The Drug Hunters

by Donald R Kirsch

  Many, many things can go wrong during the course of such toxicity studies. I remember one set of FDA tests in which everything was going well until we saw gastrointestinal bleeding in rats during the chronic toxicology study. We were astounded. There was absolutely nothing about the biological activity of the compound that would predict gastrointestinal bleeding, and we had not seen anything like that in prior experiments. After a long and expensive investigation we learned that the compound was crystallizing into long sharp needles when exposed to the acidic conditions of the stomach. Over time, the sharp needles accumulated and began to rip up the gastrointestinal tract lining. It was a physical and not a biochemical effect, but even so it stopped our FDA tests dead and sent us reeling back to the drawing board.

  106: groups like ACT UP petitioned the FDA to loosen its criteria for the clinical testing: Probably no incident tilted public opinion more toward the side of caution than the thalidomide disaster. This drug was first developed in 1953 by the Swiss pharmaceutical firm Ciba. The company soon discontinued its research on thalidomide because they were unable to demonstrate any clear pharmacological effects. Despite this, another firm, Chemie Grϋnenthal in Stolberg, Germany, took over the development of the drug, and thalidomide was introduced to the public on October 1, 1957. It was initially marketed as an anticonvulsant but quickly proved ineffective for this purpose. Thalidomide chemically resembles barbiturates, and the company scientists probably thought that it could work similarly and thus be effective against epilepsy, but they obviously never checked to see whether it worked the same way as barbiturates. It doesn’t—not at all.

  Although the drug failed as an antiepileptic, it was noted that thalidomide produced a deep sleep without a hangover. In addition, large doses were not fatal, so unlike other sedatives, thalidomide posed no suicide risk. Thalidomide soon became the most popular sleeping pill in West Germany, where it was widely used in hospitals and mental institutions. It was marketed for the treatment of a variety of conditions including influenza, depression, premature ejaculation, tuberculosis, premenstrual symptoms, menopause, stress headaches, alcoholism, anxiety, and emotional instability. By the end of the 1950s, thalidomide was marketed by fourteen pharmaceutical companies in forty-six countries.

  Thalidomide was also found to be an effective antiemetic (anti-nausea drug) and thus was prescribed to thousands of pregnant women to relieve the symptoms of morning sickness. At the time, it was believed that most drugs could not pass from the mother to the child across the placental barrier and thus there was little concern that the drug could harm the developing fetus. However, in the late 1950s and early 1960s there was a surge in the number of children with birth deformities, especially phocomelia (flipper-like arms or legs). In total, there were more than 10,000 such reports from all forty-six countries where thalidomide was sold. On opposite sides of the world the Australian obstetrician William McBride and the German pediatrician Widukind Lenz independently hypothesized a link between thalidomide and these birth defects, a link that was convincingly demonstrated by Lenz in 1961.

  The impact in the United States was minimal because of the actions of Frances Oldham Kelsey, an FDA reviewer who refused to approve thalidomide. There had been reports of peripheral neuropathy associated with thalidomide use, and she insisted that additional testing was needed prior to FDA approval. Kelsey also noted that the manufacturer had provided only minimal animal safety data and that long-term risk assessment and pregnancy risks assessments had not been performed. Consequently, thalidomide never went on sale in the USA in the 1950s or 1960s.

  However, it should be pointed out that no drug is ever all good or all bad, but depends heavily on the dose, individual, and context. For years after it was first prescribed, nobody knew how thalidomide actually worked. University studies eventually showed that thalidomide is a useful treatment for erythema nodosum leprosum (ENL), a painful complication of Hanson’s disease, more commonly known as leprosy. In 1991, Gilla Kaplan at Rockefeller University showed that thalidomide worked in leprosy by inhibiting tumor necrosis factor alpha (TNF alpha). TNF alpha is a cytokine, a hormone that regulates immune cells, induces inflammation, and inhibits tumorigenesis and viral replication. Further work by Robert D’Amato at Harvard Medical School showed that thalidomide was a potent inhibitor of new blood vessel growth and this finding suggested that thalidomide could be used as a cancer treatment. In 1997, Bart Barlogie reported that thalidomide was an effective treatment for multiple myeloma, and soon thereafter the FDA approved thalidomide for the treatment of this cancer as well as for the treatment of leprosy. However, before receiving thalidomide, patients must go through a special process to prevent the drug from producing birth defects. Although the FDA feels that appropriate precautions are in place, the World Health Organization (WHO) has stated that:

  The WHO does not recommend the use of thalidomide in leprosy as experience has shown that it is virtually impossible to develop and implement a fool-proof surveillance mechanism to combat misuse of the drug.

  Chapter 8: Beyond Salvarsan: The Library of Dirty Medicine

  133: the world’s first expanded-spectrum antibiotic: Benzylpenicillin has a fairly good antibacterial spectrum but is not considered to be broad-spectrum. Penicillin was the world’s first true antibiotic, full stop.

  134: Though penicillin was a true miracle drug, some bacteria-borne diseases remained impervious to it: Penicillin was not a perfect drug. After its success, many antibiotic research programs were initiated to make improved versions of penicillin. Some of the goals of these programs included finding compounds with a broader spectrum of antibiotic activity, finding compounds that could be given orally instead of by injection (benzylpenicillin cannot be given orally), finding compounds that could also fight bacteria in the central nervous system (penicillin compounds generally cannot pass the blood-brain barrier into the central nervous system and thus cannot be used to treat brain infections such as bacterial encephalitis), and most importantly, finding compounds that could reduce or overcome bacterial resistance. These research programs often focused on discovering naturally occurring penicillin-like chemical scaffolds for chemical synthesis. These penicillin-like chemicals include a specific molecular feature called the beta-lactam ring. The beta-lactam ring is usually drawn as a square in the middle of the penicillin molecular structure and serves as the compound’s “warhead,” producing the drug’s toxic attack on bacteria. Some examples of compounds with a beta-lactam ring include cephalosporin, monobactams, and carbapenam.

  134: Perhaps the most dreadful of these diseases was tuberculosis: Though tuberculosis is no longer much of a concern in the developed world, it is estimated that about one in three humans alive today is infected by Mycobacterium tuberculosis, with new infections occurring at the rate of about one per second. Though most tuberculosis infections are asymptomatic and harmless, there are currently about fourteen million chronic active cases worldwide with about two million deaths annually.

  134: known as the “White Death”: Tuberculosis also came to be known as the “great white plague” and was called “white” because of the extreme anemic pallor of those afflicted. The American physician and man of letters Oliver Wendell Holmes actually coined the term “great white plague” in 1861 when he was comparing the consumption epidemic to other horrific diseases of the era. Though tuberculosis patients famously took on a deathly pale hue, some historians suggest that the term “white” may have referred to the disease’s cultural association with youth, innocence, and perhaps even saintliness, since afflicted patients took on a quasi-angelic appearance—opalescent, ethereal, almost delicate. Some writers with a more literary (or misogynistic?) bent suggested that the wan faces of its female victims rendered them particularly attractive, with at least one male observer declaring that the disease endowed women with a “terrible beauty.”

  137: Waksman would eventually receive a Nobel Prize: Waksman received the Nobel Prize in Medicine in 1952 for his work developing str
eptomycin as a cure for tuberculosis, but his collaborator Albert Schatz was not named on the Nobel Citation. This exclusion was strongly contested by Schatz, eventually leading to litigation. Waksman settled out of court, providing financial remuneration to Schatz and stating that Schatz was entitled to “legal and scientific credit as co-discoverer of streptomycin.”

  142: fifteen of the eighteen largest pharmaceutical companies have abandoned the antibiotic market entirely: About 99 percent of all microorganisms that live in the soil will die if you try to grow them on a Petri plate. This has always been a limiting factor when searching for new drugs in the library of dirt. But in the early 2000s, two professors at Northeastern University, Kim Lewis and Slava Epstein, figured out how to culture microorganisms that previously had been thought to survive only in the soil. After this technological breakthrough, it was suddenly possible to study and develop these so-called “unculturable bugs” for the first time.

  Lewis and Epstein started a new company in Cambridge, Massachusetts, called NovoBiotic Pharmaceuticals to find new antibiotics using their new method. But even though they were able to grow soil microorganisms that had never before been culturable on a Petri dish, their basic approach was the same as previous excursions into the library of dirt: they randomly grew any microorganisms they found in the soil and screened them to see if they produced chemicals that would kill pathogenic bacteria.

  In early 2015, NovoBiotic Pharmacticals reported finding an important new antibiotic known as teixobactin. Teixobactin appears to be active against many highly drug-resistant pathogens while remaining safe in animals.

  Chapter 9: The Pig Elixir: The Library of Genetic Medicine

  151: Indian physicians observed that ants were attracted to the urine: Since diabetes mellitus roughly translates to “excessive sweet urine,” it should not be difficult to imagine what test was used to confirm the diagnosis prior to the twentieth century. Tasting urine sounds disgusting and potentially dangerous, but prior to the development of modern biochemical instruments, dipping your tongue into a patient’s urine was both commonplace and useful. Early scientists did many things that would be considered foolhardy or risky today. For example, the lab notebooks of Louis Pasteur, the late nineteenth-century microbiologist, reveal that he frequently tasted the results of his biochemical experiments. Marie Curie died at the age of sixty-six from aplastic anemia, almost certainly caused by her exposure to the radioactive chemicals she studied all her life. Even today, Curie’s notebooks are still considered too dangerous to handle because of their high levels of radioactivity. These historic artifacts are kept in lead-lined boxes, and historians who wish to consult them must wear protective clothing. When I was first trained in chemistry about forty years ago, I was taught to sniff the chemicals that I worked with in order to determine whether my intended chemical reactions had proceeded properly. Fortunately, such hands-on—and nose-on—instruction is absent from the twenty-first-century chemistry classroom.

  153: Whenever researchers ground up a pancreas in the hope of extracting insulin: Two physicians, Frederic Allen and Elliott Joslin, were among the most recognized experts in the treatment of diabetes in the early twentieth century. At the time, the major goal for diabetes treatment was to reduce the level of glucose in the blood. But since there was no access to insulin, the best that physicians could do was attempt to reduce the glucose levels in a patient’s diet. Unfortunately, animal experiments eventually demonstrated that diabetes is not merely a problem with glucose metabolism but also a problem with metabolizing protein and fat. If one simply removes carbohydrate from the diet, the body will burn fat and protein instead, producing chemicals called acidic ketone bodies, which acidify the blood. The blood’s pH (the measure of acidity in a solution) must be maintained in a very narrow range near neutrality, between pH 7.35 and pH 7.45. Acidosis, or the lowering of blood pH, results in respiratory distress, heart arrhythmia, muscle weakness, gastrointestinal distress, coma and, if untreated, death.

  Thus, in the absence of insulin, Allen and Joslin’s only available treatment for diabetes was to completely starve the patient, removing all carbohydrate, protein, and fat from the diet. Of course, you cannot live without eating something, so Joslin and Allen developed a diet that provided about 20 percent of the calories ordinarily needed for survival and in a form that was particularly low in carbohydrates and sugar. Such a diet minimized collateral damage to the patient’s cells, but still produced severe emaciation. Joslin described one of the dieting patients in his Boston clinic as “just about the weight of her bones and a human soul.” The radical diet was not a cure, but it could extend life somewhat. One might naturally ask, however, what was the use of extending life if the quality of life was so miserable that you were both ravenous and without energy for any of the normal activities of life. The only rationale for sticking to such a desolate diet was to try to survive until a real cure could be found.

  157: Collip applied state-of-the-art biochemistry techniques to refine the insulin: Even though all proteins share several physical properties, they often differ in their solubility in alcohol. Collip therefore explored a technique known as alcohol precipitation fractionation as a means to purify insulin. This meant slowly adding alcohol to an impure insulin compound until the point at which the insulin just barely remained soluble. All the other proteins in the dirty compound that were less soluble than insulin would then precipitate, forming tiny particles in the liquid that could easily be removed.

  162: Paul Berg, a Stanford University professor who studied viruses, performed one of the most important experiments of the twentieth century: Berg teamed up with two other professors working in the San Francisco Bay area to optimize the new recombinant DNA techniques: Herb Boyer at the University of California, San Francisco—an expert on the enzymes that cut and pasted DNA—and Stanley Cohen, also at Stanford, who was an expert on plasmids, tiny circles of DNA that are natural carriers of genes between organisms.

  Chapter 10: From Blue Death to Beta Blockers

  184: You are likely familiar with adrenaline’s role in the fight-or-flight response: The May 13, 2010, issue of the New England Journal of Medicine reported the case of a fifty-four-year-old woman admitted to Massachusetts General Hospital following multiple episodes of dizziness, sweating, and palpitations that caused her to fall. Upon examination she was found to be suffering from high blood pressure. However, her blood pressure varied greatly depending on her posture: it went up when she was sitting or lying down, but would drop significantly when she was standing or walking, causing her to faint when the blood pressure fell to an extremely low level.

  Eventually, the source of the patient’s high blood pressure was determined to be a rare type of tumor of the adrenal gland called a pheochromocytoma. This tumor secretes large amounts of adrenaline. Anyone who has been in a car accident or a near-accident knows what an “adrenaline rush” feels like. Your heart races, everything seems to slow down, and you feel hyperaware of your surroundings. In addition, your blood pressure goes up. All of this occurs because your adrenal gland rapidly releases a large quantity of adrenaline in moments of perceived danger.

  In most patients with a pheochromocytoma, large amounts of adrenaline are produced all the time, raising their blood pressure all the time. But in some cases, like this woman, a patient’s body can adapt to the sustained onslaught of adrenaline, resulting in more variable levels of blood pressure. When the woman was lying down with her heart at the same level as her head, her blood pressure remained high and she was able to circulate adequate amounts of blood to her brain. Normally, when you sit up the circulatory system rapidly compensates for the fact that your head is now at a higher level than your heart by increasing blood pressure in order to maintain steady blood circulation to the brain. But in this woman suffering from a pheochromocytoma, her body overcompensated for the high levels of adrenaline and could not maintain the pressure necessary to circulate adequate blood to the brain, leading to her fainting spells
.

  The patient underwent surgery to remove the tumor. Afterward, her level of adrenaline declined dramatically, as did her dizziness, and she was able to return to work.

  184: Armed with this promising idea, Black approached the British company ICI Pharmaceuticals: Black used a similar strategy to develop a treatment for stomach ulcers, but ICI was not interested in ulcer medicines, so eventually Black resigned and in 1964 joined Smith, Kline and French in order to pursue his stomach ulcer research at their labs. His work there culminated in the discovery of cimetidine (Tagamet), which soon after its launch in 1975 turned into another blockbuster drug. It became the first drug in history to reach $1 billion dollars in annual sales.

  186: an enzyme in the body known as ACE: The kidney produces and secretes a protein called renin in response to low blood pressure, which initiates a chain of events leading to increased blood pressure. In the bloodstream, renin cleaves a peptide (a very small type of protein) that is produced in the liver called angiotensinogen to produce an even smaller peptide called angiotensin I. Angiotensin I is further cleaved in the lungs by the ACE enzyme to form angiotensin II. Angiotensin II is one of the most potent vasoactive substances known to medicine, which means that it constricts blood vessels. When angiotensin II enters the bloodstream, the blood vessels get smaller and the heart tries to overcome this increased resistance by working more vigorously, causing the blood pressure to rise. Angiotensin II also causes the adrenal glands to releases aldosterone, a hormone that increases blood volume. The increased blood volume also acts to increase blood pressure.