Fighting COVID with Biophysics

by Lydia Hodgins

Recently, I went to a medical lab for bloodwork, and upon noticing my university mask while prepping my arm the technician asked the usual question, What are you studying?”. “Biophysics,” I responded, which immediately led to the follow-up, What do you do with that?”. This second question is much harder to answer, particularly when the response is only meant to fill 2 minutes of small talk. Had it still been 2019, I may have given a vague answer that would have ended the conversation. However, the pandemic has now given myself and other biophysicists much talking material about the value of our discipline.

The large impact the pandemic has had on our lives has brought to attention the importance of scientific research. With the numerous lockdowns that brought our daily routines to a halt we all began monitoring the news in hopes to hear of new scientific developments that may bring us a step closer to returning to “life before the pandemic.” People quickly became aware of the many answers this virus demanded of scientists. Not only were we waiting for a vaccine, but we also needed treatments for those infected, rapid tests to detect infection, models to predict the next wave, and a better understanding of how the virus is transmitted. Biophysicists rose to this challenge.

Biophysics can be difficult to describe because it branches down many avenues of science, resulting in numerous applications involving a variety of experimental and theoretical techniques. The diversity of this field has reflected the complexity of the COVID-19 research effort, and many Canadian biophysicists have developed research projects which focus on the various problems related to COVID-19. These projects are producing promising results that may not only aid in the COVID-19 research effort but could also help fight other diseases.

On December 9, 2020, Health Canada authorized the first SARS-CoV-2 vaccine developed by Pfizer-BioNTech. Contributing to the development of this vaccine was Vancouver-based biotech company, Acuitas Therapeutics. This company provided the lipid nanoparticle (LNP) technology used to deliver the mRNA vaccine. A key scientist behind this technology is Dr. Pieter Cullis, a Canadian physicist and biochemist at the University of British Columbia. Dr. Cullis and his team have been researching LNPs for approximately 40 years bringing this technology to the point of being applied to mRNA vaccines in time for the COVID-19 pandemic. Currently collaborating with Dr. Cullis at UBC is Dr. Sabrina Leslie who is using convex lens-induced confinement (CLiC) microscopy to simultaneously measure multiple parameters of LNPs. Leslie’s team recently published a paper in ACS Nano reporting the results of correlated measurements of the size and payload of LNPs containing silencing RNA. Leslie explained to me that by correlating the measurements of the biophysical properties of LNPs it could streamline the design process of future drugs and potentially uncover new design formulations for the current LNP vaccine delivery method.

The announcement of the Pfizer vaccine, however, did not end the search for additional original vaccine delivery methods. Recently, biophysicist Dr. Maikel Rheinstadter from McMaster University published a paper in PLOS One reporting a new technique which harnesses red blood cells to create a vaccine. I met with Dr. Rheinstadter and his postdoc Dr. Sebastian Himbert to learn more about this emerging vaccination method. Using a plastic model of a red blood cell to assist in his explanation, Sebastian described their novel technique to me. To create a vaccine they have taken the red blood cell, removed its contents, and embedded the SARS-CoV-2 spike protein into the membrane creating an endogenous particle which mimics the coronavirus from the exterior. These modified red blood cells get detected by the spleen triggering an immune response and eliciting the effect of a vaccine. But this is not the only application of what they have coined “smart red blood cells.” In fact, they were developing this technology for other applications such as the delivery of antibiotics prior to the pandemic. They described the shift to developing a vaccine as being a natural transition to use their “toolbox” of techniques to contribute to the COVID-19 research effort.

In addition to a vaccine, we also need therapeutics to treat those who have contracted the virus. Biophysics is present in this research too as is demonstrated by the work of Dr. Michael Woodside at the University of Alberta. Michael Woodside’s research project involves targeting the molecular process called programmed ribosomal frameshifting (PRF). PRF is necessary for the expression of the viral genome and is stimulated by an RNA structure called a pseudoknot. His lab is using biophysical methods to identify molecules which could bind to the pseudoknot and inhibit PRF. Dr. Woodside explained to me that the RNA pseudoknot is highly conserved across branches of the coronavirus family which means this type of therapeutic could be effective at treating a range of coronaviruses. This is the focus of a collaborative paper he recently published in the journal, Viruses. Both Woodside and Rheinstadter mentioned the importance of collaboration in their interviews. This is not a coincidence, as the interdisciplinary nature of biophysics creates the perfect conditions for communication and collaborations between researchers in physics and biology.

With the world now opening up, the need for sensitive, inexpensive, and rapid testing mechanisms is ever apparent. Biophysicist, Dr. Vincent Tabard-Cossa and postdoc Dr. Erin McConnel from the University of Ottawa are tackling this problem. The T.-Cossa lab has developed solid-state nanopores which can detect individual molecules electrically. They previously used this technology to detect pathogens such as Group A Streptococcus or to quantify disease biomarkers such as thyroid stimulating hormone (TSH) as recently published in ACS Sensors and Nature Communications papers respectively. When the pandemic hit they took the logical next step to apply this technique to detecting the SARS-CoV-2 virus. This project involves developing an isothermal enzymatic amplification technique that requires minimal tools and time to prepare a sample. This testing method could be miniaturized and mass produced resulting in a cheap, decentralized testing mechanism. The T.-Cossa lab is connected with the start-up company Northern Nanopore Instruments which, he explains, offers them the ability to easily commercialize promising detection schemes. It is not uncommon for biophysics labs to generate spin out companies, demonstrating that biophysics is not just about pure research, but is also connected to industry.

Each researcher I spoke with is tackling a different problem related to COVID-19, yet they all demonstrate why biophysics lends itself well to COVID-19 research. When asked how they came about their COVID-19 focused project, a common theme that emerged in their answers is that they were able to quickly adapt their research to a new question. I think this speaks to the very nature of biophysics, which consists of approaching problems in the life sciences with techniques rooted in the fundamental sciences to try to find general principles governing living systems. This approach, both broad in its scope and reductionist by design, enables the ideas, techniques and solutions to be applied to a variety of biological systems including the SARS-CoV-2 virus.

In order to make research possible scientists need to receive funding. When the pandemic hit the government responded with an impressive extent of emergency response funds. NSERC provided over $19 million distributed amongst 369 projects in the form of the Alliance COVID-19 and College COVID-19 grants. The CFI dedicated $28 million to a COVID-19 Exceptional Opportunities Fund. And, as of January 2022, the CIHR has invested $328.8 million towards COVID-19 research across 31 competitions funding 818 projects. This response has been welcomed by scientists across Canada, but the question is, with its great potential to contribute to the COVID-19 research effort, what portion of this emergency funding was received by biophysicists? In my search through the award databases, I found searching the keyword biophysics led to disappointingly few results. I knew more biophysicists were out there and what I found was that many grants given to biophysicists did not explicitly contain keywords identifying them as biophysics research. When I spoke with Maikel Rheinstadter he expressed concern that research based in the fundamental sciences can be difficult to get funded by agencies such as the CIHR due to the selection committees having a bias towards research in the health sciences departments. This may explain why it was so difficult to identify biophysics research amongst successfully funded grants, as this aspect might have been played down in order to get approval in this biased system. Nevertheless, biophysicists have received grants from COVID-19 research funding projects at each of the agencies mentioned above, but how many exactly is difficult to establish.

When I asked the other researchers for their opinion on the response of the COVID-19 emergency funding they also offered their own concerns. Michael Woodside, although impressed with the immediate response of the government, fears this support may not be maintained long term to allow for preventative research as happened after the SARS epidemic 20 years ago. Vincent Tabard-Cossa provided a similar concern, that the funding may have gone towards more immediate research rather than “riskier” projects which could potentially have large long-term impacts. This could mean an underrepresentation of biophysics research in the funded COVID-19 related research projects as biophysics often involves innovative technologies which may be deemed riskier than the biochemical technologies we are familiar with.

Throughout this investigation I have come to appreciate the many prospects biophysics has to offer the field of medicine. When speaking with Vincent and Erin I asked for their opinion on the overall importance of biophysics research. They spoke of the need for biology to become more quantitative in order to expand on current technologies and to develop future ones. Vincent even went as far as to predict that, “biology will, in a way, evolve to be biophysics.” I asked Sabrina Leslie a similar question and she offered her opinion: “Canada is in a unique position to lead [the field of biophysics] and the largest possible investment in biophysics and applied research as well as manufacturing and biotech would be strategic at this time.”

Sitting in the chair at the medical lab, my arm prepped and ready to be poked, I was prepared when the technician asked, What can you do with biophysics?”. As she drew my blood I explained, Biophysics has many applications and is even contributing largely to the COVID-19 research effort. In fact, biophysicists have shown how to use red blood cells to make a vaccine.” Leaving the medical lab, I felt proud to be able to meaningfully answer that question in a 2-minute conversation with a stranger.

 


About the author: Lydia Hodgins is an undergraduate student at McMaster University entering her 4th year of the Honours Medical & Biological Physics program. Currently she is a member of The Fradin lab group where she is investigating the detection of transcriptional condensates in early fruit fly embryos using confocal microscopy. Outside of school Lydia enjoys playing the piano and exploring nature.

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