VX: 2 Letters that Spell Death

The assassination of Kim Jong-un's half brother Kim Jong-nam was reportedly carried out in Malaysia using VX, a nerve agent that has been well-characterized as a potent chemical weapon for decades. The delivery mechanism was allegedly via skin exposure as the assassin rubbed the substance into Kim Jong-nam's face.

VX belongs to a class of banned chemical warfare agents that includes sarin, well known after its use in the Aum Shinrikyo (they also experimented with VX) Tokyo Subway attacks in the 1990s, and all of these agents act to interfere with neurotransmission -- the way nerves speak to each other and to muscles. Specifically, these agents increase the amount of the neurotransmitter acetylcholine leading to predictable effects that medical students always memorize. Salivation, lacrimation, urination, diarrhea, vomiting, small pupils (miosis), and a slow heart rate are all part of what is known as a cholinergic syndrome. If not reversed, it is fatal. 

The most potent of nerve agents, just 10 milligrams of this tasteless odorless liquid is enough to prove fatal.

Atropine, a very commonly used medication in hospitals, is one of the antidotes that can reverse the symptoms. This is given in conjunction with another medication called pralidoxime. 

This event underscores that  chemical -- and likely biological weapons -- remain major threats and rogue nations, where individual rights are non-existent, remain a threat that merit preparing for. During the coming days, it will be critical to confirm the manner of death of Kim Jong-nam.

Dissecting Presidential Neurosyphilis Speculation

As the world tries to explain the decisions, mannerisms, and behavior of the new US president, several explanations have been proffered. One particularly interesting conjecture, made by infectious disease physician Steven Beutler, involves neurosyphilis.

Extrapolating from the president's statements to Howard Stern about his experiences trying to avoid sexually transmitted infections, Dr. Beutler raises the issue of neurosyphilis. 

Syphilis is a very common infectious disease that has a prolific and storied past in which it infected people of all walks of life, including many famous individuals. It has various stages that, if untreated, can progress. Neurosyphilis is a late stage manifestation of infection and can cause neuropsychiatric disturbances. In fact, syphilis status is often checked in those presenting with neuropsychiatric symptoms at an older age. 

While primary syphilis cases have been increasing in recent years, cases of neurosyphilis in general are rare in the non-HIV positive population. Syphilis is caused by a bacteria called Treponema pallidum and it is usually exquisitely sensitive to antibiotics of the penicillin class and it has been suggested that all the courses of amoxicillin and other medications given (appropriately and inappropriately for sore throats, bronchitis, other STIs, and the like have blunted the development of late stage syphilis in those incubating the infection. 

While neurosyphilis can definitely cause erratic behavior and psychiatric disturbances I do not believe, in this case, it is ultimately the underlying explanation for this phenomenon. But this type of speculation regarding presidents is not new.

Giardia: Coming to a Faucet Near You?

Clean water is a hallmark of civilization and the development of water sanitation systems to provide drinking water with low levels of potential microbial pathogens has played a part in much of human civilization's flourishing. Diseases such as cholera have literally cut swaths through human populations (and continue to do so in the absence of clean drinking water). 

This week, a major "boil water" advisory has been issued for approximately 100,000 residents of the city of Pittsburgh due to the discovery that chlorination levels were suboptimal allowing the possibility that the cysts of the protozoal organism Giardia lamblia might survive. 

Giardia is the most common intestinal parasite reported in the US and up to 20,000 cases of giardiasis are reported annually. In many individuals who ingest the cysts of the organism, no symptoms result. In others, the ingestion of 10-25 cysts can cause symptomatic giardiasis. This condition, in which the organism excysts, is characterized by diarrhea, abdominal bloating, and abdominal pain. The diarrhea is characteristically greasy, floating, and foul-smelling due to the presence of fat malabsorption incited by the microbe. It is easily treated with antibiotics but in those with chronic untreated infection malabsorption and weight loss can occur. Restoring safe adequately chlorinated drinking water is an obvious priority lest any disease result.

No cases of giardia have been reported with this incident thus far, but given its commonality --in 2014, 88 cases were reported in Allegheny County -- and the presence of asymptomatic cyst passers it will not be surprising if there is an uptick in numbers.

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.