Welcome to the biweekly electronic newsletter from the Bio-X Program at Stanford University for members of the Bio-X Corporate Forum. Please contact us if you would like to be added or removed from this distribution list, or if you have any questions about Bio-X or Stanford.

Seed Grant Program

SEED GRANTS FOR SUCCESS - Stanford Bio-X Interdisciplinary Initiatives Program (IIP)

The Bio-X Interdisciplinary Initiatives Program represents a key Stanford Initiative to address challenges in human health. The IIP awards approximately $3 million every other year in the form of two-year grants averaging about $150,000 each. From its inception in 2000 through the fifth round in 2010, the program has provided critical early-stage funding to 113 different interdisciplinary projects, involving collaborations from over 300 faculty members, and creating over 450 teams from five different Stanford schools. From just the first 4 rounds, the IIP awards have resulted in a tenfold-plus return on investment, as well as hundreds of publications, dozens of patents filed, and most importantly, the acceleration of scientific discovery and innovation.

In the spring of 2012, we will have a call for proposals for the 6th round of seed grants from our faculty. Competition is intense, and the criteria for the proposals include innovation, high-reward, and interdisciplinary collaboration. To view the different projects that have been funded, please click here.

Every year, two symposia are held at the Clark Center to showcase the seed grant projects. Talks that are presented at the symposia are recorded, and can be viewed here. THE NEXT IIP SYMPOSIUM WILL TAKE PLACE AT THE CLARK CENTER ON MONDAY, FEBRUARY 13, 2012. Please click here or see below in EVENTS for the list of speakers.

We are cultivating and are highly successful in building meaningful collaborations with numerous corporate colleagues. New collaborations through our seed grant projects are highly encouraged. To learn about how to get involved, please contact Dr. Hanwei Li or Dr. Heideh Fattaey.

News

Protein complex plays role in suppressing pancreatic tumors, study shows
Bio-X affiliated faculty Jonathan Pollack
A well-known protein complex responsible for controlling how DNA is expressed plays a previously unsuspected role in preventing pancreatic cancer, according to researchers at the Stanford University School of Medicine. Technological advances in the way researchers can compare normal and tumor DNA showed that the gene for at least one subunit of the multi-subunit SWI/SNF protein complex was either deleted, mutated or rearranged in about a third of the 70 human pancreatic cancers that the Stanford team examined. Additionally, the researchers found that restoring the expression of one of the missing genes slowed the growth of pancreatic cancer cells in the laboratory and caused them to enter an arresting state called senescence. “This is really strong genetic evidence that this complex plays a role in pancreatic cancer,” said associate professor of pathology Jonathan Pollack, MD, PhD, “and it suggests the influence of the SWI/SNF complex is on par with that of other well-known tumor suppressors, such as p53.” Pollack is the senior author of the research, published online Jan. 9 in the Proceedings of the National Academy of Sciences. Graduate student Hunter Shain is the first author.

Computer algorithm used to identify bladder cancer marker
Bio-X affiliated faculty Irv Weissman
Researchers at the Stanford University School of Medicine have used an innovative mathematical technique to find markers that effectively predict how deadly a cancer will be. The discovery, which in this case concerned bladder cancer, could lead to faster, less expensive and more accurate analysis of cancer risk and better treatment of the disease. The findings were published online Jan. 16 in the Proceedings of the National Academy of Sciences. This is the first study in which a special Stanford-designed computer algorithm was used to identify a clinically prognostic marker from public databases, though the search tool was introduced in a paper published two years ago that established its effectiveness in identifying markers in mice.

Adaptive Evolution of the Lactose Utilization Network in Experimentally Evolved Populations of Escherichia coli
Publication in PLoS Genet Vol 8 Iss 1 by Bio-X Senior Fellow Russell Monds
Adaptation to novel environments is often associated with changes in gene regulation. Nevertheless, few studies have been able both to identify the genetic basis of changes in regulation and to demonstrate why these changes are beneficial. To this end, we have focused on understanding both how and why the lactose utilization network has evolved in replicate populations of Escherichia coli. We found that lac operon regulation became strikingly variable, including changes in the mode of environmental response (bimodal, graded, and constitutive), sensitivity to inducer concentration, and maximum expression level. In addition, some classes of regulatory change were enriched in specific selective environments. Sequencing of evolved clones, combined with reconstruction of individual mutations in the ancestral background, identified mutations within the lac operon that recapitulate many of the evolved regulatory changes. These mutations conferred fitness benefits in environments containing lactose, indicating that the regulatory changes are adaptive. The same mutations conferred different fitness effects when present in an evolved clone, indicating that interactions between the lac operon and other evolved mutations also contribute to fitness. Similarly, changes in lac regulation not explained by lac operon mutations also point to important interactions with other evolved mutations. Together these results underline how dynamic regulatory interactions can be, in this case evolving through mutations both within and external to the canonical lactose utilization network.

The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations
Publication in PNAS Vol 109 No 2 by Bio-X affiliated faculty Calvin Kuo and Sarah Heilshorn
The small intestine epithelium undergoes rapid and continuous regeneration supported by crypt intestinal stem cells (ISCs). Bmi1 and Lgr5 have been independently identified to mark long-lived multipotent ISCs by lineage tracing in mice; however, the functional distinctions between these two populations remain undefined. Here, we demonstrate that Bmi1 and Lgr5 mark two functionally distinct ISCs in vivo. Lgr5 marks mitotically active ISCs that exhibit exquisite sensitivity to canonical Wnt modulation, contribute robustly to homeostatic regeneration, and are quantitatively ablated by irradiation. In contrast, Bmi1 marks quiescent ISCs that are insensitive to Wnt perturbations, contribute weakly to homeostatic regeneration, and are resistant to high-dose radiation injury. After irradiation, however, the normally quiescent Bmi1+ ISCs dramatically proliferate to clonally repopulate multiple contiguous crypts and villi. Clonogenic culture of isolated single Bmi1+ ISCs yields long-lived self-renewing spheroids of intestinal epithelium that produce Lgr5-expressing cells, thereby establishing a lineage relationship between these two populations in vitro. Taken together, these data provide direct evidence that Bmi1 marks quiescent, injury-inducible reserve ISCs that exhibit striking functional distinctions from Lgr5+ ISCs and support a model whereby distinct ISC populations facilitate homeostatic vs. injury-induced regeneration.

Events

Resources

To learn more about Bio-X or Stanford University, please contact Dr. Hanwei Li, the Corporate Forum Liaison of Bio-X, at 650-725-1523 or lhanwei1@stanford.edu, or Dr. Heideh Fattaey, the Executive Director of Bio-X Operations and Programs, at 650-799-1608 or hfattaey@stanford.edu.