CIRM grantees at Children's Hospital Los Angeles and the University of Southern California have succeeded in growing normal-looking small intestines in mice.
In a press release, the senior author Tracy Grikscheit said:
“The small intestine is an exquisitely regenerative organ. The cells are constantly being lost and replaced over the course of our entire lives," she explained. "Why not harness that regenerative capacity to benefit these children?”
The group took a small sample of small intestine from mice and placed them on a biodegradable scaffolding inside the abdomen of another mouse. That scaffolding basically gave the cells something to grow on that would mimic the shape of a normal intestine. What they found is that the transplanted cells were able to form all the cell types and structures that are normally part of the small intestine.
The paper was published in the July issue of Tissue Engineering.
The press release mentions the eventual hope of using the technique to help children with intestinal failure. Babies born pre-term are at risk for intestinal damage called necrotizing enterocolitis (NEC), which occurs when the intestine is injured.
At the 18th Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, two members of CIRM’s HIV/AIDS Disease Team led by John Zaia at City of Hope presented new research showing the team’s progress toward the clinic.
The team’s overall goal is to use technology developed by Sangamo Biosciences to modify the blood-forming stem cells of people infected with HIV. The modifications would effectively remove the doorway protein—called CCR5—the HIV virus uses to enter immune cells. The less than one percent of the population who lack CCR5 are naturally resistant to HIV infection and one HIV patient in Berlin who received a complete bone marrow transplant from someone born lacking the CCR5 receptor has been functionally “cured” of HIV.
In a presentation on Monday, Sangamo Biosciences released preliminary data from 6 HIV patients in its gene therapy clinical trial targeting T-cells, which are the primary immune cells invaded by the HIV virus. The study uses Sangamo’s zinc finger gene modification technique to remove the CCR5 receptor from T-cells taken from the patients with HIV. Those modified T cells were then returned to the patients’ blood system. The patients saw both survival and expansion of the modified T-cells—a critical finding since this implies some competitive advantage for cells protected by CCR5 deletion over cells that are not protected.
This finding is not itself a cure, since T-cells are just one type of immune cell that HIV attacks. However, it is encouraging for the CIRM funded Disease Team project, which seeks to use the same gene modification technique on a HIV patient’s blood-forming stem cells in the bone marrow. These tissue-specific stem cells give rise to all of the blood cells in the body and modifying them successfully could lead to protection for all of the immune cells that HIV attacks – not just the T cells. A full bone marrow transplant replacing the entire blood-forming stem cell compartment with modified cells carries significant risk, with mortality close to twenty percent. However, partial replacement of the stem cell compartment with CCR5 deleted cells and successful survival and expansion might be a safer and more accessible avenue for replicating the functional cure achieved in the single Berlin patient.
In a presentation Wednesday at CROI supporting this approach, Paula Cannon from USC and a member of the same Disease Team, will expand on her research on the use of hematopoietic stem cells genetically modified with the Sangamo zinc finer technology to remove CCR5 in mice with humanized immune systems. In her previously published study (here's a link to the Nature paper), the partial replacement of the bone marrow stem cell compartment with a minority of gene-modified cells led to competition between modified and unmodified cells with the CCR5 deleted modified cells (here's our blog entry on the work). In the humanized mice, the modified cells were eventually selected to the point where the humanized immune systems of the mice were able to control HIV successfully to a level where HIV is undetectable and without the use of antiretroviral therapies.
Together these two studies suggest that the Sangamo technology is able to effectively remove the CCR5 protein from modified cells, and that those cells are able to resist HIV infection.
Advanced Cell Technology has filed an application with the FDA to begin an early phase trial of an embryonic stem cell-based therapy for macular degeneration. If the company name sounds familiar, that’s because it’s the same company that on November 22 received FDA approval to begin a trial for Stargardt’s macular degeneration. Both trials are testing the same cells. In a press release, the company said:
Company scientists view the use of the same hESC derived RPE cells for both trials as the most efficacious approach, as it permits the Company to leverage its experience with the FDA that it gained through the process of obtaining approval for the Stargardt’s clinical trial to expedite the approval of its clinical trial in Dry AMD.
As with the company’s Stargardt’s trial and Geron’s spinal cord injury trial, this new trial will be assessing safety in a very small number of patients — standard practice for any new therapy being tested. After proving safety in a phase I trial, a larger trial will assess whether or not the potential therapy is effective.
It’s exciting to see embryonic stem cell derived therapies reaching patients. In general, more trials fail than succeed and we don’t know in advance which ones are going to work. That’s why there are hundreds of cancer trials going on around the country, and why we need hundreds of stem cell trials too. Hopefully CIRM’s macular degeneration disease team led by Mark Humayun at USC won’t be far behind ACT with their own version of an embryonic stem cell-based therapy for macular degeneration. And hopefully, one of them will provide a cure for the roughly 30 million people worldwide who are losing or have lost vision due to the disease.
Here’s a video about the CIRM disease team project:
The FDA has given the green light to the second trial based on embryonic stem cells — this one for a genetic form of blindness called Stargardt’s Macular Degeneration. The treatment, developed by Advanced Cell Technology, involves replacing the the layer of the retina damaged by the disease, called the retinal pigment epithelium, with new RPE cells derived from embryonic stem cells.
This approach is similar to one under development by a CIRM macular degeneration disease team led by Mark Humayun at the University of Southern California.
In the trial, 12 individuals at several US medical centres will receive injections of the cells directly into the eye to test the safety of the procedure. (Although the disease begins to take its toll at around 6 years of age, the trial will start with patients who are over 18.)
The small size of the trial is typical for a Phase I/II trial, which is primarily looking to ensure that the technique is safe before testing it in more people. Nature went on to quote ACT’s chief scientific officer Robert Lanza:
The advantage, of course, is that we’re talking about a very small number of cells going into a very local area,” he says. Using instruments that can track a single retinal cell in the eye in real time, the researchers will also be able to easily monitor patients’ progress.
“Also, with the eyes there are very objective tests for visual acuity,” he notes, “so we can measure performance gains very objectively.” Tracking improvement after spinal cord injury, on the other hand, is notoriously tricky.
This video features Mark Humayun discussing his macular degeneration work:
A story by Nick Wade in Monday’s New York Times rubbed some scientists the wrong way — and I must admit the piece was not too popular around CIRM headquarters.
Wade equated research funding with picking stocks. His idea is that a broad portfolio is bound to include some winners (he attributes this approach to the NIH and NSF) whereas attempts to only buy the big winners can produce a risky portfolio (an approach he attributes to CIRM).
This is not right.* Wade goes astray in thinking of science in terms of hits and misses. Basic research is not like being at bat, with the occasional single base hit or home run being the exception in a sea of strikeouts.
Most research is simply conventional and incremental. Most of the time it's not a miss, a disaster, or a failure - it's a small, sometimes not too surprising addition to our knowledge of a subject. Most research projects and NIH grants end in success, not failure - but the successes are usually small. In fact, there probably aren't enough failures, because, unlike the venture capitalists Wade compares it to, the NIH is very unwilling to take risks in search of the spectacular winner. Funded projects are the ones almost guaranteed to work.
CIRM grantee Paul Knoepfler at UC Davis also takes objection to the piece. His point: CIRM isn’t just investing in one big thing. Three billion dollars to just fund one area of stem cell research, that would be narrow. But CIRM has funded an incredible range of research, from the most basic science to translational work, and in approaches spanning stem cell transplantation therapies to modeling disease, drug testing, and models of regeneration (the very research Wade suggests we should fund).
Clearly [Wade] knows very little about CIRM and about stem cell research. He makes the argument that because CIRM only funds research in 'a single field' that chances are high that Californians will lose out. First, he is wrong that CIRM only funds one field. The breadth of research funded by CIRM spans a few dozen fields from cancer biology to neurological disorders, to heart disease, diabetes, HIV/AIDS, etc. Second, Mr. Wade ignores the substantial accomplishments that CIRM has already made in just its first few years.
Where CIRM agrees with Wade’s piece is in his suggestion that we look to how animals such as zebrafish and newts naturally regenerate, and use that knowledge to improve human regeneration. Deepak Srivastava from the Gladstone Institutes, who has been looking at tissue regeneration in mouse hearts, is making tremendous progress in part through CIRM funding (here is his research summary), as is USC’s Gage Crump, studying zebrafish jaw regeneration as a model for bone regeneration (here is his research summary).
For people interested in seeing the range of what CIRM has funded, we have this searchable list of all our funded stem cell research awards. We also have this list of our rounds of funding, explaining the role that funding plays in creating CIRM’s broad research portfolio.
We’re in the middle of a big week for CIRM-funded research facilities. UCLA opened the doors to their new CIRM-funded stem cell research space Monday (here's a video about that building) and today Stanford cuts the ribbon on the largest of the CIRM buildings — a gleaming 200,000 square-foot state-of-the-art facility. According to the Stanford press release about their Lorry I. Lokey Stem Cell Research Building:
The building’s 200,000 square feet of floor space, serving about 550 occupants, makes it the largest dedicated stem cell research building in the country, if not the world. But just as important, it was financed without any federal funding — buffering its occupants to some degree from the vagaries of embryonic stem cell politics.
The buildings are part of CIRM’s Major Facilities RFA, given out in May 2008 when federal funding could only be spent for stem cell research involving a small number of approved cell lines. That included working with unapproved lines in buildings created or supported through federal funds, which ruled out most available research space for work involving unapproved human embryonic stem cell lines. The CIRM buildings provide space free and clear for working with whichever stem cell lines scientists think will move the field toward new cures.
CIRM awarded $271 million to 12 institutions, each of which was required to raise additional funds through private donations. Altogether, CIRM’s investment brought in an additional $800 million in financial commitments and created construction jobs throughout the state at a time when those jobs were very much needed. This week's building openings came about thanks to a $20 million donation to UCLA and a $30 million gift to USC by The Eli and Edythe Broad Foundation and a $75 million gift from Lorry I. Lokey to Stanford University.
Following today’s ceremony at Stanford, the University of Southern California will hold their grand opening Friday. Altogether, those three buildings created 322,000 square feet of new research space, all of it free of federal funding and therefore available for research into all types of stem cells regardless of what happens with the current court cases. This space has the capacity to house nearly 1,000 members of research teams.
Stanford gave a nice description of how having stem cell researchers housed together in well equipped space will speed the research that takes place. They quote Theo Palmer, who works on stem cell therapies for neurodegenerative diseases:
“We used to have to plan our day around getting our samples where they needed to be when they needed to be there. Now some of the best resources in the world are immediately available — including extraordinary cell-sorting capabilities and some of the most advanced single-cell genetic-profiling equipment. At other places in the country these resources are essentially not available, or available only by special arrangement.”
That time saved means CIRM grantees can work faster than ever toward new disease therapies.
On left and right, Berkeley Stem Cell Center co-directors David Schaffer and Randy Shekman, and center, Mary West, manager of the new lab. (Photo by Jan Ambrosini)
Berkeley is the most recent institution to open new stem cell space funded by CIRM. Their CIRM-funded stem cell facility, which had its opening Oct. 5, is also a core facility for QB3, a bay area biotech incubator. David Shaffer, co-director of the Berkeley Stem Cell Center, said of the facility:
“The new facility will serve as a central resource to greatly enhance stem cell research amongst Berkeley and QB3 investigators, as well as collaborators at Lawrence Berkeley National Lab and Children’s Hospital Oakland Research Institute.”
To date, University of California campuses at Irvine and Davis have both opened their new stem call buildings amidst much fanfare. By the end of October, UCLA, University of Southern California, and Stanford will all have cut their respective ribbons.
These buildings are, to a one, beautiful, gleaming, well equipped centers for cutting edge research. But they are more than that. They are also a safe haven for stem cell research, protected from the ups and downs of federal funding. CIRM first dreamed up and approved funding for these stem cell buildings when President Bush was in office and most stem cell research had to occur in isolation from the microscopes, the pipettes, the refrigerators, the reagents, and the latex gloves most labs purchase with their NIH funds. The research had to take place in space and on lab benches supported only through private or state dollars.
That space was hard to come by, making the early days of stem cell research a considerable challenge. Take Susan Fisher at UCSF who lost her stem cell lines to a power outage while working in a converted dentist office in San Francisco in order to put distance between her cells and federal dollars. (Here's a video about Fisher's experience)
In the past year President Obama opened up federal funding for more stem cell research, but now recent events put that funding back in question. During this time of uncertainty, it’s reassuring to know that so many institutions in California have space where their work toward new therapies can continue uninterrupted by political turmoil.
