In a cavernous space in Professor Sabrina Leslie鈥檚 lab, recent PhD graduate Dr. Daniel Berard is analyzing 鈥攕hort molecules of DNA鈥攁s they are trapped in three-micron-wide "wells鈥�. To the untrained eye, the images he is inspecting on the computer screen look much like static on antiquated television sets, yet he perceives the entire trajectory of the molecules as they search for and bind to a target.
The molecular information Berard is receiving is expanding our understanding of DNA conformations and protein-DNA interactions in the nucleus of a cell, information that may pave the way to the development of DNA-based therapeutics. All this is thanks to the single-molecule imaging technique developed by Professor Leslie and her lab. It is a technology she has patented: Convex Lens-induced Confinement, or CLiC 鈥� and it is unlike any other imaging tool on the market.
Trained in math and physics at the University of British Columbia, optical and materials physics at UC Berkeley and biophysics at Harvard, Leslie is a self-described experimentalist.
鈥淎t every career stage, I鈥檝e always interviewed for different kinds of positions, mostly to see how it felt,鈥� she says. Her current faculty position at 捆绑SM社区 is in her eyes a hybrid of the various fields and research passions she has pursued so far, including atomic and optical physics and applied bimolecular engineering. What鈥檚 more, she is a leader among a growing group of researchers whose skill for fundamental research is matched by a start-up mindset.
鈥淲hile I started my career in theoretical physics and mathematics, visualizing interactions of atoms in ultra-high vacuum at nano Kelvin temperatures, this work eventually felt somewhat abstract and remote,鈥� she reflects. 鈥淚 was drawn to find ways to apply my technical training to the challenge of looking at interactions between biomolecules.鈥�
Not only frustrated by, but in her words 鈥渁llergic to,鈥� the complex techniques for molecular imaging, Leslie began crafting a wish list for a simpler and better solution. Her desires included being able to watch individual molecules for a long time and to follow their complete trajectories, as well as to observe their many copies鈥攁ll at once. It was her hope to see single molecular events in more 鈥渃ell like conditions,鈥� such as in the presence of a much higher concentration of molecules, and in crowded and confined environments. At the same time, she aimed to control the shape of molecules for technological applications, such as long-read DNA sequencing, and to create a bridge between in vitro and in vivo measurements to uncover mysteries in biology. Most of all, she desired a solution that was relatively easy to use and accessible as far as instrumentation for researchers is concerned, and she wanted to work on problems that translated to real-world applications.
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It was in 2009 that Leslie took the first steps toward making this dream a reality. In fact, she took a giant leap as a Mary Fieser Postdoctoral Fellow in Harvard Professor Adam Cohen鈥檚 group in the Department of Chemistry and Chemical Biology鈥攆ields outside her area of expertise鈥攁t Harvard. Once at Harvard, she found herself immersed in a culture of innovation, where it was the norm to transition ideas born in a lab into practical application outside academia.
As a young scientist entering the world of entrepreneurs, a steep learning curve lay ahead for Leslie. Lab work encourages team work, but the collaboration involved in launching a technology into the world demands an entirely different set of skills.
鈥淚magine you want to do a new experiment in a lab,鈥� Leslie explains. 鈥淭his is creative work where there is no particular timeline and you plan to share your results openly with other scientists. But now imagine that you are bringing an innovation developed in a lab to market. Suddenly, you are subject to new levels of quality control, demands for increased robustness and performance. You need a team with a different level of skill and maturity to handle new kinds of tasks, such as manufacturing and product development, and who have a high attention to detail, rigor, and professionalism. Now, you're not just doing measurements inside your lab, you're interfacing with other scientists, some of whom are based in companies. You鈥檙e also engaged in customer discovery and business development. And your technology can鈥檛 just work once, or once in a while, it has to work every time.鈥�
Leslie鈥檚 innovation grew from a simple hypothesis, that by squeezing molecules between two glass surfaces, in the resulting thin layer of liquid, molecules could be more clearly seen 鈥� and that this could all be done without breaking the glass.
鈥淲hen I started to share the imaging data, there was an immediate and positive response from the chemists and biologists in the Department,鈥� she says. 鈥淚t seemed like such a simple trick, but one that would be really useful for many applications, like protein-DNA binding, protein folding, nanoparticle encapsulation, or understanding how molecules like DNA behave in nano-scale environments.鈥�
Feeding off the encouraging response of her fellow researchers, Leslie pursued the idea and experiments, and CLiC technology was born. It is indeed built around the concept of using a curved glass surface that is squeezed into contact with a flat glass surface often containing patterned, embedded features, a process that enables improved imaging of molecules trapped between the two glass surfaces.
Leslie admits that as she built and tested the first prototype, she was surprised that no one had attempted this method before. Yet the novelty of the CLiC technique was not a one-off. CLiC is what is called a 鈥減latform technology,鈥� a jumping-off point from where many additional steps can be taken.
For Leslie, the joy of creating something new for practical applications means that she is enthusiastic to continue developing new capabilities and new applications for the technology. For example, while she started with the idea of squeezing a thin layer of liquid between thin layers of glass and tracking the motion and interactions of the confined molecules, she next explored bringing molecules into features etched on the surface of the glass to trap, isolate, and control the molecules鈥� shapes while taking very high quality images. Given these capabilities, first established in Leslie鈥檚 patent, CLiC is a significantly better solution than TIRF (Total Internal Reflection Fluorescence), the most commonly used method of wide-field, single-molecule imaging. In addition, CLiC offers a number of advantages over TIRF in terms of simplicity of use and cost.
Though the images CLiC provides may look like TV static, Leslie asserts that the technology in fact removes a great deal of the messiness and noise associated with biological processes, distractions that have clouded the vision of researchers for decades.
鈥淔rom a basic biophysics standpoint, CLiC enables for the first time the ability to see the entire interaction trajectory of the molecules confined in the wells, searching for and binding to their targets, and at the same time providing information about the molecular search, hybridization, binding and unbinding rates, and subsequent dynamics. This is very powerful in terms of the potential applications,鈥� says Leslie of her innovation.
鈥淭he end result is new, accessible microscopy tools designed to dramatically improve our ability to investigate and manipulate a wide variety of biomolecules and to understand how they work. What this means in terms of practical applications is that we can look for 鈥榥eedles in the haystack鈥� 鈥� rare events that might be, for example, a signature of the onset of disease.鈥�
Having caught the innovation bug, there was no turning back.
鈥淚t was at this point in my career that my work became very exciting again鈥攂ut at the same time complicated,鈥� she adds. 鈥淚 find it really rewarding to engage on two fronts simultaneously: to develop new imaging tools for practical applications, such as in the pharmaceutical sciences; and to use my training as a physicist and scientist to understand the basic mechanisms that underlie biological and biophysical processes.鈥�
In 2012, Leslie joined 捆绑SM社区 as an Assistant Professor and founded her research group, which is now 15 members strong and with 40 alumni. CLiC technology has since transformed from 鈥渇inicky prototypes鈥� to an expanding suite of tools designed to visualize biomolecules in liquids. The technology has made possible a multitude of new studies of nucleic acids, proteins, polymers, nanomaterials, biologics and cells.
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鈥淎s we increase resources and understanding of the pathway from idea to innovation, and as we create science-focused hubs and maker-spaces that are technically oriented, students will start to develop more professional skillsets while also putting their degrees in action,鈥� says Leslie.
The Leslie lab is a vibrant鈥攁nd remarkably tidy鈥攅nvironment for people from various academic and professional backgrounds to learn, explore and grow as researchers. Their mission statement: new tools yield new discoveries.听Dr. Radin Tahvildari, one of four academic associates who joined the Lab thanks to funding from a NSERC Idea to Innovation Phase 2B grant, which was awarded in partnership with Leslie鈥檚 start-up company ScopeSys, emphasizes the important role collaboration has played in the successes they have had to date. For example, Leslie鈥檚 lab makes extensive use of the 捆绑SM社区 Nanotools Microfab (MNM), a state-of-the-art facility in nano-technology when producing the flow cells used for CLiC experiments.
Dr. Romain Berti, another academic associate in the group, transitioned to the lab from the pharmaceutical industry. Like Leslie, he felt a drive to pursue new challenges in a curiosity-driven environment. Having worked in the corporate world, he has been coaching his colleagues in the skills they need to succeed outside the lab: how to run meetings, how to speak with diverse audiences, and how to interface with other scientists.
Graduate students are partnered with undergraduate students, providing hands-on training in setting up and using the tools.
鈥淚t鈥檚 nice to be exposed to what it is like to participate in research,鈥� says honours Physics undergraduate student Zach Friedenberger. 鈥淚t鈥檚 important to me to see the impact of my coding, though it can be challenging to juggle my time in the lab with my coursework!鈥�
In 2015, Leslie founded ScopeSys, a start-up company with a technical and business team based in Canada. In 2017, as Leslie was promoted to Associate Professor with tenure, she energized her business performance, working closely with Derrick Wong in 捆绑SM社区鈥檚 Office of Innovation and Partnerships (I+P), as well as with the Office of Technology Transfer at Harvard. In 2018, Leslie at long last received word that she had successfully secured a United States patent for CLiC.
Since the first spark of CLiC imaging, Leslie has had to acquire an entirely novel skillset 鈥� one designed to propel her technology into the world. It鈥檚 not been an easy road, but one almost custom designed for her experimenting predilection.
As she worked to secure the patent, she engaged relentlessly with scientists, both in industry and academia, to identify what was truly unique about the technology. She spent part of her sabbatical year in the pharmaceutical industry, in the UBC Pharmaceutical Science Department, as well as in the Chemical Engineering Department at Stanford to help broaden her understanding of the potential applications of the technology. She presented at the 捆绑SM社区 Dobson Cup competition鈥攖aking home fourth prize and $5,000鈥攁nd secured interest from a local law firm, Fasken Martineau, which supports technology-based start-ups in Montreal.
These and other mentors, including those from TandemLaunch and the Hatch, incubators in Montreal and Vancouver respectively, have encouraged her to continue filing reports of invention as the technology develops. At the time of writing, Leslie has four additional patents under examination based on her work at 捆绑SM社区.
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Having walked the path, Leslie strongly believes that universities will lead the way in producing a new future-ready generation of scientist-innovators. 鈥淎s we increase resources and understanding of the pathway from idea to innovation, and as we create science-focused hubs and maker-spaces that are technically oriented, students will start to develop more professional skillsets while also putting their degrees in action,鈥� says Leslie.
In her opinion, the training involved in running a start-up has significantly advanced her science, by bringing a level of sophistication and understanding to the tools she has created. As her company continues to grow, she is excited to support others who are inspired to make the leap from basic science to commercialization.
Just as glass can bend to create a better microscope, so too can scientists learn the skills to be innovators and start-up founders, she believes. The secret for a smooth ride?
鈥淎bove all, you need the backing of your university and mentors, and a great team.听捆绑SM社区, my department, and ScopeSys鈥� advisory board have been extremely supportive of my pursuits.鈥�
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This article is the first in the series, "Future-Ready", featuring 捆绑SM社区's most innovative researchers. Stay tuned to this space for more, or听subscribe to our mailing list to receive stories in your inbox.听
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*Dr. Daniel Berard and Dr. Radin Tahvildari are Research Associates in the ScopeSys/LeslieLab idea-to-innovation Phase2B grant
Frank Stabile and Albert Kamanzi are PhD students in the LeslieLab who will do Mitacs Internships with ScopeSys as part of their PhD program