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.



A.A.

Finding stem cell clinical trials made easier

At CIRM we routinely get emails and phone calls from patients desperately seeking clinical trials for themselves or for family members. With all the talk about future stem cell cures, it only makes sense that people would be looking to stem cells for help.

CIRM doesn't maintain our own list of stem cell-based trials. Instead, we've always referred people to the national listing of all registered clinical trials maintained by the NIH: clinicaltrials.gov

Now we have a good resource for European patients, too. The European Medicines Agency yesterday revealed their new database of registered clinical trials in the EU: https://www.clinicaltrialsregister.eu/

Nature ran a story about the database on their blog:

Information on interventional trials run in all 27 EU member states, as well as Iceland, Liechtenstein and Norway, will now be searchable via the EU Clinical Trials Register website. The register effectively opens up the agency’s previously closed EudraCT database and brings Europe into line with the United States, which has long publicly listed all clinical trials online.

The old system attracted criticism from researchers concerned it would make it easier to bury bad results and hinder proper evidence-based medicine. (See, for example Europe's clinical trial database criticized in Nature Medicine or New EU trials database is criticised for lack of openness from the BMJ, both 2004.)

People turning specifically to stem cells for hope can search either database by the term "stem cell". A quick search of the U.S. database brought up 3459 results, most of them variations on bone marrow transplants for blood cancers and some immune diseases. A search of the new EU database pulled up 116 results, similarly focused on cancer and bone marrow transplantation. (It's the blood forming stem cells in the bone marrow that reform the blood system after a transplant.)

Bone marrow transplants have been taking place for about 50 years now, so it's no surprise trials to improve and expand on that technique dominate the databases. Over the past few years, some other types of adult stem cells have begun early phase clinical trials, including mesenchymal stem cells and neuronal stem cells, and now three trials based on embryonic stem cells are underway.

The NIH site has an especially good FAQ about clinical trials and how they are run, including a description of the different phases of the trials. Watching how people react to stem cell news it seems like an announcement of a new Phase I trial starting is often taken as proof that the cells are effective. (As in, there are more adult stem cells in phase I trials so obviously they are better than embryonic cells.) What that FAQ makes clear is that an initial Phase I trial is only intended to ensure that the potential therapy is safe in people. It's not until Phase II that scientists expect to find some indication that the technique is effective and in Phase III that they might find proof that it works.

In time we should see more diversity in the types of stem cells that come up in a search of either clinical trial database. Hopefully these early trials with various types of adult or embryonic stem cells will produce some winners in addition to the inevitable failures.

- A.A.

California stem cell scientists comment on the federal funding fracas

Yesterday's decision by a U.S. Appeals court to allow human embryonic stem cell research to move forward pending a full appeal (see Reuters story) marks a good time to look back at how this legal back and forth impacts the field.

In late August, after the initial injunction halting federal funding for human embryonic stem cell research, CIRM issued a survey to grantees, roughly a quarter of whom reported having NIH funding for their stem cell work (here's our blog entry about that survey). The following are some comments from survey respondants:

"Interestingly, the early days of molecular biology were also filled with similar religious protests suggesting that scientists were playing god, but those objections were eventually discarded. Since then molecular biology has been so fundamental to medical research that few would admit to ever opposing it. I wonder if many organizations that opponents hESC research were also against molecular biology."

"I believe that after about 50 years, physicians will recognize the CIRM program above all others as being singularly instrumental in redefining the methodology of treatments and cures."

"My laboratory does not currently work with hESC but it is a possible future direction. If NIH does not fund this type of work, I will abandon it as a future long term project."

"CIRM funding for basic research on hESC is now more important than ever. without this the years spent developing this knowhow will be wasted"

"This ruling is extremely shortsighted. It will not aid the development of adult stem cell therapies and research. It is detrimental to the entire field and will hinder the development of therapies. At present we cannot predict which stem cell approach will work for which disease. Research is needed to establish a comparison base."

"This illustrates the problem with legislating by executive order, rather than changing the legislation itself. What will stop a new administration from banning hESC research and then another one permitting it again? Financially unstable research environment made worse by yo-yo policy making."

"I am just devastated, yet trying to be creative and optimistic to generate new funds for my research program and the investigators I am training.

"This turn of event is a sad day for stem cell researchers in America in particular and for all scientists in general. It will delay our progress in stem cell research and ultimately it is the people who will suffer more."

"Ironically, I don't disagree with the "legal" decision; I think the judge read congresses directive right. The problem is in the narrow language of the law and in our (scientists) failure to correct the record: "no embryo's were harmed in the generation of these ES lines". Only medical waste blastocysts were harmed. Honestly, saving blastocysts is a non-issue for 90% of the population. We need Obama and congress to re-write the law to allow generation of new ES lines and research on ethically obtained ES lines."

"For the millionth time, I find myself being thankful for CIRM."

And to the question of what work won't occur due to the funding freeze. Note how many people have concerns about the legal wrangling slowing iPS and adult stem cell research:

"1. Learning which stem cell type works best for a particular disease.
2. Understanding early human development -- particularly how birth defects, congenital diseases (like autism, degenerative diseases), and cancers arise
3. Aspects of drug discovery
4. Improvements in iPS technology"

"Basic understanding of the behavior of human ES cells. Many of the current cell lines are not very useful so the ability to make new xeno-free human ES is crucial for future use in clinical trials."

"This ruling will significantly hamper the development of non embryo derived therapies as well as any cell replacment therapies that may require ES cells."

"The funding freeze will negatively impact not only the human embryonic stem cell research funding under new guidelines, but will also freeze many research projects that would be fundable under Bush, or even non-stem cell research which is meshed in the same grant with the stem cell research (see additional comments)"

"It is critical to compare hESCs with iPSCs and aNPC results, and to carefully characterize each. Otherwise, the work on iPSCs and aNPCs may be misleading and even wrong."

"Any new field or biomedical research having enormous potential (e.g. stem cell research) or acute challenges (e.g. HIV / AIDS) requires enormous investment to produce useful return. The sheer breadth and depth of research that is required to convert the potential of stem cell research into reality can only be facilitated by Federal funding. For this to be derailed, even temporarily, on a dubious legal basis that seeks to overturn a previous Presidential order does disservice to the millions of people living with injuries or disease states that could benefit from such research."

"Our project was to study the effects of the environmental chemical, BPA, on the early stages of human development, a huge public health issue."

"understanding ES biology; and especially understanding how to better develop iPS (in order to rely less on ES in the future)."

"All stem cell research will be hindered by banning research on ES cells. ES cells are the quintessential stem cell, the gold standard. We need to study ES cells in parallel with all other types of cells used in regenerative medicine, as they inform one another. Through studies of development (the specialization of embryonic cells) we will learn about regeneration. The two go hand in hand."

"Comparative studies between iPSCs and ESCs, which are still sorely needed to understand putative differences between these two sources of stem cells."

"To numerous to list all repercussions here, but simply being able to compare ES, to iPS to adult cells and understand what makes them different, what line is best suited for what translational problem is the first big problem that comes to mind. But also all the wasted talent and effort, all those could have beens that will never get started because the atmosphere is simply too toxic."

"We could not fully understand stem cell biology.
We could not fully characterize the iPS cells and other reprogramed stem cells because we will have good controls."

We have some information about the different types of stem cells and how the work is tied together in our Stem Cell Basics.

A.A.

The University of California enters stem cell funding battle

The University of California has now entered the stem cell funding legal fracas, filing a motion to participate in the pending lawsuit. In a statement, the UC Office of the President said they are the first institution to seek to intervene in the lawsuit:

The recent U.S. District Court preliminary injunction blocking federally funded human embryonic stem cell (hESC) research threatens ongoing potential life-saving research and undermines the time-honored system of peer-reviewed science.

CIRM funds stem cell research projects at all ten UC system campuses (you can look up those awards on our online funding chart). In their blog, Nature breaks down the impact of the funding battle on just two of the UC schools:

The University of California, Los Angeles receives a total of 16 NIH grants from nine different NIH institutes involving work on human embryonic stem cells; those grants are worth a total of $8.7 million and provide full-time support for 46.5 researchers and staff. The University of California, San Diego, meanwhile, receives 14 NIH grants from five NIH institutes for human embryonic stem cell work, worth $7 million and employing 17.17 researchers and staff.

CIRM grantee at UC San Francisco Arnold Kriegstein wrote a statement in support of the motion. Kriegstein is director of the Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research at UC San Francisco. In his statement, he says that although much of the human embryonic stem cell research taking place in California is funded by CIRM, the injunction has an impact that is disproportionate to the amount of funding received.

"The preliminary injunction has an impact on dozens of researchers and students, affecting programs across the UC campuses and across departments... Any loss of funding for the federal [human embryonic stem cell] projects will result in a loss of hours for these employees."

Kriegstein specifically cites a training program that includes 88 PhD and MD students being trained at UCSF, and which has had its funding discontinued due to the preliminary injnuction issued Aug. 23.

The court has ordered both the plaintiffs and defendants in the case to file a response to the UC motion by Thursday, September 23.

A.A.

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

A.A.

Legal wrangling slows Stanford researcher's quest for a cure

Joanna Wysocka/Stanford University

What does all the legal wrangling mean for stem cell scientists? Stanford published a profile of up-and-coming star Joanna Wysocka, who talks about her own NIH-funded research. Wysocka was awarded the Outstanding Young Investigator Award at the annual meeting of the International Society for Stem Cell Research in June and has both a SEED and a New Faculty award from CIRM. In her acceptance speech for the ISSCR award Wysocka credited her SEED award for pulling her into the field of stem cell research.

Amidst her other successes, Wysocka also received the highest of scores on an NIH grant proposal that would fund stem cell research with the promise to help children with a rare developmental disorder known as CHARGE syndrome, which leads to life-threatening complications.

That award is one of the ones that got held up in the Aug. 23 ruling that threw NIH funding of human embryonic stem cell research into a tailspin. The Stanford story says:

“I am currently funding this project largely from leftovers of my start-up funds and relatively unrestricted junior investigator awards, but we need more money to continue,” she said. While the latest ruling means that the NIH can fund grants like hers, there is uncertainty among researchers nationwide due to the unsettled state of the law.

As of September 9, the NIH can once again proceed with funding human embryonic stem cell grants, but that funding is far from settled. That uncertainty could lead to significant delays.

Although the NIH now can move forward on her grant, she’s not sure how fast it can act — and whether the next court ruling could deal another setback before that happens. She noted that the NIH committee that must give final approval for her funding met while Lamberth’s ruling was in effect, so it did not consider her grant. That committee meets only three times a year, she said, so now she may have to wait.

“The review process was disrupted — it’s not something that can change in a day,” she said. “I have no clue when my grant will get back on track.”

The stem cell researchers and people employed in their labs are disrupted by the legal back and forth, but what’s worse is the uncertainty for families of children with CHARGE syndrome who look to work like Wysocka’s with hope.

A.A.

Lawmakers look to legalize human embryonic stem cell research

For now, the NIH is again able to fund research projects using human embryonic stem cells. However, if there’s anything to be learned from the past few weeks, it’s that the funding is uncertain. The only way to ensure continuous support at the federal level would be legislation specifically legalizing research using those cells.

Reps Diana DeGette, D-Colo., and Mike Castle, R-Del, have introduced legislation to legalize research using human embryonic stem cells. In the senate, Sen. Arlen Specter, D-Penn, has introduced similar legislation as has Sen. Tom Harkin, D-Iowa. Harkin is holding a hearing on Thursday before the Appropriations subcommittee on health, which he heads.

According to a story in the Chicago Tribune:

"There is great uncertainty in the research community as to what will happen," Specter said, explaining the need to pass a law confirming the research.

He said the NIH has spent $546 million on embryonic stem cell research "and phenomenal progress has already been made."

The story goes on to question whether lawmakers have the time or political will to take on the controversial topic. Unless they do, funding for human embryonic stem cell research at the federal level will remain uncertain.

The New York Times quotes DeGette as saying:

“I’ve been inundated with calls from freshman and other vulnerable members saying it’s not only the right issue to work on, but will also be politically good for them.”

A.A.

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.

A.A.

Government appeals stem cell ruling, claims harm to patients

The US government appealed the August 23 ruling by Judge Royce Lamberth that created a temporary ban on human embryonic stem cell research. According to Nature:

The documents filed by the government consist of two actions – an appeal of last week’s decision, which will be heard by the United States Court of Appeals for the District of Columbia, as well as a request to stay the injunction, which will be heard by the same court which issued it last week.

In order to impose the injunction, Judge Lamberth had to show irreparable harm to the plaintiffs -- two stem cell researchers who claim that the competition with embryonic stem cell research grants hurt their ability to receive NIH funds. However, Nature reports:

Between 2007 and 2009, before the current NIH guidelines for stem cell research were put into place, Sherley applied for five NIH grants, but did not receive them, Collins notes, while this year he received more than $425,000 from the NIH.

Reuters reports the Justice Department as saying:

The two doctor's "remote economic self-interests do not outweigh the harm the injunction will cause NIH, the hundreds of affected human embryonic stem cell researchers, and the millions of individuals who hold out hope that human embryonic stem cell research will lead to the cure for, or treatment of, their currently incurable illnesses."

 CIRM funding of stem cell research in California is not effected by the federal injuction, however a recent survey found that more than 20% of CIRM grantees also had NIH funding for human embryonic stem cell research.

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NIH halts intramural human embryonic stem cell research

The NIH has stopped all human embryonic stem cell research being conducted on its campus, in response to the August 23 injunction on all such research.

According to Science:

The agency has eight research projects that use hESCs, most if not all of which use lines approved under the Bush Administration, say NIH officials. It also has a unit that characterizes lines added to the NIH registry of approved hESC lines.

That Science story also contains the complete text of the email sent to NIH scientists.

Scientists who have received NIH funds for human embryonic stem cell research grants have been told that they can continue to use those funds, however new funds will be suspended. The NIH is also not reviewing new grant applications for human embryonic stem cell projects, and is no longer reviewing new stem cell lines for its registry.

The story goes on to say:

But some biomedical research lobbyists worry that that interpretation of the ruling may have been too optimistic, and a shutdown of all ongoing NIH-funded hESC research could be imminent.

A Stanford Scope blog entry by Krista Conger quotes Stanford School of Medicine Dean and CIRM governing board member Philip Pizzo as saying:

Once again the politics of stem cell research has the prospect of entering center stage - just when it seemed that we had moved into a new theater.

CIRM’s funding of all types of stem cell research — adult, cancer, iPS and embryonic — is not altered by the federal injunction. You can see all CIRM-funded grants using human embryonic stem cells in this searchable table.

Halting research using human embryonic stem cells has wide-ranging effects, as this CBS news story about childhood leukemia makes clear.

A.A.

What the embryonic stem cell research ban means to California researchers

On Monday federal judge Royce C. Lamberth ruled federal funding of human embryonic stem cell research impermissible under current laws. This decision had the immediate effect of shutting down the ability of the NIH to fund research using human embryonic stem cells, a result that NIH Director Francis Collins likened to pouring sand in the engine of discovery.

California is in a better position than other states. When Californians voted for proposition 71, they created a stable source of funding for all forms of stem cell research. To date, 65 percent of CIRM’s research grants support work with human embryonic stem cells — work that will continue despite changes in federal policy.

But that doesn’t mean California scientists are entirely insulated, as a recent survey of CIRM grantees makes clear. Collaborations with colleagues throughout the country will stutter and California projects using federal money and not funded by CIRM will be on pause. Collins’ engine of discovery will be running on only one cylinder — the California cylinder. Progress won’t stop, but it could take a lot longer to reach the final destination of new therapies without those other cylinders firing.

Preliminary results from the CIRM survey show the impact of the federal restrictions on researchers in this state. Of the first 100 respondents, 22% said they had NIH funding for embryonic stem cell research and only 5% of grantees said the ruling would make no difference to their overall research strategy. Also 65% of grantees that had NIH support said that if the NIH freeze holds they’ll need to reduce or eliminate positions in their labs.

Here’s a link to the preliminary survey results. We’ll be updating this link to provide updated results.

The most telling finding from the CIRM survey was that 76% of grantees said the funding freeze would impact their ability to carry out research with adult, cancer, or iPS stem cells. This point is critical, and is one that’s often overlooked. Research with other stem cell types relies on information gained from embryonic stem cells. All of this critical work toward new therapies will be slowed.

One anonymous survey respondent wrote:

The sheer breadth and depth of research that is required to convert the potential of stem cell research into reality can only be facilitated by Federal funding. For this to be derailed, even temporarily, on a dubious legal basis that seeks to overturn a previous Presidential order does disservice to the millions of people living with injuries or disease states that could benefit from such research.

A.A.