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.

Cells derived from embryonic stem cells, iPS cells appear immature

A trend over the past few years has been comparing embryonic stem cells, adult stem cells and reprogrammed adult cells (also known as iPS cells) to each other and to other cell types. The goal is to understand what the cells are, exactly, and and how they differ from each other. Eventually this information could help researchers learn which type of cell will be most effective for developing therapies, understanding diseases or drug screening.

A group of CIRM grantees at UCLA has published the latest in the unfolding story of stem cell comparisons. In their case, they didn't compare the stem cells themselves. Instead, they matured embryonic stem cells and iPS cells into the cells that eventually form neurons, cells that eventually form skin, and cells that eventually form liver. These so-called progenitor cells also exist in adult humans, where they lurk in tissues waiting to be needed to repair damage.

The scientists compared the progenitor cells to each other and to equivalent cells taken from adult tissue as well as to developing tissues. What they found is that the progenitors for nerves, skin and liver that came from embryonic or iPS cells had a lot in common with each other and with developing tissues. However, they had much less in common with their counterparts taken from adult tissues.

A press release from UCLA quotes William Lowry, who was senior author on the paper, which appeared in Cell Research.

“What we found, looking at gene expression, was that the cells we derived were similar to cells found in early fetal development and were functionally much more immature than cells taken from human tissue. This finding may lead to exciting new ways to study early human development, but it also may present a challenge for transplantation, because the cells you end up with are not something that’s indicative of a cell you’d find in an adult or even in a newborn baby.”

The release goes on to quote first author Michaela Patterson:

“One important reason to do this is to ensure that the cells we are creating in the Petri dish and potentially using for transplantation are truly analogous to the cells originally found in humans,” said Michaela Patterson, first author of the study and a graduate student researcher. “Ideally, they should be a similar as possible.”

…

“The roles these cells play in the fetus and the adult are inherently different,” she said. “It may be that the progeny, if transplanted into a human, would mature to the same levels as those found in the adult liver. We don’t know.”

This is the first paper we've seen comparing progenitor cells to adult or developing tissues. As with all first steps, we'll likely see more papers over the next few years refining and expanding on this team's findings and clarifying what these findings mean in terms of transplantation.

CIRM Funding: William Lowry (RS1-00259-1), Michaela Patterson (T1-00005)
Cell Research, August 16, 2011

A.A.

Heart cells divide again?

One perplexing question in regenerative medicine is why the human heart muscle cells are unable to divide and multiply their numbers. If they could, maybe they'd be able to produce new heart cells to replace those lost after a heart attack. Newts and salamanders can do it, why can't we?



CIRM grantees at the University of California, Los Angeles have found one answer to the question, which could lead to a way of turning the cell's clock back to a time when they could still divide. Robb MacLellan, who was senior author on the work published in the Aug. 8 issue of the Journal of Cell Biology, said that the ability to divide is a trade off. A UCLA press release wrote:

MacLellan believes the reason adult human cardiac myocytes can’t [divide] is quite simple – when the myocytes are in a more primitive state, they are not as good at contracting, which is vital for proper heart function. Because humans are much larger than newts and salamanders, we needed more heart contraction to maintain optimum blood pressure and circulation.

MacLellan suggests that it might be possible to get the heart cells dividing again by blocking the proteins that are halting the cell cycle. The press release had this explanation:

When a heart attack occurs, oxygen is cut off to part of the heart, causing the cardiac myocytes to die and resulting in scar tissue. It’s easy to locate the damaged area of the heart, and if a way could be developed to reprogram a patient’s own myocytes, the protein manipulation system could be injected into the damaged area, reverting the myocytes to their primitive state and replacing the dead muscle with new, living muscle, MacLellan said.



“People have been talking about the regenerative potential of these lower organisms for a long time and why this does not occur in humans” MacLellan said. “This is the first paper that provided a rationale and mechanism for why this happens.”



…



“From my point of view, this is a potential mechanism to regenerate heart muscle without having to harvest or expand stem cells,” MacLellan said. “Each person would be their own source for cells for regeneration.”

MacLellan has two CIRM Basic Biology (Basic Biology I, Basic Biology III) awards to study human heart progenitor cells.



A.A.

Origin of lung mucus glands found, insights for cystic fibrosis, asthma

Last week's big news at CIRM was the election of Jonathan Thomas as the new governing board chair, as we announced late Wednesday night. He will be replacing Robert Klein, who has served the agency since its inception in 2004. Not that anyone can replace Klein, exactly, but Thomas seems eager to step in and start leading the agency.

While many of us at CIRM were distracted by our board meeting and subsequent leadership change, CIRM grantees kept on doing science, as evidenced by a paper in Stem Cells which came out today.

Scientists with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have fund the stem cell that makes all the cells of the mucus glands in the airways of the lungs. By and large, scientists assume that most tissues of the body arise from a pool of tissue-specific stem cells. These stem cells have been identified in the blood system, brain, muscle, skin and a variety of other tissues. Once found, scientists can begin developing ways of harnessing those cells to treat disease.

Until assistant professor Brigitte Gomperts and postdoctoral scholar Ahmed Hegab published this work, nobody knew the origin of the mucus cells in the airway. These cells play a critical role in protecting the body from infectious agents or toxins in the environment. A UCLA press release quotes Gomperts:

“We’re very excited that we found this population of cells because it will allow us to study mechanisms of diseases of the upper airway. For example, there currently are no treatments for excess mucus production, which we see in cystic fibrosis, asthma and chronic obstructive pulmonary disease (COPD). But if we can understand the mechanisms of how these stem cells repair the mucus glands, then we may be able to find a way to put the brakes on the system and prevent mucus over production.”

I often read about people who claim that adult stem cells are as effective at treating disease as embryonic stem cells. What people seem not to understand is that there is no one adult stem cell. Stem cells of the blood system are fantastic, but they don't repair muscle, skin, brain, or, in this case, mucus glands. Finding these tissue-specific stem cells is the necessary first step to to developing new therapies based on these cells.

Stem Cells, June 27, 2011
CIRM Funding: Brigitte Gomperts (RN2-00904-1)

A.A.

California/Scottish collaboration to heal bones

The good folks at the Scottish Stem Cell Network have pointed out an interesting relationship between CIRM and Scotland. We don't have a formal funding relationship with Scotland (you can read about our collaborative funding agreements here) but we do have a researcher with a foot in both countries.

Bruno Péault is Professor and Chair of Vascular Regeneration at the University of Edinburgh and holds a joint appointment at the David Geffen School of Medicine at UCLA. He has an Early Translational II Award to develop ways of harnessing stem cells in blood vessels to repair bone damage. The CIRM award only funds the portion of the research taking place in California.

According to the SSCN profile, Péault is in the process of setting up an exchange program between the two universities, ensuring that stem cell expertise crosses borders. They write:

Fueled by this grant and strongly supported by both Californian and Scottish Universities, this collaboration is aimed to develop in other research directions, notably ongoing studies related to normal and leukemic blood cell formation and development.

The profile was written as part of Scotland Week, which the SSCN celebrated with a series of profiles about stem cell research collaborations including Scottish scientists. In case you missed it, kilt day was Wednesday. No word on when bagpipe day was, but I'm pretty sure Friday might be scotch night at my house.

- 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.

Stem cell therapy treats HIV, basis for two CIRM disease teams

There’s a lot of buzz today over a paper in the journal Blood declaring a man who has come to be known as the “Berlin patient” cured of HIV.

The same patient was featured in the New England Journal of Medicine in February 2009. A man infected with HIV needed a bone marrow transplant for his leukemia. The doctors gave him the transplant from a person who was naturally resistant to HIV infection. The donor’s bone marrow cells contained a mutated protein called CCR5, which is required for HIV to enter the cell. This follow-up work presents the results of numerous tests that failed to find evidence of remaining HIV infection.

In the paper, the authors write: "In conclusion, our results strongly suggest that cure of HIV has been achieved in this patient."

This story discusses an interview in a German publication in which the Berlin patient discusses the difficulties he faced during the course of the treatment. Although I don’t read German, the English summary of that interview makes it clear that bone marrow transplant is not an easy answer, and that making the transplantation more tolerable needs to be part of a future therapy.

The Berlin patient is the basis for two different CIRM disease teams. Although the therapy was a success, there aren’t enough donors who lack CCR5 to provide bone marrow for all people with HIV infection. Instead, the CIRM groups are removing the patient’s own bone marrow and attempting two different approaches at manipulating those cells to remove CCR5 function. They will then give the modified bone marrow back to the patients, hopefully providing a life-long resistance to HIV infection.

Here are summaries of the CIRM disease team awards at City of Hope and UCLA. We also have a video about the technique, featuring the lead researcher at City of Hope and HIV/AIDS advocate Jeff Sheehy, who serves on the CIRM governing board.



A.A.

Protein Linked to Normal Prostate Stem Cells and to Cancer

When I was the editor of a national magazine for physicians, I told my writers to do any story they found on prostate issues, with our overwhelming male audience then, I knew those stories would get high readership scores. My readers back then would have loved today’s news out of UCLA. The team there, led by CIRM grantee Owen Witte, found that the inhibition of a certain protein slowed the growth of an aggressive form of prostate cancer in animal models.

Scientifically, though the immediate excitement is over the double life this protein leads normally in the prostate. It regulates self-renewal of normal prostate stem cells needed to repair any injured cells. But it also aids the transformation of healthy cells into prostate cancer cells. The protein, called Bmi-1, has been associated with higher grade cancers and is predictive of poor prognosis. A UCLA press release quotes Witte as saying:

“We conclude by these results that Bmi-1 is a crucial regulator of self-renewal in adult prostate cells and plays important roles in prostate cancer initiation and progression. It was encouraging to see that inhibiting this protein slows the growth of even a very aggressive prostate cancer, because that could give us new ways to attack this disease.”

You can view a video about attempts to attack cancer stem cells here:



Cell Stem Cell, December 3, 2010
CIRM funding: Rita U. Lukacs (T1-00005, TG2-01169)

D.G.

HIV/AIDS video for World AIDS Day

World AIDS Day seems like a good time to revisit a video we made this year featuring CIRM board member Jeff Sheehy, who is a long-time advocate for HIV/AIDS research:



CIRM is funding two teams of researchers working on different approaches to treating HIV/AIDS (one at UCLA and one at City of Hope). Both involve replacing a person’s blood-forming system with cells that are resistant to infection.

For more background on the work, you can watch a Spotlight on HIV/AIDS by one of the disease team leaders, John Zaia of City of Hope.

All of these resources are available on our HIV/AIDS disease page, along with information about the grants we fund that target HIV/AIDS.

Here's hoping that on this day next year we'll be able to talk about progress being made by the two outstanding teams of researchers working to cure this devastating disease.

A.A.

15 registered stem cell lines and counting

Guest blogger Geoff Lomax
Senior Officer to the Standards Working Group

CIRM reached an important milestone with the recent registration of a 15th human embryonic stem cell line created with institute funding. (Here is a description of how researchers create human embryonic stem cell lines.) In approving Proposition 71, the citizens of California entrusted CIRM to support safe and responsible stem cell research. A major early accomplishment for the institute was the development of standards requiring review and oversight of work involving stem cell line derivation. Here is a list of all CIRM registered lines.

The registration process it a testament to CIRM’s grantees commitment to these standards. To be eligible for registration, a responsible official must certify the line was created under a protocol that meets CIRM’s exacting requirements for review, informed consent and voluntary donation. In addition, the research team must certify the approved protocol was followed. This dual certification serves to put researchers and oversight officials on the same page – both literally and figuratively. The result is a common understanding of expectations throughout the research community.

Registration also supports the sharing of cell lines. Cell lines derived according our requirements are automatically eligible for use by CIRM-funded researchers. This process addresses a longstanding need of our grantees – the creation of a list of eligible hESC lines.

The latest lines were created at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at the University of California, Los Angeles. UCLA is currently working on an agreement for the distribution of the lines to outside researchers. UCLA will distribute the lines to outside investigators who provide evidence their research is approved by an appropriate research oversight committee. It is great to see UCLA taking steps to advance responsible stem cell research.

G.L.

More stem cell research space = jobs and therapies

The Lorry I. Lokey Stem Cell Research Building

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.

-A.A.

Stem cell videos make the grade

One amazing aspect of living in the era of social media is the incredible way information spreads. A butterfly batting its little orange wings in a monarch grove in Santa Cruz could influence a tweet of a blogger heard ‘round the world.

Or, in CIRM’s case, a few videos playing on YouTube could be used by a teacher heard 'round the world. In the past week a video about the difficulties of differentiating stem cells into therapeutically useful cell types has popped up in the curriculum of Harrison College, which offers a number of online and classroom courses. The video, which has been watched hundreds of times in the past week by those students, features Mark Mercola of Sanford-Burnham Medical Research Institute who is working to differentiate cardiac cells from human embryonic stem cells. Here’s that video:


In the past, a video about iPS cells featuring Jerome Zack from UCLA has made its way into college curricula, as has a video discussing the different types of stem cells with Stanford University’s Irv Weissman. These videos are all part of a stem cell basics CIRM put together to help educate people about stem cell research both in written form and in short videos.

Given the misperceptions of stem cell research in the public and in the media its nice to see these videos getting discovered and used for educational purposes.

A.A.

Patient advocates vital to stem cell research progress

Nature Medicine carried a piece Friday by CIRM governing board member Jeff Sheehy, writing about the importance of having a patient advocate voice in biomedical research. Sheehy, who is living with HIV, is a long-time advocate for HIV/AIDS research. He has been on the CIRM board since the beginning in November 2004, and is a vocal participant in CIRM working groups including the group that makes research funding recommendations to the full board (the Grants Working Group), for which he is vice-chair.

Sheehy writes:

The presence of vocal, engaged patient advocates has added an indispensable dimension to the proceedings. In measuring research quality, advocates tend to focus on a project's ability to benefit people—not just drive scientific curiosity—which keeps even basic biomedical research grounded in its ability to produce concrete health benefits.

CIRM’s governing board includes 12 patient advocates representing HIV/AIDS, MS, diabetes (type 1 and type 2), heart disease, spinal cord injury, cancer, Alzheimer’s disease, Parkinson’s disease and autism. Sheehy goes on to say:

... CIRM is made up of patient advocates from a wide spectrum of diseases and conditions who work together to advance therapies across the board. And contrary to critics' assertions, these advocates have not narrowly focused on their own diseases, but have uniformly advocated for the best approaches for moving basic research towards the clinic. They support each other.

Patient advocates serve a powerful role even if they aren’t directly involved in funding decisions. Don Reed has been a vocal supporter of stem cell research since his son Roman Reed suffered a spinal cord injury. He is sponsor of the Roman Reed Spinal Cord Injury Research Act that funds spinal cord research in California, founder and co-chair of Californians for Cures and blogger on his own site www.stemcellbattles.org and for the Huffington Post.

In a recent Huffington Post blog entry about the World Stem Cell Summit he wrote about the importance of patient advocates staying involved in stem cell research at a political level, in order to maintain the U.S. leadership in stem cell research:

But unless we in the patient advocacy community can encourage Congress to pass a stem cell research protection act the dream will have been stolen.

CIRM came about in part because of the passion and support of patient advocates like Sheehy and Reed, and they continue to be a crucial part of the success of CIRM and of the progress made in stem cell research.

Here's Sheehy advocating for a stem cell therapy for HIV/AIDS. CIRM has funded two disease teams (City of Hope and UCLA) focusing on developing therapies for the disease.

Artist inspired by HIV/AIDS therapies

Miracle of Hope I, Dave Putnam

The promise of a cure for HIV/AIDS has inspired activists, researchers and now artists. The image shown here, by Woodside, CA artist Dave Putnam, was donated to Stanford’s Positive Care Clinic in Atherton, CA. It’s one of three 36” by 48” images making up a new triptych depicting Putnam’s interpretation of the body’s triumph over HIV.

Stanford’s Scope blog describes the images:

The acrylics, which hang in the hallway of the clinic, show a cell that is permeated by multiple black dots. These represent the invasion of the HIV protease enzyme, which is essential to survival of the virus. Blue dots on the canvas are used to capture the image of the fighters – the protease inhibitors that stop cell growth. Gradually, the blue dots spread and overtake the nasty enzyme. In the last painting, a bright yellow canvas shines through, as the enzyme is destroyed (though remnants of the virus remain, as current therapies never completely eradicate it).

If the two CIRM-funded HIV disease teams at UCLA and City of Hope are successful, the disease would most resemble the final, less dramatic image. Both teams are trying to replace the person’s HIV-infected bloodstream with a new blood system that is resistant to the virus. This link provides more information about stem cell approaches to treating HIV/AIDS.




A.A.

iPS cells from women create model for muscular dystrophy, X-linked diseases

Reprogrammed skin cells showing inactivated X in red

CIRM grantees at the University of California, Los Angeles have uncovered a feature of reprogrammed iPS cells that make them uniquely excellent for understanding diseases that arise from mutations on the X chromosome.

First some background. Men inherit an X chromosome from their mother, which contains many thousands of genes, and a Y from the father, which does little except confer manhood. Women inherit one X chromosome from each parent. Those female cells overcome their genetic overabundance by shutting down, at random, one of the two X chromosomes, putting the cells at genetic par with male cells.

But the two aren’t really equal. If men inherit a mutation on an X chromosome, it is present in every cell of the body and can cause muscular dystrophy, Rett Syndrome, color-blindness and other disorders. Women who inherit a mutation on an X chromosome from one parent will only show that mutation in half their cells. The other half of the body's cells, with the non-mutated chromosome active, can generally compensate.

So what does this have to do with reprogrammed cells and disease modeling? It turns out that the process of reprogramming skin cells into embryonic-like induced pluripotent stem cells doesn’t overturn the inactivated X. Reprogramming cells from a woman’s skin sample will produce two distinct types of iPS cell lines; half with one X active, and half of with the other X active. If one of those two chromosomes carries a mutation, say, for muscular dystrophy, some of those iPS lines will also display that mutation.

In a press release from UCLA, senior author Kathrin Plath said:

“This non-random pattern of X chromosome inactivation found in iPS cell lines has critical implications for clinical applications and disease modeling and could be exploited for a unique form of gene therapy for X-linked diseases.”

In a publication in Cell Stem Cell, Plath and her colleagues report that they created iPS cell lines from a woman who had inherited one X chromosome carrying a mutation that can cause muscular dystrophy. The other X chromosome had a normal copy of the gene. Scientists can now mature both groups of cells into skeletal muscle and compare the resulting tissue as a way of understanding—and perhaps one day treating—the devastating disease.

Cell Stem Cell: September 3, 2010
CIRM funding: Sean Sherman (TG2-01169), Kathrin Plath (RN1-00564), William Lowry (RS1-00259), Jerome Zack. (RL1-00681)

Embryonic No More

CIRM grantees at UCLA have captured the first moment when an embryonic stem cell – it of infinite possibilities – chooses a more limited fate.

A press release from UCLA says the cell population (which the researchers dubbed human embryonic mesodermal progenitors, or hEMP cells) could be therapeutically useful. The cells still have broad ability to become bone, blood, muscle or blood vessels, but – and this is an important but – have lost the embryonic stem cell’s propensity to form tumors called teratomas.

Gay Crooks, a professor of pathology and laboratory medicine and senior author of the study, is quoted in the release as saying:

“The hEMP cells we isolated did not have the ability to make teratomas, so they should be a safer choice when thinking about developing therapies for use in humans.”

In addition to being useful in developing therapies, the cells are just plain cool. Scientists don’t know what it is that gives an embryonic stem cell the freedom to choose its fate (a state called pluripotency). Crooks puts it like this:

“We want to know what it is that switches on and off to make a pluripotent cell no longer be pluripotent. In this study, we found a cell population that can help us understand these processes, as it is such a close relative to embryonic stem cells, but has lost the ability to be pluripotent.”

What they learn could help colleagues who are looking for more efficient ways of reprogramming adult cells to become pluripotent iPS cells.

PNAS, July 19, 2010
CIRM Funding: Gay Crooks (RC1-00108-1)

A.A.

NIH accepts new human embryonic stem cell lines

By Geoff Lomax

The NIH has accepted three new human embryonic stem cell lines, created by CIRM grantee Amander Clark at UCLA. According to the UCLA press release:

“The addition of the three human embryonic stem cells lines to the registry brings the total number of lines available for federal funding to 64, NIH officials said. Another 100 lines are pending approval. UCLA is one of only nine institutions in the world with stem cell lines admitted to the NIH registry.”

All lines were created from blastocysts left over from IVF treatments and would otherwise have been discarded. (You can read more about how the lines are created in this CIRM Stem Cell Basics page.)

In this video, Clark describes the process of creating new lines:


It is reassuring to know that the standards CIRM developed in 2006 for hESC derivation are acceptable in the rigorous NIH policy context. This approval is important because it signals that our grantees are well positioned to support research nationally by registering cell lines derived with CIRM funding.

Geoff Lomax is Senior Officer to the CIRM Standards Working Group, which developed CIRM’s stem cell derivation regulations.

Engineered human stem cells destroy HIV infected cells

A group at the University of California, Los Angeles AIDS Institute has manipulated human blood-forming stem cells to fight HIV infected cells. The technique could conceivably be used to help the body fight any number of viral infections, the authors say.

The researchers started with blood-forming stem cells normally found in the bone marrow. These cells form all the cells of the human blood system including immune and red blood cells. They then inserted a gene from an immune cell of an HIV-infected individual. That protein can recognize the HIV virus and would ordinarily guide the person’s immune system to attack infected cells. In an HIV-infected person so few of those infection-fighting cells exist that the immune system can’t do its job. 

The idea was that blood-forming stem cells carrying that HIV-targeting protein would mature into an immune system primed to recognize and destroy HIV-infected cells.

To test their idea, the authors inserted the engineered stem cells into mice. These mice also had transplanted into them a human thymus, the organ that is responsible for making a population of infection-fighting cells called T cells. (The human T cells can’t mature properly in the mouse thymus. By implanting the mouse with a human thymus the researchers mimicked how the cells might behave in a human.) As they hoped, the blood-forming stem cells produced  human T cells that were able to kill HIV-infected cells.

The authors called this study a proof-of-principle, saying that by inserting different proteins into the blood-forming stem cells they could direct the immune system to attack Hepatitis, herpes or human papillomavirus.

A press release by UCLA quotes Jerome Zack, an author on the paper and CIRM grantee, as saying:

"This approach could be used to combat a variety of chronic viral diseases. It's like a genetic vaccine."

PLoS ONE, December 7, 2009
CIRM funding: Jerome Zack (RC1-00149)

A.A.

Genetic differences found between adult cell and embryonic-derived stem cells

Researchers at the University of California, Los Angeles have found genetic differences that distinguish induced pluripotent stem (iPS) cells from embryonic stem cells. These differences diminish over time, but never disappear entirely. iPS cells are created when adult cells, such as those from the skin, are reprogrammed to look and behave like embryonic stem cells. But until now, scientists didn’t know if the two types of stem cells were actually identical at a molecular level. This latest research shows that iPS and embryonic stem cells differ in which genes they have turned on or off. All early iPS cells share these genetic traits, regardless of what animal they come from, the type of adult cells the iPS cells start as, or what method was used to reprogram those adult cells. However, later cultures of iPS cells show that most, but not all, of these differences disappear over time, making later cultures of iPS cells more similar to embryonic stem cells. If scientists want to use iPS cells in medical therapies, this research will give them a better idea of how similar they are to embryonic stem cells.

Cell Stem Cell: July 2, 2009
CIRM funding: Mike Teitell (RS1-00313), Kathrin Plath (RN1-00564-1), William Lowry (RS1-00259-1, RL1-00681-1)

Related Information: Press Release, University of California, Los Angeles

iPS Cells Mature into Functional Motor Neurons

Researchers at the University of California, Los Angeles have matured induced pluripotent stem (iPS) cells into what appear to be normal motor neurons. This work shows that iPS cells can mature into cells that appear similar to those derived from human embryonic stem cells – a finding that has important implications for people hoping to create new therapies based on iPS cells. These cells are created by reprogramming adult cells back into a pluripotent state that resembles embryonic stem cells. One question has been whether these reprogrammed cells have the same capacity as embryonic stem cells to turn into mature, functioning cell types. This work shows that, at least for motor neurons, iPS and embryonic stem cells have the same capacity to form mature cells. Scientists can study these motor neurons in the lab to learn about – and find cures for – diseases such as amyotrophic lateral sclerosis (Lou Gehrig’s Disease), spinal muscle atrophy or spinal cord injury.

Stem Cells:February 23, 2009 (online publication)
CIRM funding: William Lowry (RS1-00259)

Related Information: Broad Stem Cell Research Center, Lowry lab page