Interview with Dr. Roger Linington

Department of Chemistry (Natural Products Drug Discovery via High-throughput Screening)

Tier 2 Canada Research Chair (Chemical Biology - High-Throughput Screening)

Joined SFU in July 2015

Dr. Linington’s research program applies marine microbiology, natural products isolation and structure determination, bioassay design and development, synthetic medicinal chemistry, and 'omics' techniques to tackle biomedical problems. His group develops high-content approaches to natural products discovery that use modern methods in image-based screening and high resolution mass spectrometry to create powerful tools for the functional annotation of natural products libraries. His strategy integrates high-throughput chemical and biological annotation of the libraries to predict biological functions of compounds early in the discovery process. His ultimate goal is to discover novel natural products that possess bioactivity against targets in disease areas such as infectious disease and cancer.

How did you end up in natural products research?
During my Ph.D. at the University of British Columbia I took a class offered by Ray Andersen, a preeminent natural products chemist, on NMR spectroscopy and organic structure determination. That course brought together all of the pieces of chemistry that I found so attractive as a high school student because it was beautifully methodical. When you finish your analysis there really is only one correct solution and while you can look at your data set from many perspectives, it still complies with that solution. I like that sort of science; it has a Lego-type of modularity. I could see how these methods could be applied to medicine and environmental problems, which seemed like the perfect intersect for me.

Of all the possible applications of your natural product discoveries, which one motivates you the most?
I really want our group to make a substantive contribution to human health through antibiotic development. There is a pressing need for new classes of antibiotics but they are extremely difficult to find. The rate of rediscovery in antibiotics research is >99.5%, so finding new ones isn’t easy. They are out there, but you have to be much smarter about it to find them.

How do you plan to find new antibiotics?
Our lab works on microbial natural products. One of the things we learned recently is that the capacity to produce natural products is not evenly distributed in the microbial world. If you look at the DNA sequence of an organism and their capacity to make natural products you find that many organisms cannot make much beyond the regular sugars; the way they survive isn't by defense, rather it's about rapid replication.

In the taxonomic tree there are hotspots of hyper-productivity of natural products. The question then becomes how do you develop tools and methods to selectively isolate one genus from a soil or marine sample that contains a billion cells per gram and thousands of genera? How do you sort the producers from the non-producers?

We are developing methods of using genomic information to look at how organisms survive in their environment, to determine whether there are survival tactics that are unique to the organisms we are seeking. It's undeniable that the genomic revolution has touched a huge swath of biological and physical sciences, right down to collection strategies.

Does sample collection and the idea of grabbing samples randomly in the ocean keep you awake at night?
If you make a poor decision in any of the early steps of library generation then the library will not contain the type of chemistry and structural novelty you want and all the screening you do after these early steps is for naught. So, yes, library creation is quite stressful. It’s not so bad now because my lab is more mature and we have built a very large library of interesting compounds, but during the first five years of my program, making these decisions was a daunting task.

How did you go about creating the most useful library?
At the beginning I leveraged some contacts I had in industry. Without their advice we would have naïvely pursued things that were wasted time.  We presented our ideas and they shared their lessons learned, i.e., “we tried that, it won't work.” The whole experience was rather crushing, but they saved us over a year of work and made a world of difference in the quality of the library we built.

What personal strengths and educational backgrounds do you look for in prospective group members?
I am less concerned about whether someone has the appropriate training and organic chemistry background than finding students who have the enthusiasm and determination to take on a complex scientific problem and succeed. If you don't know a lot about synthesis we can teach you that, but if you don't have the spark to be a leader in your area, then that's not something we can teach.

My program engages people from a broad variety of undergraduate disciplines like microbiology, marine biology, computing, biochemistry and organic chemistry. The great thing about joining a graduate program at the interface of chemistry and biology is that there is room to include different fields; the flipside is that you won't know everything you need to know, so you must have the initiative and determination to learn those things. I am not an expert in all things the lab does, it's impossible, so we rely on individuals to seek the training they need and bring it back into the fold to enhance the knowledge of the group.

The source locations for your natural products range from oceans to rainforests and even Antarctica – are there any special skills that you look for in prospective students?
You don't need to know how to dive to be a member of the group, although lots of people have learned that skill as part of their training. It depends on the projects that are funded and the collection strategies that are being used at the time. Some of the fieldwork is on land, some in the ocean. The only thing you can be sure of is that it's not going to go as planned, so it needs people who are both persistent and resourceful enough to solve problems on the fly.

What contemporary scientific issue concerns you the most and needs more attention?
Antibiotic resistance and the gap between that and antibiotic discovery. I also worry that the push to publish and the metrics of scientific output run the risk of generating a large number of mediocre studies. As scientists we need to exercise due diligence to the scientific process; and as academics, we have a responsibility to go after the large, harder problems, even if it takes time.

What other interest or occupation fascinates you so much that you might choose it if you were to start over again?
This I know for sure – I would be an entomologist. I find the insect world  fascinating. Insects occupy almost every niche on earth and evolution has gifted them with an incredible array of skills and a mixture of physical and chemical defenses. This is a wonderful, intriguing world that is macroscopic and easily studied, yet still comparatively poorly understood.

Which scientists completely boggle your mind?
Emil Fischer determined the structure of glucose – that is one of the most incredible pieces of logical reasoning you will ever see, an amazing scientific achievement.

In fact, if you look at historical science—like that depicted in the Aldrich catalog—people learned a lot about the periodic table without analytical tools. It's spectacular when you think about it. Dmitri Ivanovich Mendeleev had that insight. He brought order to a set of data that was very convoluted, incomplete and wrong in places and put it all together in a unifying theory of chemical elements, the Periodic Law. It turns out that he was right and that is just awesome.

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Dr. Linington’s presence enhances SFU’s expertise in natural products chemistry and high-throughput screening. With experience spanning metabolomics, screen design and development, drug discovery and chemical biology, he is an exceptional complement to his colleagues at SFU. The soon-to-be opened SFU High-Throughput Screening Facility will benefit from his extensive experience and it will support his research program objectives of discovering new compound classes for drug development and chemical probes to treat diseases and disease-causing organisms.

Read more: Dr. Linington’s personal website, profile on the Chemistry website, the New Science Faculty page, and research features on Nature of Things, Motherboard and Seeker Digital Network

Interview by Jacqueline Watson with Theresa Kitos