U.S. Appeals Court decision–good news, but not the final word

Nine months after a U.S. district court first sent federal funding for embryonic stem cell research into a tailspin, the U.S. Court of Appeals ruled that those opposing embryonic stem cell research were unlikely to win their case. The ruling means that, for now, federal agencies such as the NIH can continue funding embryonic stem cell research.

That doesn’t mean the saga is over. The story began when two scientists filed a case arguing that federal funding for embryonic stem cell research harmed the ability of adult stem cell scientists to get grant money. They also argued that embryonic stem cell research violates the Dickey-Wicker amendment, which prohibits the destruction of human embryos for the sake of research.

In response, the federal government claimed that there is no competition between adult and embryonic stem cell scientists for grants. Furthermore, the federal government does not support the creation of new stem cell lines, which is what destroys the embryo. They only fund research with selected embryonic stem cell lines, which does not violate the Dickey-Wicker amendment.

Fast forward a year. On August 23, 2010, the U.S. District Court hearing the case issued a preliminary injunction blocking the federal government from funding any embryonic stem cell research on the grounds that even though they hadn’t ruled on the actual case, people were getting hurt. (We blogged about that decision here.) Those people getting hurt being the adult stem cell scientists, presumably. That ruling brought federal funding for embryonic stem cell research to a standstill, and left scientists wondering how to handle ongoing experiments.

On August 31, 2010 the federal government appealed that preliminary injunction (blogged about here).

Then, on September 9, 2010, the U.S. Court of Appeals put a hold on the preliminary injunction, temporarily allowing the federal government to resume funding embryonic stem cell research (blogged about here). Basically, since nobody was actually getting hurt, there was no reason to halt federal funding until the courts had ruled on the case.

Then we all waited. The district court heard arguments in the main case back in December, but still hasn’t issued a ruling. Today’s announcement is from the U.S. Court of Appeals—the one that put a hold on the district court preliminary injunction back in September. Today they ruled that, after looking at the arguments, they don’t expect the adult stem cell scientists to win the case. And since they probably won’t win, the judge’s preliminary injunction can’t stand.

In their conclusion, the U.S. District Court of Appeals wrote:

We conclude the plaintiffs are unlikely to prevail because Dickey-Wicker is ambiguous and the NIH seems reasonably to have concluded that, although Dickey-Wicker bars funding for the destructive act of deriving an ESC from an embryo, it does not prohibit funding a research project in which an ESC will be used. We therefore vacate the preliminary injunction.

Having heard that the appeals court doesn’t think the adult stem cell scientists will win, we still have to wait for the district court to make it’s final ruling. After that, it’s likely that the case will make its way to the Supreme Court.

UCSF’s Arnold Kriegstein had this to say about today’s ruling in a UCSF press release

“This is a victory not only for the scientists, but for the patients who are waiting for treatments and cures for terrible diseases,” Kriegstein said. “This ruling allows critical research to move forward, enabling scientists to compare human embryonic stem cells to other forms of stem cells, such as the cell lines which are derived from skin cells, and to pursue potentially life-saving therapies based on that research.”

What’s at stake here is more than just the fate of embryonic stem cell research. Back in August when the injunction was first announced, CIRM’s Geoff Lomax sent a survey to grantees in order to learn how the injunction alters their research plans. What we learned (shown in this powerpoint) is that grantees working with adult stem cells and iPS cells all worried that that a lack of federal funding for embryonic stem cell research could slow their work as well. Halting funding for one area of stem cell research slows all areas of research toward stem cell-based therapies.

Genes at the heart of heart deformities found through stem cell studies

CIRM grantees at The Gladstone Institutes have, over the past few years, been hard at work learning about the origins of heart deformities by studying how stem cells mature into heart tissue.

What they’ve learned is that small relatives of DNA, called micro-RNAs, help control when and how cells mature into heart tissue (blogged about here and here) or blood vessels (blogged about here). In recent work out of the lab of Deepak Srivastava, they also discovered three genes are activated by a key micro-RNA whose absence can lead to heart deformities. That work is published in the April 17 Developmental Cell.

The work was in fruit flies, but many basic discoveries in fruit flies directly translate to humans.

Isabelle King, who works with Srivastava at the Gladstone Institutes and led the study, said discovering those genes could help scientists understand and treat cases where the heart failed to form properly in development. A press release from Gladstone quotes King:

“In the fetal heart, subtle changes in gene dosage and timing can yield heart defects in children.”

This work is a great example of how basic stem cell research can lead to new areas to explore for disease therapies. People often think of stem cell therapies as exclusively transplantation therapies in which stem cells and their derivatives are transplanted into a diseased organ to restore function. We do fund scientists trying to do just that, but we also fund basic stem cell scientists who are discovering how diseases arise, and the genes responsible. These discoveries made possible by studying stem cells could lead to new drugs or other interventions that have nothing to do with transplantation.

On the topic of basic research, we’ll be funding our third round of Basic Biology Awards at our governing board meeting next week (here are review summaries of those applications). These awards are intended to foster the kinds of basic stem cell and disease discoveries that keep new ideas — and eventual cures — flowing.

Developmental Cell, April 17, 2011
CIRM funding: Deepak Srivastava (RC1-00142); Li Quan (TG2-01160)

CIRM grantees directly create neuronal stem cells for research and therapies

CIRM grantees at the Scripps Research Institute, University of California, San Diego and Sanford-Burnham Research Institute have taken an intriguing step toward producing neural progenitor cells for research or therapies. The team, led by Sheng Ding who has recently moved to the Gladstone Institutes in San Francisco, started with mouse skin cells and converted them directly to an early stage of neural cell. The work was published in the April 26 online issue of Proceedings of the National Academy of Sciences.

This work falls somewhere between two other pieces of research starting with skin cells. Since 2006 it has been possible to convert mouse skin cells into reprogrammed iPS cells that are similar to embryonic stem cells in their ability to create all cell types. Scientists could then mature those cells into whatever cell type they are interested in studying.

Over the past year, other groups have started with skin and converted those cells directly to neurons or heart cells.

Ding and his colleagues fall somewhere in the middle, sidestepping some issues with both direct reprogramming and generating iPS cells.

  • Converting skin directly into neurons has the major limitation that neurons can’t divide. The number of neuronal cells available for research or therapies is limited by the number of starting skin cells.
  • Going all the way back to iPS cells has limitations of its own. The cells multiply in a lab dish to create as many cells as a scientist might need for therapies or research uses, but maturing those cells into the appropriate cell type can be an arduous task any traces of the original iPS cells could lead to tumors.

Converting skin to these neural precursors avoids both problems. Those neural cells are already pushed down the pathway to become neurons, and they can multiply. The researchers also showed that the cells can integrate into a mouse brain without developing tumors.
In a press release from the Gladstone Institutes, Ding says:

“These cells are not ready yet for transplantation,” Dr. Ding said. “But this work removes some of the major technical hurdles to using embryonic stem cells and iPS cells to create transplant-ready cells for a host of diseases.”

That’s all good, but the work is a long way from ending the need for iPS cells. First, it’s in mice. There’s no evidence yet that the protocol will work with human cells. Also, the resulting neural progenitors can only divide a few times, so they aren’t an unlimited source of cells.

Those caveats aside, it’s exciting to watch how quickly the field is evolving. Not long ago, the idea of converting one cell type into another was nothing but a dream. Now, scientists (many of them CIRM grantees) are finding ever more ingenious ways of converting skin, fat and other starting tissues into embryonic-like stem cells, adult cell types, and now in-between progenitors, each of which could be useful in their own way for understanding and treating disease.

PNAS, April 26, 2011
CIRM Funding: Sheng Ding (RN1-00536-1); Stuart Lipton (RC1-00125-1); Maria Talantova (T2-00004)

– A.A.

Stem cell hope, hype, and hypocrisy according to Arthur Caplan

Ethicist Arthur Caplan had an excellent piece about stem cell hype last week on Science Progress, a publication of the Center for American Progress. Caplan is Director of the Center for Bioethics and the Sidney D. Caplan Professor of Bioethics at the University of Pennsylvania.

He starts by saying that yes, some have over-hyped the promise of stem cell research, saying:

Anyone who has followed my advocacy for embryonic stem cell research would know I have long been critical of claims that funding today means people tomorrow will leap from their wheelchairs and walk.

However, he goes on to say that some of the most over-hyped claims in stem cell research come from those who oppose work with human embryonic stem cells. His list includes:

  • Hyped claim #5: The Bush “compromise”
  • Hyped claim #4: Adult stem cells can do it all
  • Hyped claim #3: If embryonic stem cell research is so promising, then why isn’t private research behind it?
  • Hyped claim #2: IPS cells are the magical solution to the embryonic stem cell quandary
  • Hyped claim #1: Frozen embryos should be put up for adoption rather than used as sources of stem cell lines. Of this hype, Caplan adds:

While I am on this particular bit of hype, I should add that those who do not favor the use of unwanted and certain-to-be-destroyed frozen embryos languishing in clinics worldwide never ever say what they propose be done with them. Conservatives say destruction is unthinkable, however, since it is inevitable then what are they talking about? ( I suppose this constitutes hypocrisy and not hype.)

His arguments regarding items on the list are worth a read. He says:

There is plenty more hype to be had from what has passed as debate over the past decade or so since human embryonic stem cells were first isolated. I don’t mean to suggest that most of the hype has come from critics rather than proponents. I do mean to suggest, however, that those who live in very fragile houses often constructed of hype ought not be quick to cast stones.

CIRM funds work with adult stem cells and iPS cells in addition to embryonic stem cells because until people in wheel chairs can get up and walk it’s too soon to start ruling out therapeutic options.

– A.A.

Guest blogger Alan Trounson – April’s stem cell highlights

Alan Trounson is President of CIRM

Since I arrived at CIRM late in 2007 I have maintained a tradition of presenting some of the top science journal papers from the previous month or two at each of our Board meetings. Beginning last month, I decided this would be easier to digest in a written document than in PowerPoint slides amid a harried board meeting. You can see an archive of these periodic stem cell reports on our website.

This month I want to start a second part of the new tradition, a brief blog note to let you know why I, as someone who toiled in stem cell labs for many years, chose these items as some of the most important papers in the field in the past month or so.

The first paper is a true breakthrough, something no one had accomplished before. A Japanese team was able to create an “organized” tissue in a dish, not just drive stem cells to become a specific adult cell, but rather two types of cells in two distinct layers. In this case they created an optic cup that resembled a post-natal retina. With one of the holy grails of stem cell research being the ability to replace complex organs, this was a brilliant paper to see.

You will see that in last month’s stem cell report I discussed “this year’s problem” with iPS, or reprogrammed cells, which is their much higher rate of genetic anomalies compared to embryonic stem cells (as we blogged about here). Well, this month I am discussing “last year’s problems” with iPS cells. For the past couple years there has been much hand wringing about the possibility that the transcription factors used to reprogram cells, if left in the cells, could be turned on at the wrong time and lead to cancer, and that the reprogramming processes were all hugely inefficient. Now, only five years after the first iPS cells were created in mice, a number of papers came out this month showing major strides to reprogramming with only transient integration of the reprogramming factors and exponential improvement in efficiency in creating iPS cells. I have to hope that “this year’s” iPS problem will be even more quickly solved or at least its relevance determined.

Last, I chose a paper that does two things: it explains a clinical result that had many purists in the fields shaking their heads in doubt and points the way to another major goal of the field, a way to stimulate endogenous stem cells to make repairs when needed. The study found a protein that can induce endogenous stem cells in heart attack patients and may explain why certain bone marrow stem cells, ones that have no ability to form heart tissue, nonetheless seem to offer some small but genuine improvement for many patients.

Alan Trounson

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.

– A.A.

Global Clinical Trials: Spreading the Wealth Yields Diversity

Geoff Lomax is CIRM’s Senior Officer to the Standards Working Group

In my role coordinating CIRM’s Standards Working Group, I often participate in conversations about ethical implications of participating in clinical trials. In that capacity, I recently attended the annual conference for the Association for the Accreditation of Human Research Protection Professionals (AAHRPP).

These conversations are especially important given CIRM’s Targeted Clinical Development Awards, which will be discussed at our next board meeting May 2-3 (information about that meeting will be available on our website 10 days before the meeting). Those awards will fund the clinical development of novel cell therapies derived from pluripotent stem cells.
The conference had a strong emphasis on international clinical research. One talk of particular interest was by Luc Truyen of Johnson & Johnson Pharmaceuticals. The talk titled, “Migration of Clinical Trails Outside of the United States: Is it a Problem?”, presented data on the current international clinical trial landscape.
The punch line first, Dr. Truyen’s data suggest (1) the overall volume of trial activity has grown substantially, (2) there continues to be an increase in patient enrollment and new trial sites in North America and (3) the increasing geographic diversity of trials is a measure of success.
Here are a few key points I thought were interesting:
  • Cost may be a factor in limited cases. The cost of trials in the US is roughly 45% higher than China, India and Brazil – countries where increased numbers of trials are being conducted. These countries, however, also have experienced rapid growth in research and clinical capacity. Further, these countries have high incidence of diseases not common in the Untied States (e.g. hepatitis). Therefore, it is a success that they are initiating large trials to address diseases impacting their populations.
  • Overseas trials are not a means of avoiding regulatory scrutiny.  Major trials by manufacturers for therapeutics intended for international markets are generally conducted under a FDA Investigational New Drug (IND) application. International FDA investigator inspections have quadrupled since 2002. These trials are highly regulated.
  • Trials performed overseas support scientific validity. Many overseas trial sites are chosen for scientific reasons. Reasons include (1) there is a higher concentration of disease in the area, (2) individuals have not been treated with other therapies so the effect of the trial may be measured accurately and (3) therapy development / trials have the support of the local public health / medical community.
  • Globalization is creating the need for therapies suitable for a diverse world.  We need international collaboration to ensure that clinical research in the U.S. and elsewhere stays applicable to the all populations.

– G.L.

    Building stem cell-based cures brick by brick

    There’s an image I love in an interview with Northwestern University stem cell scientist John Kessler. He is a neurologist who turned to stem cell science after skiing accident left his daughter with a spinal cord injury.

    In the Q&A, Kessler has this to say about how science progresses:

    I often use this analogy: science is like building a building. You can’t just say you want a 50-story building and then start building the 50th floor first. It doesn’t work that way. Your goal is to get to that 50th story, but you have to build brick by brick. Then others can come along and start building on top of that brick. That’s how science works. I believe this will be one of those bricks that gets people closer to that goal. The beauty of science is once you put a brick in place, it’s there forever.

    I think that’s a terrific way of looking at how science progresses. There’s much ballyhoo these days about which types of stem cells are best, with those opposing the use of embryonic stem cells saying that so far those cells have produced no cures. This is true, but there was a time when you could say that construction workers had yet to build a complete skyscraper yet now they are commonplace.

    The building image also works when you think about how the branches of stem cell science intertwine. Lessons learned on the embryonic stem cell building directly resulted in science that led to reprogrammed iPS cells. Those iPS cells are now producing fascinating insights into how disease conditions play out in individual cells. The same is true for adult stem cell and cancer stem cell research, all of which benefit from and contribute to embryonic stem cell progress.

    When you look at CIRM funding as the construction site, we have apprentices learning the ropes (our stem cell research training programs), people developing new and better ways of making the bricks and mortar, and senior people climbing high in the sky to lay down the latest bricks. Together, we’re building not just one building, but a village made of many different types of stem cell bricks.

    Kessler has more to say about stem cell research, including this comment about the controversy over human embryonic stem cell research. I appreciate his balanced approach that recognizes both sides of the controversy: He writes, “People oppose it for a host of reasons. Some having to do with religion, with not understanding what it actually entails, or having to do with a dislike of science in general.”

    He then provides his personal view:

    There are at least a half million frozen blastocysts sitting in in vitro fertilization centers. They will either sit in liquid nitrogen where they will eventually die, or if no one wants to pay to store them, they will get thrown into the trash. I always try to make the point that I find it hard to believe that it is morally or ethically superior to throw them in the trash rather than allow scientists to use them to try to cure a disease.

    And this, about the difference between iPS and embryonic stem cells:

    I’m sometimes asked, ‘Why not just work with IPS cells and everybody will be happy?’ The IPS cell is not absolutely identical to the human embryonic stem cell. There are some very, very clear differences. I think the human embryonic stem cell is the gold standard. That’s the cell that we have to measure these against. We have to continue working with both kinds of cells.

    I highly recommend giving the article a read.

    – A.A.

    Shifting the balance of stem cell renewal and cancer

    There’s an interesting story from CIRM grantees at Sanford-Burnham this week, showing a relationship between tissue-specific stem cells in the body and cancer. It all started with an observation in people with Down Syndrome: they are less likely than other people to develop cancers.

    This observation eventually led to the discovery that a gene called Ets2 — an extra copy of which is present on the spare chromosome 21 in people with Down Syndrome — can protect against colon tumors. The reason why has to do with the stem cells lurking in the colon.

    Stem cells do two things: They make more of themselves (self-renewal) and they mature into tissues such as those lining the colon (differentiation). The more self-renewal, the higher the risk of developing tumors because as the cells divide they might incur cancer-causing mutations. Ets2 seems to lower the risk of tumors by slowing how quickly the stem cells turn over and driving those cells to differentiate instead.

    A blog entry by Sanford-Burnham quotes senior author Robert Oshima, who previous to this study had been investigating Ets2 in breast cancers:

    Dr. Oshima sees this study as more supporting evidence for an unconventional type of cancer treatment called differentiation therapy. “If we can shift the balance to decrease stem cell proliferation and increase differentiation, we might be able to decrease tumor appearance or growth.”

    The relationship between stem cells and cancer is long-established. CIRM funds many awards studying the so-called cancer stem cells that drive the growth of many tumors. Here is a list of those cancer stem cell awards.

    Stem Cells, March 21, 2011

    – A.A.

    From stem cells to schizophrenia in a dish

    Kristen Brennand

    CIRM grantee Fred Gage at The Salk Institute for Biological Studies and his lab are creating a veritable cellular hospital of disease conditions playing out in laboratory dishes. What they learn from these diseases-in-miniature could lead to new ways of creating and screening drugs to treat the disorder.

    In 2008, he matured embryonic stem cells into the type of nerve cells damaged in ALS. This study led to insights in how the damage occurs and could provide a way of screening new drugs. Then in November of 2010, Gage and his colleagues published a paper in which they reprogrammed skin cells from people with a genetic form of autism spectrum disorders. They then matured those iPS cells into neurons that they could study in the lab.

    Now, Gage and his team have published a paper in Nature in which they pulled off a similar feat, this time with schizophrenia. They took skin cells from people with a genetic form of the disease and reprogrammed those cells back to an embryonic-like state. They then matured those cells into neurons — neurons that produced significantly fewer connections than is normally seen. What’s more, the drug Loxapine, used to treat schizophrenia, helped restore those connections. No other frequently prescribed antipsychotic medication was able to restore those connections.

    A Salk press release quotes Fred Gage, who is professor in the Salk’s Laboratory of Genetics and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases:

    “Schizophrenia exemplifies many of the research challenges posed by complex psychiatric disorders,” says Gage. “Without a basic understanding of the causes and the pathophysiology of the disorder, we lack the tools to develop effective treatments or take preventive measures.”

    The group also found almost 600 genes whose activity was different between normal neurons and those from the schizophrenia cell. Roughly a quarter of those had been implicated in schizophrenia in the past.

    The press release quoted Gage again:

    “For many years, mental illness has been thought of as a social or environmental disease, and many thought that if affected people just worked through their problems, they could overcome them,” says Gage. “What we are showing are real biological dysfunctions in neurons that are independent of the environment.”

    We produced a video of Gage discussing the role of stem cells in understanding diseases:

    CIRM Funding: Kristen Brennand (T3-00007); Fred Gage (RL1-00649-1)
    Nature, April 13, 2011

     – A.A.