The Unborrowed Vision of Stanley Prusiner

It is a rare treat to get a glimpse into the unrelenting pursuit of truth by a genius. Nobel laureate Dr. Stanley Prusiner, in his biography Madness and Memory: The Discovery of Prion—A New Biological Principle of Disease, provides such a glimpse.

The book recounts Dr. Prusiner’s painstaking struggle to uncover the secrets behind such diseases as scrapie, kuru, Creutzfeld-Jakob Disease, and Mad Cow Disease, which, before his intellectual power was brought to bear on the problem, defied explanation. This chasm in scientific knowledge and the inability to isolate a traditional infectious agent from patients caused scientists to invent tortured concepts like “slow virus” and “unconventional virus.”

The book provides a detailed accounting of the mountains of evidence and data Dr. Prusiner and his associates amassed over decades of work, the inductive leaps that they justifiably made, and the converging evidence that a new infectious agent had been discovered necessitating the creation of a new concept, perfectly designated by the word “prion.”

A prion, or proteinacious infectious particle, unlike all other infecting agents, is exclusively comprised of protein and is devoid of any genetic material yet is able to replicate and cause illness.

While it may seem that Dr. Prusiner proceeding down a relatively straightforward path without many obstacles to surmount, it is far from the truth. It is almost a general, but unfortunate, principle that those who bestow new knowledge on mankind are not greeting with the fanfare that they deserve, but derision, ad hominem attacks, and persecution. Such was clearly the case with Dr. Prusiner and his unborrowed vision that propelled science and human understanding further. As Dr. Prusiner traversed the incalculable distance of an “odyssey” from “heresy to orthodoxy,” he was met with skeptics that ranged from scientific journalists to Nobel-prize winning scientists. (As a student in a virology class I vividly recall my professor expressing open skepticism). But, despite the opposition, Dr. Prusiner’s persisted. He importantly identified that “distorting my understanding to fit other people’s desires was dangerous” and that “for a scientist, the most important trait is intellectual honesty within himself.”

The story of Dr. Prusiner, who eventually was awarded with a well-deserved Nobel Prize in 1997 is instructive and inspirational. It is instructive in that it concretizes how a dogged pursuit of the truth no matter where it led and what scientific dogma it ran contrary to led to an unprecedented breakthrough that caused textbooks to be rewritten. It is inspirational in that it shows how such determination, integrity, and productivity are virtues and lead to the achievement of values.

The best treat of this book is the ability to hear directly from a genius exquisitely conscious of the intellectual process that he exemplified. His description of the Nobel Prize as “a celebration of civilization, of mankind, and of what makes human unique—that is, their intellect, from which springs creativity” perfectly captures how I evaluate this book thatI recommend in the highest possible terms.

Visions and Revisions: A Scintillating Glimpse of HIV's Early Days

"How many sexual partners have you had?" I asked the 20-something male patient who was seeing me in clinic for oral syphilis. 

"This week? This month? This year?" he replied. 

When I said "this year" -- since I had to pick something -- he gave me a relatively large number. 

"Are you jealous?" were the next words out of his mouth.

Clearly, I was ill equipped for this exchange which left me a little puzzled. A new book, however, provides some important context that I did not yet have a full grasp of when the above encounter (now 5+ years old) occurred.

Dale Peck's Visions and Revisions: Coming of Age in the Age of AIDS provides a vivid whirlwind 1st person tour of the early HIV years from the perspective of someone immersed in the culture of bath houses, sex clubs, and navigating a world in which a killer the virus was lurking everywhere. As Scott Kramer's review in Metrosource noted, the book is akin to reading Peck's diary -- with all the lurid details no one ever found in their older sister's version. 

Peck, as a journalist in the early 1990s also reporting on serial killings of gays, freely switches contexts from a killer virus to a killer human allowing the reader to concretize the dual threats Peck was facing at the time. His analysis of serial killer Jeffrey Dahmer definitely brings a new level of insight and understanding of his victims and the patterns of their murders.

The book provides a unique bird's eye view into how one man coped with stigma and fear in the early days of a pandemic that still rages. As more and more people--infectious disease physicians included--have dimmer recollections of the horrible march of HIV in 1980 and 1990s America, immersing oneself in the early days of the plague with a colorful tour guide becomes increasingly more important.

Life Changing Medicine: More Than a Slogan & Tougher than Mold

As I write this, the institution I work for is in the midst of a comprehensive investigation into a small outbreak of mucormycosis in transplant patients. The discovery of these often deadly infections--triggered by the astute mind of a critical care physician--led to rapid action to safeguard patients on the part of the hospital. 

My institution is not just any transplant hospital--it is arguably THE most storied, most innovative, and most aggressive transplant institution on the planet performing nearly 400 transplants a year, including the rarely obtainable small bowel transplant. In short, pathbreaking work in transplantation has occurred here for decades and the human race is better off because of it. For example, transplant candidates that have no where left to turn come to Pittsburgh and are successfully transplanted. From pioneering work transplanting livers into HIV+ patients to transplantation of lungs into cystic fibrosis patients infected with a particularly nasty bacteria, my institution breaks the mold (no pun intended)--much like the city in which it is located in has.

This unfortunate and tragic outbreak has prompted the hospital to take many bold and unprecedented steps that include closing a major ICU, literally breaking down walls, a voluntary halting of transplantation, changing anti-fungal prophylactic guidelines, leaving no etiologic stone unturned, hiring world renown experts to join our own world experts, and even creating a blog to provide a level of transparency and public communication rarely seen.

These actions speak to the integrity and honor of the system and its leadership, whom I have extreme confidence in.

To me (and any intellectually honest observer), this is indisputable. 

This leads me to discuss another facet of my institution: the unjust persecution it continually faces from the state government, the press, unions, and many other parties.

For years, the health system has been locked in a battle with the state government which has sought to interfere--time and again--with its business practices. It has been damned for the very practices that have made it immensely successful, a boon for the economy of the state, and a destination for patients from all over the world. 

Just a few examples of the state's dictatorial meddling should suffice to sketch out a picture that shows the state's snarling attitude toward value creation. In recent months, the state government blocked the merger with an ailing hospital that has been forced to curtail services because it so desperately needs rescuing. The state would rather see a hospital continue to ail rather than be healed by merger. Additionally, the state has forced the health system to enter into absurd agreements with a direct competitor--a matter that the state Supreme Court has now taken up. The current executive branch of the state's attacks are so blatant that no less than the leader of the state senate called the governor biased against the system. These and many other actions and statements are nothing short of  a nihilistic desire to destroy the system on behalf of a power-lusting executive branch of the state government. It may attempt to hide its vicious motives behind platitudes regarding "consumer protection," as voiced by our state secretary of health, but their intentions are clear. I have spoken out against this envy-laden attack by the state many times and will continue to do so (despite bullying and even a piece of rotting meat sent to my doorstep).

The fact remains that no matter how much the governor and his cabinet seek to bully the health system and its employees, they cannot change the facts of reality. These facts unequivocally demonstrate the prowess of this system in delivering care, fostering innovation, and providing nothing short of life changing medicine. 

Getting this transplantation program back on line safely is not just a priority for the region, but the world. I am completely confident it will happen as soon as is possible.

Pyrimethamine and the Market

The latest controversy in the world of infectious disease is the price increase of the drug pyrimethamine, the primary component of the treatment of the parasitic disease Toxoplasmosis. Toxoplasmosis is a ubiquitous infection which, for most people, causes mild to no symptoms. It is acquired by eating undercooked meat or ingesting the cysts shed by cats. It is really a fascinating disease that is responsible for changing the behavior of infected rats, making them less afraid of cats--the ultimate destination of the parasite. It is estimated that 11% of the US population is infected.

The parasite causes problems, like many microbes, in those that are immunosuppressed. Those with AIDS and a CD4 count less than 100 are particularly prone to developing a brain infection with the parasites as are newborns borne to infected mothers, transplant patients, and others with immuno-suppressing conditions. 

Pyrimethamine is a drug that was initially FDA approved in 1953 and is no longer under patent, meaning any company is free to manufacture it. The fact is, however, that there is currently one US approved manufacturer who recently increased prices substantially. This has provoked a heated societal debate regarding drug prices. 

I have a few thoughts about this event (similar to those I have regarding hepatitis C medications) which many in my field no doubt disagree with but I think they are worth contemplating even if it changes no one's mind. As an infectious disease physician, who has taken care of several patients with toxoplasmosis, I don't want to see toxoplasmosis morbidity and mortality rise but pyrimethamine, in its current formulation, is the property of Turing Pharmaceuticals which has the right to set the price wherever they choose. I do not believe that anyone has a right to this product and strongly oppose any effort to expropriate or set price controls on this, or any other medication. While I have no understanding of how the new price was determined, it will eventually have to withstand the scrutiny of the market. If the price is set higher than the market will bear, because it is no longer under patent, other manufacturers will enter the market lowering prices. Ideally this would happen near instantaneously but, because of legislative barriers to entry, which include a multi-step approval process, it will take some time. Better alternatives to the current regimen may also appear in time as well.

Overall, however, infectious disease products have become less attractive to pharmaceutical companies and this, at root, is why we are left with just one manufacturer for many important non-patented products. The disincentives to enter this market are myriad and the ultimate answer to this scenario is not more intervention but to remove artificial barriers to entry, inviting the appearance of competitors in the market. The anger directed at Turing would be better employed if used to facilitate dynamism in the infectious disease market--it's the only long term solution.

The World is Short One Astute Clinician

It's almost a cliche in my field to speak of the "astute clinician" -- the physician of unborrowed vision who sees something amiss to which others are blind. They find the needles in the haystacks, the outliers, the one aberrancy among homogeneity. Behind every outbreak, you will always find one of this rare breed of physician.

Every infectious disease story has a hero like this and there is news today that one of the best recent examples of this pantheon of infectious disease doctors has died: Dr. Deborah Asnis. 

While Dr. Asnis might not be known to the general American public, the work she did surely is. Dr. Asinis was the first physician in the US to alert public health authorities that something unusual was happening in Queens in 1999. in particular, Dr. Asnis noted an unusual cluster of encephalitis cases some of which had polio-like features. Fast-forward through a major investigation led by Dr. Marcie Layton (another astute clinician) and extraordinary veterinarians and at the end it was announced that West Nile Virus had made its first foray to this side of the planet.  

Were it not for her brilliant identifications it is unclear how long it would have taken for public health authorities to realize what was occurring, delaying mosquito control efforts and physician awareness.

I never formally met Dr. Asnis but I recall atleast one occasion passing her at a meeting and glancing at her name badge. As someone who devours stories of outbreaks and knew of her work, I was star struck. The infectious disease world is a little less astute without her.