In 1936, there was some inkling that environmental factors could be contributing to cancer. Tobacco, radiation, hormones, and asbestos were seen as possible, although unconfirmed, influences. If World War II had not monopolized the need for scientists, some researchers believe these early findings would have been acted upon. Although impossible to know, perhaps our approach to cancer would have been more coordinated, more rational.
By the 1940s and 1950s, we were suffering under the weight of a huge number of cancer diagnoses, about 200,000 each year. We kept the disease shrouded in mystery as a matter of propriety. Very little money was spent on research. The media largely avoided the subject. In fact, the word cancer was prohibited from being said aloud on NBC (the National Broadcasting Company).
Much like the stigma generated by HIV, cancer was both incomprehensible and shameful. It was described as the “disease of civilization,” blamed on modern life, even considered a punishment. Patients hid their disease, afraid to talk openly about their fate. Incurable diseases expose our vulnerability, inciting fear, provoking judgment, and rousing our worst instincts in society. At the same time, they inspire some individuals to make radical choices. This is what happened to Mary Lasker, a socialite in New York City.
Beautiful, charming, and rich, Mary was born to an extraordinary fate. Raised in an upper class family in Wisconsin in the 1920s, Mary became plagued with childhood ailments, from dysentery to recurring painful earaches. Illnesses that today can be treated with simple antibiotics caused Mary to be isolated and lethargic.
As a young girl, Mary remembered standing outside a shack at the edge of town with her mother. They were dropping off laundry. Mary’s mother paused outside the door to warn her daughter before they entered the room. “Mrs. Belter has cancer and her breasts have been removed.” Mary replied, “What, cut off?” Mary’s mother nodded and they entered the room. Mrs. Belter was lying in a low bed, her bedclothes failing to cover the scars of her surgery prominent on her chest. Seven noisy, demanding children crowded around her reclining figure. The moment would become a part of Mary’s identity. She would later recall, “I’ll never forget my anger at hearing about this disease that caused such suffering and mutilation and my thinking that something should be done about this.”
By the time Mary was in college, her father had become frail, hardly eating. Her parents suffered from hypertension, a disease that would take both their lives when Mary was in her thirties. This left her “deeply resentful” of physicians and medical research. She scorned the medical institution that had not been able to help her family. She would later look back at these early experiences as the inspiration for her work, saying, “I found out that it all went back to my violent reaction and hostility to illness for myself or for anybody else.”
When Mary Woodward secretly married Albert Lasker, the advertising legend, on a June day in 1940, there was no reason to think she would become a powerful advocate for medical research. Or that her advocacy not only would impact cancer patients but would form the foundation for all the HIV drugs we have today.
In the year before she met Albert Lasker, a shift had occurred in Mary’s life. A divorcée living in New York City, she was close friends with Margaret Sanger and began raising money for the Birth Control Federation of America, the predecessor of today’s Planned Parenthood. Her eyes were opened to the inadequacies of the public health system.
Following her wedding to Lasker, she became concerned about the declining health of her longtime housekeeper. The woman, although obviously ill, would not specify what her disease was, so Mary resorted to confronting her housekeeper’s doctor directly. He told her, in a time before privacy laws, that the woman was hiding uterine cancer. A short time later, Mary was horrified to learn that her ill housekeeper had been sent to an institution “called something like the home for the incurable.”
Mary, now armed with strong allies, thanks to her marriage to one of the most powerful men in New York City, decided to take on cancer. Upon learning the minuscule size of the budget for the American Society for the Control of Cancer, a tiny organization with only a thousand members and no research agenda, she decided to reform it. She used a fresh tactic to bring the need for cancer research to the public: advertising. With her husband’s help she was able to convince David Sarnoff, the CEO of NBC, to lift the ban on saying cancer on the network. So convincing were her arguments that he not only lifted the ban but also agreed to have Bob Hope deliver a message on-air about the dire need for cancer research funding. She convinced editors at Reader’s Digest to publish articles about cancer, suggesting writers capable of stirring emotions on the subject, and on at least one occasion writing a piece herself for the magazine. All in all, she raised an incredible amount of money.
But, sadly, science failed her once again. In 1952, her husband died of colon cancer. Many women might have become embittered, angry at both the disease and those who claimed they could fight it. Not Mary. She returned to her fight against cancer renewed; her beloved husband’s death only strengthened her advocacy and lobbying.
Renaming the small cancer organization the American Cancer Society (ACS), she successfully lobbied Congress for research funding for the National Cancer Institute (NCI), boosting cancer research funding from $1.75 million in 1947 to an astounding $110 million in 1961. By the early 1960s, half of this enormous budget was spent by the NCI on screening thousands of possible drugs and sifting through a sea of chemical compounds to identify a few drugs with promise. Although this newly defined “war against cancer” was progress, the approach left much to be desired. The science of throwing random compounds and drugs at mice with leukemia was not innovative or exciting.
Jerome Horwitz, who worked at the Michigan Cancer Foundation, part of Wayne State University, in Detroit, was a young chemistry professor who wanted to find an intelligent approach to tackling cancer. He postulated that if it wasn’t possible to directly target the cancer itself, he could target what the cancer needed: the cell. Since cancer was an overgrowth of cells that simply could not stop dividing, the best way to kill the cancer was to kill the ability of the cell to divide.
Before a cell divides, splitting itself into two cells, it has to make a copy of its own DNA. Each cell needs its own set of identical genetic material. This DNA is formed from nucleotides, the “building blocks of life.” The helix itself unwinds until the DNA is stretched out like a ladder. The rungs of this ladder break open, splitting up the DNA strand. The DNA looks like a zipper, the molecular bonds slowly coming apart. Each half of the DNA strand will eventually separate into different cells. New building blocks enter the opening DNA zipper, forming brand-new strands of DNA. The idea here is to make two identical copies of DNA from the one original. Like a zipper, the newly made DNA strands form the opposite tread. Each new strand fits perfectly into the original strand, forming two new functional zippers.
Because they are complements of each other, each half of the DNA strand carries all the genetic information for the cell. The DNA strands make a simple pattern of bases, each base intimately pairing with its one and only complement on the other side of the aisle. Adenine (A) invariably pairs with thymidine (T), and guanosine (G) pairs with cytidine (C). These building blocks are intimately connected; the correct binding of each of the nucleotides is necessary to the growing chain of DNA. A simple sheath of sugars and phosphates, all wrapping around each other and forming the double helix, connects them. Once two identical DNA strands are made, the cell can divide, forming two cells where there was only one.
Horwitz had a devilish plan to attack the replication of DNA. He devised the idea for a “trick nucleotide.” Instead of a simple thymidine, one of the DNA building blocks, his thymidine would be altered. Once his trick nucleotide was incorporated into a cell, it would abruptly cut off the growing DNA strand. The cell couldn’t divide; the cancer would be stopped. Horwitz worked tirelessly to make these trick nucleotides for all of the four bases, A, T, G, and C, that make up DNA.
Horwitz had a wife and growing family at home. Yet he was drawn to the lab, spending nights and weekends alone at the bench. He believed in his strategy. Perhaps this is why it was so devastating when it failed. He treated leukemic mice with the new family of drugs. Nothing happened. The tumors continued to grow; the runaway cells didn’t even slow down.
It was 1964 and the world seemed to be coming apart at the seams. The Vietnam War was gaining momentum, violence was erupting at home as the Civil Rights Act was passed, and in labs all over the country, researchers were desperate to find a drug to treat cancer. Horwitz wrote up his failure. In his heart, he believed the drugs had a purpose to them. When describing the failure to his colleagues at Wayne State University, he would describe the drugs fondly as “a very interesting set of compounds that were waiting for the right disease.”
Despite the tantalizing promise of these compounds, he didn’t bother patenting them. Patenting drugs was not cheap. Why bother wasting money on patenting failed drugs? He had already wasted precious resources on developing the drugs to begin with.
The failed compounds were archived, their records collecting a thick layer of dust in the Detroit lab. In one of those boxes was 3'-azido-3'-deoxythymidine, or AZT, one of many seemingly useless compounds. And there it would sit for two long decades.
• • •
While David Barry was mobilizing a team to develop the first drug effective against HIV at Burroughs Wellcome, a different sort of team was forming at Mary Lasker’s National Cancer Institute (NCI) in Bethesda, Maryland. Wedged next to the National Institutes of Health (NIH), the NCI was a small campus of labs and offices surrounded by flowering dogwoods. Researchers could be found wandering the curving paths at all hours. With great forethought, the institute was located next to a hospital, giving researchers and clinicians the opportunity to mix. It also allowed blood samples to flow easily from hospital to lab bench.
Like Jerome Horwitz, who tinkered with cancer cellular machinery drugs in Michigan, Sam Broder was born and raised in Detroit. Broder started at NCI as a young clinical researcher in the early 1970s. At rapid speed, he moved up the ranks from clinical associate to head of the oncology department. By 1980, he was a vital member of the research force, poised to take on what he couldn’t possibly know was coming: a new and unprecedented epidemic.
A molecular evolution was under way at NCI. Many of the basic molecular techniques that are commonplace today—sequencing, cloning, protein expression—were just beginning to emerge, all from the famed institute. It was a renaissance for molecular biology, at an institute that happened to comprise a group of unique young scientists filled with passion and poised to become the next generation of scientific leaders. Broder learned about the new disease, GRID (gay-related immune deficiency), in 1981. A young man who had recently visited Haiti had a strange set of symptoms, none of which fit together. Broder had never seen anything like it before. He said to a colleague as they discussed the unusual case, “I hope we never see anything like this again.”
Despite the politicized nature of the burgeoning epidemic, to most scientists it was clear from the earliest days that the disease was not based on lifestyle. When a colleague at the NIH referred to the disease as relevant only to gay men, Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases (NIAID), pointed out that the disease could be passed from mother to child and angrily responded, “What lifestyle did the fetus undertake to acquire the disease?” He presented clear evidence to critics, both scientists and journalists alike, that the disease was not based on a lifestyle or sexual orientation. He, like many other HIV researchers, was passionate about exposing the true nature of the epidemic.
When Robert Gallo, also at the NCI, announced that AIDS was caused by a retrovirus, HTLV-III, there was considerable excitement among policy makers, who were eager to calm the public’s fears with a promised cure, but little enthusiasm from scientists. Standing next to Margaret Heckler, Ronald Reagan’s secretary of Health and Human Services, that day in April 1984, Gallo felt increasingly uneasy about Margaret’s words. He was exhausted, having rushed from an overnight flight from Italy to the packed, hot room. His pride stung from an article published only the day before in The New York Times giving credit for the discovery of the AIDS virus to the Pasteur Institute in Paris. He felt he had been unwittingly roped into doing a press conference. Now Margaret was making fantastic claims about the pursuit of new therapies. In fact, she announced that a cure would be available in only two years. Gallo felt hopeless to correct what he knew was obviously false. The press conference would continue to haunt him years later as it served to widen the growing rift between him and the French scientists.
Although the discovery of a cause for the rapidly growing disease should have been a relief, in fact, finding the agent behind AIDS only brought more worry.
For most clinicians, the news that AIDS was caused by a retrovirus meant one thing: There would be no quick and easy therapy. Retroviruses were notorious for their complex life cycles and the distinct lack of research on them. Retrovirologists had little experience in clinical drug development. This was not good news.
Not surprisingly, Gallo found that identifying partners interested in developing therapies for AIDS was not easy. Pharmaceutical companies in general were staying far away from the disease whose mechanism of transmission was far from certain, making it dangerous to work with, and whose market was still relatively small. At the end of 1984, while Gallo searched for pharmaceutical partners, there were fewer than 8,000 cases of AIDS in the United States. No one yet realized how soon that number would explode. Few companies wanted the risk of working on this new, dangerous disease. Companies were concerned that it would take heavy financial investment while profits were far from certain. The concern was part scientific since there was so little known about the infection. But in addition to the medical confusion surrounding the virus, reticence to work on the disease was also fueled by homophobia. AIDS was viewed as the “gay plague,” a perception that dampened initiative from some pharmaceutical companies and research scientists.
In addition to homophobia, the disease itself inspired fear; some hospitals refused care to those who were HIV-positive, unwilling to admit patients whose condition frightened them. Firefighters banned the “kiss of life,” afraid mouth-to-mouth resuscitation would transmit the deadly virus. Police officers in New York City began carrying masks and gloves for dealing with “suspected AIDS patients.” The debate even spread to parents who worried about sending their children to school with children infected with the virus. The most famous of these cases was that of Ryan White, who, in 1985, as a thirteen-year-old hemophiliac with AIDS, was banned from school.
Despite the difficulties, the NCI decided to pour resources into research. They began pumping out massive quantities of the newly discovered virus, searching for a blood test that could be used to screen donated blood. Even though the institute encouraged its scientists to work on HIV, not everyone wanted to. Many believed that the politics of the disease were too complicated. Unlike other diseases, to work on HIV made researchers the subject of scrutiny from activist organizations that were not afraid to protest against companies and research centers they disagreed with. It also drew political lines. Activists believed that President Reagan’s response to the AIDS crisis was poor (Reagan didn’t mention AIDS until 1985), further politicizing the response to the epidemic. Many simply didn’t want to waste time adding another project to their busy schedules.
Broder was not one of those scientists. From the time he saw the first HIV patient at the NIH in 1981, he found himself fascinated. As an oncologist, he couldn’t help comparing the way the virus replicates to the way a tumor cell does. In both diseases the cell is overtaken, given signals and commands that are not within the realm of normal development. As the diseases progress, tumors metastasize, spreading from one part of the body to another. HIV similarly grows, from a single genetic variant to a diverse genetic circus able to infiltrate almost every tissue imaginable. Later, Broder would compare the development of therapy for HIV to that of cancer, saying, “Principles, drawn from the world of cancer, had significant implications for the development of antiretroviral agents, starting with AZT.”
As he stood in his office, contemplating adding yet another project to his full roster, Broder stroked his thick, bushy, black mustache and adjusted his glasses. Now that the virus had been identified, the next step was obvious. He and Gallo needed a way to test for the virus. They needed to develop a system that could diagnose those with the disease. All the researchers knew that the national blood bank supply was in jeopardy if people donating blood didn’t know they were infected. The supply of blood critical for saving lives could be massively reduced overnight. . . .
Broder’s mind raced to the next step. Identifying the virus was necessary, but what about finding a treatment? How could they manipulate the science further to screen for drugs? There was only one place this work could be done: the NCI. Looking back, he would say, “It was clear that we needed a focused laboratory that was used to drug discovery and was willing to work with live AIDS virus. The only institute in the NIH that historically had focused heavily on new drugs is the cancer institute.”
At Dave Barry’s urging, in 1982 a small team at Burroughs Wellcome had begun pulling antiviral drugs off the shelves. What began as random shots in the dark changed radically in 1984 with the discovery that AIDS was caused by a retrovirus. Suddenly, the known biology of retroviruses could be manipulated.
The most obvious way to target a retrovirus, the Wellcome team reasoned, was to target the one unique cellular process that all retroviruses desperately needed: reverse transcription. Retroviruses, starting as simple strands of RNA, need to take over our cell machinery. Since they don’t have cells of their own, they need ours. So they cleverly insert themselves into our DNA. The Wellcome team believed that this process would be the easiest to disrupt. Most of the team was focused on the known antiviral drugs lining the pharmaceutical company’s shelves, but one woman had a radical idea.
Janet Rideout, an organic chemist working on the Wellcome team in North Carolina and interested in antibacterial drugs, had recently pulled out an old drug from the archives of the Michigan Cancer Foundation. It was the early 1980s and she was curious to see if these old drugs, developed in the 1960s, might be repurposed to fight bacteria. One drug in particular was effective against bacteria, azidothymidine, or AZT. Rideout had spent the last few years learning all about AZT, fascinated by its unique nature. As the team’s focus shifted from bacteria to HIV, she didn’t forget the unusual drug that attacked the cell. As she saw one by one the Wellcome teams’ antiviral drugs fail, her interest in AZT grew.
Just as Horwitz had spurned throwing random compounds at cancer, Rideout also believed in a rational approach to the hunt for an AIDS drug. Her intimate knowledge of the mechanism behind AZT allowed her to see the big picture. The drug made sense: By terminating the growing chain of DNA that the virus created to insert itself into a host cell, it could stop the virus in its tracks. Of course, Rideout knew that lots of drugs make logical sense and yet still fail. The only way to test AZT’s effectiveness would be to test it on actual HIV, not on other, related retroviruses. The company realized they would need collaborators; they simply didn’t have a safe way to work directly with the deadly virus.
As fate would have it, at the same time that Wellcome began looking for partners, Sam Broder at NCI and Dani Bolognesi at Duke University came looking for them. Broder had developed an exciting new way to screen for HIV drugs. After failed attempts with other companies, Broder was desperate to find a pharmaceutical company that could contribute a library of potential drugs for screening. In addition, he wanted to find a company that was willing to make the substantial investment (at the time the average cost of bringing a new drug to market was $400 million) needed to turn a promising drug into a clinical trial.
When the HIV team at NCI met with the team at Wellcome, it seemed to be a match made in heaven. Years later, when the patents became more valuable, it would turn into an ugly brawl. For the moment, though, the stars were aligned, and the first AIDS drug, AZT, was born. Horwitz’s failure had turned into a dramatic, unexpected success twenty years after the fact.
In the crosshairs of AZT were thousands of dying AIDS patients. “Trials are treatment,” demanded AIDS activists, desperate for any kind of therapy. The idea that safety should be considered in clinical trials was secondary. The architects of AZT believed that if patients were going to die, they might as well die with some hope.