Yellow Fever Emergency in Brazil: A Disease to Watch

There has been increasing alarm regarding the appearance of yellow fever in the state of Minas Gerais in Brazil where over 100 people have been infected and over 30 killed. A state of emergency has been declared. It may seem, in today's context, yellow fever -- a major historical killer that, to this day, underlies, much government policy on infectious diseases -- shouldn't raise concerns given the availability of an efficacious vaccine, however there is more to the story.

Yellow fever, famously discovered to be transmitted via Aedes mosquito by Walter Reed and his team in Cuba, is a disease that has a spectrum of symptoms ranging from none to jaundice, death, and hemorrhage. Yellow fever has two cycles of infection: a sylvatic one and an urban one. In the sylvatic cycle the virus is passed between non-human primates and humans who come into contact with the mosquitoes in rural areas. In the more dangerous urban cycle, urban mosquitoes become seeded and transmission between humans accelerates.

Vaccination against yellow fever is not universal and is often reserved for travelers to regions at high risk. It is unclear how high the vaccination rates are in Minas Gerais but over 700,000 doses of vaccine have been deployed.

In the days to come, vaccination campaigns and other activities (facilitated by the emergency declaration) will be ramped up and hopefully be able to staunch this outbreak before it becomes widespread as occurred in Angola last year where cases spread to various nations including China.

Searching for The Elusive Billion Dollar Molecule -- A 23 Year Old Book, Highly Relevant Today

When you contemplate how hard it is to bring a drug from a hypothetical construct in a scientist's mind to something you can pick at a drugstore it is really unfathomable how many false starts, blind alleys, toxicity concerns, capital expenses, and regulatory considerations will occur over the years of development. In all, it is often estimated that it takes one billion dollars to bring a drug to market. 

This level of capital expenditure may explain why large-sized pharmaceuticals companies are market leaders because past historical successes have provided them the resources to engage in this field. I recently came across an important book, published in 1994, that provides an in-depth biographical view of a company being born. The Billion Dollar Molecule by Barry Werth is an incredible book that really, for the first time, concretized to me how hard pharmaceutical research is and provided a full context for the heroic achievements of those who engage in this extremely challenging -- yet absolutely vital field. 

The company profiled in this book (and also the subject of a sequel by Werth) is Vertex Pharmaceuticals. Vertex, founded by visionary former Merck star scientist Joshua Boger, was premised on what was then a novel concept: structural and rational drug design in which the structure of a target and a candidate molecule were given paramount importance in an industry which largely relied on mass compound screening. Werth details the company's dual efforts in immunosuppression and HIV -- a disease Vertex deemed of "planetary significance" -- protease inhibitors.

My current work often has me discussing and contemplating emerging infectious disease and the relative lack of treatments against them and The Billion Dollar Molecule provides much needed explanations for this insoluble dilemma. Several important takeaways with respect to emerging infectious disease:

  • "Diseases are not treated first as diseases, but as markets"
  • "You don’t see blockbuster drugs for acute situations. You see them for chronic cases."

  • "A molecule, he knew, was worthless, a laboratory curiosity, if it couldn’t be made cheaply enough to sell at a profit."

  • "Vertex wouldn’t pick the project that would benefit the most people or target the most pressing need; no company would. It would pick the project with the best overall chance of success."

The goal of any pharmaceutical company is to sell product in order to earn revenue and the bigger the market, the bigger lure. An emerging infectious disease, even in the most dire zombie apocalypse scenario, is dwarfed by hypertension, diabetes, heart disease, depression, and the like. If the market does not exist or is minuscule, it follow that market entrants will not be abundant. This is often termed a "market failure" when, in reality, it truly is very obviously just normal market functioning. Realizing these objective facts, without damning the industry like many are wont to do, leads to a whole different type of strategy to make these smaller markets attractive -- a project I am currently engaged in (more to come).

The book also contains great historical information about Merck -- an incredibly successful company with an almost unrivalled historical interest in infectious disease amongst giant pharmaceutical companies -- as well as important insights into the personality traits of the highly motivated scientists who were at the forefront of drug development.

One of the other absolute treasures of the book, to someone from Pittsburgh, is the time devoted to Dr. Thomas Starzl, one of the fathers of organ transplantation and a heroic pioneering visionary figure of unrivalled stature, who was absolutely instrumental to the success of the immunosuppressant tacrolimus.

Today, Vertex has revenues over $1 billion (and was responsible for the hepatitis C protease inhibitor telaprevir as well as an innovative treatment for cystic fibrosis) and The Billion Dollar Molecule, published 23 years ago, contains important lessons for those trying to understand the mechanics of this crucial industry as well, like me, trying to understand the considerations as the apply to emerging infectious diseases. In an era in which we have a president-elect who openly derides this life-saving industry, understanding -- and defending -- the pathbreaking efforts of this industry is more crucial than ever.


RFK Jr's Anti-Vaccine Camelot: Giving More Horsepower to The 4th Horseman of the Apocalypse

President-elect Trump's supposed appointment of Robert F. Kennedy Jr. to head a "vaccine safety" commission is alarming on many different levels for myriad reasons. (For the record, the Trump transition has not confirmed the formation of this committee but the interview RFK Jr did with Science post-meeting is pretty suggestive). 

RFK, Jr. is known, not for the Kennedy mystique, but as someone who unrelentingly spreads anti-vaccine mythology. He is most associated with his vociferous opposition to thimerosal, the innocuous mercury-based preservative used in some vaccines. Because of his last name, he is given an outsized platform to promote his irrational views, notably Rolling Stone and The Daily Show. Now that platform has metastasized and risks derailing the precarious progress the human race has made in the fight against infectious disease. 

A vaccine "safety commission" led by someone whose primary involvement in vaccines does not involve the actual study of vaccines, the administration of vaccines, or the development of vaccine is puzzling on its face. When that person's primary role with vaccines is to foment doubt on the biotechnological marvel of vaccination is even too far-fetched a scenario to call Orwellian, it is the height of absurdity. Yet, that is what we have devolved to.

But what could be the deeper purpose of this action? What does it accomplish? The president has no direct control over which vaccines groups such as the American Academy of Pediatrics recommend or which vaccines schools require as a condition of enrollment. Thus, this commission is a farce with no real jurisdiction. So the only purpose, in my estimation, of this ludicrous action is to reward and pander to the anti-vaccine movement by giving them a quasi-official standing and the explicit acknowledgment that they have a "friend" in The White House who gave one of their most prominent spokespersons an official sanction. 

Such a "commission", with the support of the President, can, however, wreak havoc. For example, I anticipate RFK Jr. will interfere with state or local vaccine campaigns (as he has done before), will spread disinformation and propaganda (as he has done before), and will amplify all sorts of anti-scientific arbitrary blathering against vaccines (as he has done before). 

The value of vaccines are self-evident given the immeasurable successes they have achieved. Vaccines have transformed childhood from a period in which friends succumbed to infections into one of idyllic joy with their protection against 16 (!!) childhood infections. Vaccines have rid the planet of smallpox under DA Henderson's able hand. Vaccines have relegated polio to just two countries. Vaccines against HPV and hepatitis B have and will seriously diminish the incidence of various cancers (cervical, vaginal, vulvar, penile, head/neck, and liver).

The doctors President Obama mentioned in his farewell address that stop "pandemics in their tracks" have achieved these pathbreaking feats almost exclusively through vaccines. Right now scientists are working on a slew of vaccines that will stop future pandemics as well as halt the spread of endemic infectious diseases in their tracks and allow civilization to progress. While the President-elect and RFK Jr. may say they are "pro-vaccine" their habitual sowing of doubts about vaccine safety and questioning the number of recommended vaccines belies their true positions.

The level of evasion required to deny the efficacy of vaccines is, to me, pathological and to reward or embrace that level of mental dysfunction is tantamount to surrendering one's own mind. The twisted illogic of RFK Jr. has caused him to liken the impact of vaccines, which have saved hundreds of millions of lives, to the Holocaust.

This attitude towards vaccines is nothing short of the return of the primitive and represents the nihilistic worship, not of technological progress and the genius of Jenner and Pasteur, but of the misery, death, and pestilence that vaccines delivered us from. A harbinger worth contemplating as these forces work to make America pestilential again.


Taking Candy From Strangers or Antibiotics from Injudicious Urgent Care Prescribers

One of my maxims when it comes to antibiotic stewardship is that stand-alone urgent care centers, those unaffiliated with a hospital, engage in a race-to-the-bottom to see just how inappropriate their antibiotic use can be. In an environment where patient "satisfaction" (and not patient clinical outcomes) becomes the currency, any action that pleases the "customer" and results in a repeat visit or goodwill is valued over those that do not have those attributes--irrespective of the veracity of the scientific and medical principles behind it. 

Walking out of an urgent care center with a prescription for antibiotics has become the new lollipop and is often treated that way by the providers who think of these resources as a parting gift, rather than a scientific achievement that is crucial to civilization. 

I am writing about this today because one of my friends -- a highly intelligent, assertive, and infectiously snarky nurse with an advanced degree -- related an experience she recently had with the dominant stand-alone urgent care provider in the Pittsburgh area. My friend had symptoms of an upper respiratory infection and, because of her knowledge coupled to a need to be around an immunosuppressed individual, she sought to find out if she was suffering from influenza, might benefit from antiviral treatment, and possibly need to limit her exposure to the immunosuppressed person for fear of passing the infection. Needless to say, her test (which was likely the poorly sensitive rapid influenza test that has vanishingly few uses in light of the arrival of recent CLIA-waived PCR influenza tests that everyone should be using) was negative and, instead of counseling her regarding the limitations of the test and the likelihood with high influenza circulation rates in the area she likely had influenza, an antibiotic was offered. My friend predictably balked at this, and as is her style, drew the physician out and got him to skewer science and push an antibiotic on her (which she refused) because of what he deemed the rate of secondary bacterial infection. His reply to her protestations is even more scarier than the injudicious use of antibiotics he advocated: "I teach this stuff." Suffice it say, she recovered and took no antibiotics.

We have a long way to go to properly steward antibiotics and not all patients are as astute as my friend. I realize that I am painting with too broad a brush and there is likely a lot of appropriate prescribing going on in urgent care centers. Additionally, hospital-based providers are in no way immune from injudicious prescribing either. However,  placing "patient satisfaction" above justified clinical care in a "have it your way" Burger King healthcare culture, exemplified by many urgent care centers, is something that needs addressing. 

That last part about Burger King was probably Burger King, which practices judicious antibiotic use as it has ceased serving antibiotic-laden chicken.


The Real Axis Powers: The Brain, The Gut, and The Microbiota

The last few years have seen a plethora of books published on the microbiome and the related topic of the influence of how the gastrointestinal (GI) milieu has implication that reach far beyond one organ system. I recently finished another book in this genre, The Mind Gut Connection: How the Hidden Conversation Within Our Bodies Impacts Our Mood, Our Choices, and Our Overall Health by UCLA gastroenterologist and professor and Dr. Emeran Mayer MD, PhD. The focus and theme of this valuable book is on the intricate relationships the enteric nervous system (ENS) has with the brain and how alterations in this second brain are increasingly being linked to myriad conditions. 

While the ENS gets much less attention than the brain and spinal cord, which together comprise the central nervous system (CNS), it is no less important and Dr. Mayer's book concretizes this fact in countless ways. Beginning with hypotheses regarding the signaling molecules that evolved between ancient bacterial species, when they were the only organisms to "talk" to on the planet, Dr. Mayer moves to the multicellular but tiny marine creature, the hydra, which is described as "a floating digestive tract". Eventually organism like the hydra were colonized with bacterial species and a symbiotic relationship evolved. Fast forward to our gut, minutely wired with nerves and teeming with neurotransmitters like serotonin, and you can understand how this system developed. As Mayer argues, as the primary brain evolved and  the role of the secondary brain was relegated to the GI tract with an important connection between the two via the vagus nerve which allows constant communication and feedback. The microbes in the gut are a vital component of this system as well as their metabolites directly interact with the ENS and, consequently the brain. 

To put it simply, there's a clear physiological and evolutionary reason why one gets diarrhea when nervous as a full bowel may not be the best thing to have when facing an important stressor like a lion (or the SAT exam). Taking this simple example and expanding it to reveal how perturbations in this system can lead to real pathology has led to major insight into diseases as disparate as celiac and Parkinson's disease.

There are many fascinating aspects of this book including historical observations (via a gastric fistula) made on how various emotions influence digestion rates, the role of inflammatory foods, and how psychosocial stressors (particularly early in life) can leave their mark on the gut-brain-microbiota axis. This book stands out in this ever growing field as one that provides a lot of seminal information about the ENS and the microbes it interacts with in an easily accessible manner with an emphasis on explaining real world macro-phenomena and it is for that reason I highly recommend it.