Calem Kenward wins 2021/22 Killam Doctoral Award

UBC researchers are the first in the world to publish structural images of the N501Y mutation on the SARS-CoV-2 spike protein—a change believed to be partly responsible for the highly infectious nature and rapid spread of variant B.1.1.7.

The pictures, taken at near-atomic resolution, provide critical insight as to why the B.1.1.7 variant—first detected in the U.K and now accounting for a growing number of cases across Canada—is more infectious. The images also add to the growing body of data indicating that existing vaccines are likely to remain effective in preventing mild and severe cases caused by B.1.1.7.

Dr. Sriram Subramaniam, professor in UBC faculty of medicine’s department of biochemistry and molecular biology, discusses the implications of his team’s research, recently published in PLOS Biology.

What do these images reveal about the B.1.1.7 variant?

Viruses are constantly mutating. The B.1.1.7 variant of concern, which was first reported to the World Health Organization in mid-December 2020, has an unusually large number of mutations. Of particular interest is a mutation known as N501Y located on the virus’s spike protein, which is what the virus uses to attach itself to human cells.

The images we captured provide the first structural glimpse of the N501Y mutant and show that the changes resulting from the mutation are localized. In fact, the N501Y mutation is the only mutation in the B.1.1.7 variant that is located on the portion of the spike protein that binds to the human ACE2 receptor, which is the enzyme on the surface of our cells that serves as the entry gate for SARS-CoV-2.

Will existing vaccines remain effective?

Our analysis revealed that even though the N501Y mutant can bind and enter our cells more readily, it can still be neutralized by antibodies that block the entry of the unmutated version of the virus into cells.

This is an important observation and adds to the growing body of evidence that the majority of antibodies elicited in our immune system by existing vaccines are likely to remain effective in protecting us against the B1.1.7 variant.

How did you capture these structural images?

The SARS-CoV-2 virus is 100,000 times smaller than the size of a pinhead, making it undetectable using a regular light microscope. The proteins on the surface of a virus are even smaller.

To visualize the detailed shapes of viruses and proteins, we use cryo-electron microscopes, which can be up to 12 feet tall. This powerful imaging technology uses beams of electrons to visualize shapes of tissues and cells using ultra-cooling, or “cryo” techniques—essentially, the imaging of samples at liquid nitrogen temperatures.

Are you researching other COVID variants?

We are currently examining other variants, including P.1 (Brazilian), B.1.351 (South African), B.1.427/B.1.429(Californian) and B.1.617 (Indian) variants, and trying to understand how these mutations alter how the spike protein interacts with neutralizing antibodies. We are also looking at how these mutations may change how the virus binds to ACE2.

It’s important to understand the different molecular structures of these emerging variants to determine whether they’ll respond to existing treatments and vaccines and ultimately find ways to control their spread more effectively.

Millions of Canadians have received the Pfizer-BioNTech COVID-19 vaccine, but what many may not realize is that a key component of the injection was developed right here at UBC.

Acuitas Therapeutics, a UBC spin-off company co-founded by Dr. Pieter Cullis, developed the lipid nanoparticle technology that allows the Pfizer-BioNTech mRNA vaccine to enter human cells.

For the UBC professor, he says he never imagined Acuitas’ technology might one day help bring an end to the global pandemic.

“Two years ago, I thought I had reached the apex of my career when we developed a medicine for a genetic disorder that works extremely well,” says Dr. Cullis. “But to have this sort of thing happen, it’s like a one-in-a-million possibility. And the impact that it is having, it’s putting Canada on the map for making an enormous difference to global health.”

From UBC laboratories to successful start-ups

Acuitas is among a growing number of UBC spin-off companies that are developing cutting-edge treatments and potential cures for human diseases, all while earning global recognition for their ground-breaking work. Others include Precision NanoSystems and AbCellera.

AbCellera began at UBC in 2012 with only six employees, including founder and now CEO Dr. Carl Hansen. Now the company, which pioneered an antibody discovery platform, is one of the fastest growing and most valuable biotech companies in Canada, recently partnering with pharmaceutical giant Eli Lilly and Co. to develop an antibody treatment for COVID-19.

Precision NanoSystems, developed through a collaboration between Dr. Hansen and Dr. Cullis at UBC, is leveraging its cutting-edge biomanufacturing platform, with support from the federal government, to build one of Canada’s first large-scale manufacturing facilities capable of producing mRNA vaccines and other genetic medicines domestically.

The common theme amongst each company? They all began at UBC, first as research in university laboratories and then as start-up companies. The university provides entrepreneurial support to researchers who have technology determined to have a potentially high societal impact that would be best realized through creating a spin-off company.

UBC researchers are also creating biotech companies that are helping to drive health innovation and fuel Canada’s economy. For example, Notch Therapeutics, co-founded by Dr. Peter Zandstra, is developing a pipeline of cellular immunotherapies for treating cancer and other diseases and recently raised USD$85 million in venture funding.

Establishing B.C. as a global biotechnology hub

For UBC Vice-President Health Dr. Dermot Kelleher, the pandemic has shone a spotlight on the critical role emerging biotech companies are playing in developing safe treatments for diseases, including COVID-19.

“We still have a long way to go, but the pandemic has demonstrated what can be accomplished at an accelerated pace,” says Dr. Kelleher. “As we turn towards recovery, we have an unprecedented opportunity now to invest in B.C.’s biotechnology sector and to accelerate scientific discoveries into new drugs and treatments more effectively and more efficiently for other diseases such as cancer, diabetes and heart disease.”

Investing in B.C.’s biotech sector will reduce the time and cost for new therapeutics, devices and diagnostics to move through the development pipeline and reach patients faster, as well as create employment opportunities for British Columbians, including UBC students and new graduates, says Dr. Kelleher.

“Doing so will boost Canada’s reputation for research and care, enhance collaborations with like-minded scientific groups around the world, attract and retain world-class scientists to B.C., and boost our province’s economy by increasing opportunities for the pharmaceutical and biotechnology sector,” he says. “The result will be improved patient and population health, equity and quality of life, as well as enhanced sustainability of our health care system.”

Endless possibilities for new medical treatments

For Dr. Pieter Cullis, a silver lining of the pandemic is that it has shown how fast new treatments and vaccines can be safely developed with sufficient resources and a sense of urgency.

His hope now is to extend Acuitas’ lipid nanoparticle technology, which delivers encapsulated messenger RNA to enter targeted cells, to be able to treat other diseases. He envisions a future in which patients can receive a vaccine to prevent any number of diseases, including cancer.

“This vaccine application is really just the tip of the iceberg,” says Dr. Cullis. “Almost every disease that you can name, from cancer to Alzheimer’s, could potentially be tackled by mRNA technology. My hope is that Vancouver becomes the world centre for developing these kinds of therapeutics.”

Interview language(s): English

This post originally appeared on the UBC Faculty of Medicine Webpage.