Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (44 page)

The current system of screening an endless number of substances has certainly not been notably efficacious, despite the fact that a slew of new technologies—combinatorial chemistry, improved screening, rational drug design, and pharmacogenomics—developed since the late 1970s promised to streamline the process.
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Even with these useful technologies, the time spent to develop a drug has lengthened, the cost has more than doubled, and the failure rate has not declined. Technology is merely a tool and does not by itself provide answers. Only ideas and creative thought can do that, and those are things our existing system sadly lacks and fails to nurture.

Yet, despite the paucity of innovative drugs, the drug companies
consistently rank as the most profitable among Fortune 500 companies. A lofty 25 percent of pharmaceutical revenues are profits. In 2002, the combined profits of the top ten pharmaceutical companies in the Fortune 500 exceeded the combined profits of the other 490 companies!
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Making matters worse, in recent years, the drug companies have engaged in a mania of mergers to bolster earnings by reducing costs. Mergers subordinate research to strategies determined by short-term market forces and not by a quest for the truly novel. The sad fact is that these deals, which centralize research staff, do nothing to increase overall ability to produce truly new medicine. The mergers are distracting and hinder researchers’ creativity, as they result in the reduction of multiple pursuits down to only a few that are overly managed and targeted. When it comes to research and development, bigger is not better; in fact, it appears to be worse.

E
DUCATION

Discovery is an essentially creative enterprise. Yet the education that future researchers receive does not, for the most part, foster the mind-set or the skills that are needed for that sort of creativity. The focus in medical schools and higher education institutions in the field of science is on facts, not ideas; on outcomes, not process. Incessant multiple-choice examinations put a premium on a form of quick thinking that may neglect other qualities of intelligence and creativity.
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Their curricula completely ignore the process of how discoveries and current concepts came to be accepted. Lacking is any sense of awe and wonder for the magic of discovery, and there is little attempt to teach, or even encourage, the kind of creativity and complex synthesizing of ideas that has enabled discoverers to connect the dots that led to major breakthroughs in understanding.

As is apparent in the many stories of serendipitous discoveries, it takes more than just good luck. Opportunities for discovery present themselves every day, but not everyone is able to take advantage of them. Failure to follow puzzling observations and unexpected results of experiments has resulted in many missed opportunities. For example,
depletion of white blood cells was observed in victims of mustard gas during World War I, but the agent's chemistry was not seized upon then as a possible treatment for lymphomas and leukemias. Many researchers encountered the phenomenon of mold preventing bacterial growth without realizing its significance and usefulness before Alexander Fleming discovered penicillin in 1928; then it was twelve years before Ernst Chain and Howard Florey stumbled upon its importance and figured out how to exploit it. Long before Barry Marshall, bacterial colonies in the stomach were seen but shrugged off.

Why are particular people able to seize on such opportunities and say, “I've stumbled upon a solution. What's the problem?” Typically, such people are not constrained by an overly focused or dogmatic mindset. In contrast, those with a firmly held set of preconceptions are less likely to be distracted by an unexpected or contradictory observation, and yet it is exactly such things that lead to the blessing of serendipitous discovery.

Serendipitous discoverers have certain traits in common. They have a passionate intensity. They insist on trying to see beyond their own and others’ expectations and resist any pressure that would close off investigation. Successful medical discoverers let nothing stand in their way. They break through, sidestep, or ignore any obstacle or objection to their chosen course, which is simply to follow the evidence wherever it leads. They have no patience with dogma of any kind.

The only things successful discoverers do not dismiss out of hand are contradictory—and perhaps serendipitously valuable—facts. They painstakingly examine every aspect of uncomfortable facts until they understand how they fit with other facts. Far from being cavalier about method, serendipitous discoverers subject their evidence and suppositions to the most rigorous methods they can find. They do not run from uncertainty, but see it as the raw material from which new scientific and medical certainties can be wrought. They generally share a fondness for pattern play and draw from many diverse—and seemingly unrelated—sources. An epiphany is often the result of pattern recognition. Alert to change but not made uneasy by it, discoverers demonstrate an almost aesthetic feel for the way order arises from the unpredictable odds of an infinitely varied universe.
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Today's researchers are not being educated to think in the ways described above—in fact, just the opposite. A medical education is not designed to foster creativity: rather it consists of accumulating facts without any recognition of how those facts were obtained. “Facts are the enemy of truth!” cried Don Quixote de la Mancha. Certainly, unprocessed facts, facts taken at face value, not only tell us nothing but frequently deceive us. Understanding comes from making connections between many disparate facts. Information is not knowledge. The overemphasis on memorization to the detriment of analysis, critical thinking, and overall understanding is a big problem.

We must consider whether our current educational obsessions and fashions are likely to help or hinder serendipity in the future and ask how we can nurture a penchant for serendipitous discovery in today's children and future generations.

F
OSTERING
S
ERENDIPITY

Despite all the examples given, mainstream medical research stubbornly continues to assume that new drugs and other advances will follow exclusively from a predetermined research path. Many, in fact, will. Others, if history is any indication, will not. They will come not from a committee or a research team but from an individual, a maverick who views a problem with fresh eyes. Serendipity will strike and be seized upon by a well-trained scientist or clinician who also dares to rely upon intuition, imagination, and creativity. Unbound by traditional theory, willing to suspend the usual set of beliefs, unconstrained by the requirement to obtain approval or funding for his or her pursuits, this outsider will persevere and lead the way to a dazzling breakthrough. Eventually, once the breakthrough becomes part of accepted medical wisdom, the insiders will pretend that the outsider was one of them all along.

Some scientists are beginning to recognize the value of serendipity and are even trying to foster it. In the fall of 2006 the Howard Hughes Medical Institute opened a $500 million research center, the Janelia Farm Research Campus, built on the banks of the Potomac River, forty miles northwest of Washington, D.C. The center will
emulate Bell Labs and the British Medical Research Council's Laboratory of Molecular Biology by encouraging scientists to do hands-on creative work on their own or in small, close-knit teams, and to focus on original projects. In other words, the Janelia Farm Research Campus is being set up as a serendipity incubator.

“Crowdsourcing”

Another recent phenomenon that may help research move outside the box is the “crowdsourcing” of research and development made possible by the Internet. A prime example is the Web site InnoCentive. Launched by pharmaceutical maker Eli Lilly in 2001 as a way to connect with brainpower outside the company that could help develop drugs and speed them to market, InnoCentive promptly threw open the doors to other firms eager to access the network's trove of ad hoc experts. Companies like Boeing, DuPont, and Procter & Gamble post problems that corporate R&D people have been unable to solve in the hope that outside “tinkerers”—amateur scientists, inventors, and researchers—will come up with solutions in exchange for a fee. InnoCentive boasts a 30 percent success rate. This sort of decentralized mechanism that allows fresh ideas from outside the establishment to percolate up through a broad network of diverse thinkers and problem solvers is a welcome development and can only have a positive effect on research.

One of the main reasons for the success of InnoCentive's “crowdsourcing” is its ability to tap into the fresh perspectives of nonexperts. An analysis of the phenomenon by Karim Lakhani, a lecturer in technology and innovation at MIT, who surveyed 166 problems posted to InnoCentive from more than 25 different firms, actually showed that “the odds of a solver's success increased in fields in which they had no formal expertise.”
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Discoveries are surprises. You can't plan surprises, but you can certainly create an environment in which they are apt to happen and
are likely to be recognized and pursued when they do. Our current system is set up in such a way as to discourage the kind of curiosity-driven research that leads to serendipitous findings.

To turn around this situation, we as a society should make changes in several key areas:

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General education:
Students, particularly in science, must be educated not only to know facts and the scientific method but also to be prepared to recognize and exploit departures from expected results. Essential are the tools related to thinking: pattern recognition and pattern formation, alertness to similar differences and different similarities, analogies, imagination, visual thinking, aesthetics of nature and of knowledge.

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Medical and general science education:
Current methods of educating medical students overemphasize memorization at the expense of full understanding, reinforce compulsive behavior, and stifle creativity. The curricula of medical schools and graduate programs in science should teach students about the role of serendipity in past discoveries and be honest about the likelihood that it will play a major role in the future. Creative and critical thinking and open-mindedness to unanticipated observations, not only the acquisition of facts, are essential skills for the next generation of serendipitous discoverers that should be encouraged in such institutions.

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Big Pharmaceuticals:
Restrictions should be placed on the pharmaceutical industry to shift the emphasis from “me-too” drugs to innovative drugs and to break the cozy link between drug companies and the thousands of doctors who take their gifts, consulting jobs, and trips, then turn around and write
prescriptions for their benefactors’ drugs, which may just mimic the action of easily available and less expensive generic medications.
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The FDA should regulate the incessant din of DTC commercials that flood the airwaves, along with print ads, stoking demand for very expensive me-too drugs.

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Research grants:
Agencies and foundations that fund research grants should allow curiosity-driven investigators to pursue promising findings that may deviate from the scientific question originally proposed. Some flexibility should be provided in the funding mechanisms to allow investigators to follow any unexpected findings wherever they may lead. For investigators to be forced to secretly divert funds for this purpose from their declared and approved missions incurs a sense of dishonesty and, in the end, is not the most productive path. Granting bodies should consider the qualities of creative people and the personae of the applicants as well as their proposals. The challenge is to have insight into whom to support before a track record exists.

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Peer review process:
Whereas peer review is intended to protect the autonomy and self-governance of the sciences, it has become an agent for the defense of orthodoxy and a constraint on creativity. The review process should be modified to reduce the inherent bias toward prevailing concepts and to encourage mavericks and outsiders. A firm standard should be the degree to which a researcher's work threatens to disturb conventional beliefs.

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Scientific journals:
Editors of medical and scientific journals should encourage researchers to be more forthcoming in fessing up to serendipity's contributions
to their experimental results. The widespread contribution of chance is typically obscured, so other researchers remain ignorant of the important role serendipity plays.
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It would be too bold a statement to assert that pulling out the thread of serendipity would unravel the entire tapestry of modern scientific discoveries. Yet, while serendipity is not to be overemphasized, neither should it be denied its due credit. Even with increasingly sophisticated technology and team efforts inclusive of multiple disciplines, serendipity continues to be a major influence to which a resourceful investigator cannot afford to turn a blind eye. Serendipity teaches that it matters less
where
we start looking for something interesting, and more
how
we go about looking for it.

Certain leitmotifs underlie many of the individual medical advances of the past century. Published reports are usually cool and dispassionate, but as one delves below their surface, one begins to see recurring themes: the role of unconscious factors, the ironies of circumstance, the elements of surprise and wonder, the subtle variables that influence the discovery process, and the inadvertent observations leading to breakthroughs in understanding. These factors are as ubiquitous as they are hidden. Journeying among them lands you squarely in the pathways and patterns of creative thought. In today's overly managed, bureaucratized research environment, these elements have become submerged.