The CHICKEN Came First

When asked to name the most important Emory research stemming from his groundbreaking discoveries about the immune system, Max Cooper pauses to consider.

“That’s a tall order,” he says. 

Indeed, it would almost be easier to list the immunologists at Emory and elsewhere who haven’t been influenced by Cooper’s work. 

At 92, Cooper is still working at the Emory Vaccine Center as well as the Department of Pathology and Laboratory Medicine at Emory School of Medicine. 

“He’s a little bit older and maybe a little bit wiser,” says Jeremy Boss, professor of immunology in the School of Medicine, whose own work builds on the foundations laid down by Cooper. “But the importance of Max’s work was defining.”

In the 1960s, immunology was fighting for recognition as a science, and researchers were struggling to understand the basics, such as which organs, cells, and processes in the body were responsible for recognizing and fighting foreign agents.

Many researchers had begun to suspect the importance of the thymus gland—located in the upper chest between the lungs in humans—in the creation of lymphocytes, the white blood cells that help fight invaders. But what was its role? 

“There were two contemporaneous theories about how the thymus influenced the development of lymphocytes elsewhere in the body, neither of which was exclusive,” Cooper recalls. One school of thought was that lymphocytes originated in the thymus, then traveled to other organs to do their disease-fighting work. The other was that the thymus works by controlling hormones. 

In the Beginning, a Chicken

Cooper avoided both existing theories and instead built on earlier studies showing that removing a lymph-related organ—the bursa of Fabricius—in chickens greatly reduced their ability to make antibodies, while removing the thymus in rabbits caused similar immune problems. He realized these findings might reveal how the immune system works as a whole.

To test this, Cooper and colleagues irradiated newborn chicks to wipe out any immune cells formed before hatching, then removed either the bursa or the thymus. The chicks without bursas couldn’t form plasma cells—the cells that make antibodies—while the chicks without thymuses couldn’t make lymphocytes but could still produce antibodies.

This led to the groundbreaking insight that chickens had two systems for creating immunity: one originating in the bursa, which Cooper called B cells, and the other in the thymus, T cells.

“It changed our view, in a dramatic way, of how the immune system develops and functions,” Cooper says. “It meant we could divide all immune deficiencies into defects in one or the other line of development, T cell or B cell. It also meant that malignancies of the immune system were either affecting the T lineage or the B lineage.”

These discoveries opened the way to new research on immune system deficiencies, malignancies, and autoimmune diseases.

When Cooper published his first findings in 1965, scientists still didn’t know that the immune system had two distinct parts. His discovery raised key questions: What does each part do? How do they work together to make antibodies and protect the body? And since mammals don’t have a bursa, what organ or process fills that role?

Researchers spent years carefully studying lambs, rabbits, mice, and chickens—often facing setbacks—to figure out how the two main branches of the immune system recognize and fight off antigens, the foreign substances that trigger immune responses. 

“There were many twists and turns,” Cooper recalls. Eventually, he and others discovered that in mammals, blood-forming tissues play the same role the bursa does in chickens. This opened the door to understanding a remarkably complex network of organs, cells, and molecules that work together to defend the body.

He describes one striking example: Scientists were able to transplant a fetal thymus into mice born without a working thymus and restore their ability to make functional T cells. Similarly, they could rebuild B-cell development in animals with defects in that system. These advances made it possible to design therapies targeted specifically to diseases affecting either B cells or T cells.

Cooper’s discoveries acted as the trailhead for modern immunology, from which many new paths of research branched off, as scientists gained tools such as cloning and gene sequencing. These paths have transformed the field and paved the way for immune-based cancer therapies.

What follows is a sampling of Emory researchers whose work builds and expands on Cooper’s. These physician-scientists have taken on challenges from better understanding pediatric HIV to improving antirejection medications for organ transplants.

Understanding How T Cells Remember Pathogens 

“Amazing” and “pioneering” are the words Rafi Ahmed uses to describe Max Cooper’s work. 

Ahmed, Candler Professor of Microbiology and Immunology and director of the Emory Vaccine Center, says since Cooper’s discovery of B cells and T cells, there has been “a proliferation of discoveries of many different kinds of immune cells,” including the memory T cells that form the basis for his own work.

The concept is easy to understand: people who catch measles and other infectious diseases become immune to future attacks of the same pathogen. But understanding the biological drivers of that process has been “a longstanding question, which we’ve been studying for probably 40 years,” Ahmed says. 

The key is memory T cells, a subset of ordinary T cells that multiplies when they first encounter a foreign antigen and help clear the threat. Most die once the pathogen is gone, but a small number persist in case the same disease returns, so they can quickly multiply again.

SARS-CoV-2, the virus that causes COVID-19, is a great example, Ahmed says. When it first emerged, no one had immunity to it. “But we still had the T cells. When we were infected by or vaccinated against SARS-CoV-2, those T cells got tickled by the infection or the vaccine. That changes the metabolism, and the cells start dividing and increasing their numbers. They can rapidly become killer cells.”

Ahmed’s lab studies how T cells learn to specialize in attacking different antigens. “Understanding how T cells differentiate is critical for designing immunotherapies, T-cell therapies, things that are needed for cancer autoimmunity, chronic infections, and so on,” he says.

The key was Ahmed’s discovery that memory T cells rapidly expand and clear pathogens during acute viral infections but are far less effective in chronic diseases like cancer. In tumors, cancer cells produce a protein called PD-L1 that binds to PD-1 on T cells, shutting down their ability to fight the disease. This insight led to the development of immunotherapy drugs such as nivolumab and pembrolizumab, which block the PD-1 pathway and restore T-cells’ ability to attack the cancer cells. 

“That’s why immunotherapy works,” Ahmed explains. “T cells are present but that protein is inhibiting their functioning. By blocking the PD-1 interaction, they become more functional and their numbers increase.”

Discovering How Immune Cells Know When to Attack

Ahmed worked with Jeremy Boss, professor and chair of the Emory Department of Microbiology and Immunology, to drill down into the genetic processes that control and regulate this interaction. 

“Our current goals are to find proteins that regulate PD-1 specifically,” Boss says. “We have some candidate proteins, but they also control other genes. When you target PD-1, you have to be concerned about targeting other genes in other systems and making something very specific to the PD-1 gene.”

Boss’s lab identified key genes that allow immune cells to tell the difference between the body’s own cells and foreign ones.

These genes, called MHC Class II, sit on chromosome 6. They recognize foreign antigens and present them to T cells. “You might think of the MHC molecule like a golf tee,” says Boss. “The antigen is the ball. The T cell needs to see both the golf tee and the ball to decide whether to react. If it sees the self, the T cell won’t respond. If it’s foreign, the T cell will respond appropriately.”

The main challenge is controlling when and where these genes switch on. “You want antigen-presenting cells active at the right moment,” Boss says, “but you don’t want every cell doing this and triggering autoimmunity.” His team continues to study how this system is regulated, uncovering new details each year.

Aiming for Transplants to Last a Lifetime

“We have an amazing community,” Christian Larsen says. “Max is central to it, but we have hundreds of immunologists at Emory.”

Combining the skills of a transplant surgeon and an immunologist, Larsen searches for ways to block the immune system’s natural tendency to reject foreign grafts like transplanted organs. “The problem of rejection,” he says, “is that the immune system recognizes the transplant as foreign and then lymphocytes, the T cells, attack and damage the transplant.” 

When Larsen began his work, existing immunosuppressive drugs such as cyclosporine had serious side effects. “We could control early rejections,” he recalls. “Those rates are below 20 percent in the first year. But long-term toxicities cause transplants to fail. If you take too much cyclosporine, it can cause kidney injury. The very drug that’s trying to prevent rejection is causing your kidney to fail. Our goal is for one transplant to last a lifetime. Sadly, current technology largely doesn’t achieve that.”

Seeking deeper understanding, Larsen, professor of surgery in Emory School of Medicine, joined the search for the mechanisms that cause the immune system to reject transplants, another side of the mechanisms that protect the body from foreign invaders. “Fundamental discoveries,” he says. “Like what Max Cooper did.” 

Larsen’s research showed the immune system switches on through two steps. First, receptors on T cells recognize proteins from invaders. Then, additional molecules on the T-cell surface confirm this signal and let the T cells begin their attack. Together, these two steps are known as co-stimulation.

“If a T cell gets both of those,” Larsen says, “it’ll expand, divide, and attack the transplant. If you deprive the T cell of those co-stimulatory signals, it’ll get the recognition signal but not the second signal and won’t become fully activated. In fact, most of those T cells will go on to die.”

This insight led to the development of belatacept, the first co-stimulation blocker, which targets the immune system’s attacks on transplanted organs with greater precision.

“It’s got that selectivity. The challenge is more precise and personalized,” Larsen says. “In the past you would be on two or three drugs. Now, most of our patients on belatacept are on only belatacept. One opportunity—and we’re making real progress on this—is tailoring the intensity through the composition of a patient’s immunosuppression, based on their immune risk. I think of it as getting them to the right destination. The first year is really important, but I want you to live for 20, 30, 40 years, depending on your age.”

Searching for Secrets from the Past

As for Cooper himself, he left chickens behind a few years ago for a deep dive into the immune system’s distant past. He’s exploring how the immune system began in ancient animals like hagfish and lampreys—jawless sea creatures that split off from the evolutionary line leading to humans about 500 million years ago. 

Lampreys, once consumed as a delicacy in Europe but now considered mostly a nuisance in the US, have an immune system that works very differently from ours and is, in some ways, highly effective. Lampreys make their own form of antibodies, which can detect some antigens that human antibodies cannot.

Cooper thinks these differences could be useful for treating human diseases. For example, lamprey antibodies might be able to target cancer cells in multiple myeloma without harming healthy cells. He is also looking at treating malignant melanoma of the eye. “Those malignancies are different from melanomas that arise in other places in the body,” he says. “Currently, there are no efficient therapies for it, so we’re making antibodies against the specific lymphocytes that cause melanoma of the eye.”