Potential to prevent transplant rejection, treat autoimmune diseases and immunodeficiencies.

Mark Anderson (left) and Matthias Hebrok, UC San Francisco

Raising hopes for cell-based therapies, UC San Francisco researchers have created the first functioning human thymus tissue from embryonic stem cells in the laboratory. The researchers showed that, in mice, the tissue can be used to foster the development of white blood cells the body needs to mount healthy immune responses and to prevent harmful autoimmune reactions.

The scientists who developed the thymus cells — which caused the proliferation and maturation of functioning immune cells when transplanted — said the achievement marks a significant step toward potential new treatments based on stem-cell and organ transplantation, as well as new therapies for type-1 diabetes and other autoimmune diseases, and for immunodeficiency diseases.

Starting with human embryonic stem cells, UCSF researchers led by Mark Anderson, M.D., Ph.D., an immunologist, and Matthias Hebrok, Ph.D., a stem-cell researcher and the director of the UCSF Diabetes Center, used a unique combination of growth factors to shape the developmental trajectory of the cells, and eventually hit upon a formula that yielded functional thymus tissue.

The result, reported in today’s (May 16) online edition of the journal Cell Stem Cell, is functioning tissue that nurtures the growth and development of the white blood cells known as T cells. T cells are a central immune cell population that responds to specific disease pathogens and also prevents the immune system from attacking the body’s own tissues.

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Shinya Yamanaka’s feat brings fresh attention to promise of regeneration medicine.

Gladstone scientists took skin cells from a patient with a heart disease and reprogrammed them into something known as iPS cells, which act very much like embryonic stem cells. In this magnified image, the iPS cells are growing into heart cells (blue) and nerve cells (green).

Stem cell science blasted across front pages worldwide when Shinya Yamanaka, M.D., Ph.D., won the 2012 Nobel Prize in Physiology or Medicine.

The UCSF professor and senior investigator at the UCSF-affiliated Gladstone Institutes received the award for discovering how to transform ordinary adult skin cells into cells that, like embryonic stem cells, are pluripotent – capable of becoming any cell in the human body.

The news – bringing UCSF’s total of Nobel laureates to five – brought fresh attention to something UCSF long ago sensed and seized: the promise of regeneration medicine for repairing or replacing damaged cells, tissues and even whole organs.

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UCSF Magazine

Discovery shows positive effects of drugs that may lead to effective new therapies for A-T.

Richard Gatti, UCLA

Led by Dr. Peiyee Lee and Dr. Richard Gatti, researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have used induced pluripotent stem (iPS) cells to advance disease-in-a-dish modeling of a rare genetic disorder, ataxia telangiectasia (A-T).

Their discovery shows the positive effects of drugs that may lead to effective new treatments for the neurodegenerative disease. IPS cells are made from patients’ skin cells, rather than from embryos, and they can become any type of cells, including brain cells, in the laboratory. The study appears online ahead of print in the journal Nature Communications.

People with A-T begin life with neurological deficits that become devastating through progressive loss of function in a part of the brain called the cerebellum, which leads to severe difficulty with movement and coordination. A-T patients also suffer frequent infections due to their weakened immune systems and have an increased risk for cancer. The disease is caused by lost function in a gene, ATM, that normally repairs damaged DNA in the cells and preserves normal function.

Developing a human neural cell model to understand A-T’s neurodegenerative process — and create a platform for testing new treatments — was critical because the disease presents differently in humans and laboratory animals. Scientists commonly use mouse models to study A-T, but mice with the disease do not experience the more debilitating effects that humans do. In mice with A-T, the cerebellum appears normal and they do not exhibit the obvious degeneration seen in the human brain.

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It could be the next pillar of medicine.

David Baylink (left), professor of medicine at Loma Linda University, asks a question during the bacterial therapeutics panel discussion at the Cell-Based Therapeutics symposium at UCSF, while Carl June (right), listens.

Old-line pharmaceutical companies and maturing biotech businesses both are graybeards compared to newer ventures focused on cell therapy.

With cell therapy the drugs are alive. Cells are engineered and reprogrammed outside the body to perform specific tasks – and then given as treatment.

“Cells are like soft robots,” said Wendell Lim, Ph.D., director of the Center for Systems & Synthetic Biology at UC San Francisco and an organizer of “Cell-Based Therapeutics: The Next Pillar of Medicine,” a daylong symposium held at UCSF’s Mission Bay campus last month.

Lim and other scientists aim to take advantage of the modules that already function within cells, and to manipulate them for specific therapeutic goals – sometimes by introducing new functions.

“We want to build therapeutic cells with precisely controlled activities,” Lim said. “We want to control how cells proliferate, where they go, how they are activated and how to turn them off or even destroy them when they are no longer needed.”

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UCLA study IDs small molecule that destroys potentially dangerous cells.

Michael Teitell, UCLA

Pluripotent stem cells can turn, or differentiate, into any cell type in the body, such as nerve, muscle or bone, but inevitably some of these stem cells fail to differentiate and end up mixed in with their newly differentiated daughter cells.

Because these remaining pluripotent stem cells can subsequently develop into unintended cell types — bone cells among blood, for instance — or form tumors known as teratomas, identifying and separating them from their differentiated progeny is of utmost importance in keeping stem cell–based therapeutics safe.

Now, UCLA scientists have discovered a new agent that may be useful in strategies to remove these cells. Their research was published online April 15 in the journal Developmental Cell and will appear in an upcoming print edition of the journal.

The study was led by Carla Koehler, a professor of chemistry and biochemistry at UCLA, and Dr. Michael Teitell, a UCLA professor of pathology and pediatrics. Both are members of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at UCLA and UCLA’s Jonsson Comprehensive Cancer Center.

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Scientists will develop stem cell lines that can be stored and distributed to researchers.

Kang Zhang, UC San Diego

University of California scientists received five grants totaling more than $4 million in the latest round of funding from the state’s stem cell agency.

The grants are part of the California Institute for Regenerative Medicine’s efforts to set up a stem cell bank. Applicants will work together to collect tissue samples from people who have different diseases, turn those samples into high quality stem cell lines – the kind known as induced pluripotent stem cells – and create a facility where those lines can be stored and distributed to researchers who need them, according to CIRM.

The CIRM board approved nine grant proposals to create and store 9,000 cell lines from 3,000 individuals representing 11 diseases at a total cost of $32.3 million. UC grant recipients include:

UCLA: $934,515: Brigitte Gomperts

UC San Diego: $2.6 million: Douglas Galasko, Joseph Gleeson, Kang Zhang

UC San Francisco: $865,370: Jacquelyn Maher

Overall, CIRM’s governing board has awarded about $1.8 billion in stem cell grants, with half of the total going to the University of California or UC-affiliated institutions.

Related links:

• UC San Diego
• CIRM release

Human body carries personalized “patch kit,” say UCSF scientists.

Somdutta Roy (left) and Thea Tlsty, UC San Francisco

UC San Francisco researchers have found that certain rare cells extracted from adult breast tissue can be instructed to become different types of cells – a discovery that could have important potential for regenerative medicine.

As with human embryonic stem cells, the newly found cells are pluripotent, or capable of turning into most cell types, the authors said. The scientists discovered that when the cells were put either in mice, or in cell culture, the cells could differentiate to produce multiple cell types, including those that proceed to make heart, intestine, brain, pancreas and even cartilage.

The finding is significant, the authors said, because scientists previously believed that pluripotent cells did not exist in the body after the embryonic stage of human development.

While a therapeutic use of the cells has yet to be determined, they could potentially generate new tissue – a “patch kit” – to heal wounds or reconstruct damaged or missing organs. They also could be used as a resource to study how cells become pluripotent, and how they repair and replace themselves.

“The ability of cells from an adult body to make so many tissue derivatives was completely unexpected,” said senior author Thea D. Tlsty, Ph.D., a UCSF professor of pathology. “When we saw that they could make cartilage, bone, gut, brain, pancreas cells – and even beating heart tissue – we were excited and intrigued.”

The study was published today (March 4) in the online Early Edition of the Proceedings of the National Academy of Sciences (PNAS).

UCSF has pioneered research on regenerative medicine in a broad array of animal and human cell studies. Last year, Shinya Yamanaka, M.D., Ph.D., a senior investigator at the UCSF-affiliated Gladstone Institutes and a UCSF professor of anatomy, won the Nobel Prize in Medicine for his discovery of a way to reprogram ordinary human skin cells into stem cells that can be used to better understand and treat a number of human diseases. Other projects at UCSF include work by Allan Basbaum, Ph.D., to modify stem cells to treat pain and rebuild damaged nervous systems.

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Mizutani Foundation grant to UC Davis scientist will advance understanding of cell function.

Frederic Troy II, UC Davis

Frederic A. Troy II, professor and chair emeritus of biochemistry and molecular medicine, has received a globally competitive research grant from the Mizutani Foundation for Glycoscience to better understand structural changes associated with metastasis of adult cancer cells and stem cells.

Troy’s study, titled “Functional Analyses of Polysialic Acid DP on Human Cancer and Stem Cells,” specifically focuses a compound found in neural cell adhesion molecules that can regulate the cell-to-cell adhesive processes on human cancer and stem cells. His laboratory will investigate the degree of polymerization of polysialic acid and its role in activating key cancer signaling pathways.

“A key question that remains unresolved in cancer, glyco-neurobiology and stem cell biology is how can the polysialic acid (polySia) glycotope on neural cell adhesion molecules modulate such a variety of functions in the developing nervous and immune system?” said Troy, one of the first faculty members hired by Nobel Prize winner Edwin G. Krebs when Krebs chaired the biological chemistry department at UC Davis School of Medicine in 1968. “These functions include cell migration, cell contact dependent differentiation, tumor metastasis, neural stem cell proliferation and differentiation, immune response, cell signaling and cytokine response, axon path finding, synaptogenesis, neural plasticity and cognition and memory.”

PolySia is an oncodevelopmental tumor-associated surface antigen that can be re-expressed on the surface of adult cancer cells. When this re-expression occurs, polySia becomes a metastatic factor that promotes tumor-cell detachment, invasion and colonization at distant sites. This fundamental event is a key molecular determinant in allowing polysialylated human cancer cells to detach and spread or metastasize throughout the body, a hallmark of malignancy.

The polySia glycotope modulates neuronal development. It is also expressed on human hematopoietic stem cells and regulates immune responses. In this case, the DP of polySia on human NK cells is responsive to their activation state.

“The Mizutani Glycoscience grant will allow us to test the hypothesis that the degree of polymerization of polySia chains on neural cell adhesion molecules is a critically important structural and conformational feature in regulating the myriad of cell adhesive and cell migration processes,” said Troy. “Such studies have not been previously reported.”

Troy is also a member of the UC Davis Comprehensive Cancer Center and the UC San Diego Glycobiology Training Center. He is past president of the professional Society for Glycobiology and an internationally renowned expert in the field of glycochemistry.

The Mizutani Foundation is a nonprofit organization established in 1992 to advance studies in the field of glycoscience, especially glycoconjugates, important compounds involved in cell-to-cell communications, from recognition to detoxification processes.

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UC San Diego’s Napoleone Ferrara, UCSF’s Shinya Yamanaka among first recipients.

Napoleone Ferrara

Two University of California scientists are among the first winners of the Breakthrough Prize in Life Sciences, a new award recognizing advanced research. Founding sponsors of the prize include Google co-founder Sergey Brin; Facebook founder Mark Zuckerberg; Anne Wojcicki, founder of 23andMe; and Russian entrepreneur and philanthropist Yuri Milner.

Among the 11 honorees are Napoleone Ferrara, distinguished professor of pathology and senior deputy director for basic sciences at Moores Cancer Center, UC San Diego, and 2012 Nobel Prize winner Shinya Yamanaka, senior investigator at the UC San Francisco-affiliated Gladstone Institutes and a UCSF professor of anatomy who also holds appointments at Kyoto University. Ferrara is recognized for research leading to therapies for cancer and eye diseases; Yamanaka is recognized for his work in induced pluripotent stem cells.

Each honoree will receive $3 million — more than twice the amount of the Nobel Prize. The prizes are intended to provide recipients “with more freedom and opportunity to pursue even greater future accomplishments.”

Shinya Yamanaka

“I am delighted to announce the launch of the Breakthrough Prize in Life Sciences and welcome its first recipients,” said Art Levinson, chairman of the board of Apple and chairman of the board of the foundation overseeing the Breakthrough Prize. “I believe this new prize will shine a light on the extraordinary achievements of the outstanding minds in the field of life sciences, enhance medical innovation and ultimately become a platform for recognizing future discoveries.”

Read more:

• Breakthrough Prize in Life Sciences
• UC San Diego release
• UCSF release
• Gladstone release

Beckman Foundation funding will be used explore blindness-prevention therapies.

The first-floor Gavin Herbert Eye Institute clinical center will be named the Arnold & Mabel Beckman Foundation Center for Vision Care in honor of the late inventor and his wife.

The Gavin Herbert Eye Institute, which is part of UC Irvine Health, has been awarded a $3 million grant from the Arnold and Mabel Beckman Foundation for fellowships and instruments that advance research to prevent blindness caused by such diseases as age-related macular degeneration and retinitis pigmentosa.

“We are grateful to the Arnold and Mabel Beckman Foundation for demonstrating confidence in the quality of scientific discovery taking place at the Gavin Herbert Eye Institute,” said Dr. Roger Steinert, professor and chair of ophthalmology and director of the Gavin Herbert Eye Institute. “Researchers here share the late Dr. Beckman’s commitment to excellence and will use this grant to strategically support our bold goal of eradicating blindness by 2020.”

The Beckman Foundation grant includes $1 million for state-of-the-art instruments designed to perform promising medical procedures such as stem cell transplantation for retinal degeneration.

Dr. Henry Klassen, associate professor of ophthalmology, and his Gavin Herbert Eye Institute team have shown that stem cells can repair damaged retinal cells in retinitis pigmentosa, the most common form of inherited retinal degeneration. If proven effective in humans, this treatment could change what it means to be diagnosed with age-related macular degeneration, a disease that affects the vision of 1 in 27 Americans.

The other $2 million from the Beckman Foundation grant establishes fellowships for young researchers to contribute to stem cell studies and other exciting new avenues of eye research. Working alongside some of the nation’s leading ophthalmologists, these fellows will participate in the discovery process and learn the latest clinical procedures in vision care.

An earlier grant from the Beckman Foundation provided $2 million to support construction of a new center for the Gavin Herbert Eye Institute on the UC Irvine campus. The 70,000-square-foot medical facility, which is slated to open for patients in September, includes design features recommended by the Braille Institute that will make it easier for low-vision patients to navigate within the building. The first-floor clinical center will be named the Arnold and Mabel Beckman Foundation Center for Vision Care in honor of the late inventor and his wife. The building, which is funded entirely through local private philanthropy, will be Orange County’s first university eye center.

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Autophagy key to blood and immune system health, but may increase cancer risk.

Leukemia cells

Stem cells of the aging bone marrow recycle their own molecules to survive and keep replenishing the blood and immune systems as the body ages, researchers at UC San Francisco have discovered.

The recycling process, known as autophagy, or self-eating, involves reusing molecules and the chemical energy obtained from these molecules to withstand the killing effect of metabolic stress that intensifies as the body ages.

The discovery, reported online Feb. 6 in the journal Nature, showed that autophagy allows stem cells to avoid the alternative response to stress, which is programmed cellular suicide, in which cells that aren’t up to snuff kill themselves for the greater good.

While this trick of autophagy may help delay the onset of anemia, immune-system failure and other maladies that occur with age, as a survival strategy it is a bit of a compromise, said the senior author of the study, Emmanuelle Passegué, Ph.D., of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.

Autophagy might increase cancer risk, she said, by allowing old stem cells to survive despite having accumulated risky mutations over a lifetime.

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UC Berkeley discovery offers hope for age-related degenerative diseases.

A new study led by researchers at the University of California, Berkeley, represents a major advance in the understanding of the molecular mechanisms behind aging while providing new hope for the development of targeted treatments for age-related degenerative diseases.

Researchers were able to turn back the molecular clock by infusing the blood stem cells of old mice with a longevity gene and rejuvenating the aged stem cells’ regenerative potential. The findings were published online today (Jan. 31), in the journal Cell Reports.

The biologists found that SIRT3, one among a class of proteins known as sirtuins, plays an important role in helping aged blood stem cells cope with stress. When they infused the blood stem cells of old mice with SIRT3, the treatment boosted the formation of new blood cells, evidence of a reversal in the age-related decline in the old stem cells’ function.

“We already know that sirtuins regulate aging, but our study is really the first one demonstrating that sirtuins can reverse aging-associated degeneration, and I think that’s very exciting,” said study principal investigator Danica Chen, UC Berkeley assistant professor of nutritional science and toxicology. “This opens the door to potential treatments for age-related degenerative diseases.”

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