- Stanford University, Stanford, CA, U.S., Beckman Fellow in Developmental Biology and Genetics, 2001-2002.
- Stanford University, Stanford, CA, U.S., Research Fellow in Developmental Biology and Genetics, 1999-2001.
- University of Toronto, PhD in Molecular and Medical Genetics, 1999.
- Dalhousie University, Halifax, BSc in Biology and Neuroscience, 1993.
MY RESEARCH OVERVIEW (GO TO SCIENTIFIC OVERVIEW)
Using the Smallest of Animals to Find Drugs to Better Understand Biology and Cure Human Disease
While considering what to do as a graduate student in the summer of 1993, I sat in the office of Joe Culotti, who would later become my PhD supervisor, as he explained the beauty and simplicity of the tiny nematode worm Caenorhabditis elegans as an experimental animal model system. He explained how one could easily see stereotypical cell extensions like axons in the worm, and then look for mutants that disrupt their stereotyped patterns of extension. By identifying the mutated genes, we could better understand how genes controlled this biological process. Being a relatively simple animal with only 959 cells, yet having a sophisticated set of tools with which to study it, the worm seemed like the ideal experimental system to study animal biology. I joined Joe’s lab that fall and have been working on worms ever since.
Our current main interest in the lab is to exploit the C. elegans nematode to identify novel drugs to treat a variety of human diseases and learn a ton of biology along the way. We are focused on identifying novel drug leads for the human conditions listed below.
One third of the world’s population is currently infected with a parasitic nematode. We have demonstrated that C. elegans, which is non-parasitic, is a useful model system to identify molecules that are likely to kill parasitic worms, which are much more difficult to work with compared to C. elegans. We have screened through more than 60,000 previously uncharacterized molecules to find 67 molecules that kill nematodes, but do not kill other types of animals. We currently working to better understand how these molecules specifically kill nematodes.
We are currently developing several C. elegans models of neurodegeneration with the hopes of screening both uncharacterized drug-like small molecules and current FDA-approved drugs that are used to treat other diseases aside from neurodegeneration with the hopes of re-purposing them.
Mood Disorders and Other Disorders of the Central Nervous System
We have developed a novel high-throughput assay that allows us to screen for novel modulators of neurotransmission with a particular focus on those neurotransmitters involved in a variety of mood disorders. We expect to not only discovery novel drug-like molecules with neuromodulatory capabilities, but novel drug-targets that can be further exploited for the development of novel medicines.
In collaboration with Sick Kids researchers Brent Derry and Jim Dowling, we are screening for molecules that might correct defects in the vasculature of the human brain as well as diseases associated with muscle dysfunction, called myopathies.
In each of our screening campaigns, our objective is not only to identify potential drug leads, but importantly, we also hope to use these molecules as tools to better understand animal biology through understanding how the drug’s target is involved in the process that we are studying.
SCIENTIFIC RESEARCH OVERVIEW
In 1974, Sydney Brenner published his seminal description of C. elegans as a genetic model system. In it, he described his preliminary investigation into C. elegans’ sensitivity to small molecules. Only 2 of the ~100 bioactive molecules he tested exhibited activity. Consequently, no one has championed the worm as a model system for the discovery of novel bioactive molecules that could be developed as biological reagents or potential drug leads. My group’s work over the past 10 years, however, has challenged this general view by demonstrating that the worm has heretofore untapped potential to serve as a powerful platform with which to identify and characterize new small molecule tools.
Our lab has had a growing interest in discovering new drug-like compounds that could be used to treat human disease.
To date, we have had success in identifying and understanding novel drug-like compounds with unique biological activities by using the nematode C. elegans as our discovery platform.
We have discovered compounds that target a calcium channel, a P450 enzyme, and a component of the electron transport chain, each of which are conserved in humans.
More recently, we have been developing C. elegans as a model for several human diseases, including those related to neurodegeneration, myopathies, vascular malfunctions, and psychological disorders. We are also interested in using the non-parasitic C. elegans as a model of parasitic nematodes, which infect over one third of humans.
With these models in hand, we will identify small drug-like compounds that can ameliorate the defects, and partner with other labs to test our compounds in corresponding disease models in fish and mice
Our current projects include:
1. Biologial Characterization of Nemadipine
To identify new small molecule tools for the biological analysis of C. elegans, my lab has screened over 70,000 small molecules for the induction of a variety of phenotypes, including those that resemble the disruption of conserved components and pathways. We have found over 600 potent bioactive molecules. Our first detailed characterization was of one that we call nemadipine (pronounced ne-ma-dee-peen) and discovered that it is a new L-type calcium channel antagonist that is active in both worms and vertebrates. Nemadipine has unique properties compared to other FDA-approved calcium channel antagonists in that it is effective in whole living worms. Thus, nemadipine allows us to investigate the genetics of how animals interact with this important class of calcium channel antagonists for this first time. We published this work in Nature (Kwok et al., 2006, Nature), and have two follow-up papers on the screening method (Burns et al., 2006. Nature Protocols) and the use of nemadipine to study calcium channels (Kwok et al., 2008. PLoS Genetics).
2. Biological Characterization of Dafadine
The second molecule that we characterized, called dafadine (pronounced daf-a-deen) extends lifespan. Dafadine induces a highly penetrant dauer phenotype in C. elegans. Dauer is a stress-resistant alternative third larval stage that is engaged in response to stress. The genetic analysis of dauer engagement has led to many fundamental insights, including the discovery that the insulin pathway, which is one of two key pathways that controls dauer formation, negatively regulates lifespan. Through a series of phenotypic, chemical-genetic, cell-based, and biochemical experiments, we demonstrated that the DAF-9 cytochrome P450, which functions within the insulin pathway, is the direct and physiological target of dafadine. We also found that dafadine can also antagonize DAF-9’s human ortholog, called CYP27A1. Because of the insulin pathway’s role in regulating lifespan, we tested whether dafadine could extend the life span of C. elegans, and found that it did so by inhibiting DAF-9 activity (Luciani et al., 2011. Nature Chemical Biology).
Since publication, both nemadipine and dafadine have been commercially available and are being used by several others in the community as research tools. We are in the process of characterizing several other molecules of interest, including pipersma, HBAC, migrazole, and mezole.
3. Characterization of Novel Anthelmintics
Nematode parasites exist for nearly every agriculturally important animal and plant on earth, and currently infect over 2 billion people. Resistance to existing anthelmintics is rapidly growing and the need to develop novel anthelmintics is pressing. To identify potential anthelmintic leads, we screened the 600+ bioactive molecules that we have identified using C. elegans in the bovine parasitic nematode Cooperia oncophora in collaboration with John Gilleard (Calgary). C. oncophora also serves as a model for several nematode parasites of humans. We counter-screened our bioactive molecules in preliminary models of parasitic hosts, including zebrafish and a human cell line. We discovered 73 compounds that: i) kill both C. elegans and C. oncophora; ii) fail to induce obvious phenotypes in fish or HEK293 cells; and iii) have no obvious structural relationship to any characterized anthelmintic. Our work now focuses on exploiting C. elegans genetics and whole-genome sequencing to identify the target of ~45 of these molecules. With Prof. Gilleard, we will further investigate the anthelmintic potential of the most potent molecules that we find to have distinct mechanisms of action. At the very least, this project will yield over 20 new small molecule tools with defined targets that will enable future discoveries. We are optimistic, however, that we can develop many of these compounds into new anthelmintic drug leads for the benefit of human health.
We are also currently developing & screening models for diseases related to:
defects in CNS vasculature
- Caenorhabditis elegans is a useful model for anthelmintic discovery. Burns AR, Luciani GM, Musso G, Bagg R, Yeo M, Zhang Y, Rajendran L, Glavin J, Hunter R, Redman E, Stasiuk S, Schertzberg M, Angus McQuibban G, Caffrey CR, Cutler SR, Tyers M, Giaever G, Nislow C, Fraser AG, MacRae CA, Gilleard J, Roy PJ. Nat Commun. 2015 Jun 25;6:7485.
- EVA-1 functions as an UNC-40 Co-receptor to enhance attraction to the MADD-4 guidance cue in Caenorhabditis elegans. Chan KK, Seetharaman A, Bagg R, Selman G, Zhang Y, Kim J, Roy PJ. PLoS Genet. 2014 Aug 14.
- Dafadine inhibits DAF-9 to promote dauer formation and longevity of Caenorhabditis elegans. Luciani GM, Magomedova L, Puckrin R, Urbanus ML, Wallace IM, Giaever G, Nislow C, Cummins CL, Roy PJ. Nat Chem Biol. 2011 Nov 6;7(12):891-3.