Breaking through for breakthroughs: the problem of normal science in rare disease research

Abstract

Scientific breakthroughs themselves often do not carry the force needed for acceptance or adoption. By their very nature, scientific breakthroughs challenge the status quo or Normal Science. Therefore, those who forge scientific breakthroughs will have to break through Normal Science if their discoveries are to be adopted. Needing to break through Normal Science may not come as a surprise to people educated and training in the biosciences, but it will to many people who come to rare diseases from outside the biosciences and through necessity. In this commentary, I describe the basis and components of Normal Science, and how it can impede the progress of scientific breakthroughs. I refer to Thomas Kuhn’s concept of the ‘structure of scientific revolutions’ as an explanatory model, and I use three case studies to illustrate it. I also provide ideas on measures that can be taken to help people in rare disease research recognize and prepare for the resistance Normal Science may pose for their breakthroughs.

Keywords::

• breakthroughs
• Kuhn
• normal science
• rare disease research

Dr. Barry Marshall, during the early 1980s, knew he had a breakthrough in the treatment of peptic ulcer disease. He found a certain bacterial species was often present in cases of peptic ulcers. Eradicate this bacterium, heal ulcers, cure disease. Q.E.D., asserted Marshall. Not so, said researchers and clinicians. They maintained only gastric acid can cause peptic ulcers; antimicrobial agents can have no place in their treatment. Marshall realized his scientific breakthrough required something further. He had to break through the scientific way if he were to ever see his idea adopted into clinical practice. Marshall’s example – one of many – is worth considering when evaluating research methods needed for advancing rare disease research. Breakthroughs in rare diseases will often require developing sophisticated research methods directed at therapeutic benefits, but also methods directed at breaking through science.

Thomas Kuhn, a noted, contemporary philosopher of science gives us a way to conceptualize this idea. He teased apart how science evolves to resist change [1]. He called this stage ‘Normal Science.’ Normal Science comprises a presumably settled consolidation of general theories, basic concepts, central questions, selected research methods, custom instruments and permissible interpretations-presumably settled, that is, because a critical mass of scientists say so. The business of Normal Science is working out the finer points of operating theories and concepts, solving remaining puzzles with stock methods and instruments, and producing interpretations filtered through a prescribed lens. Normal Science is further attended by faith, strengthened by commitment and carried forward by tradition [2,3].

Woe onto those who challenge Normal Science. Marshall was ridiculed and disparaged, and his funding proposals were rejected. As he recounts, ‘Everything we claimed flew in the face of accepted dogma’ [4]. ‘I realized then that the medical understanding of ulcer disease was akin to a religion. No amount of logical reasoning could budge what people knew in their heart to be true … A bacterial cause was preposterous’ [5]. When confronting Normal Science, Marshall discerned what he needed was daring and guile.

Drawing from Koch’s postulates on causation of infectious disease, Marshall drank an inoculum of Helicobacter pylori, the bacterial species he linked to the cause of peptic ulcers. He became very sick. Serial gastric biopsies implicated the inoculation as the cause of his severe gastritis. Still this action alone wasn’t enough to prove his case. His action was, however, enough to bring more research and reflection to his theory, which in turn led to gains in credibility and acceptance. Ten years after his self-inoculation, and > 100 years after the first suggestive findings, a National Institutes of Health consensus conference recognized the causal link between H. pylori and peptic ulcer disease, and the importance of antimicrobial agents in treatment regimens [5,6]. Marshall’s breakthrough finally broke through Normal Science. He forged what Kuhn calls a scientific revolution.

Inferring Marshall’s experience involving a very common disease to rare diseases is not just theoretical. John Crowley confronted Normal Science in his efforts to enable the discovery and development of enzyme-replacement therapy for Pompe disease, efforts made particularly urgent by two of his own children needing treatment. Crowley eventually came to understand he had to do more than be successful in the laboratory: ‘We need to beat science – and we need to beat time’ [7].

Dr. Stanley Prusiner encountered persistent and intractable doubt and skepticism over his discovery of infectious proteins that could replicate without genetic material. He called these proteins ‘prions,’ and he further linked them as the cause of several neurological diseases, including the rare disease Creutzfeldt–Jakob disease. Normal Science required infectious proteins to have genetic material in order to replicate and anyone who thinks otherwise is wrong and should be disparaged: ‘I was the embodiment of the word ‘pariah’’. Buoyed by his familiarity with Kuhn’s concept of scientific revolutions, Prusiner persevered over the course of a decade and a half to attract enough adherents to win the 1997 Nobel Prize for Physiology or Medicine. He had completed his ‘odyssey … from heresy to orthodoxy’ [8].

Rare disease research, driven by novel theories and methods, designed with adaptive processes, and fueled by urgency, often collides with the requirements and pace of Normal Science. Research in common diseases is driven similarly, but is configured and proceeds in ways that essentially form Normal Science. Advances in rare disease research will thus be dependent on more than just new and sophisticated research methods. Advances will also depend on methods to break through Normal Science, and on people with perseverance and ingenuity to forge revolutions.

The rare disease research community has demonstrated its perseverance and ingenuity before. But, rare disease research programs are often originated and shepherded by rare disease patient organizations, and consequently by people who come into the research world from other realms – business, education, trades, home – and only by necessity when people in their families or communities are stricken. Thus, unlike people who come to research through the sciences, some of the people directing rare disease research will be unaware of how Normal Science can impede clinical adoption of scientific breakthroughs. When they encounter this hidden force for the first time, they are surprised, frustrated, enraged, and sometimes, tragically defeated. This cannot be countenanced. Private and public organizations that provide research training for people involved in rare disease research could help them by also providing training on breaking through Normal Science. The training programs could comprise two primary components: i) how to affect the impact of Normal Science at the institutional level; and ii) how to overcome Normal Science at the individual research program level. The types of training already made available by government agencies and patient advocacy groups could accommodate these particular elements.

Training on how to affect Normal Science on the institutional level could focus on the current funding patterns that favor familiar research programs and known researchers. Both private and public institutional funding organizations have low risk tolerances. Thus, they prefer research proposals with little to no novelty and investigators with successful track records [9]. In contrast, rare disease research is mostly novel, and attracts new investigators. Rare disease advocacy groups could be trained on ways to establish requirements, incentives or arguments for allocating more funding for novel programs. If there is more funding for novel research programs, then the resistance to novelty from Normal Science should diminish accordingly. The National Institutes of Health (NIH) new and early investigator policies were established in the last few years to address just this problem [10].

Training for the individual research program level could focus on identifying the specific elements of a particular research program that are likely to encounter resistance from Normal Science. Specific elements could include the underlying theory, instrumentation, research methods and interpretations of data among others. The training could concentrate on the arguments and data needed to attract researchers to the novel research program. After all, a novel research program becomes the dominant approach when a critical mass of researchers say it is, or so Kuhn says.

Rare disease research is challenged enough, indeed vexed by a paucity of research methods that can help us discern the safety and effectiveness of proposed treatments. This is no secret, though, and the problem is getting increasing attention. But, to ensure that scientific breakthroughs in rare disease research have the best chance of clinical adoption, resistance to them coming from Normal Science must be taken into account. Thus, as researchers and advocates are trained on research methods for scientific breakthroughs, they should also be trained on how to break through Normal Science, lest they be tempted to risk their own health to make a case as Marshall did.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Acknowledgment

Alexis Leigh Teagarden, PhD provided important guidance in constructing the argument I make in this commentary.