^{“HHMI's flagship program in biomedical research rests on the conviction that scientists of exceptional talent, commitment, and imagination will make fundamental biological discoveries for the betterment of human health if they receive the resources, time, and freedom to pursue challenging questions. Approximately 350 investigators, selected through rigorous national competitions, include 14 Nobel Prize Winners and 131 members of the National Academy of Sciences. Hughes laboratories, found at more than 70 distinguished U.S. universities, research institutes, medical schools, and affiliated hospitals, employ nearly 700 post docs and provide training opportunities for more than 1,000 graduate students each year.”  (Quoted from the HHMI web site.)  The two scientists selected in the past year are Karl Deisseroth at Stanford University, and Matthew Freedman at Dana- Farber Cancer Institute, and the scientist selected in 2008 was Seung Kim, also at Stanford.}

Summaries

^{Seung Kim: 
Our efforts in the past several years have created opportunities for harnessing knowledge about the molecular and cellular basis of pancreatic development and growth to restore pancreas islet function and to treat endocrine cancers. Our work with Drosophila, mice, human islet organogenesis and diseases, cell purification, and chromatin regulation has revealed mechanisms underlying islet development, adaptations, and disease pathogenesis. Coupled with our clinical collaborations, our discoveries will provide tools and expertise that may lead to production of islet regeneration therapies for type 1 diabetes, improved treatments and tests to mitigate or prevent type 2 diabetes, and new therapeutic strategies for neuroendocrine cancers.}

Judy Shizuru is using transplantations of purified blood stem cells (also call hematopoietic stem cells) to condition recipients to accept donated organs without immune suppressive medications and to treat patients with severe autoimmune disorders.  Blood stem cell transplantations are known to powerfully affect the immune system and in conjunction with her studies to apply this therapy to patients, she studies the basic mechanisms by which these transplantations confer the immune tolerance inducing effects.  One goal of this research is to decrease the morbidity of the treatments applied to recipients in order to achieve engraftment of the blood stem cells.  The approach her group has taken to achieve engraftment is to specifically target recipient cells with antibodies.  Antibody treatment has significantly reduced toxicity as compared with standard chemotherapy drugs that are currently used to prepare patients for transplants. Her studies have broad implications for the field of cellular therapy in general.  The ultimate goal is to utilize blood stem cell transplantations to permit acceptance of organs and tissues from the same donor source without the need for immune suppressive drugs.  Thus, she envisions that a similar strategy can be applied to transplantations of tissues generated from novel sources such as those derived from embryonic stem (ES) or induced pluripotent stem (IPS) cells. For example, ES or IPS derived neural stem cells can be co-transplanted with blood stem cells generated from the same donor cell line, and recipients will permanently accept the neural tissue without further intervention.

http://med.stanford.edu/profiles/Judith_Shizuru/

Karl Deisseroth has developed optogenetics, a technology that uses light to control millisecond-precision activity patterns in genetically defined cell types within the brains of freely moving mammals.  He is the founder of this technology that didn’t exist only a few years ago.  His group is now extending this technology to probe the dynamics of neural circuits in health and disease.  For a complete summary of his work for the past year, go to the following web site for a detailed description.  Karl has also been appointed a Howard Hughes scientist for the next five years with the ability to renew this appointment every five years.  Recent awards from the Society for Neuroscience are The Golden Brain Award and the Young Investigator Award.

^{http://www.hhmi.org/research/ecs/deisseroth_bio.html}

Chih-Pin Liu, Ph.D., City of Hope Medical Center. Disorders associated with the inability to maintain a physiological balance between different subsets of T cells may result in T cell-mediated destructive autoimmunity. For example, activation and expansion of CD4⁺ or CD8⁺ T effector (Teff) cells that produce pro-inflammatory cytokines can lead to target tissue destruction and induce autoimmune diseases, as can attenuation of either the number or function of CD4⁺ T regulatory (Treg) cells. Establishment of effective in vivo immune tolerance as a treatment for autoimmune diseases such as type 1 diabetes requires simultaneous targeting of more than one T cell population subset. Recruitment of pathogenic T cells to pancreatic islets is a critical cause of inflammation (insulitis) leading to type 1 diabetes. Studies exploring the effectiveness of therapies that could inhibit insulitis and potentially prevent diabetes by suppressing Teff cells and expanding Treg cells will help develop treatments to prevent the disease. Therefore, clinically relevant agents or methods that induce immune tolerance by affecting different T cell subsets may represent an effective approach to treating human autoimmune diseases.

To identify such agents, we asked whether an immune regulatory drug used to treat cancer patients could also be used to induce immune tolerance and inhibit type 1 diabetes. All-trans retinoic acid (ATRA) is a potent derivative of vitamin A that has been used clinically to treat acute promyelocytic leukemia and skin disease. Both vitamin A and ATRA have important immune modulatory functions. Our novel findings demonstrate that ATRA treatment effectively induced immune tolerance in vivo, which inhibited islet inflammation and progression to overt type 1 diabetes. These novel findings extend the effects of ATRA on immune tolerance induction beyond its previously observed in vitro effects on Teff cells. Treatment of animals with ATRA suppressed the number and function of CD8+ Teff cells. Our histological studies further showed that ATRA-treated non-diabetic animals were free of destructive insulitis and their islets remained intact, suggesting that the effects of ATRA on Teff cells might have also prevented their trafficking to and infiltration of islets, thus inhibiting diabetes. In addition to its effect on Teff cells, our results showed that ATRA treatment promoted in vivo expansion of Treg cells. In fact, the protective effects of ATRA were impaired in the absence of a sufficient number of Treg cells.

^{Altogether, these novel findings support a model in which ATRA exerts its in vivo disease protective effect, at least in part, by suppressing proinflammatory Teff cells, while promoting expansion of Treg cells. In addition, this suppressive effect required the presence of Treg cells. Therefore, our data provide novel insights as to how ATRA treatment induces immune tolerance that effectively inhibits type 1 diabetes.}

^{Because ATRA is an FDA-approved treatment for leukemia and skin disease, its well-studied toxicity and metabolic kinetics in humans suggest a clear advantage for more rapid translational potential into clinical use over other methods that may require extensive human trials. Overall, our data support the use of ATRA treatment to induce immune tolerance and suggest an effective method to inhibit type 1 diabetes.}

^{We published one paper describing the research described above that was supported by the Snyder Medical Foundation.}

Van, Y., Lee, W.-H., Ortiz, S., Lee, M.-H., Qin, H., and Liu, C.-P. 2009. All-trans retinoic acid inhibits type 1 diabetes by Treg cell-dependent suppression of IFN--producing T cells without affecting Th17 cells. Diabetes. 58:146-155. E-pub Nov, 2008. (This paper was accompanied by an encouraging editorial commentary, p24-p25).

            Dr. Phillip Kantoff 

.       

                 Dr. Bill Hahn