Karly Raber expected to spend her final months of medical school finishing up her last rotations, but her plans were upended by the pandemic. So Raber got involved in COVID-19 monitoring efforts, calling people across the Chicago area who had tested positive for the virus to track how they were feeling, monitor their symptoms and refer them to more intensive care as needed.
On the outer edge of the color spectrum of visible light lies a mysterious place on the far side of violet. As red morphs to orange and then fades to yellow and so on, the wavelengths become shorter and shorter. Until finally — concealed by the diffraction limit — there is a wavelength so short that it cannot be viewed by common optical microscopes. But this is exactly the hidden place where Vadim Backman believed he might find the secrets of life.
“The theory of the diffraction limit goes back almost 200 years,” says Backman’s longtime collaborator Allen Taflove ’71, ’72 MS, ’75 PhD. “It says that with normal microscopy, you cannot detect structural changes within cells much smaller than about 200 nanometers or so. But Vadim posited that the key to cancer detection lay at much smaller length scales — 20 to 50 nanometers. The skepticism he met was profound. People thought he was violating 200 years of theory. It seemed like absolute science fiction.”
In the face of great doubt, Backman teamed with Taflove to develop partial wave spectroscopy (PWS) nanocytology, a new technology that not only views cells at these elusive length scales but also uncovers the shrouded malignancies that Backman hypothesized.
“Cancer is a terrible way to die, and it is a traumatic experience for the patient’s family,” says Backman, the Walter Dill Scott Professor of Biomedical Engineering in Northwestern’s McCormick School of Engineering. “I knew that I had to at least try to address this question, because it could end up saving a life.”
There is a vast treatment gulf between stage 4 cancer, which is almost untreatable, and stage 1, where the rate of survival is close to 100 percent. The problem is that very early-stage cancers rarely exhibit symptoms and are difficult to detect, so physicians have no indication to treat them. But with PWS nanocytology, diagnosticians can detect details of “pre-precancer” in cells, something that could not be done with conventional microscopes. That means that this new technology would save more lives than the one that Backman initially aimed for. It could potentially prevent thousands of cancer-related deaths each year.
“When Vadim started this work in 2003, he was greeted with a lot of skepticism from the cancer research community,” says Hemant Roy ’89 MD, another longtime collaborator. “But Vadim was clearly ahead of his time.”
Breaking the Diffraction Limit
When Backman joined Northwestern’s faculty in 2002, he and Taflove, a professor of electrical engineering in McCormick, began collaborating almost immediately. Newly graduated from the Harvard University and Massachusetts Institute of Technology combined program in medical engineering and medical physics, Backman was establishing himself as an expert in biophotonics, a field that uses light to study biological molecules, cells and tissues. Taflove, on the other hand, is a world-renowned expert in Maxwell’s equations, which explain how electricity and magnetism interact to form electromagnetic waves.
“We are like puzzle pieces,” Taflove says of his relationship with Backman. “Our connection is simple. Vadim studies light, which is an electromagnetic wave. And in the visible spectrum, the interaction between light and materials is governed by Maxwell’s equations.”
To study the minute ways cellular nanostructures react and interact with ordinary visible light in the range of 20 to 50 nanometers, Backman needed to overcome the diffraction limit. For that, he needed Taflove to solve Maxwell’s equations to determine these interactions.
“Many people have tried to circumvent the diffraction limit,” Backman says. “But I thought, ‘Maybe we don’t have to visualize very small structures in order to measure them.’”
That is exactly how he designed PWS nanocytology to work. Instead of visualizing particles smaller than the diffraction limit, it senses their presence and organization by analyzing the light they scatter. The different angles of scattered light tell a story about the health of cells, which can lead to an accurate cancer diagnosis at even the earliest stages of cancer formation. This provides information not only about individual cells but also about cells’ fundamental building blocks, such as proteins, DNA and RNA.
“We essentially don’t have a limit for how small the structures are that we can sense,” says Backman, co-leader of the Robert H. Lurie Comprehensive Cancer Center’s Cancer & Physical Sciences Program and a resident faculty member of Northwestern's Chemistry of Life Processes Institute. “This can be done fairly easily in a robust, reproducible manner, so it can be translated to real health care.”
Making a Difference
The impulse to improve the lives of others comes naturally for Backman. Growing up in St. Petersburg, when it was still part of the Soviet Union, he discovered an interest in mathematics. As a child, he eagerly read the textbooks from junior high, high school and even college math courses. But then his enthusiasm began to wane.
“The problem I had with math was that it’s too decoupled from the world,” Backman says. “I wanted to study something that could make more of a difference for people.”
When he entered college at the St. Petersburg Polytechnic Institute, Backman decided to study physics. He went on to earn his doctorate in health sciences and technology from Harvard and MIT.
“It was the perfect combination for me,” Backman says. “I don’t think I would be as excited to do purely theoretical work in physics, even though it’s intellectually stimulating. And I wouldn’t be fully satisfied doing translational work either, because I would miss the physical sciences.”
In the Harvard-MIT program, Backman completed rotations with other medical students and learned he enjoyed being on the hospital floor interacting with patients.
“I love working in the laboratory,” Backman says. “But seeing a patient connects my work to a real person. That gives me a sense of urgency.”
His desire to help others not only guided his career but helped attract his wife, Luisa Marcelino, who is also a close collaborator. In 2002 Marcelino was struggling with her molecular biology research at MIT and had completely hit a wall. Thinking that Backman could give some insight, a mutual friend connected the couple. Backman brainstormed an algorithm that helped Marcelino get unstuck, but that’s not what impressed her. She was spellbound by the amount of time he spent trying to help.
“I realized on July 4, 2005, that I was going to marry him,” she says. “He was planning to go to a barbecue, but he missed the whole party because we were on the phone for seven hours discussing my project. I was really impressed by his commitment. To me, that sealed the deal.”
A New Pap Test
Backman’s PWS-based test makes use of the “field effect,” a long-debated biological phenomenon in which seemingly normal cells located some distance from the malignant or premalignant tumor undergo molecular and other changes.
The new technology is so sensitive that it can detect cancer in one organ by using more accessible cells from a neighboring area. Backman and Hemant Roy, a physician formerly at NorthShore University HealthSystem in the Chicago area and now a professor of medicine at Boston University, tested the technology on field-effect alterations associated with seven different cancers. Time and time again, they saw the same results.
Cells swabbed from inside a cheek, when examined with PWS nanocytology, showed signs of lung cancer. Cells from the duodenum showed pancreatic cancer. Cells from the cervix showed ovarian cancer. Cells from the rectum showed colon cancer. The list went on.
“The technology is highly innovative,” Roy says. “But the biological and clinical applications are astonishing.”
These findings translated into a minimally invasive early detection test using cells collected with a swab, exactly like a Pap smear. In 1928 Greek physician Georgios Papanikolaou discovered that if he gathered cells from an easily accessible area, he could examine them under a microscope and detect early signs of cervical cancer. Soon physicians worldwide began administering the “Pap test” during routine patient visits. Early diagnosis naturally led to early treatment, significantly reducing cervical cancer incidence and death rates.
“If we had comparable screens for other types of cancer, we could reduce cancer deaths tenfold,” Backman says. “When else have we seen such a discovery? Never.”
Until now, that is. Backman’s early detection technique could soon be available for physicians to use with their patients. Several large clinical trials are already in progress, and within three years tests for lung, colon and prostate cancer — which are among the most common types — should enter the market. Much like the Pap test, these new screens could become part of regular primary care, putting physicians one step ahead of cancer — poised to prevent it from getting out of control and untreatable.
Suspicious Signature Gives Way to New Treatments
In testing samples from seven types of cancer, Backman noticed they all exhibited the same signature. The way the chromatin — or genome structure — was arranged seemed to determine whether or not the cancer would easily or stubbornly respond to treatment. Chromatin is a group of macromolecules — including DNA, RNA and proteins — that house genetic information within cells and determine which genes get suppressed or expressed. In the case of cancer, chromatin has the ability to regulate the capacity of cancer cells to adapt to treatment by expressing genes that allow the cancer cells to become resistant to treatment.
“If you think of genetics as hardware, then chromatin is the software,” Backman says. “Just by looking at the cell’s chromatin structure, we can predict whether or not it will survive ordinary treatments.”
Chromatin is packed together at different densities throughout a cell’s nucleus. By using PWS, Backman examined chromatin in living structures in real time. He discovered that the packing density of chromatin in cancer cells produced predictable changes in gene expression. The more heterogeneous and disordered the packing density, the more likely cancer cells were to survive — even in the face of radiation and chemotherapy. The more ordered and conservative the packing density, however, the more likely the cells would die during treatment.
When Vadim Backman paired his chromatin-protection therapeutics (CPT) with chemotherapy, nearly every cancer cell in a cellular culture died within days. Illustration by Juan Hernandez, Northwestern University; rendered here by James Graham.
This discovery lit a lightbulb. Backman realized that cancer might not require new treatments. Maybe it just needs to be made more vulnerable to existing treatments.
Backman developed a solution to alter chromatin’s structure in a way that prevents cancer from evolving to withstand treatment, making it an easier target for existing drugs. He tested the strategy in cellular cultures, and it almost completely wiped out the disease.
“There is one thing that all cancers do,” Backman says. “They have a phenomenal ability to change, to adapt, to evolve in order to evade treatment. Cells with normal chromatin structures die because they cannot develop this resistance.”
Backman says the treatment has shown promising results in an animal model, and he aims to start human trials within a year.
“Whether or not this ultimately leads to a treatment, we don’t know yet,” Taflove says. “But I’ve learned to keep an open mind with Vadim. He does genius work.”
Backman believes this cancer treatment could be his most important research yet. As his diagnostics near implementation in the hospital, he has shifted his focus to pursuing chromatin-protection therapeutics. And his collaborators, including Taflove, who is nearing retirement age, are right there with him.
“I am going to ride shotgun alongside Vadim the entire time,” Taflove says. “I could retire, but I don’t want to because I want to see this through. This is the most excited I’ve been in my career, and I’m in the game to win.”
Amanda Morris ’14 MA is a science and engineering writer in the Global Marketing and Communications department at Northwestern.