his outreach to include a regular podcast. It's worth checking out. He's listing the most recent podcast at the top of his main blog page: http://www.ipscell.com/ .

Knoepfler includes some science, some policy, and a nice comment on the value of CIRM's funding in advancing stem cell science. As he admits, he's not exactly unbiased. He has a New Faculty II award from CIRM and is at an institution with a shared lab and major facility funded in part by CIRM. Still, we think he's right when he says:

"In a state where there s so much going wrong Californian's should be proud of their foresight in creating CIRM and in all that CIRM has already accomplished. CIRM is one of the things in ca that is actually going really well and we should be happy about it."

There are a few groups competing for the public's attention on stem cell topics. Those opposed to stem cell science have a few blogs, which they promote heavily. These generally tout advances with adult stem cells. Many of those advances are very hopeful, and we tout them too, but telling one side of the story doesn't ever give a complete picture of the field.

Several organizations such as CIRM, the Canadian Stem Cell Network and the Australian Stem Cell Centre also have blogs that promote stem cell science and attempt to put recent scientific advances into context. However, to my knowledge Knoepfler is the only stem cell scientist attempting to reach the public online. I look forward to hearing more podcasts from Knoepfler, and wish him much success in providing accurate information about stem cell research at a time when it is so clearly needed.

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Techniques for tracking stem cells necessary for possible therapies

Last week The Scientist carried a story addressing a topic near and dear to the heart of anyone trying to develop a therapy based on transplanting stem cells, whether they are embryonic, adult, or iPS cells: Where do the cells go once they are transplanted?

The problem is this — if you, as a scientist, transplant stem cells near some damage that you are hoping they will repair, you've got to hope those cells actually make it to the damaged tissue. If they make a run for the liver when you are trying to treat the heart, or simply sit in a lump where you implanted them, those cells aren't going to fulfill their mission.

The story quotes CIRM grantee Joseph Wu of Stanford University who has SEED and Basic Biology III Awards to detect stem cells implanted into the heart and to develop stem cell transplantation therapies for hypertrophic cardiomyopathy.

“If you want to understand what happens to these stem cells, it’s important to track the fate of these cells without having to kill the animal,” says Joseph Wu, a cardiologist at Stanford University School of Medicine in Palo Alto, California. Stem cell transplants may settle down, proliferate, and differentiate as desired; they may form dangerous tumors; or they may simply falter and die.

The issue is also one CIRM grantee Paul Knoepfler of the University of California, Davis, touched on in his blog last week, saying:

Once these cells, which have spent weeks in a lab environment, are injected into a person, what happens next?

This is arguably the most important question in the regenerative medicine field, but there are few answers. We are literally mostly in the dark about what cells do after transplant, but there are some things that can be predicted pretty confidently.

He goes on to discuss some of what's known about the issue using Geron's clinical trial as an example.

In their article, the Scientist discusses a few techniques scientists are using (including some nice images) to address the question of where the cells go. The story includes a technique being used by CIRM grantee Eduardo Marban at Cedars-Sinai Medical Institute, who has a Disease Team Award to develop a therapy for heart disease.

This is the type of research that comes to mind when people who don't follow the science comment on the lack of cures. CIRM is funding a broad range of science, some of which is primarily dedicated developing new therapies, and some of which is working to understand these kinds of basic questions that need to be addressed before those therapies can become widespread.

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Blood from stem cells?

Blood has been among the most sought after and hardest to achieve tissue that CIRM grantees are attempting to derive from embryonic stem cells. It's an obvious target. The medical system needs a constant influx of blood, which comes entirely from volunteer donors. Creating that blood in an unlimited supply from human embryonic stem cells would significantly ease concerns about blood shortages at hospitals. We blogged about a Los Angeles Times story last January that discussed the value of this type of work.

The National Blood Data Resource Center has this to say about how much blood was used in 2001:

U.S. hospitals transfused nearly 14 million units of whole blood and red blood cells to 4.9 million patients in 2001 - that's an average of 38,000 units of blood needed on any given day.

Given those needs, the findings in a Nature paper by CIRM grantee David Traver at the University of California, San Diego could prove helpful. He and his team have discovered a gene called Wnt16 that, in the lab animal zebrafish, is key to the animal eventually developing a pool of hematopoietic stem cells, which are the source of all blood in the body.

In a press release from UCSD Traver said:

“What we need is the ability to generate self-renewing [human embryonic stem cells] from patients for treatments. But accomplishing this goal means first understanding the mechanisms involved in creating HSCs during embryonic development.”

Traver's work follow that of another CIRM grantee Inder Verma of the Salk Institute, who last month published a protocol for creating blood-forming progenitor cells from human embryonic stem cells and reprogrammed iPS cells. Discussing this work in his monthly stem cell research update, CIRM President Alan Trounson wrote:

Many more cancer and blood disorder patients could benefit from stem cell transplants if large numbers of blood forming stem cells could be grown in the laboratory. Because mature hematopoietic stem cells (HSCs) don’t expand well in culture, researchers have been trying to grow these cells from pluripotent stem cells, both embryonic stem cells and reprogrammed iPS cells. Most of these attempts have generated very low numbers of bone marrow colonizing blood precursors, and none have shown robust generation of transplantable HSCs. Now, Verma’s team has shown that with five iPS cells lines and two embryonic lines that they can efficiently generate precursors and progenitors of HSCs.

This work brings up another point often made by CIRM grantee Paul Knoepfler at the University of California, Davis. In his blog and in the Sacramento Bee Knoepfler has argued that supporting stem cell research is a matter of national security. Soldiers wounded on the battlefield need a source of blood for transfusions. Knoepfler wrote in his Sacramento Bee Op-Ed:

I hope that in the future stem cell research can perhaps slightly lessen the burden on our servicepeople and their families through technologies to save the lives of wounded soldiers.

Nature, June 9, 2011
CIRM funding: David Traver (RN1-00575-1)

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CIRM a leader in iPS cell publications

Yesterday, stem cell blogger and newly tenured CIRM grantee at UC Davis Paul Knoepfler had an interesting blog entry on iPS cell publications.

After mining the literature for publications with the phrases iPS cells, induced pluripotent stem cells, induced pluripotent or induced pluripotency in the title, he found a consistent increase in publications each year after the first creation of mouse iPS cells in 2006 by Shinya Yamanaka. That is, a consistent increase until this year, where the first third of the year contained fewer than expected publications. Knoepfler doesn't speculate on what this decrease means—and by the end of the year the discrepancy might disappear.

He did find more diversity in the researchers publishing in the iPS field and in the journals where those papers were published. That makes sense for a field that is becoming ever more mainstream. Knoepfler writes:

I think this is a good thing as the iPS cell field grows. The range of journals publishing iPS cell papers has greatly broadened, which is also a positive for the field as it matures.

Knoepfler doesn't speculate on what his findings mean for the field of iPS cells, either as potential therapies or as disease in a dish models. The cells have been the source of much consternation recently as they are shown to differ in significant but clinically unknown ways from embryonic stem cells (as we blogged about here). At the same time, they are also proving their worth in mimicking genetic disease (blogged about here, here, and here).

One discovery that stands out is CIRM's rank as second most prominent funder of iPS papers, following only the NIH. CIRM funds 4.8% of papers that Knoepfler found in his search. Coming in third was the National Natural Science Foundation of China.

CIRM's searchable grants database shows 66 awards to grantees working with iPS cells, worth a total of $146,882,748 or 12% of CIRM funding. You can see those awards here. By contrast, CIRM provides $384,709,412 toward awards working with embryonic stem cells, or 32% of our funding, and $194,221,598 or 16% toward grants working with adult stem cells.

Some CIRM grants fund work using more than one type of stem cell, including several awards to grantees trying to understand differences between iPS and embryonic stem cells.

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Stem cell research like picking stocks? We don't think so.

A story by Nick Wade in Monday’s New York Times rubbed some scientists the wrong way — and I must admit the piece was not too popular around CIRM headquarters.

Wade equated research funding with picking stocks. His idea is that a broad portfolio is bound to include some winners (he attributes this approach to the NIH and NSF) whereas attempts to only buy the big winners can produce a risky portfolio (an approach he attributes to CIRM).

Writing for the science portal Science 2.0, Michael White writes:

This is not right.* Wade goes astray in thinking of science in terms of hits and misses. Basic research is not like being at bat, with the occasional single base hit or home run being the exception in a sea of strikeouts.

Most research is simply conventional and incremental. Most of the time it's not a miss, a disaster, or a failure - it's a small, sometimes not too surprising addition to our knowledge of a subject. Most research projects and NIH grants end in success, not failure - but the successes are usually small. In fact, there probably aren't enough failures, because, unlike the venture capitalists Wade compares it to, the NIH is very unwilling to take risks in search of the spectacular winner. Funded projects are the ones almost guaranteed to work.

CIRM grantee Paul Knoepfler at UC Davis also takes objection to the piece. His point: CIRM isn’t just investing in one big thing. Three billion dollars to just fund one area of stem cell research, that would be narrow. But CIRM has funded an incredible range of research, from the most basic science to translational work, and in approaches spanning stem cell transplantation therapies to modeling disease, drug testing, and models of regeneration (the very research Wade suggests we should fund).

Knoepfler writes:

Clearly [Wade] knows very little about CIRM and about stem cell research. He makes the argument that because CIRM only funds research in 'a single field' that chances are high that Californians will lose out. First, he is wrong that CIRM only funds one field. The breadth of research funded by CIRM spans a few dozen fields from cancer biology to neurological disorders, to heart disease, diabetes, HIV/AIDS, etc. Second, Mr. Wade ignores the substantial accomplishments that CIRM has already made in just its first few years.

Where CIRM agrees with Wade’s piece is in his suggestion that we look to how animals such as zebrafish and newts naturally regenerate, and use that knowledge to improve human regeneration. Deepak Srivastava from the Gladstone Institutes, who has been looking at tissue regeneration in mouse hearts, is making tremendous progress in part through CIRM funding (here is his research summary), as is USC’s Gage Crump, studying zebrafish jaw regeneration as a model for bone regeneration (here is his research summary). 

For people interested in seeing the range of what CIRM has funded, we have this searchable list of all our funded stem cell research awards. We also have this list of our rounds of funding, explaining the role that funding plays in creating CIRM’s broad research portfolio.

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The fate of embryonic stem cell research funding is in the hands of...

Thanks to UC Davis stem cell scientist and CIRM grantee Paul Knoepfler for ferreting out the three judges who will preside over the September 27 D.C. Circuit Court hearing regarding the August 23 injunction on federal funding for human embryonic stem cell research.

In his blog entry, Knoepfler writes that of the three judges one is a Clinton appointee and two were appointed by Bush Jr.

After some speculation about the outcome of this hearing, Knoepfler goes on to say:

However, keep in mind, as far as I understand the process, even a longer-term stay will only allow ES cell research to proceed until Lamberth makes a final ruling in the case and as we've said before, be assured he will against ES cell research. The questions are when will he rule, what happens then, and will a law already have been passed making the whole thing moot?

Bills have been introduced in both the House and Senate that would secure the legality of federal funding for human embryonic stem cell research

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The ups and downs of federal funding for stem cell research

They can’t fund stem cell research...
They can...
They can’t fund stem cell research...
They can..

For now. In the “He loves me; He loves me not” game of stem cell research funding, the current petal removed by the U.S. Court of Appeals puts funding for human embryonic stem cell research back within the pervue of the NIH. Today the court put a hold on Judge Royce Lamberth's ruling that effectively halted NIH funding of human embryonic stem cell research. Bloomberg wrote:

“The purpose of this administrative stay is to give the court sufficient opportunity to consider the merits of the emergency motion for stay and should not be construed in any way as a ruling on the merits of that motion,” the appeals court wrote in its decision.

So far, the timeline of NIH funding of human embryonic stem cell research looks like this:

2001: Then-president George Bush limits federal funding for embryonic stem cell research to a handful of existing stem cell lines.
2004: Californians support proposition 71, creating the California Institute for Regenerative Medicine to administer $3 billion in bonds to fund stem cell research (adult and embryonic) in California.
2009: President Obama lifted the Bush-era restrictions, directing the NIH to create guidelines for approving new embryonic stem cell lines into the pool of those that can be included in federally funded research.
August 23, 2010: Judge Royce Lamberth ruled federal funding of human embryonic stem cell research impermissible under current laws. He put an immediate injunction on all federal funding for such research. Much confusion and uncertainty amongst stem cell scientists ensued, as documented by CIRM grantee at UC Davis Paul Knoepfler on his blog.
August 31, 2010: The U.S. Government appealed the ruling, citing irreparable harm to researchers, taxpayers and scientific progress.
September 7, 2010: Judge Lamberth refused the federal government's request to stay the order.
September 9, 2010: The U.S. Court of Appeals put a hold on Judge Lamberth’s ruling, allowing the NIH to continue funding research involving human embryonic stem cells.

The latest ruling is good news, but there are still many petals to remove before we know whether the NIH can fund, or fund not. For those scientists who have NIH funding for human embryonic stem cell research or who have grants under review, they still live with uncertainty over whether they’ll be able to complete those projects (or find cures for those diseases they hope to treat).

Throughout this, CIRM continues to fund stem cell research (embryonic and adult) in California, accelerating the pace to new cures, creating jobs, and building California’s biotechnology leadership. But as CIRM grantees told us in a survey, they need NIH funds in addition to CIRM. In the survey, 76% of CIRM grantees who have NIH funding said the funding freeze would impact their ability to carry out research with adult, cancer, or iPS stem cells.  Only 5% of grantees -- with or without NIH funding -- said the ruling would make no difference to their overall research strategy.

This table provides links to all CIRM-funded grants involving human embryonic stem cells.

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Reducing teratoma risk from transplanted stem cells

By Paul Knoepfler

The two most serious obstacles to regenerative medicine therapies are potential immune rejection of transplanted cells and the possibility that such cells could form a type of tumor called teratoma.

CIRM grant recipient and professor of Biology at UC San Diego, Yang Xu, is tackling both of these hurdles. He and his colleagues have recently discovered a method to reduce the ability of embryonic stem cells to form teratoma. The approach involves interfering with the function of a key gene, called Nanog, that is involved in maintaining stem cells. Nanog is one of several genes known as plurpotency factors, which work together to keep cells in their embryonic state.

The paper describing this work, entitled “Phosphorylation stabilizes Nanog by promoting its interaction with Pin1”, was published this week in the Proceedings of the National Academies of Science. Xu and colleagues found that by inhibiting Nanog function in stem cells, those cells still formed teratoma, but they were only about one-third the size of tumors that formed by control cells.

Xu was quoted in a press release by UCSD as saying the method is only partially effective because “we are targeting only one pathway” and he speculates that targeting multiple pathways simultaneously might provide a more robust inhibition of teratoma formation.

Some important unanswered questions remain. Would inhibition of any key pluripotency factor, for example Oct3, produce the same effect? Are cells with reduced levels of pluripotency factors still able to give rise to normal differentiated cells of diverse types and in sufficient numbers to be useful for therapies? Could a similar effect be achieved by withdrawing growth factors, such as removing LIF from the media of mouse stem cells or FGF from the media of human stem cells?

Despite these remaining gaps in our understanding, this study provides an exciting foundation for improving the safety of regenerative medicine therapies, any area in the stem field that requires more attention.



PNAS, July 5, 2010
CIRM Funding: Yang Xu (RC1-00148)

Paul Knoepfler is assistant professor of Cell Biology and Human Anatomy at UC Davis School of Medicine. He publishes a blog about stem cell research.

Stem cells and preventive medicine

CIRM grantee and UC Davis stem cell scientist Paul Knoepfler has an important new entry on his blog: Five simple ways to protect your stem cells. In it he says:

If one can prevent a problem for occurring in the first place, it is far better than trying to treat it after the fact.

So true. Of course, many of the diseases CIRM scientists are involved in trying to treat aren't ones with known causes. We can't prevent our way out of all disease. But in the process of making discoveries to develop therapies, CIRM scientists are learning more about our own natural stem cells and how to keep them healthy. For example, exercise seems to fortify the neural stem cells that rebuild our brain.

Among his recommendations:

• Protect your skin stem cells
• Avoid plastics exposure
• Eat food, not chemicals
• Exercise
• Avoid radiation

So for the good of your stem cells get outside and exercise. But first, put on sunscreen.

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Cancer genes also involved in embryogenesis, stem cell maintenance

CIRM grantee Paul Knoepfler at UC Davis just published an interesting paper. He also publishes a blog, so we'll let him describe this findings in his own words:

We just published a paper supported by CIRM funding showing that knocking out c- and N-myc in mESC leads to a wave of differentiation-associated gene expression, decreased cell cycling, and a moderate elevation of apoptosis.  The myc-deficient mESC also fail to contribute to early embryogenesis. This is the first analysis of a role for myc genes in early embryogenesis.

We think that in part that Myc contributes to iPS formation by repressing differentiation-associated gene expression (ala Sridharan, et al).

So to induce pluripotency Myc appears to be doing what much the same job as it does to maintain pluripotency in ESC.  A role in cell cycle is also involved.

Differentiation, May 26, 2010
CIRM Funding: Paul Knoepfler (RN2-00922)

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Stem cell therapies: Not just transplants

Paul Knoepfler, a CIRM grantee at UC Davis, has a recent blog entry in his Stem Cell Myths series. The myth he debunks this time: Stem cell therapies are all transplants. As he so rightly points out, embryonic, iPS or tissue-specific stem cells can also be studied in the lab as a way of developing drugs that activate our own body's stem cell to heal the diseased organ or tissue. He writes:

In this way of thinking, specific drugs are given to a patient to put their own stem cells to work against the disease. Such drugs may stimulate the endogenous stem cells to expand and increase greatly in numbers as well. This kind of stem cell therapy is inherently far safer than anything done with a transplant.

 Knoepfler's previously debunked myth was that embryonic stem cells are no longer needed.

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Questions About iPS Cells

In his blog, CIRM grantee Paul Knoepfler at UC Davis posted a response to the journal Stem Cells, which had published a list of the most pressing questions about iPS cells:

“What I found most striking is that not one of their 10 questions had anything to do with safety or tumorigenicity, the question I rank #1, but otherwise my top 5 most important questions about IPS cells are similar to theirs. I know they think safety is a crucial issue, which is why I'm so surprised it wasn't on their list.”

Knoepfler's focus on tumorigenicity stems from his lab's work, which he discusses in this video about the safety of stem cell-based therapies (embryonic or iPS).



Knoepfler is taking suggestions for additional top 5 lists.

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