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Robert Campbell,
Adjunct Scientist
Robert Campbell's CV>>
My research at the MBL reflects two interests. One is to understand the mechanisms by which evolution creates complexity. The other is to apply knowledge from diverse fields to solve problems that impact global health. Much of the research relating to global health is also connected to the graduate level Drug Discovery course that I teach at Brandeis University.
Facilitating drug discovery for neglected diseases
My research at the MBL relating to global health addresses parasitic diseases that affect millions of people. These diseases are increasingly resistant to treatment and the World Health Organization (WHO) has highlighted several of as being in urgent need of new drug discovery. These include the protozoan infections African sleeping sickness, Chagas disease, and Leishmaniases, and the worm infection Schistosomiasis. My research uses bioinformatics to identify the candidate druggable genome in the associated organisms (Figure 1). The disease relevance of selected drug target candidates is then assessed using molecular and cell biology. Starting from a set of over 1200 known targets from the human genome we found that about 25% have homologs in African trypanosomes (T. brucei), a species that is readily amenable to molecular cell biology for target validation. The majority of these target homologs were also found in other disease-related kinetoplastids (T. cruzi, L. major, L. infantum). Over 40 of the targets with homologs in T. brucei are associated with drug discovery programs reporting compounds with low polar surface areas that could potentially reach primary sites of trypanosome infection in the brain (including nine targets with drug candidates for other diseases in Phase 2 testing or beyond). One of these trypanosome target classes is being assessed by RNAi with members of Steve Hajduk's lab at the University of Georgia, while a second is being subjected to chemical validation with Mike Pollastri's lab at Boston University. All of the parasite target sets identified in this work are being shared with the Target Database consortium sponsored by WHO TDR and placed into that database.
Figure 1.
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Useful Links:
DrugBank
TDR Targets Database
World Health Organization
Drugs for Neglected Diseases Initiative
Brandeis Graduate Program in Bioinformatics
Other research activities:
Evolutionary origins of multi-component systems.
All life relies on multi-component systems to perform and regulate metabolism, reproduction, and successful adaptation to the environment. I am interested in how these systems emerge through evolution. Most of my work in this area has focused on the vertebrate endocrine system, with more recent studies looking at eukaryotic cell growth control and regeneration.
Publications:
Campbell, R.K., Satoh, N., and Degnan, B.M. Piecing together evolution of the vertebrate endocrine system. Trends Genet. 20:359-366. (2004)
Dehal, P., Satou, Y., Campbell, R.K., Chapman, J., Degnan, B., De Tomaso, A., et. al. The draft genome of Ciona intestinalis: insights into chordate and vertebrate origins. Science 298:2157-2167 (2002)
Evolutionary "invention" of novel proteins and functions
I am also interested in the mechanisms underlying the evolution of complex features in proteins. Proteins are often thought of as single entities, but they can also be considered complex systems with multiple amino acids (and sometimes other compounds) connected through both covalent bonds and weaker interactions. Many protein functions involve specific multiple amino acids to work in concert. Our research has identified multiple mechanisms by which diverse functions dependent on multiple amino acids can arise by small numbers of stepwise changes. For example, with regard to the creation of new binding interactions, our mutagenesis studies with glycoprotein hormones and their receptors support a model for the evolution of protein selectivity by gene duplication followed disruptive mutations to reduce cross-activity between the resulting family members. This accounts for the varying degrees of cross-selectivity seen within protein families in nature. It also explains the ability to recruit binding activities by the non-specific substitution of amino acids. My more recent research has expanded these studies to the superfamily of cystine knot proteins, and mechanisms for evolving major changes protein stability, circulating half-life, binding interactions, and biological function.
Publications:
Campbell, R.K. Molecular pharmacology of gonadotropins. Endocrine. 26:291-296. (2005)
Campbell, R.K., Bergert, E.R., Wang, Y., Morris, J.C., and Moyle, W.R. Chimeric proteins can be more than the sum of their parts: implications for evolution and protein design. Nature Biotechnology 15:439-443. (1997)
Moyle, W.R., Campbell, R.K., Myers, R.V., Bernard, M.P., Han, Y., and Wang, X. Co-evolution of ligand-receptor pairs. Nature 368:251-255. (1994)
Campbell, R.K., Dean-Emig, D.M., and Moyle, W.R. Conversion of human choriogonadotropin into a follitropin by protein engineering. Proc. Natl. Acad. Sci. USA 88:760-764. (1991)
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