David Kirkpatrick

March 19, 2009

Stem cell differentiation breakthrough

Looks like this research is helping to uncover the building blocks of stem cells and should lead to even bigger breakthroughs.

The release:

Protein is Key to Embryonic Stem Cell Differentiation

 

Burnham Scientists Identify Protein that Controls Differentiation in Human and Mouse Embryonic Stem Cells

 
LA JOLLA, Calif., March 18, 2009 — Investigators at Burnham Institute for Medical Research (Burnham) have learned that a protein called Shp2 plays a critical role in the pathways that control decisions for differentiation or self-renewal in both human embryonic stem cells (hESCs) and mouse embryonic stem cells (mESCs).

The research, led by Gen-Sheng Feng, Ph.D., differs with some earlier findings that suggested hESCs and mESCs differentiate as a result of different signaling mechanisms. The discovery that Shp2 has a conserved role between mice and humans suggests an interesting common signaling mechanism between mESCs and hESCs, despite the known distinct signaling paths and biological properties between the two types of pluripotent stem cells. The study was published online in the journal PLoS ONE on March 17, 2009.

Embryonic stem cells (ESCs) are pluripotent cells that can differentiate to become more than 200 different cell types. Because of their plasticity, ESCs have been suggested as potential therapies for numerous diseases and conditions, including neurodegenerative diseases, spinal cord injury and tissue damage. Development of such therapies is largely dependent on fully understanding and controlling the processes that lead to differentiation of hESCs into specialized cell types.

“There are many signaling pathways that help embryonic stem cells decide their fate,” said Dr. Feng. “We found that the Shp2 protein acts as a coordinator that fine-tunes the signal strength of multiple pathways and gives us a better understanding of the fundamental signaling methods that determine whether a stem cell’s fate will be self-renewal or differentiation.”

In the study, the Feng lab created mutant Shp2 mESCs and showed that differentiation was dramatically impaired as the cells self-renewed as stem cells. The researchers also demonstrated small interfering RNAs in hESCs reduce Shp2 expression and subsequent cell differentiation. Feng and colleagues screened chemical libraries and identified a small-molecule inhibitor of Shp2 that, in small doses, partially inhibits differentiation in both mESCs and hESCs. Taken together, these results suggest a conserved role for Shp2 in ESC differentiation and self-renewal in both mice and humans.

“This opens the door for new experimental reagents that will amplify the self-renewal process to create more stem cells for research and potential clinical use in the future,” Dr. Feng added. “This research also suggests that comparative analysis of mouse and human embryonic stem cells will provide fundamental insight into the cellular processes that determine ‘stemness,’ a critical question that remains to be answered in the stem cell biology field.”

About Burnham Institute for Medical Research
Burnham Institute for Medical Research is dedicated to revealing the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. Burnham, with operations in California and Florida, is one of the fastest-growing research institutes in the country. The Institute ranks among the top-four institutions nationally for NIH grant funding and among the top 25 organizations worldwide for its research impact. Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, infectious and inflammatory and childhood diseases. The Institute is known for its world-class capabilities in stem cell research and drug discovery technologies. Burnham is a nonprofit, public benefit corporation.

January 10, 2009

Search engines contribute to medicine

Believe it or not.

The release from yesterday:

Digital Communication Technology Helps Clear Path to Personalized Therapies

LA JOLLA, Calif., January 9, 2009 — Researchers at the Burnham Institute for Medical Research (Burnham) have shown that search algorithms used in digital communications can help scientists identify effective multi-drug combinations. The study, led by Giovanni Paternostro, M.D., Ph.D., was published in the December 26, 2008, issue of PLoS Computational Biology.

Using the stack sequential algorithm, which was developed for digital communications, the team of scientists searched for optimal drug combinations. This algorithm can integrate information from different sources, including biological measurements and model simulations. This differs from the classic systems biology approach by having search algorithms rather than explicit quantitative models as the central element. The variability of biological systems is the fundamental motivation for this strategy.

“Combination therapies have demonstrated efficacy in treating complex diseases such as cancer and hypertension, but it is difficult to identify safe and effective combination treatment regimens using only trial and error,” said Dr. Paternostro. “As personalized medicine moves from the present emphasis on diagnosis and prognosis to therapy, the problem of searching for optimal drug combinations uniquely suited to the genetic and molecular profile of each patient will need to be solved. This research is a first step in that direction.”

Current methodology for identifying effective combination therapies involves exhaustive testing. However, the exponential expansion of possibilities precludes exploring large combinations using this approach. For example, many chemotherapy regimens include six drugs from a pool of 100. A study that included all combinations (including partial combinations containing only some of these compounds) at three different doses would have to digest 8.9 x 1011 possibilities. The problem requires a new approach rather than more efficient screening technology.

In the study, a small subset of the possible drug combinations identified using the algorithms were tested in two biological model systems. One system studied improvement in the physiological decline associated with aging in Drosophila melanogaster (fruit flies) and the other system tested for selective killing of cancer cells. In both cases, effective drug combinations were identified by combining the algorithm with biological tests.

“Our work was greatly helped by collaborators with expertise in medicine, engineering and physics from Burnham, University of California, San Diego and Michigan State University,” said Dr Paternostro. “We especially benefited from suggestions from Dr. Andrew Viterbi, inventor of the Viterbi algorithm so widely used in digital communications, who pointed to parallels between this biological problem and signal decoding.” Dr. Andrew Viterbi cofounded Linkabit Corporation and Qualcomm Inc., with Dr. Irwin Jacobs. He is currently the president of the venture capital firm, The Viterbi Group.

This work was funded by the Ellison Medical Foundation, National Institutes of Health and the National Science Foundation.

About Burnham Institute for Medical Research
Burnham Institute for Medical Research is dedicated to revealing the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. Burnham, with operations in California and Florida, is one of the fastest growing research institutes in the country. The Institute ranks among the top four institutions nationally for NIH grant funding and among the top 25 organizations worldwide for its research impact. Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, infectious and inflammatory and childhood diseases. The Institute is known for its world-class capabilities in stem cell research and drug discovery technologies. Burnham is a nonprofit, public benefit corporation. For more information, please visit http://www.burnham.org.