Despite its dreadful reputation, the genital form of Herpesviridae infection, HSV-2, tends to be remarkably similar and almost as benign as its HSV-1 cousin. Contrary to conventional wisdom, outbursts of HSV-2 are generally limited to localized, albeit uncomfortable, ulcerations on and near the genitals. Like HSV-1, these sores tend to heal and indeed may go completely unnoticed, as evidenced by a 1997 CDC report. This study revealed that while one in five adult Americans was infected with HSV-2, 80 percent were unaware of the fact.44 The notable exception to the idea that genital herpes is relatively benign arises with the very young. When an infected mother delivers an infant vaginally, the infant may encounter an active sore during the vaginal birth. The relative weakness of the newborn immune system can allow the virus to run rampant and cause irreversible brain damage, respiratory or liver failure, and death. Fortunately, even the most extreme infections with Herpesviridae tend to respond favorably to a series of medicines developed in the early 1970s, with thanks to a gift from the briny depths.
Tectitethya crypta is a species of sponge found in the shallow waters of the Caribbean Sea.45 These sponges are among the oldest multicellular creatures on earth, with origins in the period that immediately followed the Cryogenian period three quarters of a billion years ago. This period is known as “Snowball Earth” (or perhaps more accurately but less sexy from the standpoint of popularizing science, “Slushball Earth”), when the entire planet was encased in ice, snow, and magnitudes of dirty slush (not unlike a typical Boston January). Somewhat more recently, in 1950, a descendent of these early sponges was isolated from the waters off the Elliot Key in Florida. This specimen was shipped to New Haven, Connecticut, where Professor Werner Bergmann of Yale University dissolved a sample of the sponge in acetone (better known as finger nail polish remover).46 The reason for doing this was not based upon an interest in aquatic creatures but because Yale was amidst a scientific and medical frenzy to develop new medicines for cancer. As elaborated in greater detail in A Prescription for Change, Yale was the epicenter in the postwar years for identifying compounds that could restrain the deadly disease.47 The Yale study was disproportionately successful as it identified a series of molecules that would revolutionize cancer treatment, including the antimetabolites, cytarabine, vidarabine, and gemcitabine. An antimetabolite is generally a natural molecule that somewhat resembles an essential metabolite (or foodstuff) needed for the growth and survival of normal cells. As such, one can think of metabolites as the medicinal version of the Trojan horse supposedly invented by Odysseus and popularized by the ancient Greek poet Homer three millennia ago.
Cancer cells are often characterized by a literal feeding frenzy as they gobble up all nutrients that might be useful to support their rapid growth and metabolism. As such, the feeding of so-called antimetabolites that sufficiently resemble a potential foodstuff but are different enough to cause lethal indigestion can provide a means to target cancer cells. This basis of “selectivity” allows these drugs to be particularly noxious to cancer cells, while the fussier benign cells generally ignore antimetabolites. The strategy of discovering and deploying antimetabolites was exploited in the late 1940s and throughout the 1950s to identify new medicines. The need for ever more new medicines propelled the discovery of novel species across the planet (and under the seas), most of which were harvested to sample their antimetabolite activities.
Partnering for Cures
The concept of developing new medicines based on nature-derived (or natural) products was the hallmark of drug discovery since the earliest discoveries of botanicals such as the willow tree and the poppy, which ultimately led the way to aspirin and morphine, respectively. Arguably, the most prolific duo ever to harvest the potential of nature to target disease is the unlikely team of Gertrude (“Trudie”) Elion and George Hitchings. According to the autobiography she composed to commemorate her 1988 Nobel Prize in Medicine (one of the most entertaining ever written for such an occasion), Gertrude Belle Elion was born in New York City “on a cold January night (in 1918) when the water pipes in our apartment froze and burst.”48 The precocious daughter of an immigrant family from Eastern Europe (whose fortune, like that of so many other families, was lost in the 1929 stock market crash), Gertrude’s fertile mind was particularly drawn to thoughts of travel to distant lands though the family’s limited financial means precluded such dalliances. Her father, Robert, had arrived in the United States from Lithuania at the age of twelve. He not only quickly assimilated into the new language and culture of his adopted land but also rose to become a successful dentist.49 Likewise, Trudie’s mother, Bertha Cohen, came to the United States from Poland at the age of fourteen and enrolled in night school, both to master the language and to gain skills needed for a career in the textile industry. The young and hardworking family expanded with the birth of Trudie’s younger brother, Herbert, in 1924, and by the immigration of Bertha’s family to the United States. Trudie excelled at her studies, skipping a grade on two separate occasions, thus allowing her to graduate from high school as a young adolescent of fifteen. Trudie was contemplating college versus the job market when her grandfather finally succumbed to an agonizing bout of stomach cancer. In her sorrow, Trudie proclaimed, “No one should suffer that much” and later recognized this to be a major turning point that started her down the path to develop new medicines for cancer.50 Despite severe constraints on the family’s financial resources that might have precluded further study, the family urged Trudie to enroll in college. Her high marks earned her a full scholarship at the all-girls Hunter College of the City University of New York (CUNY). Fascinated by the sciences and motivated by the fresh desire to alleviate the types of suffering she witnessed during the long, agonizing demise of her grandfather, she chose to major in chemistry rather than biology, due to her repulsion at the idea of having to perform research on animals.
The young graduate, who crossed the stage of Hunter College in 1937 to accept her bachelor’s degree in chemistry, summa cum laude and Phi Beta Kappa, was nonetheless consistently rejected in her many attempts to apply her new knowledge.51 Despite hard-earned credentials and a promising young intellect, the ongoing economic strains of the Great Depression aligned with the prevailing misogyny of the day to preclude Trudie from receiving offers of employment from the research laboratory jobs that had motivated her from the time of her grandfather’s death. Women of that time (and for years to come) had essentially three career paths: secretary, schoolteacher, or nurse. Unqualified for the latter, Trudie enrolled in secretarial school but soon realized this path was not sufficiently fulfilling. She bounced among a bevy of part-time jobs (mostly as a secretary or teacher) and volunteered in a research laboratory at night, all the while saving the little money she earned to pay for the tuition needed to earn a master’s degree in chemistry. Whereas her interest in chemistry had been rather unexceptional at the all-women’s Hunter College, where she’d been one of seventy-five chemistry majors in her class, Trudie was the only woman enrolled in the master’s program at New York University. During the two years needed to achieve the degree, Trudie lived a double life, serving during the days in the stereotypical role as a secretary and substitute high school teacher while at night she devoted herself to completing a master’s thesis in advanced chemistry.
As she was embarking on her professional development, her personal life would first blossom and quickly wither. Within weeks after her graduation from Hunter College, Trudie fell in love with the man who would change her life forever, though perhaps not in the conventional way. The subject of her affection was a fellow CUNY alumnus by the name of Leonard Canter. Leonard had majored in statistics, and the two were well on the way towards planning their lives and settling down, a particularly impressive feat given the time commitments Trudie was juggling. On a spring day in 1941, Leonard began to develop chills and experience sudden weight loss and night sweats. Within days a shortness of breath was accompanied by pains in the chest and reflected the fact that a bacteri
al infection had taken hold of Leonard’s failing heart. The resulting bacterial endocarditis likewise broke Trudie’s heart with the death of the 21-year-old Leonard Canter on June 23, 1941. This tragedy renewed Elion’s commitment to alleviate suffering through the development of new medicines. She would forever forsake additional romantic partnerships in deference to her love of both Leonard and science. (On a personal level, Trudie doted upon her brother’s children and occasionally referred to them as “my children” rather than as her nieces and nephews.)
On the same day Leonard’s heart stopped beating, the radio airways were filled with news that German tanks had begun pouring across the Soviet border, greatly expanding the war from a Western European conflict into a full-scale Second World War. As we know in hindsight, the global nature of the war would extend further with the inclusion of the United States and Japan; preparations for the looming war had already begun in Washington by the summer of 1941. The Selective Training and Service Act signed in September 1940 by Franklin Roosevelt disrupted the career aspirations of many American men and had the unintended effect of offering opportunities for Trudie. Her first work experiences as a chemist were admittedly menial as Trudie was hired by the Quaker Maid Company to perform a series of food quality tests such as testing the color of egg yolks destined to be used for mayonnaise production.52 Despite the fact that she’d obtained a laboratory role, her desire to perform original research predominated, and she applied for and finally received a position as a research chemist at Johnson & Johnson in 1944. Again, excitement turned to frustration as the company disbanded that particular research team later that same year.
Within days after being furloughed from Johnson & Johnson, Gertrude was visiting her father’s dental office when she noted that the anesthetic he routinely administered was produced by a local company just up the road in Tuckahoe, New York. By the end of that week, Trudie had interviewed with and accepted an offer by George Hitchings at Burroughs Wellcome, which was not a local company at all but an English-American pharmaceutical conglomerate that was well-known for developing innovative medicines.
George Hitchings, like Elion, was inspired to develop new medicines by a personal tragedy: the death of his father when George was only twelve.53 The young Hitchings was also captivated by the life and work of Louis Pasteur. After obtaining his bachelor’s and master’s degrees from the University of Washington, Hitchings obtained a PhD at Harvard focused on the chemistry of purines, which comprise two of the four letters of the DNA alphabet. He later focused his research at the Wellcome Research Laboratories in Tuckahoe. Working largely alone at first, Hitchings hired Gertrude Elion based on the enthusiasm and intellect she displayed during her interview. This ignited a professional bond and partnership that would persist for many decades to come.
Hitchings was actively exploring concepts that would later provide the pair with the foundation for developing antimetabolite medicines in the fight against cancer. Trudie’s early work identified molecules that were similar but different from the constituent components of DNA, especially the purine molecules that Hitchings had focused upon during his doctoral studies. To put this work in proper perspective, Elion and Hitchings’ work predated the seminal discovery of the structure of DNA by James Watson and Francis Crick by three years and before the comparably groundbreaking research that would be started by Werner Bergmann at Yale a year later. Despite the fact that the Yale group gained the initial fame for discovering the impressive sponge that yielded such wonderful new options for cancer therapy, Elion and Hitchings went on to discover an even wider variety of new antimetabolites with applications for a broad set of diseases. The pair also realized that these same approaches might be useful to selectively targeting viruses. The dreaded (though not terribly dreadful) herpesviruses provided an early proof for these concepts.
The brilliance of viruses in avoiding drug-mediated extinction lies in their hijacking the machinery of their hosts (such as humans) to perform most of the work needed for their replication and further spread. The Burroughs Wellcome team realized the key word in this statement is most, and that the small number of essential proteins that viruses carry themselves (rather than stealing from their hosts) might provide targets for new medicines. In the case of herpesvirus, Elion and Hitchings exploited the fact that this family of viruses utilizes its own enzyme, known as thymidine kinase, to perform a function that is essential to allowing the virus to carry on its path of destruction. Humans also have their own version of this molecule, but, for reasons that are fortuitous for our species, the virus is biased towards its own version of thymidine kinase. By developing compounds that could selectively target the viral thymidine kinase, new medicines could theoretically be made to prevent herpes infection.
Theory became reality when Elion and Hitchings unveiled acyclovir (trade name: Zovirax) to the world in the mid-1970s. This revolutionary medicine provided a means to treat a wide array of herpesviruses, including not only oral and genital herpes but also those behind other well-known maladies such as chicken pox (and shingles), in addition to cytomegalovirus (which can cause extraordinarily painful infections of the eye) and Epstein-Barr virus (the cause of mononucleosis).
In these pioneering studies, Elion and Hitchings pioneered an approach that is still utilized today: exploiting the differences between humans and viruses to develop effective countermeasures. Hitchings went on to lead all research at Burroughs Wellcome from 1967 until 1976, and Elion led the Department of Experimental therapeutics through the early 1980s. The pair developed an unprecedented array of new medicines using their innovative approaches until and beyond Elion’s retirement from Burroughs Wellcome in 1983. In retrospect, retirement seems to be a bit of an overstatement, given Elion’s role in a plague that was coming to light just as she was stepping down as department head.
At roughly the same time Trudie was clinking champagne glasses and receiving heartfelt congratulations for her retirement from Burroughs Wellcome, a French laboratory at the Pasteur Institute was reporting on the identification of a virus implicated with the spread of a new disease that was quickly rising to epidemic and pandemic levels on both coasts of the United States (though focused at first in New York and San Francisco) as well as more sporadically throughout the rest of the United States, Western Europe, and Africa.54 The so-called “gay cancer,” or Gay-Related Immune Deficiency (GRID), underwent a series of name changes, finally gaining the less offensive and more familiar moniker of Acquired Immune Deficiency Syndrome (AIDS). Once the virus had been identified and the severity of the growing crisis was made known to the American people, a collective effort was made to identify molecules that could selectively target the virus with minimal collateral damage to normal cells. While the recognition of the slowness of the official response has been profiled in many outstanding reports, both old and new, within four years after the identification of HIV in 1983, the first new medicine targeting the deadly virus was approved by the FDA.55
Though technically “retired,” Trudie was still at work in the laboratories of Burroughs Wellcome. A breakthrough in the early treatment of HIV/AIDS came from the discovery of the enzyme that the virus uses to reproduce its genetic material. This molecule, known as reverse transcriptase, was a particularly tempting target because it differs greatly from human enzymes, which provided an opportunity to develop medicines that could safely target the vital viral molecule. Trudie quickly mobilized her colleagues to screen for antimetabolites that might intervene against the reverse transcriptase molecule that was so essential for the new invader. Within four years, Trudie’s team had spearheaded a scientific and medical campaign to expedite and gain FDA approval for another antimetabolite called zidovudine. The metabolic Trojan horse, also known as AZT, was carried by reverse transcriptase and incorporated into the viral genetic material, where it poisoned further viral nucleic acid synthesis, preventing its further spread.
Over the following few years, increasing understanding of how the virus infects
host cells, hijacks their functions, and spreads to other victims allowed researchers to identify additional viral targets. One example is the HIV-1 protease, a protein encoded by the virus that effectively functions as a pair of scissors. It cuts and forms the lethal molecules of the virus in a manner analogous to the use of pattern shears in the deft hands of fashion designers as needed to craft intricate designs from formless pieces of fabric.56
At the same time, a committee of scientists in Sweden was secretly conferring to recognize Trudie and George with a Nobel Prize. Trudi never did earn a PhD in the conventional manner, but she’d been awarded no fewer than twenty-five honorary (but certainly earned) doctorate titles. Moreover, Trudie was invited to talks all over the planet, which finally sated her desire for travel. On a more practical level, while the discovery of acyclovir and AZT were landmark events, the value conveyed by medicines were, are, and will forever be limited by an evolutionary battle between viruses and man. While we occasionally win battles (such as the discoveries of the aforementioned therapeutics), we are unfortunately predestined to lose the war against HIV using conventional weapons such as AZT.
Collateral Damage, Insurgents, and Spider Holes
The militaristic-sounding name of this section reflects the fact the development of medicines and vaccines against viral diseases can be regarded in many ways as analogous to an arms race between two superpower rivals. Offensive and defensive measures are constantly deployed and modified by attackers and defenders. Tactics need to change constantly for both because defenders readily deploy countermeasures that are provided by evolution or technology. A virus has a particular advantage in this battle due to its inherent ability to rapidly and frequently mutate and evolve. As we have seen, propagating its genetic material (generally DNA or RNA) is one of the few activities for which viruses consistently rely upon their own machinery. To do so, the virus encodes for a molecule known as a polymerase, whose job it is to reproduce the virus’s genetic material (DNA or RNA, depending on the virus). One example of such a “polymerase” is the reverse transcriptase (RT) targeted by AZT, which made up the first generation of antiretroviral drugs for HIV. This rather awkward nomenclature reflects the fact that the genetic material for HIV is RNA. Whereas most conventional human (and all eukaryotic life) uses DNA as a means to produce RNA through a process known as transcription, HIV does the opposite. To make copies of the virus RNA, it uses RT to create DNA (the reverse of the normal situation in humans) and using this DNA intermediary, the RT then transcribes the DNA into RNA. Hence the combination of the words “reverse” and “transcriptase”. The advantaged for humans combating the virus is that RT tends to have a different set of restraints than human DNA polymerases and thus will utilize some Trojan-horse like molecules such as AZT, whereas human polymerases prefer not to do so.
Between Hope and Fear Page 19
