Putting Lipstick on a Pig by Removing PERVs

The New England Journal of Medicine, in its Clinical Implications of Basic Research column, covered a remarkable new study that shows just how revolutionary and pathbreaking the CRISPR-Cas9 gene may be. 

The column -- and the research it is based upon -- integrates across the seemingly disparate field of retrovirology and xenotransplantation. Xenotransplantation is the transplantation of organs from an animal species into humans. Even if a safe and effective technique that minimized organ rejection could be found, however, the problem of xenozoonosis would still exist. 

Xenozoonosis is the transmission of an infectious agent via organ transplantation from one species to another. While screening donor animals for exogenous potential pathogens and raising them in sterile environments may be possible, it is not enough. Endogenous retroviruses integrated into the genomes of animals could activate and infect human cells causing novel zoonotic diseases. The fact that these viruses are literally part of the organism whose organs are being transplanted is a very daunting obstacle to overcome. But not for CRISPR-Cas9. 

CRISPR-Cas9, a revolutionary gene-editing technique that is part of bacteria's immune system, can be used to cut and paste genes in a relatively simple manner. In the study (originally published in Science by Yang along with transplant infectious disease pioneer Jay Fishman and the extremely innovative George Church) detailed in The New England Journal of Medicine, CRISPR-Cas9 was employed successfully to remove porcine endogenous retrovirus (PERV) from pig cell lines. For many reasons, pigs will be the most likely source of organs for humans and PERV is known to have the capacity to infect human cells. 

While this is an early study, its implications are far-reaching -- just imagine the impact on organ transplantation waiting list if pig organs could be safely transplanted into humans.

CRISPR-Cas9 may be the discovery of the millenium. 

Be Specific: A Review of Pneumonia Before Antibiotics

When I lecture on existential infectious disease threats -- a subject I am writing a book on -- antimicrobial resistance is what I usually will list as #1, above influenza, above Ebola, above HIV, and definitely above Zika. To me, as a practicing infectious disease and critical care physician, treating infections with multiple-drug resistant organisms is something I do all day and all night. 

When I am asked how to reverse the trend of injudicious antibiotic prescribing which has driven antimicrobial resistance to new heights, I reply we have to be more specific. By being specific I mean that we have to not be satisfied with a generic diagnosis of upper respiratory tract infection, community-acquired pneumonia, or the like. Such non-specific diagnoses engender empiric broad-spectrum antimicrobial therapy when a narrower agent--or often no antibiotic at all--is actually indicated. It seems like it may have always been this way, but that is not the case.

In Pneumonia Before Antibiotics: Therapeutic Evolution and Evaluation in 20th Century America, Harvard's Dr. Scott Podolosky (someone who I have heard lecture before) provides the much needed history of how such a menace as the Captain of the Men of Death was handled prior to the advent of antimicrobials (first sulfa drugs and then penicillin). In a word therapy was specific.

The chief means community-acquired pneumococcal pneumonia -- still a major infectious disease killer--was treated was with type-specific serum. Typing individual patient's strain of pneumococcus might sound as extremely complex and delay-ridden to a modern physician, but it was neither in an era before antibiotics. Podolosky's book, which is ripe with historical detail, illustrates just how this was accomplished and how pneumonia was construed as a public health threat that spawned typing and serum centers nationwide to get the correct type-specific serum to the patient in hours!

The most interesting part of this book which is littered with mentions of such iconic figures in infectious disease as William Osler and Maxwell Finland (to me) is how once sulfa drugs -- cheap, easy to administer, and non-specific -- appeared, the clinical paradigm rocked and shifted as physicians contemplated which countermeasure to use and when combination therapy might be warranted. I expect this same debate to recur soon as the market in infectious disease therapeutics begins to expand to include such specific therapies as monoclonal antibodies, bacteriophages, lysins, and the like.

It will be essential for the forthcoming debates and research on the optimal treatment of infectious diseases to be informed by the important context Dr. Podolosky's work provides. 

What Does the Space Station Mir Have to do With Wisconsin?

The thing about infectious diseases is that they have a penchant for surprising us, popping out of nowhere, and behaving in ways that were not appreciated in earlier cases. This is the case of Zika, but also with a less known bacterial illness: Elizabethkingia, named for the famed CDC microbiologist Elizabeth O. King (who discovered it as well as the Kingella genus of bacteria).

Elizabethkingia is an interesting class of bacteria, one species of which was discovered on water that had condensed within the Mir space station. This bacterium, specifically the meningosepticum species, is usually linked to neonatal meningitis and infections in the immunocompromised. Clusters related to contaminated fluid solutions and similar products have been noticed. One of the challenges associated with this bacterium is the fact that it is highly resistant to many antibiotics, though fluoroquinolones are usually effective. 

However, an unusual cluster of infections in Wisconsin has been noticed. 

This cluster of nearly 50 people with bloodstream infections includes 18 deaths and spans several counties. Most of the patients are elderly and with underlying conditions. The source is, as yet, undetermined and it will be interested to how these infections emanated and spread over several counties. Important questions regarding the commonalities between the patients, their exposures, and their clinical trajectories will be important to determine in order to control this outbreak and prevent future occurrences.

Understanding Vaccination Through the Lens of Inoculation: A Review of Defying Providence

When the history of vaccination is discussed it, naturally, begins with the path-breaking step taken by Edward Jenner in the late 1700s. Jenner’s use of cowpox to protect against smallpox—an action that would culminate in the eradication of smallpox from the planet under the aegis of DA Henderson—is often discussed without any knowledge of the context that conditioned the development of the first vaccine in history.

Dr. Arthur Boylston’s Defying Providence: Smallpox and the Forgotten 18th Century Medical Revolution provides that valuable context. Boylston’s book, which is the result of extensive research, adds much detail to the means of controlling smallpox that existed before vaccination – i.e. inoculation. Inoculation is often treated as a historical relic in the path towards vaccination and given short shrift by many and often damned as a means by which smallpox spread but it is much more than that, as Boylston shows.

Inoculation was an ancient practice that rose in prominence in England and Boston (under the direction of another Dr. Boylston) in the 1700s. It involved the intentional infection of someone with smallpox via a small cut in the skin. Such artificial cases allowed an often minor infection to ensue conferring immunity against natural infection. Make no mistake, the artificial infection was true smallpox and, in rare instances, could kill and also had the ability to spread. However, it is crucial to not drop the context in which it was used – a time in which smallpox was a major killer in which risk-benefit ratios strongly favored the use of inoculation.

Boylston’s book provides a much-needed history of how this practice gained in acceptance, how the evaluation of its efficacy led to the foundations of evidence-based medicine, and how a specific phenomenon led to Jenner’s innovation. 

The phenomenon of those who had cowpox being protected from smallpox is cloaked in the myth of the fair complexion of the milkmaid but the actual truth is much more interesting scientifically.

Cowpox was an affliction known to farmers and the inability of an inoculation to take (i.e. produce a case of mild smallpox) in those with cowpox began to be known before Jenner. Jenner and others reasoned that because of the resistance to inoculation, cowpox might be protective against smallpox infection. In effect, Jenner sought to substitute vaccination (with cowpox) for inoculation, seeing if artificial cowpox would work the way natural cowpox did with respect to smallpox protection. Vaccination was a relatively safer alternative to inoculation and could not spread smallpox. The resistance to Jenner’s vaccination that occurred upon introduction can be seen not just as a reaction against the use of material from a cow but also hesitancy to discard inoculation, which had been a major component of smallpox control until then.  Indeed inoculation, as the title of the book makes explicit, allowed humans to defy Providence and take charge of the trajectory of their lives by protecting themselves from smallpox.

Dr. Boylston deserves much credit for writing this important history and illuminating the origins of vaccination—another means to defy Providence—by giving much due credit to inoculation and the inoculators.

Measles: Still "A Thing" (in the US in 2016)

Buried amongst the myriad Zika virus headlines, so hard to find it took some looking, is news of measles cases in the US...again. While not as explosive as the recent Disneyland-linked outbreak the 2 cases that have occurred this year are instructive as they are cases that should not be occurring in the US.

The cases occurred in the states of California and Texas. In Texas, an unvaccinated child who traveled internationally -- where measles is rampant -- was infected and later exposed classmates at an elementary school early in January. That this happened in Texas is not surprising as it is the 2nd least vaccinated state and this low rate of vaccination is reflected in the fact that some of the students exposed were not vaccinated. It appears, however, that herd immunity as well as luck delimited the impact of this case as no secondary cases occurred and the incubation period has since passed.

California, where the other 2016 case occurred, is the state in which a new law was enacted to increase the rates of vaccination in schools by eliminating religious and "philosophical" exemptions. California, being the epicenter of the 2014-2015 outbreak, also had a major reminder of the danger of measles that had ripple effects that led to increased vaccine confidence among the vaccine-hesitant. The details of the California case haven't been released and it will be important to determine the circumstances surrounding this case.

More measles cases will occur in the US this year and many children will remain unvaccinated kindling for this virus.