For a Nobel Prize–winning immunologist, Peter Doherty is a funny guy.
He graduated from veterinary school in Australia in 1962, initially focusing on how vertebrates—like sheep (and humans)—control infection. He did so with zeal. Even in the latter half of his seventies, when I had the privilege to interview him, he talked a blue streak, an enthusiast with a sense of humor. When he was a teenager, he told me, he read Aldous Huxley, Jean-Paul Sartre, and Ernest Hemingway, and was inspired but confused. Dr. Doherty, in his own words, was a man “who was either going to go big, or crash and burn.”
In his 2005 book The Beginner’s Guide to Winning the Nobel Prize, he reflected with humor on his adolescent naiveté. “I decided to be the man of action rather than the philosopher, and resolved to graduate in veterinary science and pursue a research career,” he wrote. “At this stage I was just seventeen years old, and would probably have made a very different decision if I had been more mature.”
When we spoke, Dr. Doherty colorfully explained that while much had been discovered about the immune system by the time he was delving into his research, even more was still in doubt. In fact, there were still holdouts who were not convinced that there even were two main immune system cell types, the T cells and B cells. “That fact had become obvious. But some of the old guys were horrified by having to confront such complexity,” Dr. Doherty told me. “They’d say that B and T were the first and last letters of bullshit.”
As the pioneering immunologists pushed ahead, there was predictable resistance from people unsure if the course was correct. This was true with every advance. Meanwhile, the progress and pace of the breakthroughs were accelerating. It was here that science would discover the levers and knobs to permit more precision health treatment, care, and counsel. The next few chapters, before I return fully to Jason, Bob, Merredith, and Linda, will carry you deeper, joining the scientists on their journey beyond ideas and into the very molecules and systems that make you tick and that are responsible for your health. When we surface again, you’ll be equipped to see more clearly the profound role of the immune system in virtually every facet of your health—both physical and emotional.
Dr. Doherty earned a PhD in 1970 at the University of Edinburgh in Scotland, where he studied sheep brain inflammation (meningoencephalitis). He returned to Australia and applied that work to mice, then started a historically significant collaboration with a visiting Swiss doctor and scientist, Rolf Zinkernagel, who had used mice to become expert at a technique for looking at the concentration of T cells when they are called into action to attack a virus.
The two scientists infected mice with a virus that can cause meningitis—an infection of the lining of the spinal cord. Then they watched as the T cells gathered around the infected cells and unleashed their fury. Most of this was actually done in a test tube. The mouse would be infected; then its infected cells were mixed together with T cells isolated from the spinal canal.
Dr. Doherty told me that “right from the outset, our brain-derived T cells were causing the most dramatic killing anybody had ever seen.
“As disease and death guys,” he added, “we were delighted!”
With further experimentation, the pair realized something crucial about the nature of this mass murder: The T cells weren’t just killing free-floating infection; they were targeting mouse cells that were infected, meaning the cells that were being annihilated were part alien and part self. This was very interesting but maybe obvious. It meant the T cells were diagnosing illness inside the cell, not merely identifying freestanding viruses.
Then came a punch line—“an unexpected discovery,” the Nobel Prize committee wrote in its 1996 award for the science (for work published in 1974). “The T-lymphocytes, even though they were reactive against that very virus, were not able to kill virus-infected cells from another strain of mice.”
In other words, the immune system was able to discern a cell that was self and had been infected from a cell that was not self. The immune system killed only the infected ones that were self. An individual’s elegant defense didn’t care simply about the infection; it cared about the infection when it attacked its own personal habitat. Italicized because it’s a key scientific insight.
If you pull back the lens, and picture the day-to-day cinema inside our bodies, what the pair of scientists had discovered was that our “killer” T cells are roaming widely to discern whether other cells that make up the tissues and organs of our bodies are normal and healthy or have been damaged in some way that’s dangerous—infection, mutation to cause cancer, etc. These T cells are often considered the equivalent of hit men. But this work showed these cells have a broader function. They carry specific “receptors” that prompt them to ask questions first before they attack.
The T cells first determine if you specifically have come under attack. The concept is called the major histocompatibility complex, or MHC—another immunological term that goes down like cold lemonade on a freezing day.
The net consequence of MHC is that it allows T cells roaming the Festival of Life to avoid killing what Doherty calls the “normal guys” that happen to be nearby. “The assassination is precise, local, and very specifically targeted!
“The MHC is a central component of our immune surveillance system,” Doherty said. “It’s the key to self-recognition.”
MHC is the single most varied or polymorphic of all human genes. Every human being has roughly the same MHC genes, but they are all slightly different. They are the immune system’s fingerprint.
This is one of the key markers that differentiate an individual from everyone else in the world.
This extraordinary notion led to one of the most fascinating pieces of scientific theory I ran into while researching this book. The theory has to do with mate preference, incest, and the MHC.
Studies have shown the MHC gene gives off a scent. The scent is used as a factor in how people choose their mates. If one person’s MHC is too similar to another’s, the MHC will act as a repellent. The scent of MHC that is sufficiently different will act as a magnet.
This is significant from several perspectives. For one, it shows the unconscious drive for a certain level of diversity, given that diverse couplings provide to offspring a broader set of abilities. Relatedly, it also creates the possibility that the immune system originated not just to keep us away from pathogens but also to help us choose mates that are sufficiently self but not too much. In fact, the MHC could be part of the reason that incest has evolved to be so abhorrent.
Finally and more broadly, the role of MHC also raises a possibility that the immune system is so primitive and fundamental that it evolved in concert with a seemingly unrelated survival function: the need to reproduce. This question hasn’t been answered. It is a viable theory explained to me by Dr. Thomas Boehm, a pediatrician and researcher at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg, Germany.
As humans developed, he told me, “We had to make sure we did not kill ourselves by homogenizing. The one system that is ideally suited is the MHC.”
In a 2006 paper, Dr. Boehm wrote: “I have proposed that this mechanism to assess genetic individuality was initially used for sexual selection and only later became incorporated into immune-defense systems. Whether this primordial system provided only transient coverage against the emerging possibility of self-reactivity and was later replaced by the MHC, or whether it directly evolved into the MHC, is unclear.”
This is partially speculation. It also speaks to the likelihood that the immune system is so fundamental to human existence as to be part of the essence of the species.
I mentioned earlier that the T cell and B cell, and other core aspects of the immune system, have been in place for around 500 million years and that the foundations of our elegant defense go back so far in our evolutionary history that we share it with the world’s other jawed vertebrates—a massive category that includes sharks, skates, and rays. “They have an immune system like ours, a thymus like ours, that makes T cells,” explained Dr. Cooper, who has become one of the leading authorities on the evolution of the immune system.
Even as evolution led creatures to walk onto land, turned them (or us) bipedal, saw the transformation of our communications, and enabled the development of modern tools, the immune system remained largely the same. And recall that to find a different immune system (at least on this planet) you need to go back to a point in biological divergence where the jawed vertebrates split off from the non-jawed vertebrates.
This tells us that, while the immune systems are different, certain defense functions seem essential for survival. One such function is redundancy. There are multiple molecules and cells in both systems, including some proteins that seem to do virtually the same thing—whether it be attacking, inducing attack, or slowing it.
Why so much redundancy? For instance, Dr. Cooper has asked why do we need both T cells and B cells? Wouldn’t one such set of specialized cells be enough? Couldn’t one of the systems have evolved to take care of that? The answer to these questions remains elusive except for one basic point of proof, Dr. Cooper notes: If they weren’t both necessary, they wouldn’t both exist—“we don’t maintain things that are not useful.”
Overall, though, the scientists were getting closer, and deeper, pressing even beyond the microscopic. And with each advance came the chance to explore questions that had, previously, seemed almost pointless to ask. I’ll give you one: what is a fever?
You think you know, right? I did too. The body heats up. But it’s a much more profound question than I had realized, one that would illuminate a new level of understanding of the immune system, namely, that it has a vast, virtually unmatched telecommunications system. This helps explain how, when your body gets invaded, the defense signals can be sent so quickly and effectively, when necessary, calling all hands on deck.
Fever also helps explain inflammation, a concept I also figured was fairly self-evident. Not so much.
What is inflammation?
What is fever?
A stubborn scientist obsessed with rabbit fevers discovered truths previously thought unattainable.