When Carl F. Nathan, Microbiology and Immunology, Weill Cornell Medicine, received his acceptance to Harvard University Medical School in December 1966, he did not celebrate. Earlier that day, he had watched his mother die from cancer.
“I made an emotional and intellectual commitment to the field that day,” Nathan says. “I wanted to express my gratitude to her and try to pay back, too late, by helping other people in the same situation.”
Nathan went on to medical school, a residency, and an oncology fellowship, but he soon became frustrated with chemotherapy as the default, and usually ineffective, treatment at the time. Already torn between clinical oncology and fundamental research, Nathan saw that going to the root of the problem—to understand how the body’s immune system works—could uncover new approaches to combat not only cancer but infectious diseases as well.
The Immune System versus Bacteria
“The immune system has enormous destructive power,” says Nathan. “It can destroy any tissue it thinks is infected. But at that time, we didn’t know anything about what the firepower consisted of and how it was regulated.”
In 1977 Nathan began full-time research at The Rockefeller University to find out, looking specifically at immune response to infectious diseases. “I thought I could make faster progress using infectious disease,” he says, “because that was the situation in which these immune capacities evolved, whereas cancer typically afflicts people after their reproductive age.”
Nathan knew that neutrophils and macrophages were the cells of the immune system that could kill pathogens directly, rather than killing infected host cells. Over the next decade, he would discover that macrophages are activated by a protein, called interferon-gamma. Interferon-gamma is produced by T lymphocytes when they detect bacteria. His lab also found that, to his and others’ surprise, this activation enables the production of reactive oxygen species such as superoxide and hydrogen peroxide, which the cells then use as weapons against the bacteria.
“We were then able to introduce interferon-gamma as a treatment for children who were deficient in this system, who would have died from bacterial or fungal infections,” Nathan says. The treatment also worked for leprosy, which is caused by a mycobacterium. This pathway didn’t explain everything, however. “We were keenly aware that something was missing,” Nathan says.
When he moved to Cornell in 1986, he discovered the second major killing pathway. The immune response to infectious disease also included neutrophil and macrophage production of another protein, the enzyme iNOS (inducible nitric oxide synthase), which makes reactive nitrogen species—another weapon.
When both of these pathways were knocked out in mouse models, the result was not compatible with life in the wild. “They had the normal number of macrophages and neutrophils and could even mobilize them to infected sites, but the cells couldn’t kill the bacteria,” Nathan explains. “It is the most severe immunodeficient phenotype toward bacterial infections I know of with normal numbers of mobilized phagocytes, and it shows that these two systems are partly mutually redundant but collectively indispensable for going about daily life.”
Studying an Enduring Infectious Disease, Tuberculosis
Nathan and his team began testing to find which diseases thrived when the iNOS pathway was blocked. Tuberculosis—caused by Mycobacterium tuberculosis (Mtb)—the leading death-causing bacterial infection in the world, was at the top of the list.
“So I started learning about Mtb,” Nathan says, “and I realized there’s an enormous amount of human biology that Mtb is trying to teach us if we would listen to it.”
Scientists think that tuberculosis (TB) has been around for at least 70,000 years. Nathan says, “If we stop to think about that, we haven’t eliminated it, and it hasn’t eliminated us. So there’s some kind of equilibrium.”
“Mtb gets the immune system to destroy lung tissue, making us cough or sneeze. Then it takes a ride on little droplets—liquefied lung tissue.”
This is related to the pathogen’s lifecycle and that humans are its only natural host. “Before we lived in cities, it would have been really important for TB to not kill everyone in a village quickly before they had children,” Nathan explains, “because then there would be no new hosts.”
Mtb needs to take its time to cause overt disease. It also needs to be recognized by the immune system in order to infect new victims. “Mtb gets the immune system to destroy lung tissue, making us cough or sneeze,” Nathan explains. “Then it takes a ride on little droplets—liquefied lung tissue. “Mtb has to walk this tightrope,” he continues, “inciting our immunity but also titrating it, surviving it, and then exploiting it in order to get to the next host.”
This relationship spurs many questions: After being recognized by the immune system, how does Mtb survive? What are its defenses? “To me, it’s a textbook that tells us what human immunity brings to the battle,” says Nathan. In very broad terms, he and others have found seven strategies the bacteria use, from degrading the immune system’s chemistry, to repairing damage, to sequestering damage.
This work also brings Nathan 180 degrees from researching how the immune system kills bacteria to how the bacteria fight back. “The goal is to see it from both sides, and then maybe you can be the puppet master,” he says. “Then you have a chance to make the immune system more successful more of the time.”
Nathan has found enzymes that help Mtb carry out many of its defense mechanisms. He’s also found inhibitors of those enzymes. “But unfortunately that doesn’t mean we’ve found drugs,” he says.
Wanted: New Drugs for Tuberculosis
As Nathan learned more about Mtb, he became aware of another problem, one that has vast implications for global health—antimicrobial resistance. “I became alarmed, because the rise in resistance coincided with the retreat of most of the pharmaceutical industry from trying to make new antibiotics.”
Economics have played a role in this withdrawal, but Nathan says it’s also because companies were struggling to find new antibiotics. “The practices they used in the 1950s and ‘60s were so efficient that they turned into a dogma, a mind freeze,” he says. “Here’s where people who come to the problem from a different discipline might be able to bring new ways of thinking.”
While academics have often provided research and technology for industry, there have been few opportunities for side-by-side collaboration. Nathan, with many others, is working to break down the boundaries. “Now we’re working with industry partners from the very beginning,” he says. “This arm-in-arm collaboration is incredibly efficient, and when you come to the inevitable problems, you have a whole multidisciplinary team to think about it.”
Nathan is involved in three projects that support the collaboration of academics and industry colleagues: the Bill and Melinda Gates Foundation’s TB Drug Accelerator program, the Tri-Institutional Therapeutics Discovery Institute, and Tres Cantos Open Lab. Nathan is also principal investigator for a seven-year grant from the National Institute of Allergy and Infectious Disease (NIAID), which brings six institutions, five Weill Cornell Medicine labs, and industry partners together in a TB Research Unit. Contributions from the NIAID could reach $46 million.
To these endeavors, Nathan is contributing his new understanding of Mtb, including what he’s learned about its defenses and the enzymes involved. “But there’s a big learning curve,” he says. “Drug discovery is full of failure, and I’ve been learning how many ways there are to fail.”
Compounds that Nathan has had high hopes for end up being toxic in some way or don’t work for inexplicable reasons. “But there’s enormous enthusiasm about the next group of compounds, so we spring back up,” he says. “I don’t think you can last this long in science if you can’t get up when you’ve been knocked down.”
Through the joys and disappointments, Nathan is always driving forward. “It’s a thrill to discover something that answers a question you didn’t even know you were asking,” he says. “It’s a thrill to see people in my lab bring their own insights and launch their own paths. But we haven’t succeeded nearly well enough yet. We have so much farther to go.”