A Paean to Pharmaceutical Innovation: A Review of Miracle Cure

When you think about the power of the human mind to solve problems, it is difficult to overestimate what impact the discovery of antibiotics have had for the human race. They almost single-handedly rendered many deadly infectious instantly benign (of course until antibiotic misuse exacerbated resistance). While many people know the story of the moldy petri dish, there is a lot more to tell. William Rosen, in Miracle Cure: The Creation of Antibiotics and Modern Medicine, tells that story expertly.

This book, published earlier in the year, spans the entirety of modern medicine using antibiotics as the lens from which to view the field. This might seem odd as antibiotics represent only one component of medicine but Rosen shows just how their discovery changed the game.

The discovery of antibiotics was scientifically dependent on many antecedent discoveries regarding the causes of disease, microscopy, the theory of the cell, and the search for magic bullets to name but a few.

Once antibiotics were discovered, the fact that a "miracle cure" with true efficacy (unlike patent medicines, folk remedies, and homeopathy) a whole structure of medicine that could actually do something to ameliorate illness was created. And with that the need for randomized controlled trials, rational drug design, and the pharmaceutical industry. Indeed, Rosen states that "the machine of pharmaceutical innovation...wouldn’t exist, would never even have been built, but for the antibiotic revolution”

Rosen is clearly thankful and appreciative (as am I) for the innovators in pharmaceutical firms that made miracle cures like antibiotics possible. As Rosen aptly writes, "Tens, perhaps hundreds, of millions of victims of a thousand diseases from leukemia to river blindness are alive and thriving entirely because of a drug breakthrough. For them, and especially for the literally uncountable number of people whose bacterial infections, from strep throat to typhus to anthrax, were cured by a ten-day regimen of antibiotics, the bargain probably seems an extraordinarily one-sided one.”

Miracle Cure takes you from contemplating Galen's ideas about the four humors all the way to thinking about aplastic anemia caused by chloramphenicol -- a difficult task the book accomplishes excellently. I highly recommend it to those interested in the history of medicine, the history of the pharmaceutical industry, and the world of infectious diseases.

DA Henderson's Legacy Will Continue

One year ago, the world lost one of its benefactors, Dr. DA Henderson. I've written about DA's incredible career and insights before and I will continue to do so as his prowess was, in my estimation, without equal. 

DA was the architect and commanding general of the WHO's smallpox eradication campaign -- the one and only successful effort to rid humanity of an infectious disease. His merciless assault on the virus gave it no quarter and gave humanity new hope that they would never again be haunted by this virus and that such feats as the eradication of an infectious disease eradication were possible with the use of one's mind. 

DA's ability, his field vision, with infectious disease is what I think the world will miss the most. He had developed the ability to see an infectious disease outbreak with such precision as to transcend the predictions and assumptions of mathematical models. It was as if he and the microbe were looking each other in the eye, each anticipating the other's move. 

What I miss most,  is his unending enthusiasm for infectious disease and his boundless energy to infect others with that enthusiasm while imparting priceless wisdom.

In the Center, his portrait hangs on the wall and one can look at it for inspiration and ask "What Would DA do?"

WWDAD about the scary changes with H7N9 avian influenza, the ongoing cases of MERS in the Arabian Peninsula, the whispered threats of North Korean biological weapons, the longer chains of human to human monkeypox transmission, Candida auris, the roll out of a malaria vaccine, the ongoing spread of cholera in Yemen, the recognition of Zika as a teratogen, and so many of the challenge our species will continue to face from the microbial world? 

We will never know the answer to that question and we are all worse off for it. But, we do know that DA's brilliant legacy lives on in all those infectious disease physicians, microbiologists, public health practitioners, epidemiologists, and world leaders who had the opportunity to learn from him.

The fact that DA existed, succeeded against incredible odds against smallpox, and told us all how to approach the field gives our species an incredible tool we can use to flourish in this microbially-dominated planet.

This Pig is not a PERV: Major Xenotransplantation Advance

One of the most exciting fields of medicine which represents the integration of several disciplines is organ transplantation. The advances that have made such an innovative and life-enhancing feat possible were the result of breakthrough insights by heroic pioneers in the life sciences. However, despite the feasibility and almost routine nature of solid organ transplantation today, the full benefits have not been achieved. It is basically universally known that there are not enough organs procured per year to meet the needs of those on waiting lists. Several partial solutions have been proposed including more efficient allocation algorithms, increased public outreach campaigns to increase organ donation, and the use of "high risk" organs but even with all these initiatives combined demand is still outpacing supply. 

Using organs from animals closely related to humans -- such as pigs -- has been a proposed fix that has, unfortunately, not been able to reach fruition for several reasons. One reason xenotransplantation from pigs has been stalled is the presence of viruses integrated into the chromosomes of the pig. The fear is that porcine endogenous retroviruses (PERVs) could reactivate in the transplanted human, as several viruses can do in the presence of immunosuppression, and cause unknown effects which may be benign or not. A xenozoonosis would have major implications as it would virtually unprecedented, with no treatment protocol (though HIV drugs may work), and unknown contagiousness. To date, pig heart valves, pig skin, pig-derived insulin, and encapsulated pig islet cells are being used in humans with no evidence of PERV infection. 

A team from Harvard, which included the visionary George Church, recently harnessed the power of CRISPR to clean pig DNA of these viruses and allow PERV-free piglets to be borne. The study was published in Science. This is an unequivocally major achievement and has removed a major roadblock while illustrating the enormous value of CRISPR in furthering human life. 

Now that this hurdle has been cleared, it will be necessary to ensure that the human immune system is not too aggressive in rejecting the organ, which will need some further genetic modification in order to not tip off the immune system to its origin.

There is no timeline for how long it will be before pig xenotransplantation is adopted on a larger scale as protocols and regulations that govern these procedures will have to be rewritten, but each step forward should be applauded. 

Exploration, Integration: A Review of An Unnatural History of Emerging Infections

One of the best aspects of infectious disease is the grand scope which they encompass. It can be very hard to tell the story of just one infectious disease let alone the entire field. A 2013 book which I just finished attempts to do that and, in my view, is highly successful. Emory University professors Ron Barrett and George Armelagos's An Unnatural History of Emerging Infections is a must read for anyone interested in the field of emerging infectious disease. 

The book is written from a philosophical viewpoint that seeks to integrate the microbiological world with the human world. The human world, characterized by a litany of changing conditions, is shown to be very explanatory when it comes to the infections we contract. A key theme of the book is understanding human epidemiological transitions of which there have been three: from  a nomadic lifestyle to a sedentary one 10,000 years ago; the Industrial Revolution; and the modern era of urbanization/globalization coupled to population aging. Through these epidemiologic transitions disease patterns change from an age of pestilence to a period of receding epidemics to an era of manmade/degenerative diseases. It is important to realize that a nomadic lifestyle is not one in which large infectious disease outbreaks can flourish given the low population density and the constant movement. "Heirloom" infections (those that infected hominid species pre-humans) and "souvenir" infections (acquired in activities of daily living) were likely the majority of infections during these times.

From this lifestyle humans increasingly moved to agricultural societies which provided many advantages over the prior lifestyle -- principally in the ability to store calories via agriculture. On balance, this was the right choice for our ancestors but it did create kindling for infectious disease outbreaks as population density increased, contact with animals became more frequent, and food sources changed. This new set of conditions was conducive to zoonotic spread of infections as well as the persistence of endemic infections. Only with the advent of sanitary and, later, medical innovations characterized by the Industrial Revolution would these pestilences be tamed. 

There are countless additional pearls in this book that include a discussion of the competing Attenuation and Virulence Hypotheses and the role of non-human primates in human diseases. 

To me, this book is a valuable resource that I thoroughly enjoyed reading. It greatly deepened my understanding of the field reinforcing my knowledge and helping me make wider integrations with history and anthropology. I highly recommend it.

Chimeric Outbreak: Low Risk and Indolent but Nonetheless Deadly

To me one of the more underappreciated forms in which an outbreak can take hold is through contaminated medical equipment. There are several unique aspects of these types of outbreaks I believe makes them particularly difficult to detect and control. First, is the fact that the individuals getting infected are accessing the healthcare system for some reason that may mask the signs and symptoms of infection. These patients can also be at higher risk for ordinarily acquired infections making it less likely that someone would attribute their infection to a specific medical procedure and when infection occurs in these patients, it may be more difficult to treat because of coexisting conditions or, because of the nature of exposure, a deep-seated invasive location. Another factor is that the dose a patient may be exposed to may be small enough that a clinical latency period may occur before exposure and onset of symptoms, making linkage difficult. Indeed some exposures may not result in infection at all. Finally, these infections may not necessarily be clustered geographically and disparate locations may take a while to be knitted together delaying recognition of the outbreak. 

This was all very apparent in the deadly Exserohilum steroid contamination meningitis outbreak and is also apparent in the Mycobacterium chimaera outbreak linked to contamination of heater-cooler units used in cardiac surgery. This outbreak involves at least 79 patients, 17 of whom have died -- a fairly high fatality rate.

Mycobacterium chimaera, a non-tuberculous mycobacterium (NTM), is an indolent slow growing pathogen that can be difficult to diagnose. In this outbreak devices were contaminated during manufacture (in a very large manner) and, because of the fact that the majority of cardiac surgeries in the US use this type of machine, the breadth of exposure is large. However, the complicating factor is that despite exposure to this particular organism the risk of infection is low and symptoms can be non-specific. CDC advises hospitals should consider notifying patients who had exposure to this device after January 1, 2012. Some facilities have notified patients, others have not given the nuances (including the medicolegal implications) of this low risk exposure. A recent piece in the Tribune Review details one patient's experience with his possible exposure and subsequent symptoms.

When people think of outbreaks, it is often in the setting of explosive case counts and calamity. However, medical device outbreaks -- which can carry high fatality rates --  are an important species of outbreaks that are no less impactful or disruptive. Like the two-headed Greek monster that the bacteria is named after, this outbreak possesses a dual nature: both indolent/low-risk but but potentially deadly.