A Tangled Mess
Why do people respond differently to the same drug? It’s a deceptively simple question, obscuring the monumental challenge of unravelling the myriad genetic and environmental factors related to drug reactions.
Yet to realize the goal of pharmaceutical science, which in a nutshell can be described as the advent of fully personalized medicine, this complex challenge must be tackled.
Dr. Corey Nislow and his team of fellow researchers at the University of British Columbia have recently taken us one step closer to predicting how a drug will affect us individually by untangling, for the first time, specific genetic and environmental factors related to drug reactions.
Major Step Forward
By exposing 6,000 strains of yeast to 3,000 drugs, Dr. Nislow found that the modified yeast cells had about 50 main ways in which they react to any drug. These 50 major response types, known as chemical-genetic signatures, are like fingerprints that identify all genes and their relevance to a specific drug treatment.
This relatively small number of signatures means that it might be possible to eventually use a person’s genome to predict their drug response. It could also make it easier to identify more effective therapies.
“This research will help us better understand how and why some drugs work and others don’t,” says Dr. Nislow. “While it won’t be easy, our research has shown that we emphatically can develop a roadmap for understanding how and why people vary in their responses to drug therapies.”
If there is an overarching theme to Dr. Nislow’s work, it can be summarized as his passion for tackling these kinds of complex biological tangles and figuring out the appropriate angles of attack.
“An investigative researcher needs to take the question or hypothesis that needs to be tested and step back,” explains Dr. Nislow. “They need to assess what tools are available, how they've been used in the past, how they might be utilized in different ways in the present, and most excitingly, they have to try and imagine what tools need to be invented to answer the question at hand.”
Dr. Nislow’s first exposure to this type of scientific thinking came as an undergraduate at New College (Sarasota,Florida)where he had to devise a project with two tools – an intertidal beach rich with sea urchins andan old scanning electron microscope. A year later, he already had his first publication under his belt and knew there was no other vocation that would compare for him.
“This experience taught me two important lessons,” he recalls. “First, given the right environment and environment and support, one can fall in love with any scientific question and, secondly, the technologies available to biologists could transport me to new worlds.”
Since graduate school, where he obtained a Doctor of Philosophy in Cell and Molecular Biology at the University of Colorado, Dr. Nislow has had the good fortune to address important biological questions many of which required new technologies, some of which had only recently been invented, and some of which his team had to invent.
“Together we created tools and we built maps and we constructed networks,” he explains. “Among the most exciting projects was producing the first full genome wide map of each and every nucleosome in a cell. To our satisfaction over 500 scientists have cited this work.”
Dr. Nislow and his team have also figured out how to turn a next-generation sequencer into a molecular counter capable of computing thousands of experiments simultaneously. Dr. Nislow and his wife Guri Giaever, who holds the Canada Research Chair in chemical genetics, have devised so-called “chemo genomic assays” to understand drug gene interactions. These experiments are basically massive competitions between populations of thousands of mutants to see which particular yeast mutant can survive a particular drug insult.
“We run these competitions daily and tally the results and after a decade have been able to define the number of different ways that a cell can respond to a drug,” explains Dr. Nislow. “It just so happens that the tools to accomplish this have been developed within the past two years, and we can now address questions that were impossible before we arrived at the University of British Columbia in 2013.”
“This is just another example of what I try to convey to my students and trainees every day; namely that these are the most exciting days to be a working life scientist,” he says.
Prior to joining the University of British Columbia, Dr. Nislow was Associate Professorat the University of Toronto and Director of the Donnelly Sequencing Centre. He has also served as group leader in two biotechnologycompanies (MJ Research and Cytokinetics, Inc. in the San Francisco Bay Area) and as a Senior Genome Scientist at Stanford University.
Dr. Nislow’s work has even been to outer space - when NASA's final space shuttle mission launched in July of 2011, it carried yeast cell growth experiments developed by his team at the University of Toronto's Donnelly Centre for Cellular and Biomolecular Research.
Indeed, yeast plays a central role in Dr. Nislow’s work.
“Yeast is the organism that has been domesticated for longer than any other on the planet,” explains Dr. Nislow. “Half of the genes in yeast are shared in humans. What that boils down to is that there experiments that you can design and execute on yeast that you could never do on a mammalian cell, allowing us to make very accurate inferences about how our cells would respond to the same experiments.”
Dr. Nislow’s recent breakthrough study using modified yeasts will help researchers better understand how and why some drugs work and others don’t.
The findings may also be relevant to cancer treatment. His team identified all genes that are essential for growth when cells are chemically stressed. Because cancer is principally a cell that grows out of control, the research points to different strategies to develop new drugs that target these genes.
Dr. Nislow’s next challenge is to ask how he can use his new ‘gene reference map’ to understand how patients respond to drugs, and how to can discriminate between efficacious responses and potential adverse responses. He believes that this is the challenge that will define his future failures and successes.
“Our team is embarking on an effort to decode the genome sequence of a large swath of the population to uncover those unique variants in the genome that influence how we respond to drug, and how we don't,” says Dr. Nislow.
“Our goal is to realize the goal of pharmaceutical science, which can be summed up as the right drug, for the right patient, at the right time, in the right dose.”