Active Research in the Campbell Lab
Dr. Robert Campbell studies the origin and function of biological systems. He started his research career using protein engineering to understand the basis for selective functions of human hormones. In the course of this work he showed how mutation could combine different hormone activities within a single protein. These findings showed that binding selectivity in protein families might have evolved by mutations that restrict cross-activity of homologs after gene duplication. Dr. Campbell then used comparative genomics to investigate the origin of the vertebrate endocrine system, and found that this most likely entailed specific introductions of “keystone” links to bridge isolated ancestral signaling systems plus structural changes that enabled local paracrine factors to acquire endocrine actions. As a Visiting Researcher at the MBL he collaborated in the discovery of homologs of human drug targets in Giardia lamblia, which inspired his use of comparative genomics studies to comprehensively identify candidate drug targets from Neglected Disease pathogens. This was incorporated into the creation of the WHO-sponsored TDR Targets Database. The Campbell lab is now using this target knowledge with Michael Pollastri (Northeastern University) to mobilize “old” medicinal chemistry from industry for “new” drug discovery against African sleeping sickness. Most recently he and his collaborators received in November 2012 approval from the Tres Cantos Open Lab Foundation for work at their lab in Spain that will bring the expertise, resource, and chemical collections of GlaxoSmithKline into this sleeping sickness effort.
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.
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.
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.