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.

400th CIRM-funded paper clarifies link between gene variant and Alzheimer's

The 400th paper published with CIRM funding also marks the five-year anniversary of the first CIRM board meeting (the actual date was December 17, 2004). The paper, by researchers at the Gladstone Institute and the University of California, San Francisco, illustrates how far the field has come in the five years since the organization’s inception, and in the three years since the organization has been funding research.

The paper reveals why people with a particular gene variant called ApoE4 are more likely to develop Alzheimer’s disease and identifies possible drug treatments to block the effects of that gene variant. The gene ApoE makes a protein that is involved in lipid metabolism and neuronal repair and remodeling. As with all genes, people can inherit different variants, and each variant makes a slightly different protein.

People with the variant called ApoE4 have long been known to be at higher risk of developing Alzheimer’s disease, but nobody has known why. In a press release by the Gladstone Institute, senior author Yadong Huang said:

“Our findings suggest that apoE4 inhibits the development of newborn neurons by impairing the GABAergic signaling pathway and that boosting this pathway with drugs may be of therapeutic benefit. It might allow us to encourage the development of new neurons from stem cells to replace those lost in apoE4 carriers with AD.”

The ApoE4 protein prevents the brain’s pool of stem cells from replacing cells lost to Alzheimer’s disease. Understanding this basic biology could result in a new drug that blocks the inhibitory effects of ApoE4 and acts as a call to action to the brain’s stem cells. (The image shows the brains of mice, with ApoE in green and neural stem cells in red.)

CIRM was voted into existence by 59% of California voters eager for new disease therapies. CIRM has only been funding research for three years due to a lawsuit. In that short time several CIRM grantees have made discoveries about how Alzheimer’s develops, how stem cells might be used in a future therapy, and now how drugs might be used to treat the disease in a particular group of people. Each of these is a step toward fulfilling the hope of Calfornians who voted for Proposition 71.

Typical of most CIRM-funded papers, at least one of the authors on the 400th paper is on a training grant. These graduate students, postdocs and clinical fellows working on stem cell projects contributed to 69% of all papers published with CIRM funding. Their work spans the most basic biology – work that is needed in order to understand the basic functionality if stem cells – and projects that are moving those basic discoveries toward the therapies.

The incredible productivity of these grantees is not a surprise. The CIRM Governing Board recognized the importance of pulling students into stem cell projects and funded the first training grants in April 2006 with Bond Anticipation Notes before the agency’s legal battles had completed.

Of the 400 published papers, almost a quarter were in high profile publications such as Science, Nature, and the Cell journals.

Cell Stem Cell, December 4, 2009 PMID: 19951691
CIRM funding: Yudong Huang (RN2-00952), Gang Li T2-00003 (T2-00003)

A.A

Lever found for switch to re-grow your tail—if you’re a fish

Embryonic stem cells stand poised to grow into various tissues, but are held in check by chemical switches that keep the necessary genes turned off. Researchers at the Salk Institute for Biological Studies found that genes responsible for limb regeneration – in this case the snipped tail of a zebrafish – are held in a similarly poised state by those same chemical switches.

It turns out that both embryonic stem cells and regenerative cells of the fish tail require enzymes called demethylases to release them from the poised state. In fact, zebrafish missing one of those enzymes are unable to re-grow their tail, something they routinely do in about a week.

A press release from the Salk Institute quotes first author Scott Stewart, postdoctoral scholar and CIRM training grant recipient, as saying:

“This is the first real molecular insight into what is happening during fin regeneration. Until now, how amputation is translated into gene activation has been like magic.”

While this sort of regeneration is common in fish and certain amphibians, it is unheard of in mammals. The Salk team plans to use this new finding to ask more specific questions about how we might be able to cross the barrier and induce limb regeneration in mammals.

The Salk Institute press release quotes the senior author Juan Carlos Izpisúa Belmonte, as saying:

“This finding will help us to ask more specific questions about mammalian limb regeneration: Are the same genes involved when we amputate a mammalian limb? If not, what would happen if we turned them on?”

 Proceedings of the National Academy of Science: November 24, 2009
CIRM funding: Scott Stewart (T3-00007-1)

D.G.