by Matt Richtel
First, they found the gene, or fragments of a gene that looked like the human version of the one in the fly. Then they did experiments to see if they could show that the gene was not just instrumental but essential in causing the T cell to act upon a pathogen. One night in February 1996, Medzhitov was checking the lab results on his computer. This is one of those experiments that is too technical to describe and, in its own way, not the stuff of Hollywood; first there were some mixtures, or assays, and then the data was crunched digitally and the results came over the computer.
But those results? Now that part is the stuff of Hollywood.
Medzhitov and Dr. Janeway had found the fundamental mechanism that allowed the body to determine if it was dealing with a pathogen, a bad guy such as a harmful virus or bacteria.
This was the discovery of what happens at first contact. The Toll-like receptor is as elemental a concept as in all of our survival and in the science of immunology, and it had taken years to uncover.
“It was Holy Grail at the time, the dream result, to find something that provided evidence for a hypothesis that at the time only two people cared about,” Medzhitov says. “It was eight o’clock at night and it was well known that Dr. Janeway didn’t like to be bothered at home. I couldn’t even contain myself and wait until the next day. I called him and told him the result: ‘I saw induction in the genes.’ He knew what that meant.”
The discovery became the basis for our understanding of the concept of a second kind of immunity. It is called innate immunity.
The innate system shows up, discovers a pathogen, and mounts an initial but generic attack, meaning the attack is not specific to the pathogen. It can hold off the evildoers but often cannot kill them completely. That requires specific attacks from a particular T cell or B cell armed with the receptor or antibody that matches the antigen on the surface or inside the bacteria or virus or parasite.
The innate system informs the adaptive system: I need help. Bring the heavies.
The innate immune system scans organisms for the presence of one of a handful of key identifying markers that are shared by viruses and bacteria. For instance, most bacteria have wiggly tails. Toll-like receptors scan for these. Or they look for a particular variety of large molecules—called lipopolysaccharides—that characterize a class of bacteria called gram-negative bacteria (such as E. coli); or they look for nucleic acids associated with viruses.
Compare now several scenarios, one in which you get bitten by the cat, another in which you ingest a banana. In the first scenario, the cat’s saliva trickles into the wound on your hand, setting off the cascade of immune cells, carried through opened blood vessels, bringing redness and heat. Among the cells at the scene are macrophages and dendritic cells with Toll-like receptors on the surface. The receptors can instantly determine whether the foreign substance entering the body has the hallmarks of a major pathogen. If a pathogen presents itself—say, a noxious bacteria—not only does the immune system unleash a first-line attack but also the dendritic cells, now aware of the pathogen, begin their journey to find the T cell and B cell necessary to provide a more specific defense.
By contrast, when you eat a banana, the food travels down into your stomach and intestine. The gut breaks down the food, and nutrients leak into the body. Those nutrients, by the time they are broken down, may look much like “self” and thus not attract attention from the immune system, or our elegant defenses may identify the scraps of nutrients as foreign but not see any of the hallmarks of a pathogen. They have been accepted into the body, permitted to survive in the Festival of Life.
The role of the Toll-like receptor represents a relationship between human beings and the outside world that is as ancient as our existence. It was cultivated through epochs of evolution so that the human genetic code has developed the ability to scan for the ancient markers shared by hundreds of thousands of pathogens.
In a 2002 paper, Dr. Janeway and Medzhitov described it like this:
The innate immune system is a universal and ancient form of host defense against infection. These receptors evolved to recognize conserved products of microbial metabolism produced by microbial pathogens, but not by the host. Recognition of these molecular structures allows the immune system to distinguish infectious non-self from noninfectious self. Toll-like receptors play a major role in pathogen recognition and initiation of inflammatory and immune responses.
Thus, microbial recognition by Toll-like receptors helps to direct adaptive immune responses to antigens derived from microbial pathogens.
To break the findings down further: We are born with primitive detection mechanisms that can discern not only what is alien but what is pathogen. As a first-line defense, the molecules of the innate immune system recognize a large class of pathogens and signal the T cells: That thing you just identified as alien is bad—go kill it.
With this discovery, the major pieces of immunology had been put into place. Much was still to be discovered. But immunology suddenly faced a crisis that crystallized much of the science into a very practical threat.
A plague was afoot.
The greatest modern challenge to immunology and the immune system happened in the 1980s. Or rather, that’s when it became clear the apocalypse lurked. AIDS led to a turning point in the story of immunology. The study had been so much about the lab and the mice, about inscrutable language and piecemeal science. Then came this crucible.
So our story turns too, moving more and more out of the lab and into the clinic, into the lives of patients, and into a new era of research. While basic immunology continued, there was an exciting new emphasis on applying the decades of hard-earned knowledge to more practical things, like the interaction of the immune system with sleep, stress, allergy, cancer, or nutrition, and like poorly understood symptoms that were actually autoimmunity. Various medical specialties—heart, lung, muscular, skeletal, and on and on—began to put to work the tools and knowledge of the 1970s. In that respect, what followed was an expansion of immunology.
It was spawned by the scariest disease modern medicine had ever seen.
Part III
Bob
21
Sex Machine
Bob Hoff thought he contracted hepatitis on Halloween night of 1977. It went with the lifestyle, he figured. He’d had genital warts and syphilis and various other STDs.
As a closeted young man from Iowa, Bob viewed sex not just as a preference but as an expression of self. “I was extremely promiscuous,” Bob said of that period in his life. “I’ve visited every single bathhouse in the United States.”
There was the Library in Minneapolis, Man’s Country in Chicago, the Ballpark in Kansas City, and the Arena in Denver, and others in St. Louis and San Diego. The 1970s were a coming-out party for the gay community, an awakening for many gay men. As Bob put it, “I wasn’t the only one out there.” They’d lived closeted and in fear for so long, and they let loose with abandon.
Bob, a senior government litigator, was traveling the country, and he jetted around having unprotected sex. His wife, a flight attendant, also traveled frequently, giving him ample opportunity to have fun at home too. One day in 1978, Bob was working out at his gym in Crystal City, Virginia, where many in the D.C. political community lived, and he met a guy named Ron Resio. Ron had a triple doctorate and worked at a Navy base in Virginia helping update the F-4 Phantom fighter jet. Not the construction end, but the design side, the genius end.
Robert Hoff, 1973. (Courtesy of Robert Hoff)
“He looked like Conan the Barbarian,” Bob recalled. Long hair and big muscles. The pair became friends, and one day while Bob’s wife was gone, they went to Bob’s house and had sex.
Ron, it turned out, wasn’t just another friend with benefits.
What happened next was one of the most excruciating trials that the human immune system ever passed through. It’s also a story of how a search for a cure drew from the tremendous discoveries science had made over the prior fifty years.
The bedeviling search to stop AIDS would also eventually come to draw from the exquisite immune system of Robert Hoff.
22
GRID
In August 1980, at Denver General Hospital, medical student Mark Brunvand was sent up to the ninth floor, critical care, a regular rotation for a third-year student. Years later, Dr. Brunvand would be Jason’s cancer doctor. Now, in med school, he was forming the philosophy that would guide him in his career. His world view, like that of other doctors and researchers at the time, was being formed by a strange new disease and the havoc it wreaked.
On that August day, on the ninth floor, Dr. Brunvand went into the room of a patient who had come in with an unidentified illness. The man now lay in bed, hooked to a ventilator, unable to talk. Dr. Brunvand felt the man was trying to communicate through sad and terrified eyes.
Another med student told Mark: Nice guy. We don’t know what’s going on. He’s probably going to die. Looks like pneumonia, and he’s gay.
In a way, this is part of medical training; students take the labs and babysit the terminal patients. The labs in this case didn’t make sense.
“Everybody was baffled. Nothing cultured out,” Dr. Brunvand reflected. Then it looked like a parasite. “But we didn’t get any confirmation.”
They looked for reasons. What was unusual about this guy? Nothing to explain this. “We don’t know if this guy has been smoking crack, has been exposed to toxic gas or other guys in the neighborhood.”
Dr. Brunvand remembered looking at the guy and feeling completely helpless.
It was the kind of story unfolding all around the country.
June 5, 1981. The CDC put out case studies of five patients in Los Angeles. They were treated for pneumocystis carinii pneumonia. Two died. All were labeled “active homosexual.” A lab at UCLA reported the cases. It’s a novel place, this lab; it has been set up to combine clinical work with immunology. The researchers at UCLA discovered that the patients had “profoundly depressed numbers of T lymphocytes.” T cells.
On July 3, a second CDC report came out reporting twenty-six cases in Los Angeles, New York City, and San Francisco.
Here’s a snapshot of the kind of patient who showed up, baffling doctors.
At a bedside in Memorial Sloan Kettering Cancer Center in New York City, that same month, July 1981, a greenhorn physician, Dr. Mike McCune, looked at the racked body of a twenty-four-year-old man whose symptoms made no sense.
“His lungs were concrete,” Dr. McCune said, reflecting back.
He’d been moved from Cornell, where they couldn’t find a cause. He was surviving thanks to what McCune called a “super-duper ventilator” that managed to get air into his failing lungs. The patient was African American and had a history of intravenous drug use. In medicine the term differential diagnosis basically means: What’s the likeliest cause among a list of probable causes?
“Cancer, cancer, cancer. What else could be causing it? An infection? But what kind of infection?” Dr. McCune said. “We put a tube down his throat and brought stuff up, and looked under a microscope. And what did we see?
“Not cancer. Not bacteria.”
It was a parasite called pneumocystis carinii. Under the microscope, this looks like round clumps. The lungs of McCune’s patient were swarming with these things.
The thing is, ordinarily they’re not that dangerous. “You probably have them growing in you right now,” McCune told me. “But your immune system is keeping them down.”
Dr. McCune was transfixed. “I went back to the lab and thought: What’s this guy got?”
The man held on for weeks, and then he died.
They were all dying.
Not Bob Hoff.
Bob’s phone rang in mid-1982. The caller was Michael Ward. He was a good friend of Bob’s and an undertaker at Fort Lincoln Cemetery. He’d been a lover of Ron Resio, a man Bob had had sex with too. Michael was calling with bad news and with a request. The news was that Ron had been admitted to Building 10 at the National Institutes of Health with an unusual illness. The request was that the NIH wanted to take the blood of Bob and four other men whom Ron had been with.
By now, there was a term for a new kind of STD showing up in the gay community. The illness was called GRID, gay-related immunodeficiency. Bob Hoff read about it in The Blade, a newspaper for and about the gay community in Washington, D.C.
The five men showed up at the NIH. They were met by a team heading up a small, elite research group that had been set up by Dr. Tony Fauci. Team members included two accomplished physician-scientists, Dr. Cliff Lane and Dr. Henry Masur. Dr. Fauci was baffled, concerned—and fascinated.
“I looked at this and said, ‘Oh my God, I don’t have any idea what’s causing this,’ but when we look at the immune system, it’s completely messed up. It’s a disaster,” Dr. Fauci said.
These guys started showing up who couldn’t fight off basic infections, the kinds of viruses and parasites that the rest of us kick as a matter of course. The human defense system had been breached.
“Holy shit, if there ever was a disease I should be studying, this was it. This has to be an infection, but I didn’t know what it was,” Dr. Fauci said. “It’s clearly attacking the immune system. It’s an unbelievable situation where a virus is attacking the immune system. We’ve never had that before. We didn’t know what the hell we were dealing with.
“I stopped everything else I was doing.”
Fauci had found his dragon. Or was it really a windmill? Could it be fought or was it so elusive as to be practically illusory?
When Bob Hoff and four other men showed up at the request of the NIH to see their good friend Ron Resio, they were first asked to give blood in the auditorium at Building 10. Bob Hoff’s blood test was a near disaster. The doctor, in search of a vein, nicked an artery.
“Blood spewed all over this doctor,” Bob recalled. “He was scared to death.”
The blood draw was something of a shot in the dark. Fauci and his team didn’t know what they were looking for, maybe something in the blood, anything that might tell them what they were dealing with. At the very least, Dr. Fauci said, “we wanted to store their blood for future study.”
After the blood draw, the men went to see Ron in the critical care ward. This once long-haired behemoth looked emaciated; he was covered with purple lesions, and tubes protruded from all over his body. Beyond the mystery illness, Ron was very interesting to Dr. Fauci because Ron had a twin brother. Might his twin shed light on what the hell was going on inside Ron’s immune system?
That day, Ron’s friends and lovers stared at him, shocked. They tried not to cry, because as Bob put it: “That would’ve made it about us, when this was about him.”
After the men left the room, they let their emotions go. “Then we went to Glenn’s house and we all had sex,” Bob said.
You read that correctly. The group of men, having seen the first of their friends dying of something terrible, went to one of their homes and had an orgy.
Bob put it to me just as plainly as I’ve shared it with you. I asked what prompted such a response, and he said, “Well, we practiced safe sex.” But there was more to his answer than that, and it was another instructive moment for me in the conversation about how we define ourselves in terms of self and other, just as the immune system seeks to do. Bob and his friends had one another, and they had sex as a defining characteristic and a sign they were not as alien as they’d felt growing up.
Plus, Bob told me, many of these men were part of Washington, D.C.’s elite in-crowd. One of them in the orgy that day had been a campaign manager for a presidential candidate. Many others in that inner circle—just not there that day—were part of the “upper echelon of the Republican Party,” Bob told me. He’d been a Republican too for many years. They hewed to what let them feel safe and as if they belonged, one another and sex.
That was how the day ended for Bob, in catharsis. “For me, it was the last time I’d see a lot of those
guys.”
On September 24, 1982, the Centers for Disease Control and Prevention put out a report saying it had received 593 cases of what is now called acquired immune deficiency syndrome (AIDS). The condition that Dr. Brunvand had seen in Denver and Dr. McCune had observed in New York now had a name. Of the reported cases, 41 percent had died. Many of them had the parasite pneumocystis carinii; others had Kaposi’s sarcoma or another opportunistic disease that was ultimately proven to have a viral basis. These were viruses that took advantage of a suppressed immune system. In many of us, such infections would be held in check and certainly wouldn’t kill us.
There is a telling sentence in the CDC note: “The CDC defines a case of AIDS as a disease, at least moderately predictive of a defect in cell-mediated immunity, occurring in a person with no known cause for diminished resistance to that disease.”
To repeat: occurring in a person with no known cause for diminished resistance to that disease.
Less than 1,000 cases had been reported. Still, the medical community took notice. The immune systems of these patients were so befuddled that they were failing to hold in check viruses and other pathologies that ordinarily caused no problem. And not just one pathology, but multiple ones. In other words, some new thing was unraveling our most basic and elegant defenses.
Fourteenth-century Florence in the grip of the Black Death. (Wellcome Collection)
It is not an understatement to say that some big thinkers saw this as an end-of-days scenario. “We were in a full-blown panic. It was the plague,” one immunologist told me. “We thought everyone would die.”
