Ian Winters isn’t quite sure why he started liking science. But for one reason or another, when Ian was just four years old, he came home from preschool one day and declared that he wanted to be a scientist. During his early childhood, when he asked his father (an agricultural development economist) scientific questions on the way to preschool – why do the leaves change color in the fall? – he would get an unsatisfactory answer about supply and demand and be told to ask a scientist for more answers. This curiosity about the natural world has formed Ian’s sense of purpose as a scientist: to answer the biological questions he finds most pressing, both for himself and for other scientists.
The questions Ian asks today are a little more complex – what are the mechanistic functions of the myriad genetic changes that occur in human cancer? – but his desire, as a scientist, to help other scientists answer tough questions has remained the same. Today, Ian’s research takes a technology-driven approach to answer fundamental questions about cancer genetics and build systems that other scientists can leverage to address those questions in their own work.
Going into college, Ian had spent much of his childhood in rural Australia, where grades weren’t a priority and teachers only marked up assignments when the weather wasn’t conducive to playing kickball outside. He’d always been motivated in his science courses, but it was through his academic and scientific advisor at the University of Richmond, Dr. April Hill, that he developed a much deeper fascination with biology, appreciation for scientific rigor, discipline, and integrity, and understanding of the impact that a good mentor can have on one’s career and life trajectory.
Now at Stanford University in Monte Winslow’s lab, Ian has centered his thesis on developing technologies that enable scientists to investigate the function of cancer mutations in a more high-throughput, quantitative manner. Advances in next-generation sequencing have allowed scientists to observe a wide range of mutations across many human cancer types. But engineering new mouse models to study the functional effects of these mutations can take years. As a result, scientists have only been able to determine the effects of a small number of mutations in depth in mouse models of cancer, while the effects of most of the millions of mutations that have been discovered in cancers during the past couple of decades remain poorly understood. Ian’s first innovation in this area was to incorporate the CRISPR system in in vivo studies in mice, specifically in modeling pancreatic cancer – a long way from asking why the leaves change colors in the fall.
Beyond significantly reducing the amount of time it takes to model new mutations, the system can also scale up to model whole pools of genetic perturbations per mouse. Indeed, Ian and his colleagues at Stanford developed a method named “Tuba-seq” to investigate the function of multiple loss-of-function mutations in tumors in mice by combining in vivo CRISPR-based gene editing with a method to quantitatively analyze tumors using high-throughput sequencing, which was recently published in Nature Methods. Although the system was used to model tens of genes, Ian’s confident it could be scaled into the hundreds or even thousands (Ian believes that the primary limitation of these in vivo cancer models is no longer how many mutations can be introduced but rather the ability to dissect the effect of each mutation). Other cancer biologists are already leveraging this system to vastly increase the speed of their work.
More recently, Ian has studied how specific amino acid changes in KRAS – the most frequently mutated oncogene in human cancer – alter its ability to drive cancer. Oncogenes often incur mutations at predictable locations, but the actual amino acid changes that occur can be very diverse. By developing a precise and multiplexed method of genome editing in vivo that leverages the CRISPR system along with DNA repair using AAV vectors, Ian has been able to simultaneously study the effects of multiple specific point mutations in tumors and, once again, creating a technology that will allow other scientists to much more rapidly study the effects of diverse cancer mutations.
After wrapping up this latest project in lab, Ian has invested some time in career development opportunities beyond his thesis work as a way to round out his PhD training. This Fall Quarter Ian is conducting research as an Intern on the Molecular Biology R&D team at Karius, an innovative genomics startup in the bay area that leverages next-generation sequencing of cell-free DNA circulating in the blood of patients to rapidly screen for several orders of magnitude more species of bacteria, viruses, fungi and protozoa in a single test than traditional infectious disease diagnostics. Next quarter, Ian will participate in Stanford Ignite, a certificate program designed to teach innovators the core business and entrepreneurship skills necessary to commercialize their ideas. Ian’s hope is that each of these experiences, which allow him to temporarily step outside of the intellectual space he’s occupied for the last five years, will serve as an opportunity for rapid learning in new fields with a whole different set of challenges as well as opportunity to network and develop a better understanding of the similarities and differences between industry and academia.
Insights and Advice
Ian credits both his parents and his research advisors with some of the most important scientific advice he’s received. Although the majority of his parents’ advice was wholly unrelated to science, many of their life-lessons continue to have a big impact on how Ian approaches his research today. For instance, one day during Ian’s childhood when he was struggling to bike up a hill, his dad pointed out that if he pedaled on the downhills before the uphills instead of coasting, the extra momentum might help get him all the way up the hill. Although Ian still likes to coast when biking down hill, he has found that this is a great metaphor for research: if you push your projects forward as much as possible when things are going well, it often pays dividends when things aren’t going so smoothly later on.
The goal of your PhD is not to become the best PhD student, but the best postdoc.
Ian’s undergraduate research advisor, Dr. April Hill, and his PhD advisor, Monte Winslow, have had the biggest impact on shaping Ian into the scientist he is today. Dr. Hill imparted Ian with the notion that you can tackle even the most complex biological questions by breaking them down into their fundamental, testable parts, that the currency of science is data and who you are or where you came doesn’t mean a thing, and that science should not be a competition but a joint societal effort to increase the quality of life of all people, both by reducing the burden of global disease and also simply by enriching people lives with interesting facts about how the world works. Some of the advice Ian has received from Dr. Winslow includes the saying “the goal of your PhD is not to become the best PhD student, but the best postdoc.” Dr. Winslow has also taught him to think about the types of questions that he’s trying to answer with his research and when he’s actually answered them. Research isn’t just about completing the next step in an experiment. It’s about answering questions that will have the biggest impact for other scientists and people in general. And Dr. Winslow emphasizes to Ian that as a scientist, he should always be the most skeptical of your own work, making sure to do all the possible experiments that could prove him wrong before being confident about the result.
By streamlining the study of functional genomics in cancer, Ian hopes his work will empower researchers to start studying the effects not only of mutations that are of clear consequence, but of mutations that are currently dismissed as artifacts. It could be that some of these overlooked mutations are more important than they seem, and could have clinical benefit.
Clearly, Ian has come a long way since asking why the leaves change color in the fall. But the nature of his interest in science has stayed the same: to develop technology that enables scientists to ask more meaningful questions, and answer them themselves.
In case you missed it up above, here’s Ian’s recipe for pizza napoletana!
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