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Keith Blackwell, M.D., Ph.D.

Research Summary

The Blackwell laboratory studies how cells and organisms defend themselves against environmental and metabolic stresses.  These stresses include high levels of reactive oxygen species (ROS) and other potentially harmful products of metabolism, misfolded proteins, and perturbations in protein synthesis.  We are particularly interested in understanding these how stress defenses influence the aging process.  Cellular stress defenses are important in diabetes in several ways.  For example, chronic elevations in blood glucose lead to high levels of ROS (oxidative stress) in endothelial tissues, one of the most fundamental causes of diabetic complications in both Type 1 and Type 2 patients.  During Type 2 diabetes, the demand for insulin synthesis can place enormous stress on the beta cell endoplasmic reticulum, eventually leading to oxidative stress and beta cell demise. 

In addition, the effectiveness of cellular stress defenses is influenced by insulin and other metabolic regulatory pathways of importance in diabetes.  Increasing evidence indicates that these defenses not only protect against stress, but also act in opposition to the aging process, during which the likelihood of Type 2 diabetes and severity of diabetic complications inexorably increase.  Cellular stress defenses, their regulators, and the aging process profoundly influence the regenerative and developmental capacity of multiple types of stem cells, and are therefore important for tissue repair.  Finally, these defense mechanisms are important in a wide variety of additional disease settings, including atherosclerosis, neurodegeneration, carcinogenesis and cancer progression, drug metabolism, and reperfusion injury.

We are studying stress defense mechanisms in the nematode C. elegans, in which these mechanisms and most basic aspects of their regulation seem to be conserved.  This organism offers tremendous advantages for genetic screening and manipulating the activity of genes, and for studying biological processes on the organismal level.  Importantly, insights obtained from C. elegans have generally proven to be applicable to humans.  Work in C. elegans has been particularly important for identifying mechanisms that influence aging, because of its short lifespan and advantages for genetic studies.
 
Most of our studies of stress and aging are centered around the transcription factor SKN-1, which is the C. elegans counterpart to the mammalian Nrf1/2/3 transcription regulators.  We have found that SKN-1 orchestrates a transcriptional response to oxidative and related stresses that is conserved among eukaryotes. More recently, we have determined that SKN-1 has a broader range of functions than realized previously.  Through expression profiling, we have obtained evidence that SKN-1 not only mobilizes oxidative stress defenses, but also regulates genes involved in metabolism, drug transport, protein homeostasis, endoplasmic reticulum stress, and insulin signaling, among other important processes.  One of our most active areas of interest is investigating how SKN-1 interacts with other stress response regulators to defend against a wide range of stresses. 

We are also very interested in understanding molecular mechanisms through which the activities of SKN-1 and cooperating signals are controlled, because we believe that harnessing the benefits of SKN-1 and other stress defenses could be important in several disease settings.  In C. elegans, we can perform high-throughput screens to identify such regulatory mechanisms.  Such studies are revealing that SKN-1 responds to perturbations in a surprisingly wide range of cellular processes.

We are particularly interested in understanding how SKN-1 cooperates or works in parallel with other mechanisms to influence the aging process.  Across species, aging is profoundly affected by the activity of insulin/IGF-1 signaling, an effect that was discovered in C. elegans.  We have determined that SKN-1 is regulated by insulin/IGF-1 signaling, and is important in the effects of this pathway on stress resistance and lifespan.  Others have determined that SKN-1 is required for lifespan to be extended by caloric restriction, and we have more recently implicated SKN-1 in additional signaling pathways that are important in aging.  Together, these results place SKN-1/Nrf as having a role in defense and metabolic mechanisms that may have profound effects on aging and chronic diseases such as diabetes. 

In parallel to these efforts, we are using C. elegans to study how other types of gene regulatory mechanisms influence the aging process, and the development and self-renewal capability of stem cells.  We expect that the fundamental mechanisms that we uncover in C. elegans will identify new areas of inquiry to be pursued in mammalian and human models, and are pursuing such collaborations both within Joslin and the broader Harvard community.

 

Biography

Dr. Blackwell was born in Greenville, SC.  He received a BS degree in Chemistry from Duke University in 1978, and the MD and PhD degrees from Columbia University in 1987 and 1988, respectively.  Dr. Blackwell performed his graduate work with Dr. Frederick W. Alt, studying how B- and T- cell antigen receptor genes are assembled. 

In 1989 he joined the lab of the late Dr. Harold Weintraub (Fred Hutchinson Cancer Research Center) as a postdoctoral fellow of the Life Sciences Research Foundation.  He then developed high-throughput systems for analyzing protein-nucleic acid interactions, and studied how regulatory proteins recognize DNA.  This work eventually established the direction for his current work, investigating gene regulatory mechanisms involved in development, metabolism, stress defense, and aging. 

In 1993 he became a Junior Investigator at the Center for Blood Research (now IDI), and an Assistant Professor of Pathology at Harvard Medical School.  Dr. Blackwell was promoted to Associate Professor in 2001, and Professor in 2008.  He was named a Searle Scholar in 1995, and an Ellison Medical Foundation Senior Scholar in Aging in 2010.  He has participated in numerous review panels at the NIH, and is a member of the editorial board of the journal Aging Cell.

In 2004, Dr. Blackwell moved his laboratory to Joslin, where he is Associate Research Director, co-head of the Section on Islet Cell and Regenerative Biology, and a principal faculty member of the Harvard Stem Cell Institute. 

Page last updated: October 30, 2014