First patient enrolls in a clinical trial funded by CIRM

Today is a landmark day for CIRM: We announced that the first patient had been enrolled in a clinical trial based on stem cell agency funding. You can read our press release here.

The patient was part of Menlo Park-based Geron's phase I trial for spinal cord injury, which was awarded $25 million from CIRM in May. Stanford neurosurgeon Gary Steinberg, MD, PhD, implanted the cells Sept. 17 at Rehabilitation Trauma Center at Santa Clara Valley Medical Center.

Stanford had this to say about the trial:

Researchers at Geron collaborated with Hans Keirstead, PhD, and his laboratory team at UC-Irvine to develop a way to coax human embryonic stem cells to become a mixture of cells that include oligodendrocyte precursors. Oligodendrocytes are cells in the brain and the central nervous system that wrap nerve cells with an insulating material called myelin. This myelin sheath is necessary for the transmission of the electric signals along the spinal cord that trigger muscles to move, and relay our sense of touch and temperature. Damage to this sheath caused by trauma is a common cause of paralysis.

To be eligible for the trial, patients must have recent (within 14 days of injury) non-penetrating damage to a specific region of their thoracic spine — an area roughly from the top of the shoulder blades to the bottom of the rib cage. The damage must cause complete paraplegia, meaning that they have normal sensation or movement to the level of the hands, but not from the trunk to the toes.

During the procedure, Steinberg applied about 2 million of the special cells, called GRNOPC1, directly into the injured area of the patient’s spinal cord.

“We are quite pleased that the surgery was completed successfully and the patient is doing well,” said Steinberg.

When the CIRM governing board voted to fund the Geron trial, spinal cord injury advocate Roman Reed wrote a guest blog entry in which he said:

In a truly historic partnership for stem cell research and cure, state funding from what has been called “Roman's Law” gave Hans Keirstead the seed money to achieve empirical evidence and proof of principle. Hans then sold his pioneering technique to Geron, and advanced biotechnology farther by founding California Stem Cell with the proceeds.

With admirable courage and determination, Geron pushed this science all the way to FDA approval to become the world's first embryonic stem cell derived human clinical trial.

Now our beloved state agency, the California Institute for Regenerative Medicine will provide funding to bring about a full and complete Human Clinical Trial!!

The Keirstead/Geron/CIRM Trials advances the entire field of stem cell research.

Today's announcement marks a milestone that is a critical step toward making safe and effective stem cell-based therapies available to patients.

A.A.

Of salamanders, mice and men - digit regeneration mechanisms revealed

Regenerated mouse digit tip/Yuval Rinkevich

 Guest blogger Uta Grieshammer is a science officer at CIRM

A form of regeneration that has captured the imagination of scientists and the general public for many decades occurs in certain salamanders, as they have the remarkable ability to regrow a severed leg. Leg regeneration is unusual not only because it is so rare among vertebrates, but also because the underlying mechanism is thought to be quite different from that operating during the regeneration of organs in mammals.

Although mammalian legs do not regenerate, the very tips of our fingers and toes, and those of mice, do sometimes regrow. A new study published August 24 in Nature from Irv Weissman’s lab at Stanford University, and partially funded by CIRM, now comes to the surprising conclusion that the mechanism at work during mouse digit tip regeneration more resembles that of our other organs rather than the way that salamanders’ legs have been thought to regrow.

Although it may not be obvious, many of the organs in a healthy person regenerate themselves throughout life, some more than others. Our whole blood forming system and our gut, for instance, turn over relatively rapidly, whereas only about half of our heart cells are replaced in our entire life. Some organs, such as our skin, muscles, and bones, also have a reasonable capacity for repair after injury, if the damage was relatively small, while much of our liver will be faithfully replaced after a large portion has been removed. Other organs, though, replace cells lost to insult or disease only poorly or not at all, such as the heart following a heart attack. The hope is, if we figure out how the regeneration superstars of our body, or those of salamanders, accomplish their remarkable feats, we can use that knowledge to coax their less talented brethren into action.

Scientists have three basic models for how regeneration occurs: 1) tissue-specific stem cells within the organ divide and mature into the additional tissue, 2) mature cells divide to produce more of themselves without contributing to other cell types, or 3) mature cells lose their specificity, become more like embryonic cells and form a blastema with the ability to divide and form the original cell type and also other cell types in the regenerating tissue.

Weissman’s work with postdoctoral scholar Yuval Rinkevich, who was first author on the paper, shows that during digit regeneration in mice, the third model is not the right one. Remaining skin cells only make new skin cells, bone cells only make new bone. This comes a bit as a surprise, as this appears to be very different from the blastema mechanism thought to be used by salamanders to regrow their limbs. However, recent experiments from Elly Tanaka’s group in Dresden have challenged that long held model, showing that blastema cells in regrowing salamander legs do not typically adopt fates different from those of the cells they’re derived from. These studies then suggest that regeneration of limbs and digits in salamanders and mice, respectively, does occur through related mechanisms, just not the one originally thought. In both cases, repopulating cells do not switch cell fate, but whether regenerated digit or limb cells are derived from tissue-specific stem cells or from mature cells remains an open question for both species, although the Weissman paper makes a cogent argument that their data are consistent with the stem cell model, at least for some of the cell types involved in mouse digit regeneration.

Concerted efforts by scientists studying animals such as salamanders and mice will likely lead to an ever more accurate picture of limb and digit regeneration, thereby laying the groundwork for translating these findings to human cells, and eventually to human treatments.

CIRM funding: Irv Weissman (RC1-00354)
Nature, August 24, 2011

Weeding out the tumor-forming cells from potential stem cell therapies

CIRM grantees at Stanford University have removed some of the risk of therapies based on human embryonic stem cells or reprogrammed adult cells, known as iPS cells.

Both of these cells types are known as pluripotent, which means that the cells can go on to form all the mature cells of the human body. The problem is that those cells also form tumors called teratomas. In the process of developing new therapies, scientists first prod the stem cells into a more mature cell type, such as a neural progenitor for spinal cord injury, an insulin-producing pancreatic cell for diabetes or retinal cell for forms of blindness. Then, they go through a laborious process to show that no tumor-forming cells still remain in that batch of cells that they hope to use in therapies.

The new technique, published August 14 in Nature Biotechnology, provides a novel way of identifying cells that are potentially tumorigenic and removing them from a batch of cells. Krista Conger at Stanford wrote about this paper:

"The ability to do regenerative medicine requires the complete removal of tumor-forming cells from any culture that began with pluripotent cells," said Irving Weissman, MD, director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine. "We've used a combination of antibodies to weed out the few undifferentiated cells that could be left in the 10 or 100 million differentiated cells that make up a therapeutic dose."

Weissman pointed out that the production of therapeutic cells from pluripotent stem cells for regenerative medicine was a major goal of Proposition 71, the ballot measure that established the California Institute for Regenerative Medicine to allocate $3 billion to advance stem cell science. CIRM funded this research.

…

"Commonly used differentiation protocols for embryonic stem and iPS cells often give rise to mixed cultures of cells," said research associate Micha Drukker, PhD. "Because even a single undifferentiated cell harbors the ability to become a teratoma, we sought to develop a way to remove these cells before transplantation."

If other research groups repeat these findings, the technique could reduce some of the risk of therapies based on pluripotent cells.

Nature Biotechnology, August 14, 2011

A.A.

A fifth group turns skin to neurons, creating a model for Alzheimer's disease

A few weeks ago, my colleague used this space to discuss the second and third papers showing teams had turned skin cells directly into neurons, noting that this replication of research results is essential to verifying the initial breakthrough while refining and improving it. She noted that only after much replication and refinement would she or anyone else want the resulting cells for therapy. Since then a fourth team reported another technique and now a fifth group is reporting the more likely short term benefit—a disease in a dish model for a neurodegenerative disease.

The first two papers came from work in the CIRM funded facility at Stanford University. The breakthrough paper in May from Marius Wernig reported a slow and inefficient process for using certain factors to directly reprogram skin cells into nerve cells without first taking them through an embryonic-like state. The follow-up paper in late July came from Stanford colleague Gerald Crabtree and showed marked improvement in efficiency and the nerve-like functioning of the cells. That same week at team from Milan reported another efficient system for creating nerve cells but this time directing them to become dopamine-producing cells like those lost in Parkinson's disease. And last week at team at the Gladstone Institutes in San Francisco, using another CIRM funded facility, reported yet another technic that also improved efficiency.

Now, a team at Columbia reported in today's issue of the journal Cell that they had developed a fifth way to accomplish this direct conversion of skin to nerve, and had done so with both skin from normal subjects and skin from patients with the inherited form of Alzheimer's disease. In both cases the cells matured and behaved like neurons, responding to neurotransmitters by letting ions like sodium and potassium cross the cell membrane. However, the cells derived form patients were also clearly abnormal. They had altered ability to process and transport the amyloid precursor protein (APP) and a resulting increase in production of amyloid beta, which has long been a suspect in the disease, but depending on what year you look at the literature, it is theorized to be a culprit or an artifact. This disease in a dish model may help to answer that question.

DG

Aggressive breast cancer treated with bone marrow stem cells

Last week brought a paper by Stanford researchers that has been a long, long time coming. It shows that 12-14 years after the experimental treatment, women with metastatic breast cancer benefited from high dose chemotherapy followed by transplantation of their own blood-forming stem cells. The paper was published online July 15 in Biology of Blood and Marrow Transplantation.

Back at the time when the group, which included CIRM grantee Irv Weissman, carried out this trial, doctors were rejecting high-dose chemotherapy for people with metastatic breast cancer. That therapy destroys the cancer, but also destroys the patient's bone marrow, which produces all blood and immune cells. That side effect would be deadly, but doctors can reinject bone marrow cells taken from patients before chemotherapy. This is the process that is used today for many types of cancers. However, doctors were finding that the whole bone marrow also contained some breast cancer cells. If those cells survived the transplantation they could spread and form a new, deadly cancer. So much for the chemotherapy.

Back when the Stanford scientists carried out their trial (between 1996 to 1998) Weissman had recently figured out how to purify the blood-forming stem cells in the bone marrow that are responsible for rebuilding the blood system. He and the team thought they could pull out just those cells from the patient's blood and use those cells to save the blood system after high-dose chemotherapy. If it worked, the chemotherapy would destroy the cancer, and the purified stem cells would save the blood system without reintroducing cancer cells lurking in the blood.

It all sounded good, but they were not sure whether their idea had worked until now. What they learned is that 23 percent of the women in their trial are still alive, compared to 9 percent of women who received unpurified stem cells.

A Stanford press release about the work quotes Weissman:

“Even with this small sample size, this paper demonstrates much-better overall and progression-free survival in those patients who received cancer-free stem cells.”

Senior author on the paper Judith Shizuru said in the release:

“Most people in the oncology community feel that this issue is a done deal, that high-dose chemotherapy does not work for patients with breast cancer. But our study suggests that the high-dose therapy strategy can be modified to include the use of cancer-free purified blood stem cells to yield better overall outcomes in women with advanced breast cancer.”

The authors are encouraging scientists to revisit high-dose chemotherapy for other cancers where it isn't traditionally offered. If it shows benefit for those patients it could open up a new form of therapy for a wide range of cancers.

This paper also highlights something that will continue to be true of all forms of stem cell research: It takes a long time to learn whether a therapy was truly effective. A decade from now we'll know whether the stem cell trials of today really worked. It's slow and frustrating, but papers like this one make the wait worth while.

A.A.

Improved technique for directly converting skin to neurons

This is the way things often go in science: One group announces a breakthrough. Yah! Then for the next several years, scientists all over the world replicate and improve on that breakthrough until it's finally believable and widely useful.

To people outside science who read about the initial breakthrough, this may look a lot like scientists twiddling their thumbs, sitting on new therapies. But really, do you want a therapy based on a breakthrough that may or may not be real? Right, neither do I.

A paper from Marius Wernig's lab at Stanford University is a great example of this process. In January, 2010, Wernig's lab had a paper in Nature announcing their transformation of mouse skin cells directly into neurons. This was exciting work, bringing with it the possibility of directly converting skin from a person with a neuronal disease into neurons that can be studied in the lab. But that work was in mice, and one thing we know from past research is that mice are most certainly not humans.

About a year and a half later, Wernig replicated his work with human cells in another Nature paper, but the transformation was much less efficient than it was with mouse cells (here's our blog entry on that work). It took weeks for the transformation to take place, only 2 to 4 percent of the skin cells transformed into neurons and those neuronal cells were on the wimpy side. It's still exciting work — I mean how cool is it that human skin can be turned into neurons with the addition of just four molecules. But ready for therapeutic prime time? I think not.

Now we've entered the next stage where scientists all over the world incrementally improve upon the original work until it's good enough, fast enough and efficient enough to be broadly useful. One such improvement came from the Stanford University lab of Gerald Crabtree, who published his findings in a Nature paper last week.

Crabtree's lab employed two of the four factors that had been effective for Wernig, but supplemented those with a different kind of molecule — called microRNAs. This change dramatically improved how efficiently the skin cells converted to neurons, and produced neurons with much stronger electrical signaling. Another group from Milan published a paper in early July using three different factors to coerce the transformation from skin to neuron. In their case, the neurons were more like those that are lost in Parkinson's disease, known as dopaminergic neurons.

A Stanford press release quotes Crabtree:

“It’s been a long time in coming to this,” said Crabtree. “But science often progresses in leaps and starts, and then all of a sudden many scientists come to the same position at the same time. Now these studies have come out, and more will be coming, all of which are going to say that not only can you can make neurons different ways, but also you can make neurons of different types.”

At this point it's too soon to know which, if any, of these techniques is going to become most widely used. We can probably expect to see more improvements on these approaches coming out of some labs, while other labs start figuring out how this revolutionary transformation can be used to treat or understand disease. Crabtree's lab, for example, says they are already taking skin cells from people with Down's syndrome and transforming those into neurons in order to understand the disease and look for therapies.

A.A.

In vitro fertilization technique receives patent

Last December CIRM grantee Renee Reijo Pera spoke to the CIRM governing board about her work identifying which in vitro fertilization embryos were most likely to result in a successful pregnancy (you can watch that video here). That work has resulted in a patent to Stanford University, with an exclusive license to Menlo Park-based Auxogyn, which was founded by Pera and her colleagues at Stanford.

In the video of her talk, Pera shows several IVF embryos formed in the lab by fusing human sperm and eggs. By videotaping those embryos and watching them develop, she can tell by day two which are going to be ready to implant in a woman's uterus, a step that normally happens on day five.

Pera has a long-standing interest in the earliest stages of human development, where she says many common diseases may originate. During her talk, Pera, who is director of Stanford's Center for Human Embryonic Stem Cell Research and Education, said:

"I can’t believe the progress we’ve made in the past years with human embryonic stem cells and embryology. We have unprecedented tools to understand human development and we can begin to understand basic questions like where does sporadic disease come from in the population.”

This new technology has the potential to help infertile couples successfully conceive children through in vitro fertilization. Having a patent on the technology also creates jobs and tax revenue in California -- one of the great benefits of having a thriving biotechnology community in the state.

Pera has a CIRM Comprehensive Award and a New Cell Lines Award.

On stem cells, aging and hopes for spryer golden years

Last week my three year old scraped up the entire left side of his face. Today, there's barely a trace of the injury. That's the glory of three year old skin, or more precisely, the glory of three year old stem cells.

Erin Allday at the San Francisco Chronicle had a story last week about the issue of aging stem cells featuring several CIRM grantees who are, like me, curious about why stem cells heal damage more slowly as we age. Her story includes Thomas Rando of Stanford University, whose work I wrote about several years ago. What I found fascinating then, and what still isn't understood, is why a stem cell grows less able to repair damage over time. Rando and his former postdoctoral fellow Irina Conboy (now at University of California, Berkeley) have found that in older muscle, the stem cells are still able to respond, but the signals themselves may not be as strong. The stem cells are there, they just don't hear damaged muscle's cry for help.

Allday quotes Rando, who is director of the Glenn Laboratories for the Biology of Aging at Stanford:

“I don’t necessarily see it as a way of reversing Alzheimer’s or making people live to 200 years old, but there’s this dormant potential that can be unleashed that can profoundly affect the way stem cells repair tissues.”

Allday also quotes Irina Conboy, who spoke at last week's annual meeting of the International Society for Stem Cell Research in Toronto:

Like physicists trying to find the unified theory of everything, we’re trying to find the unified theory of all these bad things that happen with aging. I think they all stem from a lack of stem cell responses.

Conboy has a New Faculty Award from CIRM to learn more about how stem cells age.

Nobody is arguing that studying stem cells will uncover the fountain of youth (at least, CIRM scientists aren't). Instead, CIRM President Alan Trounson said that by understanding how and why our body's stem cells age scientists could learn how to keep those stem cells more lively during a person's golden years. We wouldn't live longer, maybe, but as long as we're alive it would be nice to heal more effectively or resist disease. Just having bones heal more quickly could significantly reduce health care costs for the elderly.

“With aging, there are a lot of systems that start to become less efficient or break down or be more inclined to diseases. We may work out ways to provide stem cells that would enable people to remain vigorous.”

Remaining vigorous sounds pretty good to me, even if I don't ever again heal with the speed of a three year old.

A.A.

CIRM grantee Robert Blelloch wins ISSCR Outstanding Young Investigator Award

CIRM grantee Robert Blelloch of the University of California, San Francisco won the 2011 Outstanding Young Investigator Award from the International Society for Stem Cell Research. The society's annual meeting is taking place now in Toronto.

Blelloch presented his research June 15 at 6pm and will participate in a press briefing at noon June 16. His work focuses on the role of small molecules called microRNAs and their role in stem cell biology and cancer.

Jennifer O'Brien described Blelloch's work in a press release from UCSF:

During the last few years, Blelloch’s team has reported several key findings. In 2008, they reported that microRNAs promote self renewal of embryonic stem cells in mice (Nature Genetics, 2008). In 2009, they showed that when those same microRNAs were inserted into adult cells the cells de-differentiated back into embryonic stem cells (Nature Biotechnology, 2009). In 2010, they inserted a microRNA into embryonic stem cells and promoted differentiation, but determined that the microRNA had to compete with microRNAs that promote embryonic stem cell self-renewal (Nature, 2010). This year, his laboratory has been looking at microRNAs as a potential tool to systematically dissect the molecular pathways that regulate cell fate transitions, including dedifferentiation of adult cells to create induced pluripotent stem cells (Nature Biotechnology, 2011).

“People have come to realize microRNAs are remarkably powerful,” said Blelloch, associate professor in the Departments of Urology, Obstetrics, Gynecology and Reproductive Sciences and Pathology and a member of the Helen Diller Family Comprehensive Cancer Center.

Using microRNAs for therapeutic purposes has great potential , he said. “They could be used either to induce adult cells to de-differentiate to embryonic stem cells, which could be expanded, manipulated and returned to a patient, or to promote differentiation of embryonic stem cells to produce tissues that would remain integrated in the body once re-introduced.” They also could be used to target cancers, and they attract interest from biotechnology companies.

Blelloch has a SEED Award and a New Faculty II Award, both looking at the role of microRNAs in embryonic stem cell biology. Not to blow our own horn, but CIRM does know how to pick high quality research. Last year Stanford's Joanna Wysocka won the same award. She has a SEED Award and a New Faculty I Award from CIRM.

A.A.

Techniques for tracking stem cells necessary for possible therapies

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

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

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

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

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

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

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

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

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

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

A.A.

Hit embryonic stem cell research, hurt iPS research too

Those of you who follow this space have read our opinions on embryonic vs. adult vs. reprogrammed iPS cells. For those of you who don't watch this space, here's our opinion in a nutshell: There is no "vs." All types of stem cells could be therapeutically valuable, and what we learn in one cell type often directly translates to discoveries in another cell type.

A paper coming out tomorrow in Cell supports that opinion. Christopher Scott at Stanford University and colleagues at the Mayo Clinic and the University of Michigan analyzed more than 2,000 papers published since 2007, when human iPS cells were first reported. According to a Stanford press release:

[The team] found that the iPS field is dominated by well-established, senior hES cell researchers. Many of these researchers are publishing studies that directly compare hES cells with iPS cells, rather than focusing exclusively on one cell type.

However, stem cell scientists are not abandoning hES cells in favor of iPS cells. In 2008, only three of the 15 iPS cell papers (5 percent) published also reported hES cell results; in 2010, 98 of the 158 iPS cell papers (about 26 percent) did so.

The work is especially important given an unresolved lawsuit that temporarily suspended federal funding for embryonic stem cell research last fall.

Stanford writes:

“If federal funding stops for human embryonic stem cell research, it would have a serious negative impact on iPS cell research,” said Stanford bioethicist Christopher Scott, citing a “false dichotomy” between the cell types. “We may never be able to choose between iPS and ES cell research because we don’t know which type of cell will be best for eventual therapies.”

A.A.

Marius Wernig on why we need many stem cell approaches to new therapies

Last week we blogged about work by Marius Wernig of Stanford University, who has successfully converted human skin into nerves, skipping the step of first converting the cells into embryonic-like iPS cells.

Wernig is quoted in a Nature news story talking about whether the work could replace induced pluripotent stem (iPS) cells or embryonic stem cells:

"I would say that both approaches should be actively pursued because you never know for which cases and specific applications one or the other may be more suitable."

I think the best example of why we need many approaches to treating disease came from patient advocate Rodney Paul, who spoke to an external review committee last year about CIRM. Here's what we wrote in our Best. Analogy. Ever. blog entry on October 13, 2010:

He pointed out that on this day the world saw awe-inspiring images of the first of 33 miners rising out of the Chilean mine where they’d been trapped — and that those miners were rescued through one of three shafts that had been dug as part of the rescue mission.

The shaft in question was dubbed “Plan B”. Drilling on plans A and C didn’t go as smoothly as hoped. That’s why on an important mission where time is limited and lives are at stake it’s important not to pin all hopes on one strategy.

With embryonic, adult, iPS and cancer stem cells plus the new direct conversion techniques CIRM is drilling a series of shafts all leading toward possible disease therapies.

We have a list of all our grants online. You can use the filters to see how many awards we're funding using different types of cells. Right now, the numbers are:

• Embryonic: 215
• iPS: 78
• Adult: 47
• Cancer: 10

Those numbers are updated whenever we fund new awards.

A.A.

CIRM grantees convert skin to nerves, a step toward therapies for neurological disease

Last year a group of CIRM grantees at Stanford University directly converted mouse skin cells into neurons, bypassing the need to first convert those cells into an embryonic-like state. Now they've gone a step farther, pulling off the same feat with human cells. They published the work in the May 26 Nature.

Krista Conger at Stanford University blogged about that work , quoting senior author Marius Wernig:

We are now much closer to being able to mimic brain or neurological diseases in the laboratory. We may perhaps even be able to one day use these cells for human therapies.

This past year has seen a number of scientists managing to convert adult cells directly into other adult cell types as we blogged about here. Recent reports about immune rejection of iPS cells makes this work even more interesting because the direct conversion bypasses the need to create iPS cells. As Conger writes:

Interestingly, this direct conversion technique may offer a way around the recently reported rejection of genetically identical iPS cells by laboratory mice. That unexpected finding, which I blogged about a couple of weeks ago, has researchers worried about the potential therapeutic value of the cells. But preliminary investigations suggested that the immune response was targeted at proteins used to make the original cells pluripotent, which shouldn't be an issue with this approach.

That said, Wernig isn't ready to give up on iPS cells. He's part of a CIRM disease team that aims to use genetically modified iPS cells to treat the deadly skin condition epidermolysis bullosa. Here's a link to a summary about that epidermolysis bullosa disease team award, and a link to a videos of the team describing their approach to the CIRM governing board last year.

A.A.

iPS cells reveal stem cell origin of disease

A new Nature paper from CIRM grantees at Stanford University once again shows the value of reprogrammed iPS cells in understanding disease. Scientists can't develop a therapy for a disease if they don't know what it is going wrong. In many cases, iPS cells have provided the first ever way of peering into diseased cells and finding which proteins and genes need fixing.

In this case, the disease in question is dyskeratosis congenita, in which the caps on the ends of chromosomes shorten abnormally and causes a wide variety of symptoms ranging from abnormal skin pigmentation and nail growth to lung scarring, bone marrow failure and cancer. The question has been why people with the same disease can have such dramatically different symptoms, and what to do about those symptoms.

The Stanford group reprogrammed the skin cells of people with the disease into embryonic-like iPS cells. They knew people with the disease made low levels of a protein conglomerate called telomerase, which is responsible for maintaining those chromosomal caps. What they found in those iPS cells is that the more severe a person's disease, the less telomerase their iPS cells made.

A Stanford press release quotes senior author Steven Artandi:

"We were very surprised to find such a clear correlation between the quantity of functional telomerase, the severity of the cellular defect and the severity of the patient's clinical symptoms," said associate professor of medicine Steven Artandi, MD, PhD. "Our work suggests that, in patients with dyskeratosis congenita, tissue stem cells are losing their ability to self-renew throughout the body. This is a new, unifying way to think about this disease, and it has important implications for many other conditions."

Reprogrammed iPS cells can normally divide indefinitely in the lab. The iPS cells made from people with dyskeratosis congenita eventually stopped being able to divide and instead matured into the body's cell types. The researchers think this means the disease symptoms occur when stem cells in the tissues lose their ability to divide indefinitely. With no stem cells in the bone marrow, skin or other organs, the person's body can't repair damage or maintain tissues. That seems to be what causes symptoms of dyskeratosis congenita.

Nature, May 22, 2011
CIRM funding: Steven Artandi (RB2-01497)

Celebrating National Cancer Research Month with a cancer stem cell round-up

In celebration of National Cancer Research Month, our colleagues at Sanford-Burnham Medical Research Institute have posted a series of blog entries about cancer research at their institute. The latest installment includes CIRM grantee Robert Wechsler-Reya, who moved to California from Duke University on a CIRM Research Leadership Award.

According to their blog:

Dr. Robert Wechsler-Reya, who directs the Tumor Development Program in Sanford-Burnham’s Cancer Center, has spent many years studying how “good” processes can also cause disease. He is particularly interested in how mechanisms that are normal in embryonic development can cause cancer when turned on in children and adults.

“We work on the relationship between development and cancer, particularly in the brain,” says Dr. Wechsler-Reya. “We’re interested in how normal stem cells and progenitor cells make decisions like when to divide, when to differentiate and what to differentiate into. We’re interested in how those decisions go wrong in cancer.”

To-date, CIRM has awarded more than $130 million to cancer research, including grantees working to understand the role of cancer stem cells in the disease and other teams working to develop therapies. Among our Disease Team projects, which have the goal of reaching clinical trials by 2014, CIRM funded two teams working on therapies for glioma (City of Hope and UCSF), two working on therapies for leukemia (Stanford and UCSD), and one working on solid tumors (UCLA).

Here are a few resources CIRM offers for people trying to get information about stem cells and cancer.

• Information about stem cells and glioma
• Information about stem cells and leukemia
• Information about stem cells and solid tumors

We also produced this video with CIRM grantee Catriona Jamieson at Moore's UCSD Cancer Center at the University of California, San Diego. Jamieson has a therapy in clinical trial for a pre-cancerous blood condition. The work that led to that trial was funded in part by a CIRM SEED grant.



A.A.

IVF embryo donation approach gives donors privacy, time

A new paper by CIRM grantees at Stanford University is reporting on an innovative way of ensuring that people considering donating left over in vitro fertilization embryos to research make the best possible decision for themselves. The paper was published on April 8 in Cell Stem Cell.

People who undergo IVF are often left with excess embryos after they complete their families or abandon the process. Storing these embryos in nitrogen comes with a monthly or yearly cost, which is why many people choose to stop storing, which destroys the embryo, donate to another couple or donate to science. In some cases, donating to science includes donating the embryo for stem cell research.

The Stanford group developed a procedure for ensuring that people considering donating to research do so in privacy and aren't influenced by the scientists who could benefit from the research. A Stanford press release describes the procedure quoting senior author Christopher Scott:

In the two-part procedure described in the study, which is now used routinely at Stanford, information about potential donation for research is included in the normal embryo-storage bill from the clinic. “At that point,” Scott said, “the recipients are free to throw the information away or put it on the coffee table to consider and talk about.” Only after the couple has made the initial decision to donate do they interact with Stanford biobank staff members, who use a script to confirm donation choices and answer any questions the potential donors may have.

Specifically, people who indicated that they would like to donate were sent an informed-consent packet outlining the types of research that could be done with the embryos, such as creating embryonic stem cell lines or studying human development. (Research into human development typically occurs during the first 12 days of culture, after which the embryos are no longer grown. Embryonic stem cell research entails creating stem cell lines that can be propagated indefinitely in the laboratory and may be used for both research and therapy.)

Once the potential donors had time to review the material, they then participated in a phone interview with staff members at Stanford’s biobank who were unconnected with either the original in vitro fertilization clinic or the researchers who might use the embryos. Staff members followed a script to confirm the donors’ preferences and make sure they understood their options — including whether they wanted to be notified if the research unearthed any genetic information that might affect their health or the health of their relatives.

People were equally likely to donate to the creation of new stem cell lines or to studying human development. Interestingly, the study found that most donors were primarily concerned that their donated embryo not be used to make a baby for another person.

My colleague Geoff Lomax heads CIRM's Standards Working Group, which sets CIRM regulations for embryo donation for creating embryonic stem cell lines. He told me, "The study results demonstrating differences in research preferences reinforces the need for comprehensive consent for research. I'm glad that development of a safe and supportive stem cell research environment in California can contribute to innovative practice supporting research ethics."

The Stanford press release quotes Stanford biobank research manager and study first author Tasha Kalista:

"Many couples were very relieved to have the option to donate their embryos for research and to participate in the field of stem cell research.”

In some states, people would not have the option of donating embryos and would instead have to destroy the embryo or donate for adoption if they could not or chose not to pay the storage fees.

CIRM Funding: Renee Reijo Pera (CL1-00518-1)
Cell Stem Cell, April 8, 2011

First patient from Geron spinal cord injury trial speaks up

A story by Rob Stein at the Washington Post is reporting that the first patient to participate in Geron's groundbreaking embryonic stem cell-based trial for spinal cord injury has come forward.

This is both exciting news and no news. It's exciting because scientists and people living with spinal cord injury and their families are all watching this trial closely. Any news is of interest. However, at this point it's too soon to know if the cells have been effective.

For those who haven't been following this story, Geron is conducting a trial in which they inject primitive neural cells derived from embryonic stem cells into the region surrounding a recent spinal cord injury. In work with rodents conducted by CIRM grantee Hans Keirstead at the University of California, Irvine, the cells were able to restore movement to the hind limbs after an injury. (As an aside, that earliest work was conducted through funds from the Roman Reed Spinal Cord Injury Research Act, which is currently being debated by the state.)

The first patient was Timothy J. Atchison of Chatom, Ala. According to the Washington Post:

Atchison, known as T.J. to his family and friends, was a student at the University of South Alabama College of Nursing when his car crashed on Sept. 25, which, Atchison noted, was the birthday of Christopher Reeve, the actor who suffered a devastating spinal cord injury.

After undergoing emergency treatment at a regional medical center, Atchison was transferred to the Shepherd Center in Atlanta, which specializes in spinal cord injuries, for rehabilitation. It was there that he agreed to let doctors inject him with the drug — more than 2 million cells made from stem cells into his spine, he said.

Like all initial trials in the U.S., this one is primarily testing whether the cells are safe, but of course it is also being closely watched for signs that the cells were effective (read more from the NIH about phases of a clinical trial). It's too soon for scientists to know whether the injected cells are able to help repair damage after spinal cord injury such as the one Atchison suffered after his car crashed.

Geron intends to test the cells on 10 people at seven sites around the country, of which Stanford University recently announced it was one. The Washington Post describes the procedure:

Surgeons planned to use specially designed equipment to infuse into the first patient’s spine about 2 million “oligodendrocyte progenitor” cells, which Geron scientists had created in the laboratory from embryonic stem cells obtained from days-old embryos left over from fertility treatments. The hope is that the cells will form a restorative sheath around the damaged spinal cord. In tests in hundreds of rats, partially paralyzed animals regained the ability to move, according to Geron.

The Geron trial isn't the only approach to using stem cells to treat spinal cord injury, though it is the first to clinical trial. Here's a list of CIRM grantees working on other approaches, including some using adult, embryonic or reprogrammed iPS cells.

A.A.

New disease-specific embryonic stem cell lines from Michigan

Stem cell scientists at the University of Michigan and in Detroit have created two embryonic stem cell lines that contain disease-causing mutations: Hemophilia B, a hereditary condition in which the blood does not clot properly and Charcot-Marie-Tooth disease, an inherited disorder leading to degeneration of muscles in the foot, lower leg and hand.

For the first time, scientists will have a way of studying cells that carry the causing mutation and understanding how the disease arises. When the mutation is in embryonic stem cells, it is then carried by any cell type emerging from that line. Maturing the hemophilia line into blood cells, for example, could provide insights into genetic factors associated with disease. These cells also provide a way to test possible therapies in human cells rather than in animals that mimic the disease.

The cells came from embryos created through in vitro fertilization that were determined by preimplantation genetic testing to carry a disease mutation. A few cells from the 3-5 day old IVF embryo are sent to the clinic, and the parents can choose which embryos to implant based on the results. Embryos with possibly lethal disease mutations are generally destroyed as medical waste. Donating t research gives couples an option other than simply destroying the embryos.

The Detroit News wrote about the new lines:

U-M will soon be submitting these disease-specific lines to the National Institutes of Health to be placed on the Human Embryonic Stem Cell Registry. Researchers across the country will be able to use the lines for federally funded research. Of the 91 lines currently on the registry, three are disease-specific stem cell lines submitted by Harvard and Stanford universities.

In the story, Bernard Seigal, executive director of the Florida-based Genetics Policy Institute that hosts the World Stem Cell Summit (to be co-hosted this year by CIRM) said this discovery is a direct result of the passage of Proposal 2, a constitutional amendment that allowed for embryonic stem cell research in Michigan.

The passage of Proposal 2 wasn't just a political statement," Siegel said. "This has been followed up with real, tangible research and real results that have the potential to impact human health. It portends very well for the future of stem cell research in Michigan."

CIRM funds several awards to grantees who are developing embryonic stem cell lines that were found to carry disease-causing mutations through preimplantation genetic testing. These include Julie Baker at Stanford University and Amander Clark at UCL.

- A.A.

Parkinson's disease modeled for the first time in a lab dish

CIRM grantees at Stanford University and The Parkinson's Institute have an exciting Cell Stem Cell paper out today showing that they can mimic Parkinson's disease in a lab dish using reprogrammed iPS cells.

The team, which includes Renee Reijo Pera and Theo Palmer and their lab members at Stanford and William Langston at the Parkinson's Institute, started with skin cells from a woman with a genetic form of Parkinson's disease. They reprogrammed those cells back to an embryonic-like state and matured them into the type of brain cells that are affected in a person with Parkinson's disease. These cells normally help control movement and other functions in the body. In people with Parkinson's disease those cells slowly diminish and leave the person unable to control movement and other vital functions. There is currently no cure for the disease.

Initially the cells behaved normally in the lab dish, but after 30-60 days the cells showed some of the same conditions that are found in people with Parkinson's disease. A Stanford press release quotes Theo Palmer:

“This is the first time that neurons from a Parkinson’s disease patient have exhibited disease qualities in a petri dish,” said Palmer. “And it provides hints of what to look for in patients who have different genetic mutations or where a cause has not been identified. By comparing neurons from patients with different forms of Parkinson’s disease, we may find commonalities or differences that will help to optimize future treatments for each patient.”

Today there is no cure for Parkinson's disease, and no good way to test possible drugs. With this paper, the researchers have for the first time created a way of mimicking the disease, and testing to see if drugs can reverse the symptoms in human cells.

Here's more information about stem cell therapy for Parkinson's disease and a list of all CIRM Parkinson's disease awards. This video features grantees at the Parkinson's Institute talking about their efforts to create iPS cell models of Parkinson's disease.



CIRM funding: Renee Reijo Pera (RL1-00670-1, CL-00518-1); Aleksandr Shcheglovitov (TG2-01159)
Cell Stem Cell, March 3, 2011

- A.A.

Reflecting on muscular dystrophy awareness week

This past week was muscular dystrophy awareness week, which seems like a short amount of time to focus on such a heartbreaking disease. One in every 3500 boys in the US develops that debilitating and fatal Duchenne muscular dystrophy (DMD) - the most common and serious form of muscular dystrophy - and there is no cure.

CIRM funds a few awards to researchers studying the muscle stem cells called satellite cells. These dot the muscle fibers, ready to spring to action when there’s damage. In kids with MD, those satellite cells can’t repair the damage and the muscles eventually waste away.

Here’s a list of CIRM-funded projects that could lead to new insights or therapies for MD. One Early Translational II project to Michele Calos at Stanford University is especially interesting. Starting in mice, she’s proposing to reprogram cells from animals with MD, fix the defective gene, then grow those cells into muscle stem cells that can be transplanted back into the mice. If the technique works, she and her team hope to start working with human cells.

As with all early research there are a lot of unknowns. Can they actually fix the gene? Can they grow up enough muscle stem cells for transplantation? Will those manipulated cells thrive and be able to repair the damaged muscle? And a big question: How on earth do you get those genetically altered cells to all the wasted muscles in the body?

Hopefully in future muscular dystrophy awareness weeks we’ll be able to answer some of those questions, and one day if all goes well we’ll be writing about a cure.

- A.A.