The voicemail message from Isabel was brief. “Dr. Helfgott, please call me as soon as you can. I have a very important issue to discuss with you.” The caller was a premedical student enrolled in a tutorial on autoimmunity that I was leading at the Harvard College Biological Laboratories. Over the course of the year, we held weekly three-hour sessions discussing how aberrations in immune function lead to the development of selected autoimmune diseases. As the year progressed, students assumed more responsibility for leading the tutorials. Since the class size averaged only 10 students, I got to know each of them fairly well, and grading their knowledge and class effort was usually straightforward. Countering the grade inflation at Harvard, I limited the top grades to just a few students.
On the telephone, Isabel’s voice sounded highly emotional, as if she was on the verge of tears. She had just received her grade: B. She told me that she felt like a failure because this was the lowest grade she had received at Harvard, and possibly in her entire academic career! She described how hard she worked throughout the year and how she felt that I was failing to acknowledge her effort. I recalled an adage told to me by a former mentor about only getting an A for effort in kindergarten. Isabel spent the next five minutes anxiously describing the implications of her now-flawed college transcript. She considered her goal of securing a spot at a top medical school to be in jeopardy. Never underestimate the angst of an undergraduate! Though Isabel did not appreciate my judgment at the time, her academic “failure” in Concepts of Autoimmunity may have been a blessing in disguise. Failing at a task can be healthy. It forces us to retool, to recalibrate. Through failure we mature.
How We Fail
As clinicians, we face failure every day. We fail to observe the telltale signs of a subtle diagnosis, such as a tiny tophus on a fingertip or a splinter hemorrhage. We miss a key element of a patient’s history and a significant exposure to an infectious illness may be overlooked. We prescribe medications that turn out to be ineffective or harmful. In the lab, failure and disappointment are common acquaintances. Cell cultures get contaminated and rodents become ill. Equipment fails. Hypotheses are wrong. For example, during the early days of biological drug development, there was a myriad of therapeutic targets for investigators to choose. Should rheumatoid arthritis be treated by targeting the T cell, the B cell, the interleukin-1 or interleukin-2 receptor, or the tumor necrosis factor receptor? With billions of dollars at stake, some companies chose wisely and others did not.
Yet failures are critical elements of the natural cycle of scientific progress. In fact, failure often predates success. Its absence suggests a paucity of risk taking and a lack of innovative thinking. Failure can be a distressing experience, but its unpleasant sting serves as a formidable motivating force, driving us to redouble our effort. Sometimes, success may be disguised as failure. In The Act of Creation, the writer Arthur Koestler observed that some discoveries represent striking tours de force by individuals who seem to be so far ahead of their time that their contemporaries are unable to understand them.1 For example, the validity of a fresh, creative idea or a novel experimental approach may be attacked because of ignorance or misunderstanding, or worse, because of petty jealousy or personal rivalry. How does one proceed in such a quandary? Here are the stories of some researchers who faced these challenges.
A Patient of Extreme Interest
In the fall of 1972, a middle-aged female patient who was exhibiting progressive loss of memory and difficulty performing some routine tasks was admitted to the neurology service at the University of California San Francisco (UCSF). The junior neurology resident assigned to her case was fascinated to learn that she was dying of a “slow virus” infection known as Creutzfeldt-Jakob disease (CJD), a fatal condition that evoked no response from the body’s defenses.2 It is a blessing that CJD is one of those extremely rare diseases that we often hear about at rounds but seldom get to see firsthand.
The neurology resident began reading about CJD and, in particular, the research led by the noted medical anthropologist, D. Carleton Gadjusek, MD, of the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia. He was awarded the Nobel Prize in Physiology or Medicine in 1976 for describing a curiously similar dementing illness, kuru, among the Fore people of New Guinea and its bovine equivalent, scrapie.
Our neurology friend, now a junior faculty member at UCSF, chose the daunting task of trying to isolate and identify a slow virus in culture. Since assays in mice for the scrapie agent were tedious, slow, and very expensive, his progress was stifled. He was stuck, and had no clever idea about how to circumvent this problem. Not surprisingly, his application for support from the National Institutes of Health (NIH) was turned down.
Sound familiar? Our intrepid investigator carried on, working with some noted virologists based at the Rocky Mountain Laboratory in Hamilton, Mont., where he acquired the additional skills that allowed him to collect important data on the scrapie virus. His results, though, were quite puzzling. The scrapie culture preparations contained protein but no nucleic acids. This finding made absolutely no sense. It went against a major tenet of biology.
His lack of progress started to raise concerns among his superiors. The Howard Hughes Medical Institute, his source of research funding, declined to renew his grant, and UCSF notified him that he would not be promoted to tenure. Crushing disappointments, to say the least. But Stanley Prusiner, MD, stood firm. He truly believed in the validity of his data. With new support from, of all sources, Big Tobacco (R.J. Reynolds Company), he was able to demonstrate that his findings were not artifactual, as had been suggested by his many detractors. The scrapie agent was, in fact, a protein devoid of any nucleic acids. The publication of his manuscript in 1982, wherein he introduced the term “prion” set off a firestorm of controversy.3 Virologists were generally incredulous. The idea of a protein being an infectious agent seemed heretical. How could a string of amino acids transmit disease?
The spat spilled over to the lay media. Dr. Prusiner’s wife recalled the family’s sense of vulnerability as her husband was pilloried in the press. Being a tough Midwesterner, he refused to back down. Instead, Dr. Prusiner sought to vindicate his theories, first by sequencing the prion protein and then by cloning the gene encoding it. He finally silenced his critics when his research group identified the prion that transmitted the frightening illness known as “Mad Cow Disease,” or bovine spongiform encephalitis (BSE). His illuminating discoveries won him the 1997 Nobel Prize in Physiology or Medicine. Stanley Prusiner abided by the kindergarten proverb about the need to keep trying whenever one fails to succeed.
Fulfilling Koch’s Four Postulates
For rheumatologists of a certain age, the term “nonsteroidal antiinflammatory drug” (NSAID) gastropathy conjures up images of patients complaining of a variety of gastrointestinal ailments. There was a time when NSAID therapy was the cornerstone of rheumatologic care. They were used liberally to treat all forms of arthritis and musculoskeletal pain syndromes. Each year saw the release of a newer formulation that claimed to be safer and better tolerated than its predecessors. However, managing the frequent gastrointestinal side effects took up a significant part of each of our days. We would switch NSAIDs (recall the NSAID shuffle), prescribe H2 blockers initially and, when they became available, the ever-popular proton-pump inhibitors. In 1996, these latter drugs constituted the largest category of prescription medications in the United States.
Before the advent of endoscopy, pathologists had meager access to gastric tissue. Thus, the pathology of gastrointestinal lesions such as ulcers and mucosal erosions was not well understood.
Around this time, J. Robin Warren, MBBS, a clinical pathologist in Perth, Australia, developed an interest in studying these newly available gastric biopsies. He was struck by the observation that he could find bacteria growing in the biopsies that showed chronic active gastritis or ulcer formation, but not in normal gastric specimens. He wondered whether these unknown microorganisms might be causing the ulcers. However, there were several problems with this theory, the first being that the highly acidic milieu of the stomach provided a hostile environment for any microbial growth. Second, the accepted dogma of ulcer causation supported the pivotal roles of stress, smoking, and NSAID use. Infections causing ulcers? How preposterous! Unperturbed, Dr. Warren enlisted the help of a gastroenterology fellow working at his hospital, Barry Marshall, DSc.
Dr. Marshall was in his final year of training and was searching for a research project that would keep him busy for the remaining few months of his training. When Warren offered him the role of endoscopist, he was delighted to sign on. They studied 100 consecutive patients with abdominal pain and suspected ulcers and found bacteria in 55 of the 57 specimens obtained from patients with ulcers.4 Yet, despite their best efforts, they could not identify the curiously shaped curved bacillus because it did not seem to grow in culture. They were frustrated by their lack of progress.
As fate would have it, a work stoppage provided a lucky break. Over the Easter holiday break, their hospital’s microbiology laboratory was closed for five days, and this prolonged incubation time allowed the cultures to fully mature. The bacillus was identified as Helicobacter pylori. Yet this observation did not prove causation. Nonetheless, they submitted their study to the Lancet, but the editor had difficulty finding reviewers who believed their results. Most of the experts in the field of peptic ulcer disease either ridiculed their paper or dismissed their hypothesis as being a very silly idea. Sound familiar?
Drs. Marshall and Warren clung to their beliefs about H. pylori. After all, they believed that the first two of Robert Koch’s postulates had been fulfilled. First, the microorganism was abundantly present in those with disease and not in healthy individuals; second, it had been grown in pure culture.
To fulfill Koch’s third postulate, they would have to demonstrate that the bacteria would cause disease when introduced into a healthy organism. But there was no available animal model of the disease to study. Following in the footsteps of Marie Curie, who irradiated herself, and John Hunter, whose self-infection with syphilis and gonorrhea may have been fatal, Dr. Marshall settled the issue by drinking a liquid suspension of H. pylori that was cultured from a patient’s gastric biopsy. A few days later, he developed severe abdominal bloating, bad breath, nausea, and vomiting. Endoscopy and biopsy confirmed the presence of gastritis and H. pylori.
Dr. Marshall may have had the mindset of a reality television show contestant, but his brazen act of self-experimentation succeeded in capturing the attention of the medical world.5 Over the next few years, other investigators confirmed their findings. Subsequent clinical trials confirmed the efficacy of triple therapy for H. pylori ulcer disease, thus fulfilling Koch’s fourth postulate. A significant cause of peptic ulcer disease could now be eradicated cheaply and efficiently.
It is truly amazing that Drs. Marshall and Warren were awarded the Nobel Prize in Physiology or Medicine in 2005. These two physicians were ordinary clinicians toiling in relative obscurity, with limited access to world-class research facilities. Perhaps the simple clinical observation made by one of them would have landed in the dustbin of outlandish medical theories had the other one not chosen to infect himself.
Pill
“Pill,” as friends and colleagues called him, was born in Johannesburg, South Africa, in 1908, the son of Lithuanian parents who immigrated to the United States the following year. A tall athletic young man, Louis Pillemer was recruited to play football at Ohio State University in Columbus, but left after failing his freshman year. He transferred to Duke University in Durham, N.C., graduated, and was accepted to its medical school. At the end of his second year, he scored the second highest grades in the country on the National Board exams.6 However, due to emotional problems, he was asked to leave medical school the following year. As my friend and colleague, William D. Ratnoff, MD, of Houston, Texas, noted in a review of Pill’s career, “Pillemer’s emotional problems waxed and waned throughout his life.”7 He subsequently moved to Case Western University in Cleveland, Ohio, to pursue a doctorate degree in immunology. A brilliant researcher, he was offered a faculty position after graduation. Within a few years, he led the first group of investigators to isolate and crystallize tetanus toxin and to correctly identify the purified protective antigen of pertussis.
Though these important accomplishments won him broad recognition, Pill was restless and seeking new challenges. He had always been intrigued by the nascent field of complement immunology and immersed himself in this area. Though some components of the classical pathway such as C1, C3, and C4 had been identified, Pill discovered a new protein, properdin, which directly activated C3. Over the next few years, he described the key roles of properdin in serving as a nonspecific defense mechanism and in activating the complement pathway in a nontraditional way.
The discovery of properdin and its many potential functions was considered to be a major breakthrough. Scientists and even the general public seized upon the properdin system as a possible explanation for diverse, unsolved problems of human medicine. Properdin research became a hot topic and a parade of investigators visited Pill, seeking his advice and expertise on the topic. The drain on his time and energies was substantial.
At the same time, seeds of doubt and opposition to his research were growing, led by another eminent immunologist, Robert Nelson, MD, of Yale University in New Haven, Conn.8 He questioned whether Pill’s data was actually describing the “classical” and not an “alternative” pathway for complement activation. In other words, he suggested that Pill’s data was artifactual. Being a prominent immunologist, Dr. Nelson’s powerful arguments and stinging critique of Pill’s work held sway with many other influential immunologists. As quickly as the swell of enthusiasm about properdin had grown, it soon turned in the opposite direction.
Pill could not deal with this rejection. Though his theories about properdin, Factor B, and the alternative complement pathway were ultimately vindicated by the work of several of his colleagues, Pill did not bask in this glory. He had committed suicide a few years earlier. Success misjudged as failure. There is something dreadfully wrong with this interpretation.
Failure Is Not the F-word
How one deals with failure defines one’s core character. Failure can nurture intellectual growth and foster personal maturity. In the tech start-up world, failure is often worn as a badge of honor, because it is assumed that the disappointing experience provided some great learning opportunities. Perhaps it is time for all of us in medicine to regard failure in that way, too. By the way, B is never a failing grade. Except, maybe, at Harvard.
Dr. Helfgott is physician editor of The Rheumatologist and associate professor of medicine in the division of rheumatology, immunology, and allergy at Harvard Medical School in Boston.
References
- Koestler A. The Act of Creation. Macmillan and Company, New York 1964.
- The Nobel Prize in Physiology or Medicine 1997. Stanley B. Prusiner – Biographical. Available at www.nobelprize.org/nobel_prizes/medicine/laureates/1997/prusiner-bio.html. Accessed January 10, 2014.
- Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science. 1982;216:136-144.
- Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastric and peptic ulceration. Lancet. 1984;1:1311-1315.
- Marshall BJ, Armstrong JA, McGcchie DB, et al. Attempt to fulfill Koch’s postulates for pyloric Campylobacter. Med J Aust. 1985;142:436-439.
- Lepow IH. Louis Pillemer, properdin, and scientific controversy. J Immunol. 1980;125:471-478.
- Ratnoff WD. A war with the molecules: Louis Pillemer and the history of properdin. Perspect Biol Med.1980;23:638-657.
- Nelson RA. An alternative mechanism for the properdin system. J Exp Med. 1958;108:515-535.
