Jonathan R. Lai, PhD, develops immunotherapies and vaccines against viral infections such as Ebola virus, Dengue viruses and Chikungunya virus, which affect millions of people annually in developing nations. A native of Edmonton, Alberta, Canada, Dr. Lai earned a PhD in biophysics at the University of Wisconsin-Madison, before completing postdoctoral fellowships at Harvard Medical School. Dr. Lai joined the Einstein faculty in 2007, where he is currently the Dan Danciger Professor of Biochemistry. He is currently the Principal or Co-principal Investigator of five grants from the National Institutes of Health.
What was your first hands-on laboratory experience?
After my freshman year in college, where I majored in biochemistry, I worked in a food microbiology laboratory in Alberta where I isolated bacterial samples from meat. Livestock farming is a major industry in Alberta—hence the focus on animal science. The lab was studying the use of harmless bacteria to counteract harmful bacteria.
Your doctoral studies focused on peptides. What are they and why are they useful?
Peptides are short chains of amino acids—the building blocks of proteins. Peptides play vital roles in cell signaling and cell function and can be used to make drugs and vaccines. My PhD thesis was spent trying to understand alpha, or naturally occurring, peptides and the design principles for adapting them to make certain shapes, or conformations, which can affect their functions. The next, and more complicated, challenge was extending that information to the development of beta, or nonnatural, peptides—for example, to make synthetic proteins with antibacterial or antiviral properties.
Was there a critical skill or technology you learned in your doctoral studies?
Certainly one of the most important is a methodology called phage display, which is based on viruses known as bacteriophages that replicate inside bacteria. Phage display allows you to study protein-protein and protein-antibody interactions on a large scale and select those proteins with the highest affinity for specific targets from a large collection or “library” of mutations. It’s a powerful tool that I’ve used throughout my career. The inventors of phage display won a share of the Nobel Prize in Chemistry 2018.
How did you get interested in viruses like ebolavirus?
When I first joined Einstein, in 2007, I focused on HIV-1 and used phage display to optimize existing antibodies against HIV-1 or to isolate new antibodies. A few months in, I met Kartik Chandran, PhD, another new faculty member, who asked if I might be interested in studying ebolaviruses, which, like HIV, uses alpha-helices in its viral coat protein to enter cells. I told him, “That’s interesting, I’ll check it out.” At the time, he probably thought I was blowing him off, but I just wanted to read up on it. I went back and said, “Let’s work together,” and we’ve been collaborating ever since.
What are some fruits of that collaboration?
One of our first discoveries stemmed from Kartik’s discovery of how ebolaviruses multiply in cells they infect. They must first bind to a protein inside the host cell called Niemann-Pick C1, or NPC1, suggesting that an anti-NPC1 antibody could prevent viral multiplication by blocking Ebola from binding NPC1. The catch is that ebolaviruses sneak into cells via endosomes—cell organelles that form when pieces of the cell membrane encapsulate the virus after it comes in contact with the cell. But antibodies can’t enter cells this way, so our solution was to make antibodies with two arms: one arm attaches to the virus outside the cell, allowing the antibody to hitch a ride with the virus into the endosomes; then the antibody’s other arm neutralizes NPC1, which forms part of the endosome’s inner lining. We then showed in mice that these “bispecific” antibodies are capable of neutralizing all known ebolaviruses and also have potential activity against other filoviruses, such as Marburg. We called them “Trojan Horse” antibodies since the virus unknowingly carries the antibody with it into the endosome, and then the antibody attacks the virus.