Friday, December 23, 2011

The war on cancer: 40 years later

Forty years ago today President Nixon signed the National Cancer Act, allocating $1.5 billion over three years for cancer research.

The Dana-Farber Cancer Institute has written an excellent piece on their blog about where the field has come since 1971. They write:
Forty years later, the War on Cancer can claim countless successes against one of the most resilient and recalcitrant enemies mankind has faced.

Some cancers that were once almost invariably fatal, such as pediatric leukemia, are now cured in the vast majority of cases. In kidney cancer, the five-year survival rate – the percentage of patients alive five years after diagnosis – has increased from about 50 percent in 1971 to more than 70 percent today. In colon cancer, the rate has increased from 52 to more than 66 percent over the same time period. Death rates for cancers of the breast, liver, lung, prostate, and several other organs and tissues have been declining for the past 10-20 years.



Despite all the strides over the past 40 years, cancer remains one of the biggest health challenges we face. The good news is that advances in the understanding of cancer at the basic, molecular level have positioned us to make even greater progress in the years ahead.
CIRM is playing an active role in the ongoing search for better cancer therapies. Of our disease-focused awards, cancer makes up 22% of our funding (you can see charts of our funding allocations here).

CIRM has eight awards working towards new therapies for cancers including leukemias and solid tumors such as those that form in the colon, brain and ovaries. Of those, four projects (two in leukemia and two in brain tumors) are part of our disease team programs, which all have the goal of submitting an application to the Food and Drug Administration by 2014 to begin a clinical trial. You can see a list of all our therapy development projects with links to those project descriptions in our online portfolio.

Although we can’t know in advance which of these projects will be successful, CIRM is proud to be part of the ongoing search for new cancer therapies.

A.A.

Wednesday, December 21, 2011

CIRM Spotlight on Heart Failure: A stem cell trial shows promise for healing injured hearts

Todd Dubnicoff is CIRM’s videographer and video editor

At many CIRM governing board meeting, we set time aside to hear from researchers, clinicians, and patients about the hope of stem cell research in a particular disease area. We film each of these Spotlight on Disease seminars so that the scientists’ progress and the patients’ stories are available to the public (a video archive of past Spotlights is here). At the December 8th Spotlight, the board heard about the hope for a stem cell based heart failure treatment that is showing promising results here and now in a clinical trial for patients (watch that video here).

“An easy painless miracle.” That’s the way Fred Lesikar, one of the Spotlight speakers and a clinical trial participant, described the procedure that used his own heart stem cells to regenerate his scarred heart tissue injured by a massive attack two years ago at the age of 59.

The procedure is straight-forward: clinicians obtain a small tissue sample from the patient’s heart during a 15 minute procedure under local anesthetic. Under specific laboratory conditions, stem cells spontaneously grow out of this tissue sample. These cells are then harvested and delivered back into the patient’s coronary artery. Lesikar told the board that he is thrilled with the results:
I was in pretty bad shape…Next week it will be two years since I had the stem cells put in…it wasn’t like a light switch going off but by the time I got to a year I was feeling great…Now I’m flying down to Costa Rica tomorrow, the day after tomorrow I’ll be tromping through the jungle and my only concern is that the people with me aren’t going to be able to keep up.
Eduardo Marban, MD, PhD, director of the Cedars-Sinai Heart Institute, led this first-in-human clinical trial and was the main speaker at this month’s Spotlight. Marban summarized the hallmarks of heart failure after a heart attack and described the results of the trial:
One quarter of heart attack patients end up with so much scar that life expectancy is compromised…Once the scar occurs it’s irreversible…At one year, the subjects receiving the stem cell therapy have 12 to 13 grams less scar than they did at the beginning of the study. That in of itself is a good thing but what really got us excited was the fact that when we looked at the living heart muscle, those subjects have 22 grams of new living heart muscle…That's equivalent to restoring about half or more than half of the lost heart muscle in these subjects (compared to no change in control subjects).
Marban also showed results of pre-clinical studies funded by a CIRM Disease Team grant, which uses an alternate preparation and delivery method of the heart stem cells. These studies will form the basis of an FDA application in the second quarter of 2012 to perform a follow-on clinical trial.

T.D.

Tuesday, December 20, 2011

Stem cell science meets public health: Case study, Parkinson's disease


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

As a student of public health, I have always been a believer in public science. Public science is critical for providing sustained capacity for research. As others have pointed out, this capacity translates into important commercial potential. Historically, California has been a leader in investing in public science. From its network of universities and various health-oriented agencies, the state maintains a wealth of information, technical and human resources. Capacity such as this lays the groundwork for innovation as researchers from varying disciplines interact to imagine new ways forward.

One personally exciting conversation that has emerged in the past couple of years is the role of stem cell science in supporting our understanding of environmental influences on health and disease. In fact, the National Institutes for Environmental Health Sciences has begun to fund research addressing the potential of environmental exposures to alter function, proliferation, survival, and differentiation of stem cells (here is a link to that RFA). One area of particular interest is the development of cellular systems to model the disease process. As we reported in a report on a toxicology meeting, these model systems help us both understand disease and evaluate therapies.

At CIRM, we thought it would be informative to hear from one of our grantee institutions that has been exploring this space. At a recent seminar, researchers from The Parkinson’s Institute reported on their work studying the relationship between environmental influences and development of Parkinson’s disease. A novel study in twins conducted by Samuel Goldman MD, MPH and Caroline M. Tanner, MD, PhD, from The Parkinson’s Institute has found that exposure to trichloroethylene (TCE) – a hazardous contaminant now found in soil, groundwater and air – can raise a person’s risk of developing Parkinson’s disease by six times. That’s just one of several contaminants and pesticides that increase risk of the disease.

The Parkinson’s Institute has taken skin samples from patients with the disease and reprogrammed those into an embryonic-like state. So far, they’ve developed 45 of these so-called induced pluripotent stem cell lines (iPSCs). (Some of this work was done with a CIRM Early Translational Award.) In the process of developing these lines, researchers collected information relating to environmental factors (job and residential history, lifestyle and others) associated with health and disease. Dr. Birgitt Schuele discussed ways in which these cells could be applied in future public health research.

One intriguing line of inquiry related to examining how pesticide exposure may be associated with Parkinson’s disease risk. Goldman and Tanner reported on how certain pesticides cause Parkinson’s disease in animal models and exposure is also associated with disease in humans. Schuele suggested patient iPSCs are a valuable tool for further studying this association and the disease process. The idea is that the researchers can mature those cells into the cell type that is associated with the disease—called dopaminergic neurons. Then they can expose those neurons to the pesticide to see if the neurons show signs of the disease in a lab dish. This is a critical way of learning about the effects of compounds on human cell types.

This type of research represents a way to leverage existing investments in California’s unique information, technical and human resources. For example, the state’s pesticide use reporting and visionary investment in mapping tools offers a unique opportunity to connect basic research on disease with information relating to the distribution of environmental agents. Thanks to a bill supported by then-Senator Art Torres (now CIRM vice chair) California has the most comprehensive data on pesticide use of any state. These resources have been used previously to study other disease such as autism. Videos from a seminar on the relationship between pesticide use and autism are available on CIRM’s YouTube channel.

The application of stem cell tools from basic research towards public health and environmental protections represents a critical avenue for health promotion and disease prevention. It’s personally exciting to see CIRM grantees making use of public resources to carry out science with such a potential for public good, and to have the NIEHS recognizing the value of this research with their funding initiative.   

G.L.

Friday, December 16, 2011

Trounson predicts ripple effects from European court ruling on human embryonic stem cells

In October the European Court of Justice issued a ruling that inventions created from human embryonic stem cells are not patentable. We wrote a few blogs at the time giving voice to different perspectives on what that ruling might mean. (Those blogs are here and here.)

This month, CIRM President Alan Trounson weighed in on the possible repercussions of the decision in the journal Cell Stem Cell (The abstract is available here, full access requires a subscription). Trounson’s letter is one of several opinions on the case that appear in this issue. Writing with Nancy Koch, CIRM legal Counsel, and Elona Baum, General Counsel and VP of business development, Trounson said:
Our view is that the impact of the recent Court ruling on stem cell research and regenerative medicine will be significant but varied. In some instances, the ruling may deter European hESC research, in others such research may nonetheless continue or even increase; in still others, no impact may occur.
The group wrote that they don’t expect the ruling to have a significant impact on basic research involving human embryonic stem cells. However, they suggest that the situation is more complicated for the type of research that translates basic human embryonic stem cell research discoveries into therapies. They write:
At this stage of research and development, profit-driven biotechnology and pharmaceutical companies are more actively involved. To the extent that the lack of patent protection following the Court ruling decreases the profit available (e.g., because patented inventions cannot be licensed and injunctions cannot be obtained to protect hESC patented inventions), biotechnology and pharmaceutical companies may be less motivated to invest in European hESC research. That effect may be even more dramatic for startup companies. A strong patent portfolio traditionally has been a prerequisite for attracting venture capital in the life sciences field.
However, they don’t predict a dearth of European commercial investment in embryonic stem cell research and technology. That’s because even though companies can’t patent discoveries, they may still be able to protect their work as traditional trade secrets. Moreover, the European regulatory authorities may require data from trials conducted in the EU before approving certain future stem cell-derived products

They also suggest that the ruling could lead to relocations both from the EU to the U.S. and the reverse. European companies whose business model relied on embryonic stem cell patents might relocate to the U.S. where those patents still hold. Companies in the U.S. who are slowed by patents held by others might relocate to the EU where those patents aren’t enforceable.

How these different factors play out remains to be seen, but the group does end on a hopeful note. They conclude by saying that they expect at least some of the critical human embryonic stem cell research taking place in the EU to flourish.

A.A.

Thursday, December 15, 2011

Banking iPS and embryonic stem cells for easier access, consistent quality

The board meeting last week was a day for following up on recommendations. In additional to the Opportunity Funds, which we blogged about earlier in the week, the board also approved a proposal for creating a stem cell bank. Stay with me here. This may not sound as exciting as funding new science or creating worldwide partnerships, but it’s important. Here’s why.

Imagine for a second that you decide you want to read those last few Jane Austens that you didn’t read in college. You go to the library, check them out, and enjoy. Right? But imagine that instead of going to a library you had to call around the neighborhood to track down the books, then drive to four different homes and sign four different book loan agreements and after all that some of the books have torn pages. It might seem like a better idea to just reread one of those old Agatha Christies on the shelf.

That’s where stem cell research is today. Say a researcher wants to compare stem cell lines from people with autism to find drugs that alleviate signs of the disease in a dish. That researcher would have to call around to several institutions, navigate a variety of materials transfer agreements and, basically, spend a lot of time on the phone rather than doing research. In yesterday’s blog, my colleague Geoff Lomax quoted Steve Peckman from the UCLA Broad Stem Cell Research Center talking about how these agreements –called MTAs—can hinder access to stem cell lines.

One way for CIRM to accelerate research is by creating more of a library system for stem cells – except we don’t want the cells back. This kind of bank is what was recommended at a banking workshop we held back in November 2010. (You can read a report from that workshop here.)

At last week’s meeting, Uta Grieshammer from our science office described CIRM’s $30 million proposal for creating such a bank. It will consist of three parts. First up will be awards to investigators who will go out and collect tissue samples from individuals with genetic diseases. The goal is to get samples from 1200 people.

Next, CIRM will give a single award to an organization that will take those samples and reprogram them into embryonic-like cells, called iPS cells. These cells have the ability to form every tissue in the body, and still retain the genetic make up of the person who donated the sample. These cells can then be matured into the cell type that goes awry in the disease as a way of studying that disease in a dish. In the past few years this technique has been used to create models of ALS, schizophrenia, Parkinson’s disease and autism, among others.

Finally, CIRM will fund a group to bank all these newly created cells, along with other stem cell lines. With this resource, that same researcher hoping to study autism cell lines could go to one place, navigate one materials transfer agreement and receive cells that are consistently quality controlled. The cells will be available to people in California and worldwide.

A.A.

Wednesday, December 14, 2011

Limited access to human embryonic stem cell lines? Survey says...

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

Is the ability to obtain embryonic stem cell lines hindering research, what factors influence access, and does availability vary by state? These questions have been the subject research and their answers are not entirely clear. A recent publication in Nature by Aaron Levine of the Georgia Institute of Technology suggests that access issues do impact research. In his paper, he writes:
“an inability to acquire certain hESC lines have likely hindered hESC science in the United States.”
This conclusion is based on a survey of stem cell scientists in the United States. Levine focused his discussion on the subset who reported using human embryonic stem cells. A sizable number of these scientists--38%--reported excessive delay in obtaining lines and 28% reported they were unable to acquire a stem cell line they wanted to study. Factors attributed to delays included problems with materials transfer agreements (MTAs) and an inability to obtain approval from an institutional oversight committee. Based on these findings, Levine writes:
“These results suggest scientists in the United States cannot conduct comparative studies with a diverse set of hESC lines and suggest that access issues have contributed to this situation.”
I found these results intriguing because in a recent study quantifying the use of hESC lines by CIRM researchers, my colleagues and I found that scientists had obtained a diverse array of embryonic cell lines – 138 unique lines including 17 newly derived hESC lines. I suspected the apparent discrepancy in findings may be related to the research environment in California and other states with policies designed to support access to and creation of human embryonic stem cell lines. The answer to the question of whether availability varies by state is not clear because Levine’s responses are not geography correlated.

Our findings suggest widespread access in California, but it is important to keep in mind we examined what lines researchers ultimately accessed, not what they were unable to obtain. To gain further insight, I did a quick survey of my Science Office colleagues. Many hadn’t heard of cases where access to cell lines had been a deterrent to research for our grantees. I also queried grantees who were carrying out comparative studies. Jeanne Loring of the Scripps Research Institute has a CIRM grant to compare cell lines. When I emailed her she said:
“We've had no trouble getting hESC lines from collaborators all over the world. There are hundreds of cell lines available, and most are of good quality.”
Another colleague did recall instances where there were delays in obtaining cell lines, so I emailed Steve Peckman, who is Associate Director of the UCLA Broad Stem Cell Research Center. He did offer specific examples where material transfer agreements were a source of delay. In addition, Peckman indicated the NIH restrictions on the use of certain popular lines, such as HUES 9, did impact approval by institutional oversight committees even in cases where no NIH funding was involved, so perhaps California researchers were not immune to access issues.

Peckman also said that a game changer at UCLA was the ability to study newly derived UCLA 1-6 hESC lines created with CIRM funding (here is a list of all cell lines considered "acceptably derived" by CIRM). He suggested new cell line derivation has been a tremendous benefit for researchers, potentially attenuating problems encountered elsewhere. He noted, however, that UCLA and others are not well equipped to distribute lines outside their home institution, which could explain Levine’s findings that certain individual researchers were having a hard time accessing lines. Peckman’s solution was to support the development of a banking and distribution network with uniform material transfer agreements.

Peckman’s observations are reassuring in light of the decision by CIRM’s board to move forward with CIRM’s Human Pluripotent Stem Cell Initiative. The initiative includes a “Bank Award”. The concept proposal for this award says:
“California researchers have already generated many disease‐specific human induced pluripotent stem cell (hiPSC) and human embryonic stem cell (hESC) lines, many with CIRM funds… CIRM intends to provide funds for the establishment of an hPSC repository located in California that will bank and distribute high quality, disease specific hiPSC and hESC lines generated in California for research use.”
The comparative ease of access in California, as evidenced by Loring’s work, may be attributed to our comprehensive scientific, regulatory and facilities programs designed to facilitate research. CIRM’s programmatic efforts are consistent with Levine’s suggestion that “funding agencies … encourage research using multiple diverse hESC lines.”

We are always interested in hearing more. If you have experience accessing and utilizing hESC lines, we encourage you to comment below or contact me glomax@cirm.ca.gov.

G.L.

Tuesday, December 13, 2011

JDRF supports CIRM diabetes disease team led by ViaCyte

Today a CIRM-funded disease team working toward a therapy for type 1 diabetes received additional support and endorsement from the Juvenile Diabetes Research Foundation (JDRF). The project, led by San Diego-based Viacyte, received almost $20 million in funding from CIRM in October 2009.

The goal of the ViaCyte project is to mature embryonic stem cells into a type of cell that normally produces insulin in the pancreas. These are the cells that are destroyed in people with diabetes. The group plans to put those cells in a device that protects them from the immune system, then implant that device in the body where it is hoped that the cells will mature to produce insulin in response to blood sugar. The cells are effective in animal models, the company says.

According to a press release from JDRF:
The three-year series of preclinical studies being co-funded by JDRF will help ViaCyte prepare the information necessary to apply for regulatory approvals to study the system for safety and efficacy in people with T1D.
The release goes on to quote leaders from JDRF, ViaCyte and CIRM:
"Encapsulation research is one of JDRF's priorities because of the profound possibilities it holds for many avenues of research for type 1 diabetes," said Julia Greenstein, JDRF's assistant vice president for Cure therapies. "We're excited about partnering with ViaCyte to explore the use of encapsulated stem cell-based replacement. This type of innovative therapy could revolutionize the way people live with type 1 diabetes, and may also reduce the risk of dangerous complications that often result from extreme high and low blood sugars."

"We are thrilled to be partnering with JDRF, the leader in the field of support for diabetes research," said Allan Robins, Ph.D., acting CEO from ViaCyte. "ViaCyte's goal is to create a product that will free people with diabetes from insulin dependence for the long-term, and we believe this therapy has the potential to transform lives."

"At CIRM, we have long had the goal of leveraging the financial and intellectual capital of California with other funds and talent from around the state and around the world, and the decision by JDRF is a clear example of how these partnerships can enhance the opportunities to get to the end goal of a therapy for patients," said Alan Trounson, president of CIRM. "We are proud to have JDRF as a partner in working with ViaCyte and their scientific team to bring a potentially life-changing therapy for people with diabetes to the clinic.
Here's more information about the ViaCyte disease team project and more about CIRM funding of diabetes research.

This video features ViaCyte's Eugene Brandon discussing the company's approach:



A.A.

Opportunity Fund addresses review panel's recommendations

On December 8 of last year, CIRM received the insights and recommendations from a blue ribbon panel of external experts charged with evaluating the agency’s progress to date. (Here is a copy of that report, and CIRM’s press release.)

Less than a year later, on October 26, 2011 the ICOC approved the first of a three-part Opportunity Fund to address those recommendations. (A press release from October board meeting is available here.) And, just days ago on December 8th, a year to date from the expert’s report, the governing board approved the final two proposals. (That press release is available here.)

With all three programs of the Opportunity Fund approved, CIRM will be able to address the major recommendations of that panel: namely to create an agile and proactive grant program with flexible processes that synch up with industry, all geared at capturing great science and maintaining the progress of our strong research programs.

When CIRM first received the review panel’s report, the question was how could the agency address the recommendations within its legal and operational frameworks. All new science funded by CIRM has to go through a review by outside experts, which takes time, and state funds have to stay within California. To address these questions, CIRM held a brainstorming session to think about the most effective ways of meeting the recommendations.

What the CIRM science and legal offices came up with were three initiatives. The first of these, called the Strategic Partnership Funding Program, was approved at the October board meeting. This $30 million initiative responds to the review panel’s recommendation that CIRM attract industry partnerships through a funding approach that is more aligned with industry needs.

According to Elona Baum, CIRM General Counsel and Vice President of Business Development, who led the development of that program, the Strategic Partnership Funding Program will help our grantees team up with industry partners who can help them overcome regulatory issues and design effective clinical trials. These partners will also be needed to fund Phase III clinical trials.

The two pieces of the Opportunity Fund approved on December 8th are the $12 million Bridging fund, spearheaded by Patricia Olson, Executive Director of Scientific Activities, and the $15 million External Innovation Initiative, led by Ellen Feigal, Senior VP of Research and Development.

The External Innovation Initiative was developed as a way of leveraging California expertise to further great science taking place outside of California. CIRM has formed funding relationships with 12 countries, two international states, one domestic state, two foundations, and most recently CIRM’s collaborative relationship with the National Institutes of Health. (More information about those relationships is available here.) If great science is taking place in one of those jurisdictions, CIRM can facilitate a collaboration with a California scientist whose expertise will speed the science. CIRM only funds the portion of the research within California – protecting the state’s investment – but that funding can speed research toward disease therapies taking place around the world. Even if a therapy isn’t developed in California, Californians benefit from the results.

The Bridging Fund will play a critical role in keeping promising research moving forward. Imagine, you are a CIRM grantee with an Early Translational Award that produced promising results. But your funding ends, and you won’t know if you got your next CIRM award for several months. What do you do? You stop the research until you get more funding either from CIRM or from some other source. This stop and go nature of funding slows promising projects. The Bridging Fund will provide stopgap funding for those researchers who are waiting on the next big grant, keeping the research moving toward patients.

As Olson said, “I think these programs go a long way toward addressing the key concerns of the external advisory committee. Next comes implementation.”

The announcements describing each of these programs will be posted to the CIRM website in the first half of 2012.

A.A.

Friday, December 9, 2011

Jonathan Thomas reflects on the state of stem cell research

Jonathan Thomas is Chair of the CIRM governing board

Yesterday our governing board met for the first time since Geron announced the decision to terminate their stem cell research program. I wanted to take that opportunity to address the board and let them know my strong commitment to CIRM’s stem cell research program.

When Geron made their announcement our immediate concern was for the patients and their families who were disappointed at the termination of a trial that was a source of such hope for the future. Geron has been a true leader in the field and a source of inspiration for patients and their families. They broke new ground, becoming the first to start a Food and Drug Administration-reviewed trial based on human embryonic stem cells. Their efforts laid the groundwork for the two additional trials now underway for forms of blindness and for those trials that are close to submitting applications to the FDA.

However, Geron is a business. The company decided that their cancer therapies were farther along than the stem cell trial and when they held the stem cell program against the prism of economic reality they made a business decision to end the trial. The company is now looking for a partner to carry the research forward.

There are those who have extrapolated Geron’s business decision to question stem cell science. I say to those people: If you were to query the many researchers worldwide and companies involved in developing products you would hear unwavering enthusiasm for pursuing stem cell technology.

I was just at the excellent Stem Cells on the Mesa meeting in La Jolla where I heard from those researchers and investors. We spent the first day hearing about the incredible scientific advances taking place in the stem cell field. The next day we attended a business and investor partnering forum (sponsored in part by CIRM) where the same message of enthusiasm for stem cell science echoed just as strongly.

CIRM’s award to Geron was just one of the 44 projects in 26 disease areas that are in various stages of working toward clinical trials. (I blogged about those projects recently.) We remain optimistic about those research programs and are totally committed to the projects we have funded to-date and to the research we will fund in the future.

J.T.

Thursday, December 8, 2011

Stem cell discovery could help people regain smell

Elongated green cells are sensory neurons – which sense smells and relay that information to the brain – that originated from olfactory stem cells in the nose. Cells labeled in red are immature cells in the process of differentiating into neurons and other mature cell types. (Photomicrograph by Russell Fletcher, UC Berkeley)
A rose may smell as sweet by any name, but for those without a sense of smell a rose by any name still smells like cardboard. Now there's a glimmer of hope for those whose fine wine and roses are odorless and who can't taste. Researchers at the University of California, Berkeley have found a gene that's responsible for prodding stem cells in the nose to form new odor-sensing neurons.

A press release by Robert Sanders at the UC Berkeley quotes lead researcher John Ngai talking about the loss of smell in old age:


“Anosmia ‑ the absence of smell ‑ is a vastly underappreciated public health problem in our aging population. Many people lose the will to eat, which can lead to malnutrition, because the ability to taste depends on our sense of smell, which often declines with age.”

“One reason may be that as a person ages, the olfactory stem cells age and are less able to replace mature cells, or maybe they are just depleted,” he said. “So, if we had a way to promote active stem cell self-renewal, we might be better able to replace these lost cells and maintain sensory function.”

The release goes on to quote Gary K. Beauchamp, director of the Monell Chemical Senses Center in Philadelphia, who was not a member of the research team. He noted that the olfactory system stands out for its ability to regenerate following injury or certain diseases.

“This new paper … presents an elegant analysis of some of the underlying genetic mechanisms regulating this regeneration,” Beauchamp said. “It also provides important insights that should eventually allow clinicians to enhance regeneration, induce it in cases where, for currently unknown reasons, olfactory loss appears permanent, or even prevent functional loss as a person ages.”

The group found a gene that seemed to be involved regulating nasal stem cells. They created mice that lacked that gene and found that the mice had more than the usual number of odor-sensing cells. Sanders goes on to write about how regulating this gene -- called p63 -- could help people regain a sense of smell:

A drug that regulates p63, or modulates one of the genes that p63, in turn, regulates, might be able to boost the number of nasal stem cells as well as the number that mature into smell neurons.

Any real world result of this work would be many years off -- the path from a mouse lacking a gene to a drug that's available to humans is a long and arduous one.

Neuron, December 8, 2011
CIRM Funding: Russell B. Fletcher, Melanie Prasol (T1-00007)

A.A.

Tuesday, December 6, 2011

Mess with the body's clock, mess with stem cells

The Canadian Stem Cell Network posted an interesting item on their blog today about the relationship between stem cells and our sleep/wake cycle (also called the circadian rhythm).

David Kent, a postdoctoral researcher at the University of Cambridge, writes about the work, which was published online in Nature November 9:
The group of Salvador Aznar Benitah in Barcelona recently published research which links skin stem cell turnover and heterogeneity to the body’s internal clock. Their work has inspired many new studies that aim to understand the impacts of circadian rhythm on other stem cell systems.
The group found that when they disrupt genes that control the sleep wake cycle, they also disrupted the balance of stem cells in a dormant versus dividing state in the mouse hair follicles. The blog goes on:
This disturbance in rhythm led to premature aging as well as an increased incidence of tumours, suggesting that we might better understand how cancers grow and progress by understanding the natural cycles our bodies go through.
In the Nature paper, the authors write:
Our results indicate that the circadian clock fine-tunes the temporal behaviour of epidermal stem cells, and that its perturbation affects homeostasis and the predisposition to tumorigenesis.
Translated, what the researchers are saying is that the body's daily rhythms helps control the behavior of stem cells, at least the ones in the hair follicles. Mess with the body's clock and you mess with the ability of those stem cells to carry out their normal functions, including regulating aging and tumors.

A.A.

Monday, December 5, 2011

Clocks & stem cells: Time and tinkering to develop the best embryonic stem cells

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

The history of technology tells us that the first strategy is rarely the one that sticks. One of my favorite examples involves the English clock maker John Harris, whose many iterations of marine chronometers revolutionized sea travel. (His story is recounted in Dava Sobel’s excellent book Longitude: The True Story of a Lone Genius Who Solved the Greatest Scientific Problem of His Time.) My English grandfather also worked on clocks and marine guidance systems so I have a soft spot for the guild.

In 1730, Harris sought to produce a clock, called the H1, which could maintain accurate time on a lengthy, rough sea voyage with widely varying conditions of temperature, pressure and humidity – a great challenge in his day. This initial prototype performed well but there was a desire for a more rugged and compact design. After several iterations and another 23 years, he produced the H4, which kept time within 39 seconds during a trans Atlantic sea trial. A subsequent design, H5, was accurate within one-third of a second – revolutionary for its time.

Fast forward to 2011, in the world of human embryonic stem cell research, the cell line H9 has been revolutionary for its time – used in thousand of published studies. In a recent article, Rohun Patel and I illustrate how it is also the most widely utilized human embryonic stem cell (hESC) line by CIRM researchers. However, we also found that CIRM grantees were carrying out research with 137 other lines including 17 that had been recently derived with CIRM funding.

A recent study in Human Molecular Genetics authored by Amander Clark at University of California, Los Angeles suggests the newly derived CIRM lines may have several improvements over the earlier models. The study compared the X chromosomes of older lines, including H9, to recently derived lines. The UCLA team found that the X chromosomes in the newer lines were more active than those in the older lines, which tended to have more of the X chromosome shut down. Furthermore, the way in which those older lines shut down portions of the X chromosome deviated from how cells normally de-activate portions of the X chromosome – called “X inactivation”. In a press release from UCLA Clark said:
“The classic signature is gone, so something else is regulating X chromosome inactivation in the established cell lines,” Clark said. “It will be important not only to find out what that is, but also to discover what else is changing in the nucleus that we cannot see.”
Clark’s paper shows that in stem cell research—as in other areas of innovation—it takes time and tinkering to develop the best model. The ability of CIRM-funded researchers to develop and then investigate 17 new human embryonic stem cell lines and access hundreds of others would not be possible under federal guidelines alone. Federal agencies like the NIH can’t fund research to create new stem cell lines. Clark’s paper shows the clear need for these efforts to continue under CIRM and other agencies that fund cell line derivation. In the press release she said:
“Our data highlights the importance of maintaining hESC derivation efforts. Gold standard hESC lines should be the benchmark for human pluripotent stem cell research.”
Unlike Harris, stem cell researchers don’t have 23 years to tinker with their design. Patients need therapies soon, and therapy development will be bolstered by having optimal tools available to all researchers. Clark’s work shows the value to patients in those 17 lines derived by CIRM grantees, and by all those other new lines that have been and will continue to be created through sources other than federal funding.

Human Molecular Genetics, November 30, 2011
CIRM Funding: Amander Clark (RL1-00636-1)

G.L.

Friday, December 2, 2011

Guest blogger Alan Trounson — November’s stem cell research highlights

Each month CIRM President Alan Trounson gives his perspective on recently published papers he thinks will be valuable in moving the field of stem cell research forward. This month’s report, along with an archive of past reports, is available on the CIRM website.

This month’s literature produced a number of studies that can be glibly summarized as: Hey they work; they really work. The publications show we are starting to get a real handle on how to get stem cells to integrate and function like the desired tissue, and even to form complex structures.

The same Japanese team that was able to create a complex optic cup in a dish earlier this year, now reports that they have used embryonic stem cells to create a pituitary gland. That gland secretes the appropriate hormones and is able to correct hormone deficiency when transplanted into a mouse that lacks the pituitary gland, making the formerly lethargic animals active again.

Two teams turned embryonic stem cells into neurons that were able to integrate into the brain and show evidence that they function like the specific type of neuron that each team sought. A New York team produced dopamine-producing neurons that were able to correct some movement disorders in Parkinson’s disease models in mice, rats, and monkeys. (We blogged about that work here.) Meanwhile a Wisconsin team chose to mature the stem cells into neurons designed for memory, those in the hippocampus, and showed that they were able to integrate and fire neural signals like neighboring cells.

A Carolina team used a type of stem cell found in bone marrow and fat, mesenchymal cells, taken from the father of sheep with hemophilia, and correct the hemophilia in their sons. They did it by harvesting the stem cells and then genetically altering them so they produced Factor VIII, the blood-clotting factor that hemophiliacs don’t produce. When given to the sons, their bleeds stopped including the bleeds into their joints that had made them limp badly. The animals were able to walk normally again after the injections.

I start this month’s report with a pair of papers that seem to sort out some of the conflicting data that has been reported on stem cells for heart repair. One showed that stem cells from the bone marrow given in a couple of weeks after injury do not do improve heart function. Another showed that a different cell type—cardiac stem cells harvested from the patient’s heart—given even months after evidence of heart failure, were able to improve heart function, and in some patients for at least a year. (We blogged about that work here.) This is a critical area to gain some clarity in what cells to use and when; the burden of heart failure is a huge drain on our nation and the world.

My full report of this month’s highlights is here. I hope you will find it interesting.

A.T.

Thursday, December 1, 2011

World AIDS Day 2011 -- Buzz about a Cure for HIV, CIRM Leading

Jeff Sheehy is director for communications at the AIDS Research Institute at UCSF, and a member of the CIRM governing board.

Two articles in major newspapers—the New York Times and London's Financial Times—are highlighting the growing movement advocating for research towards a cure for HIV in the lead up to World AIDS Day on December 1.

Advocacy for a cure has been sparked in recent years by the experience of Timothy Ray Brown, the first patient cured of HIV. It has been five years since his dangerous and high-risk procedure that also cured his leukemia and his virus remains undetectable. More recently, a patient who had some of his disease fighting T-cells re-engineered with a HIV-resistant gene is showing preliminary signs of having virus suppression without antiretroviral medications for a significant period of time. (We blogged about that work here.)

Despite these successes let's be clear, a cure is still many years off and will require the active participation of patients motivated by altruism—as my friend Nelson Vergel has noted, heroes for the cure are needed. As Vegel writes, “No one really knows the degree of altruism in the community and their willingness to accept risks for the good of all.”

But recent data from UNAIDS shows us that those heroes for the cure and the cures themselves are desperately needed. While the number of new HIV infections has stabilized and the number of deaths due to AIDS is decreasing, we are seeing two new infections for every one person we manage to get into treatment globally. We are still losing ground against the epidemic.

And in the U.S., the federal Centers for Disease Control announced this week that only about a quarter of the 1.1 million people in the U.S. living with HIV have been successfully treated with antiretrovirals to a point to where they have suppressed the virus in their bodies to very low levels.
A cure is the best way to permanently change these statistics.

The California Institute for Regenerative Medicine, of which I am a board member representing HIV/AIDS, has provided historic leadership in funding future cures. The first applications were accepted for blood and immune system stem cell (hematopoietic stem cells) gene therapy projects to permanently re-engineer a person's immune system to resist HIV almost 4 years ago. Two awards were approved two years ago (one to City of Hope and one to UCLA) and should be in clinical trials within another 2-3 years. The challenge of replicating Timothy's daring proof of concept experiment in a much safer and much more scalable manner was taken up by CIRM while the head of NIH's HIV/AIDS programs was pooh-poohing the approach as ''not practicable." He has now embraced the call for a cure and it has become one of his top research priorities.

When California voters approved Proposition 71 seven years ago, none of us knew where the science might lead. And one cannot promise a specific cure for HIV or any other disease. However, I know that the existence of CIRM has greatly helped to change the research agenda for HIV globally and I suspect this is true for many other diseases and conditions.

CIRM, the California stem cell institute, does not propose temporary or episodic relief from disease, pain and suffering. We are committed to finding cures and we are working towards them relentlessly in partnership with patients, researchers and industry across California. This year on World AIDS Day, 30 long years into the HIV/AIDS epidemic, CIRM is a beacon of hope.

This video features Jeff Sheehy and CIRM disease team leader talking about a CIRM-funded project for HIV/AIDS:



J.S.

CIRM helping stem cell scientists and investors pair up

In La Jolla, stem cell scientists, companies and investors are engaging in a series of CIRM-sponsored get-to-know-you meetings as part of the first ever partnering forum in conjunction with the annual Stem Cell Meeting on the Mesa. These meetings are part of CIRM's ramped-up efforts to help scientists overcome obstacles on the path to clinical trials.

Elona Baum, CIRM General Counsel and Vice President of Business Development, was one of the primary organizers of the Investor and Partnering Forum. She said:
"The forum will feature company presentations and industry discussion panels on regulatory, finance, commercialization and reimbursement issues. The Forum will provide the opportunity for hundreds of business, academic research and investor participants to connect for one-on-one meetings and strategic partnering."
CIRM has 43 projects in various stages of working toward clinical trials (more information about those projects is available here). Getting from their current status through clinical trials will require significant investment. It takes big money to gather the kind of preclinical data the Food and Drug Administration (FDA) needs to see before allowing a product to enter first-in-human clinical trials. CIRM funds preclinical through early phase clinical trials, but researchers in academia also need to seek funding from other sources to gather sufficient data, and engage industry partners early to help carry their work into the clinic and the subsequent development steps towards regulatory approval.

Forming the partnerships that will allow academic researchers and researchers at young biotech firms to see their work eventually reach clinical trials is what the La Jolla meetings are all about. It's a chance for stem cell researchers to pitch their work to investors in the hopes of finding a good fit. They can also attend a series of sessions about how to navigate the regulatory pathway and form collaborations, among other sessions.

This forum is one of several ways CIRM is trying to help academic scientists succeed in getting their research translated into therapies. CIRM continues to hold conversations, roundtables and webinars with the FDA, the agency regulating investigational products and whether and when they can enter clinical trials. By having conversations now, CIRM can help researchers meet FDA requirements enabling them to enter their products into clinical trials. CIRM’s webinars to inform its grantees about different areas of stem cell research and the regulatory path are also publicly available to view on the CIRM website.

A.A.