Foreign Bodies: Pandemics, Vaccines and the Health of Nations

Yves here. KLG reviews the recent Simon Schama book, Foreign Bodies: Pandemics, Vaccines and the Health of Nations. While he finds Schama’s offering has a lot of merit, KLG also takes issue with some of Schama’s views.

By KLG, who has held research and academic positions in three US medical schools since 1995 and is currently Professor of Biochemistry and Associate Dean. He has performed and directed research on protein structure, function, and evolution; cell adhesion and motility; the mechanism of viral fusion proteins; and assembly of the vertebrate heart. He has served on national review panels of both public and private funding agencies, and his research and that of his students has been funded by the American Heart Association, American Cancer Society, and National Institutes of Health.

Why do plague and pandemic go together?  Displacement, which is a symptom of ecosystems under stress.  As humans push farther into lightly inhabited (by us) spaces we encounter new organisms (including viruses in this definition of the term), some of them not particularly welcoming to humans This has been a subject for a long time, sometimes appreciated, most times not.  My introduction to this goes back 28 years to October 1995, when I heard Laurie Garrettgive a talk about her new book, which is still in print, The Coming Plague: Newly Emerging diseases in a World Out of Balance.  But when the Market is the Measure of All Things, with apologies to the shade of Protagoras, including those that can only be sensed and not measured, boundaries and environmental integrity are dispensable.  For a while.  We are running out of time.

Human disruption of ecosystems and the transit of natural boundaries has given us a host of zoonotic diseases, including Lyme disease and chytridiomycosis.  The former, frightening and spreading and sometimes difficult to cure with antibiotics, is caused by a tick-borne spirochete (Borrelia burgdorferi) that thrives in disrupted ecosystems (e.g., too many deer in suburban environments).  The latter is caused by an ancient, i.e., early-diverging, fungal cousin of ours, one of the few Fungi that has a motile phase (and an organism I have used in a model of the origin and evolution of animal cell motility).  The devastation of amphibian populations across the world by this “primitive” fungus is a most likely a consequence of the trade in the African clawed frog, the well-known lab animal and sometime pet Xenopus laevis, which is apparently resistant to chytrids.  White-nose syndrome, which is devastating bat populations, is also a fungal disease.

During the last two years of COVID-19, I have waited patiently for a good, current book that covers the history of plague and pandemic.  We have found this in Foreign Bodies: Pandemics, Vaccines and the Health of Nations by Simon Schama, currently Professor of Art History and History at Columbia University.  Several of his books sit on my shelf, after having been read, which is usually but not always the case.  These include Landscape and Memory, Rough Crossings: Britain, the Slaves, and the American Revolution, and Citizens: A Chronicle of the French Revolution.  All are outstanding as history and literature.  In Foreign Bodies we have a book that places our current predicament in historical perspective that includes empire, medicine, microbiology, the practice of science, and how both the Market and politics rule it all.

What pandemics are covered?  Smallpox, cholera, bubonic plague, and, at the end and somewhat in passing, COVID-19.  Each of these diseases is frightening and lethal.  Smallpox (Variola) has been eradicated, we trust, through a heroic, worldwide effort in public health.  Cholera (Vibrio cholerae) is a scourge that still reappears too often, in places such as Haiti and Yemen for reasons entirely understood and completely preventable.  Plague still lurks, and while it is the agent of a very serious and very rare disease, Yersinia pestis has not caused a widespread epidemic recently.  COVID-19 is obviously still a “work in progress” despite the protestations of our political and scientific authorities.

The recent history of smallpox is covered very well in a series of overlapping chapters.  What is not widely appreciated is that smallpox had long been prevented by folk medicine in cultures far away from seats of learning in the Early Modern world.  The origin of vaccination lies in variolation, which is a simple procedure in which pus or encrusted “pocks” from a smallpox lesion are introduced into the lightly incised skin of the patient after which the wound is bandaged.  This usually results in a mild form of the disease (fever and a relative few pustules localized near the site of variolation) after which the patient is generally immune to smallpox.  The particularly interesting story lies in how variolation made it to Europe from “heathens” to the East.

For Voltaire, who was convinced that 200 pints of lemonade cured his case of smallpox.  But later he noted that “Smallpox inoculation was a sign of the common sense of ‘intelligent women’ like the poet Lady Mary Wortley Montagu, whose four-year-old daughter had, in 1718, been the first person inoculated against smallpox in England under something like professional supervision and in a blaze of publicity.”  The question is where did Lady Mary get this idea?  Apparently, she noticed “not least in the company of naked bathers at a Sofia hamman (public bath)” during her husband’s brief embassy to the Ottoman Empire that none of these women had been marked by smallpox.  She learned that this was due to the miracle of inoculation.  Having returned to Twickenham ten years later she became famous, along with her influential convert Princess Caroline of Ansbach, or infamous to many belligerent critics from the establishment, as the “champion of the Life-preserving, face-saving procedure.  And in the eyes of Voltaire (again) a “peerless example of practical reason and virtue.”

Lady Mary correctly anticipated that it was not the English people who would stand in the way of a Turkish medical intervention, but rather it would be the medical profession “which stood to lose financially once all their potions and powders, cordials and compresses, purges, plasters, and bleedings could all be done away with”:

I am patriot enough to take pains to bring this useful invention into fashion in England and I should not fail to write to some of the doctors very particularly about it, if I knew any one of them that I though had virtue enough to destroy such a considerable branch of their revenue for the good of mankind…Perhaps if I live to return I may, have the courage to war with them.

And there were others who kept variolation simple and effective, usually in the provinces.  Thomas Nettleton of Yorkshire conducted legitimate clinical trials in the 1720’s [1] showing that simple inoculation as performed in the Ottoman Empire works without the expensive add-ons of the typical London physician.  These country doctors were true scientists mostly concerned with the health and wellbeing of their patients, who were also their friends, fellow parishioners, and fellow citizens.  They did this while making a good living that was not at the expense of the income of their patients.  Contrast this with medicine as practiced then in London and today in the United States, for example.  By any number of metrics, current biomedical science in “better” from a technical perspective.  We do know more.  But modern medicine is oversold and misused.  As specialization and compartmentalization have taken over biomedicine, it has become more scientistic than the scientific prevention of smallpox practiced by these men and women some 300 years ago.

And apparently variolation as a simple and effective form of inoculation against smallpox is much older in England (and the provinces of Scotland and Wales) than previously believed.  One nonagenarian in the early 18^th century told of his inoculation as a young boy, with his mother telling him of hers, meaning the practice may have extended back to the first Queen Elizabeth.  It is also apparently a biographical fiction that Edward Jenner used “milkmaids and cowpox” as the inspiration for his smallpox vaccination.  Read and learn [2].

 

Cholera was another great killer through the 19^th century, from East Asia to Western Europe.  But in this case, folk wisdom and practical reason in medicine were unhelpful.  The established medical profession denied that cholera outbreaks were due to an infectious agent.  They were viewed as discrete phenomena whose virulence was dependent on local conditions of the earth and the air that led to “miasma.”  This was common both before and after the germ theory of (infectious) disease was accepted.  But Adrien Proust (1834-1903; father of Marcel) noted that “germs” travel, and their migration is reflected by the presence and duration of cholera epidemics.  The senior Dr. Proust (Marcel’s younger brother Robert was a urologist) proposed a version of the World Health Organization to deal with pandemics.  And yes, a perpetual concern regarding cholera epidemics was the economy: Whatever is to be done, the Market must be disrupted not at all or at most as little as possible.  Some things never change.

The successful management of cholera extends far beyond Dr. John Snow’s removal of the handle of the Broad Street pump (pdf) during the London cholera epidemic of 1857.  And this brings us to Waldemar Haffkine (pdf; 1860-1930), who has not been forgotten but has not been remembered as he should have been.  Haffkine, the central figure in Foreign Bodies, was a Jew from Odessa,  And variously a freedom fighter who was injured defending Jewish families during a pogrom, subsequently a target of the imperial Russian state, then a pioneering protozoal microbiologist, scientist, and vaccinologist of the first rank.  At the end of his life, he was an advocate for and a defender of Orthodox Judaism who had little use for Reform Judaism, perhaps because of his dissident experiences as a young man in the Pale of Settlement (jpg).

Waldemar Haffkine had a scientific career that could only have begun in Europe during The Age of Empire.  His early mentor was the peripatetic Élie Metchnikoff, who discovered phagocytosis, which is one of the major branches of the immune response.  Metchnikoff also got Haffkine out of the hands of the Russian secret police in Odessa.  After receiving his ScD (equivalent of a PhD) in Odessa, Haffkine worked in the Pasteur Institute while the great man himself was still present.  He later crossed paths with Richard Ross, who was awarded the second Nobel Prize in Physiology or Medicine for his description of the relationship of the malaria parasite (Plasmodium sp.) with the mosquito.  Another who drops in and out of this story was Ernest Hankin, perhaps the first microbiologist to detect bacteriophages (bacterial viruses) that kill bacteria, including Vibrio cholerae (pdf), in the rivers of India.  Hankin was also author of The Mental Limitations of the Expert (1920), which is now on my reading list!

Waldemar Haffkine was the first scientist to develop vaccines against cholera and bubonic plague.  He took his cholera vaccine from the Pasteur Institute to India, where cholera was an intermittent menace throughout the country.  There he was probably the first scientist, in the 1890’s, to test the effectiveness of vaccines against a proper control group. He also tested the safety of his vaccines on himself before using them in the field, not unlike Barry Marshall who drank a culture of Helicobacter pylori to prove this bacterium causes stomach ulcers.  This enhanced his credibility among those in need of his preparations.  Affecting photographs throughout Foreign Bodies show Haffkine vaccinating Indians against cholera and plague; an iconic example is published here at higher resolution.

Haffkine’s trial data were compiled and recorded with great care throughout his work on cholera and plague.  For example, he showed in one study that out of 2,381 vaccinations, only four (0.17%) of the subjects died of cholera.  In a corresponding unvaccinated population, 61 of 2,976 died of cholera (2.1%).  Thus, the unvaccinated population had a 12-fold greater chance of dying than the vaccinated population.  In Assam in northeastern India, vaccination resulted in a 17-fold difference in outcomes.  Other places and other vaccination campaigns produced similar results.  The people of India reacted well to Haffkine’s vaccine.  As Lady Mary Wortley Montagu would have predicted more than 150 years earlier, the only real opposition to cholera vaccination came from the military and medical establishments of the Raj, primarily in the form of the Indian Medical Service (IMS).

Haffkine’s bubonic plague vaccine was similarly successful against a disease for which the conventional wisdom was not.  Although it was clear to a disinterested observer that plague is an infectious disease (e.g., both rich and poor were equally susceptible), “filth” was identified as both the agent and the cause [3] of bubonic plague.  This hygiene hypothesis led to the destruction of housing in affected neighborhoods; the separation of families, especially those of the poor; and a regime of lime washing and carbolic acid (a dilute aqueous solution of phenol) disinfection.  These approaches did not work and contributed to the social and religious outrage, including the coming together of Hindu and Muslim, that eventually helped destabilize the Raj.

The argument regarding plague was what measures worked best to combat epidemic that at times spilled over into pandemic.  This argument continues to this day with all epidemics.  And as today in the larger world, Haffkine’s freedom of scientific action was always contingent upon imperial politics in India.  But his persistence is a model for all biomedical scientists.  His steady work by the light of microbiology as he understood it, rather than what can be called the theology of hygiene, was successful.  Almost 3,000,000 doses of the “Haffkine Lymph” were shipped in 1902, prepared according to his instructions.

The Incubation Room at the Plague Research Laboratory is shown in the photograph from the endpapers of Foreign Bodies, showing hundreds of what look like 5-gallon glass carboys or similarly large bottles incubating bacteria for vaccine preparation.  The labor involved was extensive and required great care.

Even though Haffkine was made to feel the outsider by the IMS officers at the top of the hierarchy, Dr. Anton Chekov “wrote to his friend Aleksei Suvorin in August 1899 that ‘the plague is not so very terrible here.  We already have inoculations that have proved effective, and for which we are obliged, to a Russian, Dr Haffkine.  In Russia this is the most unfamous man but in England he is known as a great benefactor.”  But not for long.  Something happened.

On 30 October 1902 in Malkowal (also spelled Mulkowal) in the Punjab a series of inoculations began.  A week later a tetanus outbreak was reported.  Nineteen had died of tetanus by November 9, and all had been inoculated with vaccine from one bottle, 53N.  It was determined much later that a medical assistant had dropped into the dust the forceps used to manipulate the sterilized rubber stopper on 53N.  Instead of re-sterilizing the instrument in a flame (still the recommended practice today) as instructions required, he dipped it briefly into a solution of carbolic acid and proceeded with the series of inoculations from there.  This was the cause of the tetanus outbreak.  Sterilization by immersion in carbolic acid takes hours. The brief wash did not kill the Clostridium tetani spores.  Sterilization by flame is instantaneous.  Hygiene theatre favored by the establishment won, while those who got tetanus, those who would have been vaccinated later in the campaign but were not, and Haffkine lost.

Although the cause of this localized catastrophe [4] was eventually revealed and Haffkine’s reputation was repaired to the extent possible by Ronald Ross of malaria fame, primarily because “Ross had come to see in Haffkine a fellow fighter for the cause of science against what he would call ‘administrative barbarism.’  Theirs was a natural comradeship of outsiders, those whose work had been beset over and again, by the indifference, ignorance, ingratitude and downright hostility of the imperial establishment: a tyranny of nonentities (and) Governments (who) appoint them to their most important scientific posts and then look upon them as true prophets (who) do not possess the brains either to make sound discoveries themselves or even understand them when made by others.” (p. 340)  Ronald Ross was not a shrinking violet.  The plague vaccine was never patented, and thus Waldemar Haffkine was the model in the 1920’s for Banting and McLeod (insulin; while not forgetting the contributions of the essential assistant, who is always present, Charles Best) and the 1950’s for Jonas Salk (polio vaccine).  Nearly 2,000,000 doses of an oral cholera vaccine have been delivered recently to Haiti.

The scientific approaches to smallpox, cholera, and plague described in Foreign Bodies worked, despite obstacles thrown up by the medico-political establishments at seemingly every turn.  Smallpox could be defeated by variolation and has been eradicated with the help of a vaccine that left large scar on the upper arms of those of a certain age.  We know how to prevent cholera, but vaccines are available when necessary.  Plague can be treated with antibiotics.  What are the lessons, if any, for our current world?

When COVID-19 appeared nearly four years ago, it was natural to hope that complementary scientific approaches to this frightening and lethal disease would be successful.  After all, SARS-CoV-2 was quickly identified as the agent of COVID-19 and the world had recent experience with SARS and MERS, both caused by similar coronaviruses.  What actually happened?

• The nature of transmission of SARS-CoV-2 was not appreciated early in the pandemic (and is still ignored). Handwashing hygiene theatre was not effective.  Those fighting bubonic plague in 19^th-century Asia had an excuse; we did not.  But as it happened, the first version of the N95 mask was invented by a Chinese scientist in response to the Manchurian pneumonic (respiratory) plague caused by Yersinia pestis.
• The scientific establishment went all-in on vaccines – primarily mRNA vaccines – even though lasting immunity to coronaviruses in vertebrates is known to be elusive. The prospect of herd immunity was a nonstarter from the beginning, requiring much higher levels of infection than admitted, but it was promoted and sometimes this discussion recurs.
• The allure of mRNA vaccines was too much to resist despite their previous failure with Zika virus. Why?  Because we could do this.  The principle of mRNA vaccines has been obvious since Francis Crick proposed the Central Dogma of Molecular Biology in the late-1950’s: DNA makes RNA makes Protein, with emphasis on “mRNA makes protein.”  The scientistic imperative is “Can implies ought.”  Waldemar Haffkine injected his immunogenic preparation directly into his body.  He was a brave man, but he was not foolish.  The inocula he used were immunogenic but biologically inert.  The assumption with mRNA vaccines is that the proteins produced in our cells will also be biologically inert.  That is a big assumption and a discussion for another time.
• The other alluring characteristic of mRNA vaccines that they are “tunable,” almost in real time as new variants of SARS-CoV-2 evolve. True in the abstract, but as Lawrence Peter Berra – Number 8 in Yankee Pinstripes during the post-WWII glory years, probably did not say but is true, “In theory there is no difference between theory and practice.  In practice there is.”  Keeping up in the laboratory is one thing that molecular biologists do on a daily basis, with experimental models.  Keeping up with a rapidly evolving human pathogen is quite another.  Also, a measurable immune response in a mouse or a monkey does not a human vaccine make.  A vaccine must be effective and safe in humans.

COVID-19 is often said to be over, or at least waning.  But we are just beginning to understand long covid, and cases seem to be increasing.  COVID-19 patients who have been boosted 4-5-6 times are not uncommon, so it cannot be said that the COVID-19 vaccines work as people have come to expect of vaccines.  The vaccine produced by Haffkine reportedly prevented and reduced the severity of disease in those who got cholera.  But it is also true that the data in the long bureaucratic reports of 19^th-century cholera and plague epidemics show that Waldemar Haffkine’s vaccines worked, unambiguously.  It is not clear we are still collecting COVID-19 data that will be useful in answering current pressing questions that must be answered for a continuing scientific response to the pandemic.  Political and bureaucratic imperatives?

In my view, the conclusion of an unpublished review of mRNA vaccines I wrote in January 2021 still seems valid in late 2023:

While the science that has led to these mRNA vaccines is not experimental, the patent experimental nature of both SARS-CoV-2 mRNA vaccines has not been discussed, very much, in public.  If either mRNA vaccine (Moderna and Pfizer/BioNTech) turns out to be ineffective or worse, harmful, the backlash will be severe…During the current pandemic, citizens of the world have been asked repeatedly to “trust the science.” Yes.  But trustees of science, including politicians, practicing scientists and physicians, and scientist-administrators at NIH/FDA/CDC and their counterparts in other nations, must at all times be careful, especially when working rapidly and under great pressure, to not oversell what can be done as what must be done.  These mRNA vaccines are also commercial products projected to return tens of billions of dollars to their manufacturers in the near term (which they did).  Eli Lilly received about $320 million, adjusted for inflation, in the first year of the Salk vaccine.

Other imperatives have indeed been at work during COVID-19.  They are not different in principle from those that affected the research and development of vaccines by Waldemar Haffkine 130 years ago in India.

Simon Schama closes with a gloss on political responses to COVID-19.  His list of miscreants is predictable in their antipathy to Anthony Fauci, who recently retired after nearly 40 years as Director of the National Institute of Allergy and Infectious Diseases (NIAID).  Much of this criticism in unhinged.  But it is also clear there is much background noise, including this backstory, even if this is difficult to parse while being ignored in the legacy media, to the early, highly publicized letter (accessed 5.88 million times, cited by 2,891) that basically denied SARS-CoV-2 could have been produced in the lab [5].

Fauci’s critics “have also challenged his claim to personify the authority of science, claiming (without the credentials to do so) that he is himself guilty of playing fast and loose with the integrity of research.”  Foreign Bodies is an outstanding book that tells a series of astonishing stories that resonate today.  It is definitely on my re-read list because I am sure I missed some very important points.  I cannot recommend it more highly.  But here is where I respectfully diverge with Professor Schama.  No one needs “credentials” to challenge any scientist who claims to “personify the authority of science.”  I have been doing basic biomedical science, albeit with a change of focus during recent years, for my entire professional working life.  I am an “n = 1” but have never met a serious scientist who would claim such a thing.  This is what Anthony Fauci has done.  Why?  I do not know.  But it is also clear to me that Waldemar Haffkine, Élie Metchnikoff, Ronald Ross, Ernest Harkin, and probably even Louis Pasteur and Robert Koch, would not make claim to personify science during a raging pandemic.  They were, each of them, too much the scientist for that.  The defense of Anthony Fauci sounds more like the scientistic nonsense the panjandrums of the Indian Medical Service of the Raj would say, similar to their dithering upon learning that the Malkowal tetanus outbreak had absolutely nothing to do with the Haffkine plague vaccine.  Arguments from authority have no place in science.  Period.  Which is not to say that individual scientists and their work cannot be authoritative.  The two uses of the word are very different.

This could be one of the problems with our collective response(s) to COVID-19.  And we can do better.  After four years, one can reasonably predict that antiviral drugs (including some repurposed against COVID-19, as thalidomide has been against lymphoma), and engineering/physical strategies will be the effective solution to COVID-19.  We might also stop interacting with likely zoonotic vectors for SARS-CoV-2.  After 40 years the vaccine to HIV is still on the way, as far as I know, but antiviral compounds, pre-exposure prophylaxis, and behavioral and engineering solutions prevent transmission of HIV and AIDS or make AIDS a manageable chronic condition for the most of those with HIV.  That is, among populations with “access” to these interventions, which is always the case in modern healthcare.

Let the discussion begin!

Notes

[1] Nettleton’s trials 300 years ago were better, with transparent data and unambiguous outcomes, than much of what passes for clinical trials today.  This, long before the development of the modern frequentist statistics of Galton, Pearson, and Fisher (p-values, correlation coefficients).

[2] Block quote from the second link:  History texts and children’s stories all focus on the supposed role of milkmaids in guiding Jenner to cowpox. Even the most recent histories of smallpox eradication say that he learned of cowpox’s benefits from a milkmaid. In many cases, the milkmaid is beautiful because she cannot catch smallpox. In some versions of this story, the fabled beauty of the unscarred milkmaids is widely known and gives Jenner his first clue. Occasionally, other names pop up but are quickly dispatched as not really significant and home in on Jenner as the man who realized why the milkmaids were so beautiful (a parallel of Lady Mary Wortley Montagu’s observation regarding the women in the Ottoman Empire?)…Sadly the milkmaid story is a lie invented by John Baron, Jenner’s friend and first biographer. Jenner himself never claimed to have discovered the value of cowpox, nor did he ever say, despite a huge volume of correspondence, how he first came across the idea. The myths of the milkmaids are just that, myths. To modern eyes, Jenner is revered for eradicating smallpox by using cowpox; in his lifetime, however, Edward Jenner faced severe criticism from jealous competitors and from many ordinary doctors who did not trust his method because, unlike inoculation, it did not give permanent immunity to smallpox. John Baron invented the milkmaid story to counteract these criticisms.

[3] Agent versus cause has been considered by many, prominently by the late evolutionary biologist, Richard Lewontin: “The tubercle bacillus became the cause of tuberculosis, as opposed to, say, unregulated industrial capitalism, because the bacillus was made the point of medical attack on the disease. The alternative would be not a ‘medical’ but a ‘political’ approach to tuberculosis and so not the business of medicine in an alienated social structure. Having identified the bacillus as the cause, a chemotherapy had to be developed to treat it, rather than, say, a social revolution.”  The agent of TB is the bacillus but that is not the cause.  Also here, from a complementary source: “There were certain social conditions that were intimately associated with the disease, linked to the industrial revolution at the time – poverty, malnutrition, and overcrowding.  Conditions for the working classes were extremely poor.  In 1838 and 1839 in England between a quarter and a third of tradesmen and labourers died from tuberculosis compared to a sixth of ‘gentlemen.’”  The agent of COVID-19 is SARS-CoV-2.  The cause(s) are still up in the air, but crowding and poor ventilation are amenable to physical, engineering methods that prevent spread of the virus.  Masks work, too.  All we lack is the political, practical, and scientific will to use them.

[4] This is not unlike the Cutter Laboratories failure with an early batch of the Salk polio vaccine.  The Salk vaccine was based on killed virus, but because of a shortcut some live virus remained in the preparation.  A local outbreak of polio was the result.  The difference between the earlier failure with the plague vaccine is the cause was identified swiftly and transparently and vaccination continued after a short delay.  From the link: “While acknowledging Salk’s mean-spiritedness towards colleagues, Offit believes that in denying him a Nobel prize, history has dealt harshly with a man who was `the first to do many things’ that have contributed to the virtual eradication of polio in the USA.  The Cutter incident led to the replacement of Salk’s formaldehyde-treated vaccine with Sabin’s attenuated strain.  Though Sabin’s vaccine had the advantages of being administered orally and of fostering wider ‘contact immunity’, it could also be re-activated by passage through the gut, resulting in occasional cases of polio (still causing paralysis in six to eight children every year in the 1980s and 1990s, when a modified Salk vaccine was re-introduced).  As Offit observes, ‘ironically, the Cutter incident — by creating the perception among scientists and the public that Salk’s vaccine was dangerous — led in part to the development of a polio vaccine that was more dangerous.’”  One of those “six to eight” children is a former student and friend.

[5] A lab leak seems perfectly logical to anyone who has ever worked in a molecular biology laboratory that uses live virus cultured in mammalian cells, as I have, albeit with viruses that were unable reproduce outside of the cell culture dish.  This does not mean that the leaked pathogen was engineered in the laboratory, perhaps in gain-of-function research.  But it is also true that such work on SARS-CoV-2 should be performed under BSL-4 conditions (BioSafety Level-4, for pathogens such as Ebola and Marburg viruses).  The advisability and utility of gain-of-function research on human pathogens may be something to (re-)consider, perhaps as recombinant DNA was the subject of deep concern in the 1970s when several scientists planned to express oncogenes in a human gut bacterium?  If it has been, I missed it.