Midway through my second year of training at UAB, I was asked to report to the office of the chairman of the department of medicine. I made a quick mental inventory of sins that might have been reported, expecting to be called on the carpet. Might someone have taken offense at the parody I wrote about my University Hospital rotation (to the tune of “Let It Snow”)?
Oh the weather outside is frightful
And the patients so … “delightful”?
What the hell am I doing here?
Get me beer, get me beer, get me beer!
It turned out I wasn’t in trouble. The recently appointed chairman, Dr. J. Claude Bennett, had me summoned so he could ask if I’d accept the honor of serving as a chief medical resident (CMR). The answer to his offer was, of course, yes. This meant that after the standard three years of residency, I would stay for a fourth, helping him and Dr. Dismukes run the internal medicine residency program. I called it my “remedial” year of training, and it turned out to be a pivotal time and role.
I’d arrived at UAB with my sights set on cardiology. Within weeks, I was having reservations. The more I experienced, the more I doubted that I’d made a wise choice. It seemed as if every question about treating a heart patient got the same answer—“We’re going to catheterize him.” In reality, thirty years ago this was often the right diagnosis and proper treatment. Even then, I wasn’t arguing about the science. But a lifetime devoted to giving the same answer to every question and performing the same procedure day after day held no appeal.
While my enthusiasm for cardiology was fading, I’d begun to explore a field that I’d earlier dismissed: infectious disease. Part of my attraction to ID was the breadth and unpredictability of the field. It covered everything from mutant cancers to bugs from Tanzania. While many of the mainstay diseases were historic and heavily studied—malaria, for example—other diseases were little more than an accumulation of observed symptoms compiled into a “syndrome” without a known cause. Truly weird things popped up from places I couldn’t spell, odd fevers in Central Africa and strange maladies known mostly off the coast of Madagascar. By its very nature, working in ID meant that you were in research, since much of what you were trying to identify and remedy came to you in the form of uncertain diagnoses and improbable, perhaps even unheard of, illnesses. If the practice of cardiology seemed utterly predictable, life amid infectious diseases seemed brilliantly unpredictable.
(And predictions being made in the ID field added a whole other layer of interest. Just a bit later, in April 1984, America’s Health and Human Services Secretary Margaret Heckler held a press conference to announce that Dr. Robert Gallo of the National Cancer Institute had found the virus that causes AIDS. At that event, Heckler postulated that a vaccine against AIDS might be produced within two years. I distinctly remember listening to that and thinking, Madame Secretary, what planet are you on? I had seen Heckler’s boss, President Reagan, take a medical issue seriously: In 1982, when seven people died after taking cyanide-laced Tylenol, the world stopped and the US government went into crisis mode, searching relentlessly for the culprit. By the time of Heckler’s press conference, some 5,000 people had died of AIDS, and the president appeared not to have noticed. He hadn’t even said the word “AIDS” in public, a fact made even more inconceivable by the fact that many of his former colleagues in the film-making business were directly affected, if not infected, by the AIDS virus. The Reagan administration’s strikingly different responses to seven Tylenol deaths and 5,000 AIDS deaths was a huge source of anger among AIDS activists. I never understood how President Reagan could remain silent on events that were having such a profound effect on the nation publicly and on him privately.)
Knowing the field would never be boring, I opted for ID.
There was also an additional lure to ID at UAB: the faculty. Dr. C. Glenn Cobbs, a onetime Marine who studied at Princeton and Harvard, started as the first director and lone faculty member of UAB’s ID division. At the end of his internship at UAB, Cobbs was hand-selected by Tinsley Harrison, the venerable chair of medicine at UAB and lead editor of the famous Harrison’s Textbook of Medicine, to study ID at New York’s Cornell University and bring his knowledge back to UAB. Upon his return, Cobbs—methodically, persistently, and with the patience of a researcher and the persuasive capacity of a car salesman—built the division into a powerhouse. Kirk Avent, a talented clinician-educator, was hired first. Then he attracted Bill Dismukes, who was known as “one of the world’s top disease sleuths” and who had trained in the prestigious Epidemiology Intelligence Service at the US Centers for Disease Control and Prevention. They worked with Claude Bennett, the chair of microbiology and namesake for the Dreyer-Bennett Hypothesis, a breakthrough in the understanding of genetic coding. These men were not only stars in the UAB faculty; they were household names in the global ID and microbiology community.
ID guaranteed a career with plenty of Sherlock Holmes to it, unraveling mysteries and pursuing the unknown. It seemed as if this field would satisfy my altruism as well as my intellect: I could solve the mystery of a disease and then hand my patients the cure. This made sense to me. This was worth climbing out of the tree for.
But I hadn’t banked on being chief medical resident. Typically, faculty members select as the CMR a candidate intent on an academic career. I still aimed to go into private practice ID and had no intention of staying in academia. But I loved teaching, found great joy in patient care, and figured I could use the extra year provided by my CMR appointment to have fun, as well as to hone skills.
Claude Bennett, who had moved from chair of microbiology to become the chair of medicine, took great pride in grooming his CMRs for academic medicine. He saw their “extra year” as a warm-up for inspiring work to be done as junior faculty in his institution. CMRs were, in Bennett’s way of thinking, prefaculty. So it was no surprise when I learned that as a required part of my CMR duties, I’d accompany Bennett to an annual meeting of the American Society of Clinical Investigation (ASCI) in Washington, D.C.
Attending that May 1985 meeting felt like the academic-medicine equivalent of attending the Academy Awards. I was starstruck at the eminences gathered there: editors I knew as names on major medical textbooks, authors of landmark papers that had shaped my training. Though I could easily have become a gawker on the sidelines, Claude—we were on a first-name basis now—was generous about making introductions. I was particularly taken by Dr. George Shaw, a young investigator from the National Cancer Institute whom Claude had just recruited to come to UAB.
George Meade Shaw was raised on a farm near Logan, Ohio. He sped through an MD-PhD degree program in five years followed by an internal medicine residency, and then he landed a postdoctoral fellowship position at the National Cancer Institute, in Dr. Gallo’s laboratory, as part of his training to become an oncologist. George went to Gallo’s lab to study HTLV-I, which was known to cause diseases including T-cell leukemia/lymphoma syndrome, a rare cancer of the immune system’s own cells. But while George was working there, others in Gallo’s lab discovered that a cousin retrovirus, HTLV-III, was the cause of AIDS.
My meeting with George lasted only two or three minutes. But George immediately came to mind two months later when, on my first day working in UAB’s ID clinic, I met a thirty-four-year-old patient from a small town in Alabama. It was the moment in which academic research and real-world healing, sterile laboratories and crowded emergency rooms, came together for me.
The woman, a schoolteacher, was twenty-one when she married her husband. She said that he had been her only sexual partner, and I believed her. They had two children, ages eight and twelve. In May 1985, as she had done every six months for as long as she could remember, the teacher donated blood at her local blood bank. But this time, a month after her blood donation, she received a letter from the Red Cross informing her that the HTLV-III test they had performed on her blood came back positive. (The Red Cross first began testing the nation’s blood supply for HTLV-III in May 1985.) The test finding meant that the teacher was infected with the AIDS virus.
The teacher was adamant that she had never, ever, received a blood transfusion. She’d never used intravenous drugs, or any drugs for that matter. She had not had unprotected sex with multiple partners. Nonetheless, when her family-practice doctor repeated the tests—a commonly used test called ELISA (enzyme-linked immunosorbent assay) and a more complex, confirming test called the Western Blot—they were both positive. By all criteria, the teacher was infected with the AIDS virus.
Thinking her virus must have come from her husband, the physician called him in and checked his blood, but he tested negative. As if her physical future—in the mid-1980s, AIDS meant guaranteed suffering and death—were not enough to cause panic, the emotional and marital stress was almost beyond measure. How could she be dying if he was healthy, unless she had been untruthful? And if she had been truthful and faithful, how was this possible? Their physician was baffled by her diagnosis and referred her to UAB. She was mine.
She arrived an hour early for her morning appointment, red-eyed from crying and desperate for answers. Through tears, she grilled me: Her hair-dresser was gay, could she have gotten it from him? Did the experts really know all the ways the AIDS virus was transmitted? I felt like a poseur, trying to answer her questions as an “expert” with so little ID training under my belt. But after listening intently, I reached three conclusions:
| (1) | This didn’t make sense; |
| (2) | Either the tests were wrong or the experts were wrong; and |
| (3) | I couldn’t work this out without some help. |
While the teacher waited in the exam room, I went down the hall and telephoned George Shaw, who had by now relocated to UAB.
I started to thank George for taking my call, but he graciously cut me off and dove straight into the case. He grilled me about the teacher’s story: Was I sure she had no other exposures? No other partners? No injections? No forgotten blood transfusions, perhaps blotted out by anesthesia when she delivered her two children? Ultimately, we agreed: This required further testing. He suggested I draw as much blood as I safely could and bring it to his lab immediately.
I wonder if it sounded as dramatic as it felt—like a scene in a movie—when I counseled the teacher about what came next. I told her I was working with one of the world’s top experts in AIDS who had been in the laboratory where the virus was discovered. I tried to sound reassuring when I said something like, “We’ll get to the bottom of this.” Then I took enough of her blood to fill twenty tubes, gave her a hug good-bye, and headed across the street to George’s laboratory, the vials bulging in the pockets of my white coat.
George and I prepared a dozen of the tubes to ship to colleagues for simultaneous testing. Four tubes to Mika Popovic in Gallo’s lab. Four tubes to Wade Parks, an AIDS pediatrician and virologist in Miami. Four tubes to Judy Britz at one of the companies that manufactured the then-new “AIDS test” used by the Red Cross. From the remaining eight tubes of blood, we placed some in vials to preserve at -70 and -150 degrees centigrade—George’s farsighted choice, and my first recognition that stored specimens might have value one day. With the remaining samples, we ran our own tests.
The way AIDS tests work is not by looking for the virus itself but by looking for the antibodies directed against the virus. In ELISA, the patient’s blood is placed in a laboratory vessel where AIDS antibodies will bond to a test medium and show up a certain color under a laser beam. If that test is positive, the costlier Western Blot may be done for confirmation. It uses a different test medium and process to get more detailed results.
In George’s lab, we repeated the ELISA and Western Blot tests that had been done by the Red Cross. Both were positive. But when we did a more specific radioimmunoassay, a more sensitive test for specific antibodies, it came out negative. The culture results from Mika Popovic and Wade Parks both returned negative, no HTLV-III identified. Through multiple studies, Judy Britz found no HTLV-III specific antibodies—but she did find some antibodies in the patient’s blood that “cross-reacted” with a substance in the standard assays and created the appearance of AIDS antibodies.
The first person I needed to talk to was my patient. To save her a trip back to Birmingham, I immediately called her and did my best to explain the good news. I listened as she exploded in tears. Sobbing into the phone, she asked if I was absolutely sure. I said yes, and explained briefly what we just had discovered about the tests.
What we had learned thanks to one woman’s agonizing experience was a critical discovery: the first known false-positive Western Blot test for the AIDS virus. For my rural Alabama patient, the discovery meant that a death sentence had been commuted, a marriage spared, and a life continued. The teacher was not infected and was at no special risk for AIDS. Of broader importance to the scientific and medical communities wrestling with the virus, the discovery meant that our testing measures, while very good, were not perfect and were subject to error on rare occasion. “False positives” was a way of saying “not true.”
At that moment, I would have done almost anything to spare another person that teacher’s ordeal. The one thing we could do, George observed, was to write up the case as soon as possible in order to alert colleagues to the possibility of false-positive Western Blots. As George and I worked with Judy Britz on the manuscript, we agreed that publication in the New England Journal of Medicine would have the greatest impact. To improve our chances of quickly getting into that prestigious journal, we decided to submit the story as a “Letter to the Editor” responding to previous articles on AIDS testing.
There was one hitch: The journal’s policy for letters was to list no more than two authors’ names. Though I argued that he had played the lead role in this discovery, George insisted that the two author names be Judy’s and mine. In an academic world where whose name is listed on a publication can make the difference between promotion and demotion, between getting a prestigious and funded chair or getting no recognition at all, George said, “Leave me off.” In that one, self-effacing act, I glimpsed the professional commitment and personal selflessness that I associate with George to this day.
The journal published the letter, and we heard from other ID docs who thanked us for the discovery. I was realizing my dream of becoming a medical sleuth: Mike Saag plays Sherlock Holmes. Though I did not recognize it at the time, this episode and the publication of our letter marked my formal career pivot into academic medicine and AIDS research. Before, I had dabbled; with this, I was committed. It was one of my life’s charmed moments, owing less to me than to a true AIDS pioneer, George Shaw, a stellar researcher and extraordinarily good man.
By the time George had earlier arrived in Robert Gallo’s famed laboratory, researchers around the world were searching in earnest for the cause of the mysterious immunodeficiency syndrome. Since that first report by the US Centers for Disease Control in June 1981, more and more American patients, mostly gay men, were coming into hospitals in major urban centers with unusual infectious diseases, including pneumocystis carinii pneumonia (PCP), Toxoplasma gondii encephalitis, Cytomegalovirus retinitis and colitis, Mycobacterium avium complex sepsis and end organ disease, and Cryptococcus neoformans meningitis. Within a year, the Latin names were common parlance in America’s gay community. Men with no medical training would whisper “pneumocystis” and know its meaning; even casual conversations in San Francisco coffee shops were laced with “cryptococcus” and a description of the drug regimen that had been prescribed.
Patients were presenting with unusual cancers seldom seen in the young. Some had rare types of lymphoma in the brain; others had Kaposi’s sarcoma, a highly vascular tumor in the skin and internal organs, typically seen only in older men of Mediterranean descent. Each of these disorders occurred in situations where the severe weakening of the immune system gave the pathogens and tumors the opportunity to flourish, so they were called “opportunistic” infections and malignancies. But why was this happening? There had to be something causing the immune systems of these patients to be so impaired.
In Los Angeles where four of the first cases of PCP were described, a young immunology fellow at UCLA looked for clues by running some blood through a new piece of lab technology. Dr. Michael Gottlieb drew blood from each of the initial patients and ran it through a Fluorescent Antibody Cell Sorter (FACS) machine, which quantitates how many immune system cells and which types are present. Among the T-lymphocytes, there are CD4 cells (so-called Helper T-cells) that orchestrate an efficient immune response to infections and tumors, as well as CD8 cells (so called Suppressor T-cells) that cool off the immune response and/or kill other T-cells as part of the cellular immune response. Normally, there are more Helper (CD4) T-cells than Suppressor (CD8) T-cells in a ratio of up to 2:1. The FACS machine counts and gives a readout of the number of cells per microliter (abbreviated as ul); a healthy patient typically has a CD4 count between 500 and 1500 cells/ul and a CD8 count of roughly half of that value.
These numbers are important to understanding what happened next. When Gottlieb ran the blood from patients with opportunistic infections at UCLA through the FACS machine, he could barely detect any CD4 cells. It appeared that one patient had ten CD4 cells/ul and another had three. Imagining that there was some error in the equipment or his procedure, Gottlieb ran the tests again. And again. Always, the results came up the same. What he’d discovered was evidence demonstrating the degree of immunosuppression, and he’d given us a standard by which to measure this suppression. For the first time, we realized that the virus was not only damaging the immune system; the virus was erasing it, explaining instantly how such opportunities existed for strange cancers and insidious infections.
Work done by investigators from the US Centers for Disease Control has largely been unheralded, but it was no less heroic than Gottlieb’s. Men and women, young and old, sleepless and committed—they descended on the medical centers in Los Angeles and New York, San Francisco and Miami, Chicago and Atlanta, looking for common threads in the stories of the patients struggling to stay alive while suffering indignities and pain. Following standard epidemiologic methodology but working at a furious pace, they gathered findings on patients and grouped the findings into constellations that formed a case definition of the new disease, or “syndrome.” Since all of the initially reported cases of the illness appeared to be in homosexual men, and since the widespread epidemic in the heterosexual communities of Africa and Asia had not yet been identified, the first name given in the United States was Gay-Related Immunodeficiency Syndrome, or GRID.
Patients who met criteria for GRID were interviewed over and over to learn their background, their behaviors, their potential exposures. Where did they travel? What food did they eat? What water did they drink? Who did they have sex with? What sexual practices did they engage in? What recreational drugs did they take? When had they first felt ill?
Some patterns emerged quickly. Most of the men had engaged in receptive rectal intercourse. Many had used recreational drugs, including amyl nitrite, so-called “poppers,” that users inhaled during sex to enhance orgasm. What in these two things, if anything, could cause AIDS?
In the space of one year, we watched an epidemic take shape, and it was breathtaking. Obviously, countless patients were never seen; they died in places and with diagnoses that went unnoticed. But within six months of the initial findings in June 1981, about 100 patients had been identified; a year later, the number was at least ten times higher, more than 1,000. During the day, those of us working with patients would say to ourselves, “Maybe the thing will plateau with this round of infections.” At night, alone with our thoughts, we worried that the truth might be the opposite: Perhaps this was only the beginning. Perhaps the epidemic would swell to tens of thousands, then hundreds of thousands, then millions. But these were merely fears. What we absolutely knew was that to be infected, to have GRID, was to bear a death sentence. And death by GRID—death by AIDS—was not an easy passing.
As the CDC teams crisscrossed the country pressing for more data, more information, more knowledge, it soon became clear that this new syndrome was striking more than gay men. Others arriving at hospitals with unusual opportunistic infections included heroin-addicted patients who were not gay, hemophiliacs who had received multiple blood transfusions, and, most strangely, immigrants from Haiti, most of them living in New York. (It was later discovered that in Haiti, a vacation destination for gay men from the United States, commercial sex was a common way for folks to make extra money.) For a brief period, the illness became known as the “4-H Syndrome,” for homosexuals, hemophiliacs, heroin users, and Haitians.
By the end of 1982, it was clear that there was no causal link between being gay and being infected; the virus was as happy infecting straight people as gay. We needed, as quickly as possible, to dissociate the illness from our own mistaken assumptions. (Retrospectively, we now know that the “gay” assumption proved to be the most damaging over the long term, and it may still be the greatest contributor to risk.) We moved to the term the CDC had adopted: Acquired Immune Deficiency Syndrome, or AIDS.
Within the first year of the burgeoning epidemic, attention began to swing toward the nation’s blood supply. If hemophiliacs were coming down with AIDS, were they being infected via blood they were being given? Or might it be in the equipment used to draw blood or infuse it? Or could it be in one of the commonly used cleaning agents? Or maybe it was transmitted through touching someone with the disease? What seems clear now was not at all clear then, in the heat and fear of the moment. Epidemiologists looked at other possibilities: Could an unusual side effect from “poppers” (amyl nitrate) be responsible? Some labs explored other possibilities including Epstein-Barr Virus, the agent that causes mononucleosis, but found nothing that would cause the immune deficiency.
Within months, a few laboratories that were exploring infectious causes began to focus on retroviruses. Most infectious agents reproduce in the same way human cells do: by copying DNA into RNA and then into proteins. Retroviruses, discovered in the late 1960s by Howard Temin and David Baltimore, go in the opposite direction: They start by copying RNA into DNA in a backwards or “retro” direction using a unique enzyme, reverse transcriptase (that is, transcribing in the opposite direction of normal cells). Gallo initially suspected a retrovirus he had discovered, HTLV-I, but the tests for that agent didn’t support this hypothesis.
At the Pasteur Institute in Paris, Luc Montagnier and Françoise Barré-Sinoussi were also focusing on a retroviral etiology. They had some initial signals of the presence of reverse transcriptase in tissue cultures of lymph nodes taken from AIDS patients, but strangely, the cells died too quickly to confirm the initial findings. In Gallo’s lab, however, Phil Markham and Mika Popovic began replenishing the tissue cultures with freshly stimulated lymphocytes every other day and were able to demonstrate that there was indeed a retrovirus in the tissue culture. At roughly the same time, the French group obtained electron microscopy images of a typical retrovirus budding from the surface of the cells in tissue culture. Two teams of scientists working intensely on two continents were finally able to explain the cause of the syndrome.
Though George Shaw had initially worked on HTLV-I in Gallo’s lab, he shifted focus to HTLV-III. He then became the first investigator to describe the presence of the virus in the brain and to link this finding to the dementia exhibited by many patients with late-stage AIDS.
A few months after George and I had partnered on the Alabama teacher’s case, George asked me to meet him in the University Hospital cafeteria. It was one of the few free moments I had in long days of training on hospital ID rounds, learning how to treat patients with all types of infections: bacterial, fungal, parasitic, viral.
As we chatted over french fries, George asked me, “Do you plan to do any research during your fellowship?”
I was a little surprised; I thought he knew. “Sure, I am working with Dr. Dismukes on studies of new drugs to treat fungal infections.”
George dipped a fry in ketchup and said, without looking up, “That’s great, but I mean lab research.”
I told him I had worked in the lab in both college and medical school. It was my way of saying “been there, done that,” and dismissing the idea.
George smiled knowingly, took time to down two more fries, then drew a sharp distinction. A student doing “research” in someone else’s lab is basically a technician, he said. If I did lab research as a postdoctoral fellow, I would have a say in what experiments were run and ultimately get to develop projects of my own. As a student, I was watching research; as a postdoc fellow, I would do it.
Well! The idea of doing research in a lab had never occurred to me. I was focused on being a physician, not a lab researcher, and the notion that I might do both was as foreign as Tranquility Base. But I admired George enormously, and I had learned so much from him in the lab on the schoolteacher’s case that his proposal was instantly appealing. Why not give the lab a spin? After all, when I returned to Louisville to make a career in private practice—as I still fully intended to do—I wasn’t likely to get the chance again to do research.
“So, interested in the lab?”
I dipped a fry of my own and heard someone say yes. The voice was mine. Magic.
On January 2, 1986, I showed up in George’s laboratory—or rather, the laboratory he shared with the formidable Beatrice Hahn. A native of Munich, Germany, Beatrice had worked with George in Gallo’s lab and came to UAB when he did. Once the AIDS virus was discovered, Beatrice was the first person in the world to clone and sequence it, which is why the original sequence’s name, BH10, includes Beatrice Hahn’s initials.
I didn’t need a microscope to see how my two lab mentors differed. George was easily knocked off task, and still is today, if asked a question that strikes his fancy. Beatrice was then and remains always on point, intensely focused, strong willed. If asked to take on projects not directly related to her research, she has no problem saying no or some variant of no often peppered with expletives. George has described Beatrice as “right 95 percent of the time, and when she is right, she is absolutely right.” He did not mention the rest of the story: She may not be particularly merciful to those who are wrong. Beatrice does her work as if lives depend on it; she takes it seriously. If you have other priorities, she has some language she’ll share with you, but no time.
On my first day in their lab, George showed me how to run a test called a Southern Blot. The test detects DNA in much the same way that a Western Blot detects antibodies. But that day, I had the sense that this test might also be used to detect something else: my seriousness, aptitude, and precision in the lab. I watched George meticulously prepare the buffers, materials, sponges, and nitrocellulose paper required to do the Southern Blot. I took copious notes. Working with cells from a patient infected with HTLV-III, we were seeking an answer to a critical question: How many different viruses exist in any AIDS patient?
Step one in the Southern Blot is to extract from the cells their DNA, which contains genetic material from the virus. Next, the extracted DNA is treated with enzymes that cut it into fragments at particular locations in its coding, much as scissors might cut a string of soft spaghetti. Then, using test agents and electrical current, the fragments are run through a gel that separates them by size, “denatured” from the usual double strand into a single-strand state and transferred to nitrocellulose paper. The paper is incubated with radioactively labeled virus fragments that bond tightly and specifically to any denatured HTLV-III virus present on the paper. It is then washed, dried, and, in a darkroom, placed into a cassette containing X-ray film. The next morning the film is developed, and any fragments of viral DNA show up as dark bands at specific locations, depending on how many times the DNA was cut by the enzymes. When the test is done properly, it will show the distinct characteristics of the individual’s virus, as unique to that patient as his or her fingerprint.
I realized immediately that this type of lab work was like gourmet cooking: There were techniques, a recipe, and a final product that could be utterly ruined by imprecision. It took two weeks for me to become comfortable performing the Southern Blot test. Once George was sure I was competent, he handed me a small vial containing clear, viscous fluid and said, “Here’s your project.” He might as well have said, “Here’s your future.”
I stared at the vial and the three letters on its label: RJS. It was DNA dissolved in water, taken from a patient who was diagnosed when the army started giving all active military personnel the new AIDS test. The R was for Redfield, a physician at Walter Reed Army Hospital. The J and S were the initials of Dr. Redfield’s patient—a guy who, before joining the army, had worked in a Los Angeles bath house in the late 1970s and early 1980s.
The medical file that came with the vial included a sexual history, in which JS estimated that he had had sex with … more than 1,500 different partners. (So much for maintaining professional composure: My jaw dropped at that number.) Sex was a fringe benefit of JS’s job at the bath house, where men came to have anonymous, typically anal or oral sex. The file said JS’s “record” was forty different partners in one night.
In their heyday, the bath houses were notorious breeding grounds for sexually transmitted diseases. During the time JS worked there, it’s likely that at least half of the patrons were already infected with the AIDS virus. If JS had unprotected sex with more than 700 different AIDS-infected partners, the question we were asking in the lab was: Could he have been “super-infected” with different strains of the virus? We knew already that each person’s virus was relatively unique in genetic sequence. My mission was to see what JS’s virus looked like and whether there were viruses from other partners present.
I meticulously prepared all of the reagents, making sure all the enzymes I would use were fresh from previously unopened vials. I paid such attention to every detail at each step of the procedure that just preparing the Southern Blot took most of the day. My last step was to place the dried, radiolabeled paper into the X-ray cassette and leave it in a -70 degree freezer overnight to facilitate a clean signal.
The next morning, I removed the cassette from the freezer, let it thaw for an hour, and took it to the darkroom. As I stood on the other side of the developer waiting for the processed film to appear, I was anxious but mostly excited. My first real experiment, in a modern lab, doing cutting-edge work on an emerging epidemic. By now, it wasn’t just an epidemic; it was also JS. Already I was experiencing what it meant to be researcher and physician, to focus my mind simultaneously and intensely on an epidemic and a patient.
The film dropped into the tray with a little clunk. I picked it up and placed it on the lighted view box. I was pleased with the technical outcome: The bands were crisp and well defined, almost handsome. But there were too many of them; way too many. The virus is 9,000 base pairs, or 9 kilo-bases (kb), long. No matter how many fragments result from cutting by an enzyme, they should add up to 9 kb. But I had fragment totals adding up to two and three times that. Something was wrong. I went to see George.
Maybe George’s contact lenses had been bothering him. He was wearing his glasses instead, and his eyes looked red. I handed him the film from my experiment. He held it up toward the fluorescent ceiling light, at arm’s length from his thick-lensed glasses, and stared. And stared. And stared. During maybe four minutes of staring, I don’t think he blinked once. Without looking away from the blot, he began pelting me with questions: Which vial of RJS DNA did I use? Which pipette tips? Where did I get them? Whose buffers did I use? Which enzymes? Were they fresh or previously opened? Did anyone else touch the DNA or my vials at any time during the procedure? The questions went on for ten or fifteen minutes, but for me it felt like hours. I wasn’t even thinking about what these test results might mean if they were accurate because I was so busy thinking that if they were not accurate, I must have screwed up.
George called Beatrice in from her office and showed her the blot. She looked at it briefly, then looked at me and said what I’d been thinking, in her own saltier version: “You must have [screwed] it up.” George came to my defense, saying that he had grilled me on the technique and that I seemed to have done it properly. “Well, repeat it,” Beatrice said, and walked out.
Sweating, I went back into the lab. I carefully looked over my notes, trying to see what I had done wrong. I remade all the chemical buffers, paying extra attention to measuring precisely. I double-washed every one of the containers they were prepared in. I used a new set of enzymes, fresh. And I repeated the experiment, paying absolute heed to every detail at every step.
When I showed up the next morning to pull my cassette from the freezer, George was in the lab staring at a Southern Blot film on the light box. He was wearing the same clothes as the day before and still wearing his glasses. Impossible as it would have seemed the previous morning, his eyes were even redder now. The blot on the light box looked like the one I had run the day before—but the handwriting on its label was George’s. He had stayed up all night, again, repeating the experiment I had done.
I went to my bench, retrieved the film from my second try on my first experiment, and held it next to George’s film. They were identical; my result was the same as George’s.
This was not a screwup. It was a breakthrough.
Typically, when someone is infected with a microorganism, all the bugs are genetically identical because they emerge from the same clone. It isn’t possible for them to be otherwise. For example, if someone has a staph infection, the first bacteria that led to the infection is genetically identical to the billionth bacteria that grows in the infected wound. What George and I had uncovered, aided by Beatrice’s indelicate direction, was that what we assumed to be true was not true. The certainty of a staph organism was not a certainty for the AIDS virus. Here, as the disease progressed and the virus replicated, we were finding more of what was genetically not-the-same.
AIDS patients are initially infected with one particular clone known as the “wild-type” of the virus, and in the early stage of infection, hundreds of billions of viruses are produced that remain identical to it. Then, as the host’s immune system begins to recognize that it has been infected and responds to the virus, mutants emerge that are highly related to but genetically distinct from the original infecting virus. The virus irritates the body, and the body responds by attacking the virus (immunity); under attack, the virus mutates, changes its character to escape the immune response. A deadly game of cat and mouse.
Clever virus? Not really, just prolific. When describing the virus to the general public I sometimes tell audiences, “The virus is like most men—all it wants to do is survive and replicate!” Women get it immediately; men just look at me dumbfounded.
Compared to most viruses, the AIDS virus replicates so often, so quickly, that the probability of a mutation emerging is vastly amplified. This change occurs because the virus’s way of replicating is inherently error prone. Each time the virus reproduces its genetic material, it uses the reverse transcriptase (RT) enzyme to make a copy of itself. RT is a sloppy enzyme, making at least one error in every 3,000 to 4,000 base pairs. Since the AIDS virus is 9,000 base pairs long, that means on average one to three errors each time the virus replicates. When the immune system begins to respond to the initial wild-type virus, one of the new copies of the virus—formed, by chance, with an error or two—suddenly has a growth advantage over the wild-type virus now spotted and being attacked by the body. What had been the mutant begins to emerge as the predominant species. Darwinism, survival of the fittest, operating at warp speed. For the duration of the infection this process continues, resulting in dozens of unique but highly genetically related viruses.
That is what I had detected with my Southern Blot experiment, and that is what George had confirmed when he duplicated my work: The simultaneous presence of multiple viruses that were highly related to the virus that initially infected JS, but definitely distinct. Such a swarm of variant viruses is called a quasi-species—and we had discovered the quasi-species nature of the AIDS virus.
This nature explains why drug resistance can so easily (and rapidly) emerge when the anti-HIV drugs are not potent enough to fully suppress replication. Naturally occurring errors that spontaneously appear can, by chance, lead to a virus that is not inhibited by the antiviral drug. All of the susceptible viruses are suppressed, but the resistant virus, unaffected by the drugs, survives, then overgrows the wild-type and becomes the predominant virus in the quasi-species. (Our finding all those years ago also has had profound implications for the development of an AIDS vaccine: If there are dozens of viruses in one person’s bloodstream, how do we create a vaccine that can protect against the transmission of all of them? It’s a tall order that we’re still trying to overcome.)
My dream of solving mysteries in ID medicine had just been realized, in spades. The ramifications of our Southern Blot results had critical ripple effects. With this discovery, we had played a role in a drama of global proportions, the race to understand AIDS. Each step forward in that race put us closer to offering hope where it mattered most: in the hospital rooms of our HIV patients.
Already then I was beginning to carry those patients with me into the lab, and when I moved to their bedsides I hauled the lab in with me. A researcher and a physician are different. I understood that. But the two roles were occupied by one person: me. What I increasingly realized was that my work in the lab—everyone’s work in every lab—was the only hope for patients I knew not just as initials on a vial of fluid but by name, face, family, history, gifts, character, and fear. The virus wasn’t just a virus; it was an enemy. My patients weren’t just patients; they were David and “Jamie,” “Kevin” and Ed, Michael and Brian.
My wife, Amy, has a favorite story about me from that era—and when I say “favorite,” I mean she loves to tell it on me as a loving but pointed reminder of how engrossed in work I can become. As she tells it, “One night when Andy was a toddler and Harry just a baby, Mike came home late at night. When he came in, I saw something in his hand as he headed for the kitchen.
“I said, ‘Michael, what did you just do?’ And he said, ‘I had to put something in the freezer.’ And I said, ‘What was it?’ And he said, ‘A vial.’ Of course I asked, ‘A vial of what?’ And he said, ‘A vial of infected blood.’ [Pause] ‘But it’s triple-wrapped.’ And I said, ‘I don’t give a damn if it’s quadruple-wrapped, you don’t ever bring home infected blood and stick in it my freezer!’”
While I’m sure that I’ve committed other work-obsessed infractions since then, I never repeated that one. But it was triple-wrapped.
In the weeks that followed our initial discovery, Beatrice, George, and I fleshed out our findings. We evaluated the genetic fingerprints of other patients and confirmed our original finding: All patients with established infection are walking around with a quasi-species of viruses. At the end of January 1986, I submitted an abstract of our work to the 2nd International AIDS Conference. The abstract was accepted for presentation at the conference, to be held in June—in Paris.
I had never thought much about the ladder-climbing in the medical profession; my attitude was that if you do good work, good things will happen. I was already having that experience: Good things were happening as if by magic.
In the wake of the discovery of which I’d been a part, it was as if I had climbed aboard a rocket ship. It felt like I was strapped in the capsule on top of the giant Atlas 2 booster rocket I’d watched lift off as a kid. I was blasting off, pulling about 4 Gs and hoping for weightlessness. I didn’t exactly know how I got there and didn’t know how I was going to land, but it was one wild ride.
When my feet finally touched ground, I was in Paris on the summer solstice, June 21, 1986. I was so excited to be on my first trip to Europe that I couldn’t sleep on the flight from Atlanta to Charles de Gaulle Airport. My eyes in Paris had taken on the hue of George’s eyes in the lab, but I remember everything about our early-morning arrival at the Hotel Franklin Roosevelt in Paris’s 8th arrondissement. We emerged from the cab to hear a man on the hotel balcony yelling, “Be-a-trice! Be-a-trice! Be-a-trice!” Raoul, a high school friend of Beatrice who was now a chef in St. Tropez, had come to Paris to meet her and be our tour guide.
As quickly as I could drop my luggage in my room and grab my Super 8 movie camera, we were off. I almost always set my movies to music I select after I shoot the footage. But from the moment I got on the plane in Atlanta, I knew this movie’s soundtrack would be Gershwin’s “An American in Paris”—and as we walked toward the Champs-Élysées, I could hear its opening stanzas in cadence with my steps. It was magical.
For six hours, we toured famous French landmarks and I shot film, going through three reels that first day. It was an unseasonably warm day, so when we stopped for a bistro lunch, I gulped a little food and washed it down with the chilled Beaujolais that Raoul ordered. When we were done, I tried standing up. Nothing. I couldn’t feel my legs or feet. The wine, the excitement, the wine, the jet lag, and the wine sent me to bed for the rest of the day.
At 9:30 p.m., I woke to a chorus of horns playing—I swear—in the cadence of “An American in Paris.” Beep, beep, beep! Honk, honk, honk! As Parisian motorists celebrated the French soccer team’s World Cup quarterfinals victory over perennial powerhouse Brazil, George, Beatrice, Raoul, and I explored the Technicolor whirl of the Left Bank. We ate and drank, mingled with soccer fans, and applauded performances of the annual Fête de la Musique street music festival. By the time we called it a night, the Metro was closed and no cabs were in sight, so we walked weary miles to find our hotel.
At 6:00 a.m. I fell back into bed, ending one of the most exhilarating and surreal days of my life. I now wonder if it’s true that, falling asleep, I heard Flohoney telling me: You belong here, Michael. Stick with AIDS.