Madness and Memory
Author: Stanley Prussiner
This account of the conceptual breakthrough that resolved the mystery of transmissible neurodegenerative diseases is written by the scientist who played the singularly central role in unravelling it. By discovering ‘an entirely new mechanism of disease‘, the author triggered one of the most seismic shifts in medical history in which proteins, and not microbes, transmit disease, and in which ‘a single illness can be both genetic and infectious‘. The book explores how the intriguing concept of prions began as an idea almost everyone in the field considered to be too preposterous, and it reveals how the concept eventually prevailed over competing hypotheses to become the established paradigm. The author narrated how his single-mindedness, and his impressively rigorous science, confirmed his irrefutable ideas, and in the process, he demonstrated how he overcame the ‘scorn, outrage, and disbelief‘ of his colleagues, and their visceral antagonism to his theory. Admitting that he was driven by ambition and hunger for success, and by the realisation that ‘whatever I wanted from life I had to make happen’, his reward was the satisfaction that his theory gained scientific validity and universal acceptance – a feat that was crowned by winning the entire 1997 Nobel Prize for physiology and medicine (pages ix, 160 and 218).
The backdrop of the book’s saga of prion diseases is the myriad of speculative opinions that were advanced to explain the enigma of such disorders as scrapie, kuru, and Creutzfeldt Jakob disease (CJD). Quipping facetiously that ‘by the early 1970’s, hypotheses about the scrapie agent outnumbered its investigators’, the author explored, and dismissed, such prevailing ideas as transmissible slow viruses and unconventional viruses called virions. Obsessed by ‘the challenge‘ of finding the cause of scrapie, and determined to solve the problem, the author recalled reading ‘everything I could find about scrapie and CJD’. The view that perhaps most influenced his approach was that of radiation biologist Tikvah Alper who, just like him, had disagreed with the dominant paradigm that the scrapie agent was a virus. What particularly struck a chord with the author, and which set him on the search for a non-viral cause for scrapie, was Alper’s observation that, unlike viruses, the scrapie agent was not visible on electron microscopy, and it is also resistant to destruction by ultraviolet light and X-rays (pages 17-19, 29-30 and 19-21).
The most inspiring feature of the book is its depiction of the author’s dogged pursuit, and eventually successful identification, of the prion protein PrP. He chronicled the steps he took to eventually identify these birefringent rods which are indistinguishable from amyloid fibrils on electron microscopy. Pointing out that his discovery ‘provoked a firestorm that continued for several years’, he went on to make even more defining discoveries such as determining that the PrP gene was a chromosomal rather than a viral gene, and that it is present in both normal and infected animals. It is significant that his work directly enabled the ‘deciphering’ of all human prion diseases, from Gerstmann-Sträussler-Scheinker to fatal familial insomnia. It is also remarkable that it generated the intriguing hypothesis that other neurodegenerative diseases that follow ‘a distinctive pattern of spread to other areas’ are also driven by prion mechanisms – disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis (pages 101-122, 133-135, 157, 208-209 and 233).
In a compelling portrayal of his research work that elucidated the nature of prion diseases, the author credited his success to his ‘disruptive innovation in thinking about proteins and how they cause disease’. This is because his advocacy that proteins can ‘reproduce and infect‘ even though they do not contain any ‘genetic material‘ went against the weight of the ‘scientific body of knowledge‘. As a reflection of his resolute commitment to resolving the mystery of prions, he vowed that he was ‘prepared to work on the problem for a long time‘, and he determined that the reliability of his findings would be such that ‘others were going to be able to confirm my work’; the consequence of these commitments was that the work ‘would soon all but take over my life‘. Almost paranoid in his zeal to carry out unimpeachable work, the author time and again repeated his experiments and applied different methodologies to purify the scrapie agent ‘from other substances in the brain, such as nucleic acids, proteins, and fat‘, all the time worried that his positive results may have been compromised by ‘some subtle artefact‘. Characterising the enormity of the task he set himself, he remarked that it was only ‘the hubris of youth…that propelled me forward’, adding that he ‘might never had started the work…if my fascination with the scrapie problem had not blinded me’ (pages x and 24-36, 82-85 and 28).
The hostility and derision the author and his ideas endured throughout his career formed a prominent theme of the book. Referring to the ‘legion of naysayers‘ that tried to discourage him, he said many neurologists thought he was wasting his time and should ‘spend my efforts devising therapies instead of studying a little-known disease of sheep‘. He also highlighted the ‘skeptical and frequently hostile reactions’ he had to contend with from his colleagues who, because of their ‘disbelief, disdain, and ignorance‘, characterised his research as ‘impossible‘. The author attributed the antagonism to his research to the recognition that it threatened ‘the sacred central dogma of biology‘, and to the perception of his colleagues that he was impudent for introducing the term ‘prions’; this name, he added, provoked unimaginable ‘animosity‘, and led to his characterisation as ‘impulsive, presumptuous, reckless, ambitious, aggressive, callous, manipulative, and egotistical‘. The virulence of the resistance he faced was evident in the unrelenting hostility of scientists such as Laura Manuelidis who were ‘unable to envision the possibility that viruses did not cause scrapie’, and the conspiracy to deny him credit for his work. And the fallouts of the resentment was such that he lost his investigator status at the Howard Hughes Medical Institute in 1979, and he received no ‘sympathetic understanding’ from the reviewers of his grant applications (pages x, 70-77, 86-93, 220-223, 123 and 32).
Another unpleasant theme the author explored was the highly charged competitive atmosphere that surrounded the prion research field, some of which had a malevolent tinge. Referring to the race to elucidate the nature of the scrapie particle as intense and nerve-racking, the author depicted it as a dangerous contest which puts ‘pervasive pressure‘ on researchers to interpret data to support their own views. He also referred to the unwillingness of participants ‘to finish second‘, a sentiment that ‘pushes investigators, including myself, to be inappropriately aggressive‘. He also described his abiding paranoia ‘that someone else would define the agent’s composition based largely on our work’, a fear that materialised when Carleton Gajdusek, ‘player number one in the competition’, attempted to claim priority over the discovery of the scrapie protein. The author alluded to how Gajdusek’s personality made him suited to making this outrageous claim, being ‘an engaging, forceful, insecure individual’ with a ‘rambunctious personality’ who was ‘addicted to hyperbole‘ and was ‘driven to dominate every conversation in any room he found himself’ (pages 46, 259, 190-191 and 50-64).
The book is as much an account of an important scientific milestone as it was a justification narrative. It is also a lesson in the dogged work ethics and the single minded focus that are required to make all scientific breakthroughs. It is also a story of steely determination, persistence, self-belief, single-mindedness, and help-seeking – all ingredients for a successful research enterprise. The author’s focus on the obstacles he faced from his colleagues and the scientific community, justifiable in the circumstances, was perhaps obsessive. The narrative however illustrates the darker side of science, and the danger that the healthy competition that drives research breakthroughs may teeter into vicious competition and mean-spiritedness. The book’s only shortcoming was its failure to fully acknowledge the contributions of the people who worked with the author on his research work.
The lessons of this book, from the value of focused and rigorous research to the benefits of seeking answers outside the prevailing paradigms, are profound and apply to all health research. The breakthrough the book highlights are relevant not only for showing how a single idea can revolutionise a whole field, it also shows how this idea can generate many new ones, in this case the realisation that many neurodegenerative disorders may turn out to be prion diseases. The book’s contents are a recipe for carrying out relevant and productive research because it outlines the dreams, the requirements, and the challenges that are the ingredients of scientific discoveries. This is clearly relevant to health care and I recommend the book to all doctors.
Publisher, Place, Year: Yale University Press, London, 2014
Number of chapters: 17
Number of pages: 320
Star rating: 5