Emory chemist Rong Ma received a $150,000 Michelson Prize for her proposal to harness the mechanical processes of cells as a new approach in the long-running quest to develop cancer vaccines. Ma, who received her PhD from Emory in 2021, is a post-doctoral fellow in the lab of Khalid Salaita, Emory professor of chemistry.
The Michelson Prizes: Next Generation Grants are annual awards to support young investigators who are “using disruptive concepts and inventive processes to significantly advance human immunology and vaccine and immunotherapy discovery research for major global diseases,” according to the Michelson Medical Research Foundation and the Human Vaccine Project, the organizations administering the awards. Ma was one of three scientists selected through a rigorous global competition to receive a 2021 Michelson Prize.
“We need disruptive thinkers and doers who dare to change the trajectory of the world for the better,” says Gary Michelson, founder and co-chair of the Michelson Medical Research Foundation. “Yet promising young researchers too often lack the opportunities, resources and freedom to explore their bold ideas. The pandemic has created additional roadblocks for many of them. With the Michelson Prizes, we aim to provide early-career investigators a vital boost for their forward-thinking approaches.”
“Rong Ma is a spectacular, highly motivated scientist,” Salaita says. “Sometimes I will tell her that a goal she sets it too lofty or difficult to pull off, but she will look back at me and say, ‘I want to do really big, difficult things.’”
“To find specific antigens on cancer cells for cancer vaccine development is extremely challenging, partly because of the ambiguity in predicting what antigens the body’s immune cells can recognize,” Ma says. “Many researchers are focused on using genetic sequencing techniques to find genetic mutations and predict tumor-specific antigens to achieve this goal.”
Ma’s proposal, however, is to use the mechanical forces transmitted by immune cells to antigens as a marker to identify and evaluate whether an antigen can trigger a potent immune response. If the method works in a mouse-model system, Ma explains, the long-range vision would be to isolate the immune cells that are mechanically active when recognizing cancer-specific antigens. The identified antigens and isolated immune cells could then be used to train the body to defend against cancer cells.
A love of complex systems
As an undergraduate in her native China, Ma majored in environmental sciences. The interdisciplinary nature of environmental sciences taught her to think about complex problems from different perspectives and to integrate knowledge across specialties.
During a masters’ program in environmental science and technology at City University in Hong Kong, Ma came across cancer research and decided to shift her focus to medicinal chemistry. “I love working on complex systems,” Ma says, “but I realized that I had a better chance of making a valuable contribution by focusing on a smaller-scale complex system, like the immune cells.”
She was especially intrigued by research published in 2016 by the lab of Khalid Salaita, which specializes in the mechanical forces of cellular processes. The Emory researchers found that T cells, the security guards of the immune system, use a kind of mechanical “handshake” to test whether a cell they encounter is a friend or a foe. The lab had developed special tools to make this discovery — DNA-based tension sensors that light up, or fluoresce, in response to a miniscule mechanical force of a piconewton — about one million-millionth the weight of an apple.
Ma came to Emory for her PhD in chemistry, so that she could work in the Salaita lab and help advance this technology. “At that point, it was a relatively new perspective to investigate the mechanical forces of cells and begin to understand these processes,” Ma says. “It opened up a whole new world of research for me.”
Harnessing molecular forces
The Salaita lab has continued to develop the tension sensors and further observe and characterize the mechanical forces of T cells. “We’ve advanced our understanding to the point where we can start exploring how to harness the molecular forces in cells for mechanically triggered therapeutics,” Ma says.
T cells continuously patrol through the body in search of foreign invaders. They have molecules known as T-cell receptors (TCR) that can recognize specific antigenic peptides on the surface of a pathogenic or cancerous cell. When a T cell detects an antigen-presenting cell (APC), its TCR connects to a ligand on the APC. If the T cell determines the ligand is foreign, it becomes activated and starts a signaling chain to recruit other cells to come and help mount an immune response.
The human body contains millions of different T cells and they specialize in recognizing specific antigenic peptides and binding with them. A current approach for research into cancer vaccines is to painstakingly try to identify which peptides are antigenic and which T cells are activated by them.
Studying the binding process in a laboratory solution, however, turns out not to be the most reliable method for pairing a cancer peptide with the T cell that it triggers. That’s because, in the body, cells are moving and sliding past each other’s surfaces. A TCR needs to grab on to a cancer peptide and give a strong “handshake” in order for it to stick.
“It turns out that testing the binding in solution is not the same as binding in more dynamic, real-world conditions,” Salaita explains. “Rong Ma has figured out a way to measure the duration of the binding ‘handshake tug’ at the interface of the cell and a glass slide presenting these antigens. We believe this method may be further developed into a much better way to determine which particular cancer peptides are going to trigger a response in which particular T cell, and even which T cell receptor is doing the tugging.”
Testing the method
In experiments, Ma will try to establish a proof-of-concept of this method. If it proves effective, then it may be possible to amplify those cancer-specific T cells and T cell receptors in a laboratory to help cancer immunotherapy development.
The challenge of pairing the body’s millions of different T cell receptors with the billions of different antigens that may exist remains daunting.
“Some of the preliminary data we have gathered looks promising, and the Michelson Award will help us get the remaining data we need to test our method.” Ma says. “A cancer vaccine is the ultimate vision. We still have a long way to go to achieve that, but we hope that our method may provide another step forward.”
This year’s Michelson Prize winners will receive their rewards in a virtual ceremony on March 10.
“It is inspiring to see their passion for innovation and their courage to think out of the box,” says Wayne Koff, CEO and president of the Human Vaccines Project. “I look forward to their future breakthrough discoveries and how their research can contribute to the Human Vaccines Project’s mission of developing the first AI model of human immunity.”