Here’s an example of some of the fascinating research being done today at the interface of mathematics and biology. The two fields have become ever more intertwined as our knowledge of genetics has deepened. The subtle and not so subtle interactions between microbes and their host, the multitudes of genes that give rise to behavior, the modeling of metabolic pathways, large-scale sequencing projects—all are stubbornly complex to puzzle out, and all bend more easily with the aid of innovative statistical techniques and advances in computing power.

Among the more pressing topics in medicine today concerns whether antibiotics have outlived their usefulness or whether we simply need to rethink how we use them. When German pathologist Gerhard Domagk discovered the antimicrobial effects of Prontosil in the 1930s, it was heralded as one of the greatest therapeutic advances in medical history. Yet even then, scientists were wary of the long-term drawbacks of their overuse. Almroth Wright predicted that bacteria would evolve resistance to these agents before we observed the phenomenon directly, while Nobel laureate Alexander Fleming (of penicillin fame) cautioned that they should be administered only in specific circumstances and in the proper dosage so as to minimize the risk of resistant pathogens.

While these words of warning have proved especially prescient in the wake of our current crisis, we are not entirely to blame. Bacteria, fungi and algae have been locked in a campaign of chemical warfare for more than a billion years. Like Darwinian selection itself, antibiotics and resistant genes long predate humanity; we merely gave them names. Microbes, moreover, outnumber us billions to one, with much greater genetic diversity and shorter reproductive cycles. This allows mutations to spread through populations quickly and gain the upper hand before new pharmaceutical trials can even get off the ground. Lastly, bacteria also are fond of passing helpful genes around to their neighbors through a process called horizontal gene transfer, and the immense diversity of the microbial jungle means there will always be resistant DNA close at hand.

As Martin Blaser writes in his latest book, Missing Microbes:
 

“Another implication of the nature of resistance is that there will be no easy solution to the problem. We will never make resistance go away, because Darwin was correct in his theories. There always will be strong selection for resistance when populations encounter stress, in this case, microbes under antibiotic pressure. A corollary is that we will never invent a superantibiotic that cures everything. Microbes are too diverse, and Nature will always come up with new ammunition.” (pp. 80-81)

 
Given the natural processes which govern life on earth, the crossroads at which we now find ourselves was perhaps a biological inevitability. Evolution is an arms race fought with genetics across time. Rewrites that give contestants a replicative edge reconfigure the battle lines; old strategies wane in strength. While most bacteria are beneficial, some, like Streptococcus and Salmonella, are pathogenic, interacting with host physiology in harmful ways. To counter them, we have antibiotics, which work well enough for wiping out particularly devastating ills but effectively wage genocide on our microbiome, killing off both good and bad residents and upsetting gut ecology. Not only can these collateral damage “grenades” lead to unintended complications down the road, evolution does not sit still. Any mutations that limit antibacterial efficacy quickly outcompete those that don’t, in the process generating more resilient microbes for us to outwit.

The doctor-patient relationship, along with common agricultural practices, have certainly not helped matters, however. For decades we have over-prescribed these broad-spectrum solutions for misdiagnosed and nonbacterial infections, relied on them as “just in case” remedies when less invasive ones would do, and pumped them into the animals we farm and the food we consume. This escalating confluence of dependence on antimicrobials and our commitment to an antiseptic lifestyle has served to fast-track evolution in the form of resistance.

Many immunologists have suggested we are moving into the “post-antibiotic” era, but what if we could predict the evolutionary trajectory of certain bacteria when subjected to antibiotics? Might we be able to substitute new drugs before resistance emerges and spreads? That’s the idea behind new research pioneered by Miriam Barlow from University of California and published in PLoS ONE this month. Together with mathematicians from American University in Washington, D.C., they were able to apply a probability analysis to bacterial evolution.

Rewinding the Genetic Clock

The researchers exposed E. coli to 15 different antibiotics, taking note of the differences to TEM-1, a protein involved in 90% of penicillin-derived drugs. A wild type TEM-1—which can be conceptualized as the “standard” form of the protein, or one unexposed to antibiotics—confers resistance to penicillin only, while its variants (other genotypes) tend to expand resistance to other classes of antibiotics such as cephalosporins.

The team’s goal was to see how consistently they could revert a population of TEM-1 genotypes to wild type status, thereby narrowing the range of resistance. Since nearly all known TEM-1 variants differ by no more than four mutations, the team used a four-digit model to map out the changes in amino acids. For example, the wild type TEM-1 was assigned a label of “0000”, and each mutation was represented by a “1” in the location where the substitution occurred.
 

A mutation network for the antibiotic cefpodoxime (Figure 13)

Though these results are encouraging, it is not clear how clinically relevant they are. A lab setting in which tight constraints are maintained throughout is one thing; a crowded hospital overflowing with bacterial and antibacterial diversity is another. Microbes living in communion with other microbes tend to share genetic defenses, a feature not available to those grown in isolation. Moreover, different host environments supply a wider playspace for natural selection to act, possibly serving up a greater variety of genotypes than those captured by the study. And while such algorithmic exploitation could theoretically aid us in our fight against resistance, we would still need a better idea of how long each drug should be in rotation and the recommended dosages necessary to complete the wild type selection process.

That under certain conditions bacteria nestle along statistically predictable alleyways is an interesting result in and of itself, but more research in the form of field tests and clinical trials will be required to comment on its real-world validity.
 

“At the heart of what everybody wants to know is how predictable is evolution—and if it’s predictable, can we reverse it?” he says. “It’s really hard, but you’ve got to try something.”

Further reading:

• New Mathematics Could Neutralize Pathogens That Resist Antibiotics (Scientific American)
• Rational Design of Antibiotic Treatment Plans: A Treatment Strategy for Managing Evolution and Reversing Resistance (PLoS ONE study)

 
 
Blink once or twice and you might mistake Whiteout‘s opening act for that other ode to mysophobia, The Hot Zone. Coming a full ten years after Richard Preston’s fan favorite, Follett administers a quick shot of déjà vu, retreading familiar themes early on before cracking the lid on a dizzyingly diverse cast and a bioterrorist plot filched straight from a Hollywood screenplay. Whereas The Hot Zone is an uneasy mix of nonfiction gussied up in sensationalist garb, Whiteout is pure novel — and quite the kind for which Follett’s reputation precedes him. While the former fixes its attention almost solely on the pathogen, even idolizing it at times, the latter sculpts its drama around the many characters tangled up in the threatening peril of a diffuse outbreak.

Renowned Scottish pharmaceutical Oxenford Medical specializes in lab-based research on some of nature’s deadliest viruses. The scourge du jour here is the fictitious “Madoba-2,” the deadliest of them all. No one has survived its acquaintance; it is the perfect pathogen. When a narrowly tested vaccine for Madoba-2 goes missing from the Kremlin lab, along with an unwell rabbit reserved for in vivo trials, the company finds itself at the center of a media firestorm. It is the arch responsibility of ex-cop turned Chief of Oxenford Security Toni Gallo to track down the culprit and contain the leak.

With public confidence at an all-time low, the gears of a far more sinister plot are about to be set in motion. Opposite Toni Gallo is the chairman Stanley Oxenford, whose own son is embroiled in a devilish agenda of malfeasance in order to settle his escalating gambling debts. A highly trained unit of heist artists taps Kit Oxenford, a computer wiz who designed the Kremlin’s security system before being fired for lifting funds from the firm’s bottom line, to break in and theft hazardous materials. Desperate to pay off his creditors, and with his life hanging in the balance, Kit finds himself throwing in with a roguish crew whose intentions are unclear. As the holidays descend upon snow-covered Scotland, the Oxenfords gather at Steepfall, the family estate, only to find themselves key players in thwarting an international crisis.

The number of characters introduced as the plot takes shape can feel like a flood, but Follett has the knack for bringing the reader up to speed with well-placed summaries of how each character factors into the immediate scene and reminders of earlier details. While some of the Oxenford clan are standard-issue, many characters turn in quite memorable performances, chief among them Toni Gallo. True to form, Follett invariably reserves the most candescent performances for his strong female leads. While not quite attaining the level of depth and sophistication of Aliena in Pillars of the Earth, Flick in Jackdaws, or Lucy in Eye of the Needle, Toni stands head and shoulders above the rest with her steely resolve and poised demeanor. Her detective training allows her to stay one step ahead of the local constabulary and outsmart the assailants who hauled off with the precious cargo.

The book is not without its faults. An early scene at the family estate borders on soap opera melodramatics and seems out of place in a Follett novel. That the security system wasn’t changed — right down to the thumbprint software on the BSL-4 chamber and the passcodes on the virus lockers — following Kit’s departure from the company reeks of dubious plausibility. A few of the twists and turns feel forced and wrap up a bit too neatly, leaving one to wonder how a more organic progression might have played out. And, though many may neither care nor notice, some of the finer points on the science side of things skew toward the problematic.

The Science of Whiteout

As part of his research, we’re told in the addendum, Follett visited biosafety facilities in Manitoba and London and corresponded with a few biosecurity professionals. Had he consulted virologists as well, he might have brought greater accuracy to the details surrounding Madoba-2 and its supposed cousin. The science in Whiteout, what little of it there is, for the most part is not bad, but, like Richard Preston before him, gives a misleading picture of Ebola.

Madoba-2 is frequently compared to the Ebola strain and even referred to as a “variant” of Ebola on one occasion. But the descriptions of Madoba-2 are at odds with what we know about the biology of Ebola and how it has adapted to circulate among human populations. Madoba-2 is airborne, so much so that the terrorists choose a perfume bottle as the delivery mechanism.

Ebola, meanwhile, is a close-contact germ; its proteins prefer to hole up in fluids like blood, saliva, feces and urine rather than in its host’s respiratory pathways. To speak of a virus that wafts on clouds of aerosol droplets emitted by a cough or a sneeze — à la influenza — is to speak of a fundamentally different virus from the strain that’s been ravaging West Africa since December 2013. Suffice to say that if Ebola were even a little like Madoba-2, the current epidemic would be global, not confined to regions with poor medical infrastructure.

Lastly, Madoba-2’s level of efficiency is unexampled in nature. With a human mortality rate of 100%, Madoba-2 is clearly not of this world. A non-free-living organism that killed too efficiently would jeopardize its ability to spread to new hosts. Dead hosts are like wet gunpowder, an evolutionary endgame. With every pathogen we’ve encountered, some portion of the susceptible population is resistant and passes on its immunity to successive generations. That is, until the virus adapts to the new regime and the cycle repeats. Even Ebola, among the deadliest viruses known, has topped out at 90% mortality in some populations. All considered, Madoba-2 sounds more like something engineered by man than something that would arise naturally.

Closing Thoughts

You’re always in good hands with Follett. The brigadier general of historical fiction delivers another suspenseful tale worthy of the big screen, this time cutting his teeth on the killer virus motif in modern-day Scotland. While this may stray outside Follett’s typical genre, all of the key elements are ported over intact. Thanks to its intriguing characters, smooth pacing and a Costco’s worth of page-turning tension without an excess of sex or violence, Whiteout joins a rich legacy of polished narrative that leaps off the page with ease. Settle in for a night of frosty weather, dueling ambition, budding romance, and a high-strung thriller just compelling enough to dispel disbelief. A fine choice for your next weekend away.

Note: This review is mirrored over at Goodreads and at Amazon.

 
 
NPR has a great piece this month commemorating the 60th anniversary of the Salk vaccine for polio. Few episodes are as deeply encoded in our national memory as the polio outbreak of the 1950s. Those old enough to remember the debilitating disease recall the widespread fear it wrought and its devitalizing effect on the postwar American psyche.

My parents have told of going to school in central Virginia and seeing classmates navigating the halls on crutches and wheelchairs, of unperturbed swimming pools and deserted theaters, of rubber-limbed paralytics vegetating away in iron lungs. For them, these images are indelible, but they also recall how this story ended — with a pair of vaccines that brought a grim-faced generation back from the brink.

While polio is an ancient disease, it didn’t ignite European and American fears until the turn of the twentieth century, when scattered epidemics began surfacing in urban centers and schools. By the early 1950s, polio had become the worst outbreak in America’s history. Children under the age of five were most susceptible to the virus, and one in two hundred infected would progress to paralytic polio. Five to ten percent of these would succumb to the illness within a year.

Salk and colleagues began their in vitro testing using HeLa cells in 1952. Similar to the seasonal flu vaccine developed by the CDC, Salk employed a “trivalent” approach using inactivated DNA from three different virus strains. Such an approach offers cross-protection from sister strains, even if the vaccine isn’t a perfect match for an individual strain. (There are a number of ways to make an antibody to a particular antigen.) In three years’ time, Salk’s remedy was licensed for use and exported to medical facilities around the world.

Prestige and history books tend to favor first to market producers, but Salk’s race to eradicate polio was far from a solo venture. Other major players included Hilary Koprowski, Herald Cox and Albert Sabin. The latter trio represented the dominant view of virology at the time. Hearkening back to the principles laid down by Edward Jenner and Louis Pasteur, they contended that all vaccination efforts should be predicated on attenuated (weakened) versions of the pathogen. Dead versions injected into the bloodstream, à la Salk, would not produce a strong enough immune protection for long-lasting prevention, they argued. Bitter rivalries broke out among all parties.

While the Salkian view was decidedly in the minority, his research was progressing much more quickly than the competition and, perhaps just as importantly, he had the support of his mentor, Dr. Thomas Francis, Jr. at the University of Michigan, one of the most renowned virologists in the field. Francis oversaw the national field trial, and when he announced the results on April 12th of 1955, the next-morning’s headlines captured the spirit of the era. “Salk Polio Vaccine Proves Success – Millions Will Be Immunized Soon,” hailed The New York Times.

Salk’s IPV (inactivated poliovirus vaccine) may have been a resounding and immediate success, but all work on polio prevention did not halt when his product went out the door. Koprowski, Cox, and Sabin trotted the globe conducting field trials and jockeying for licensure of their preferred remedy. In his book, Polio: An American Story, David Oshinsky recounts the major hurdles before them. The efficacy of the Salk booster having already been demonstrated, many people wondered why another vaccine was needed. There were also lingering fears that active forms of the virus could trigger the very disease vaccination was meant to prevent.

The latter concern was not unfounded. Just four weeks after the Salk IPV received the green light, the Surgeon General placed a nationwide ban on polio vaccine manufacturing and an embargo on exports after new cases appeared in children given the vaccines. IPVs originating from a single facility in Berkeley were found to contain live virus material; the inactivation process had failed, and lab protocols hadn’t caught it. The oversight resulted in some 200 new cases of polio, including 11 deaths. The consensus of virologists converged on a different, less virulent strain for one of the three used in the IPV, and since the incident in 1955 no vaccine-associated cases have been recorded by the CDC.

Research on alternative techniques surged ahead, including Albert Sabin’s oral vaccine, prompting the National Institutes of Health to set up a special committee in 1958 to assess the relative merits of inactivated versus attenuated immunization and oral versus intravenous transmission. Sabin had procured two strains: one based on a single viral type and another based on a mixture of all three. Over the next three years, his prototypes were used to vaccinate more than 115 million children throughout the Soviet Union, Eastern Europe and Singapore.

Due to its superior success abroad, Sabin’s trivalent vaccine won out and quickly became integral to global eradication efforts. Today, most countries use Sabin’s OPV (oral poliovirus vaccine) for reasons relating to cost, ease of use, and longer-lasting protection.

Plagues like polio have brought civilizations to their knees throughout recorded history. But thanks to the work of enterprising scientists like Salk and Sabin, and organizations like the Global Polio Eradication Initiative and its partners, we are fighting back. Today polio is near to following in the footsteps of smallpox. The virus has all but vanished save for three countries — Nigeria, Pakistan and Afghanistan — compared with 125 countries in 1988 when GPEI began. NPR speaks to the impact Salk’s original vaccine had on the American mood in the spring of 1955:
 

And yet even now, there are parents as informed about science as fish are of land refusing their kids the benefits of vaccination and their local communities the herd immunity it confers. All because of spurious claims by plastic media pundits and that thing that was said by Neighbor Joe that one time at a bbq last fall. Shame on Neighbor Joe for his uninformed banter, and shame on parents for taking Neighbor Joe even semi-seriously. Many baby boomers are alive today because they didn’t die from polio. We all would like our children to say the same about equally pernicious, equally preventable diseases in a generation. Stand up for established science and against illiterate, stark-gibbering mad dogmatism — for there’s a lot of both.

External Link: Defeating Polio, The Disease That Paralyzed America

Further reading:
— Polio: An American Story by David Oshinsky
— Splendid Solution: Jonas Salk and the Conquest of Polio by Jeffrey Kluger

 
 
The subtitle for Richard Preston’s 1994 bestseller reads: “The Terrifying True Story of the Origins of the Ebola Virus.” How much you enjoy The Hot Zone might just hinge on what you know about Ebola going in and, by extension, how seriously you take that subtitle. To say that Preston took artistic liberties is akin to saying Ayn Rand held only a little contempt for Marxism or that Christopher Nolan’s Memento had a tendency to confuse its viewers. There can be no doubt that Preston delivered a vivid and hair-raising thrill ride, a marvelously written if unevenly paced house of horrors, but on balance his book is about as accurate as a Stone age slide rule.

It might have passed for harmless over-sensationalizing, except with the Ebola epidemic in-progress and tensions wound tighter than ever, the book has become the bane of disease experts and science communicators working to tamp down the mass hysteria. In this case, thankfully, the truth isn’t scarier than fiction.

The book is structured around four events: our first contact in the 1960s with Marburg virus (MARV) — a close cousin to Ebola — named for the German city in which it was discovered; the earliest recorded outbreak of Ebola Zaire (EBOZ) in Sudan and DRC (formerly Zaire) in 1976; the 1989 outbreak of Reston virus (RESTV) in Northern Virginia; and the final act sees Preston donning a biocontainment suit for a solo jaunt in a sub-Saharan cave in search of the cagey killer.

Preston needs only the space of a few pages to subdue the reader into a state of trepidation. I was spooked almost immediately, even knowing it was all a bit light on fact. The characters, many of whom are given fictitious names, have blood spurting from every orifice, their insides “liquefying,” and at one point we read of a nurse “weeping tears of blood.” Such descriptions seem to have more in common with the active imagination that goes hand in hand with storytelling than with any viral agent identified to date. Preston himself concedes as much in a New York Times interview last month: “That almost certainly didn’t happen.”

OK. So there’s some exaggeration here and some embellishment there and the 3.5 million copies sold is probably responsible for some of the stateside hysteria. But let’s not point too much of the blame in one direction. An invisible pest that moves from person to person and leaves a high mortality rate in its wake is bound to generate a level of fear, with or without The Hot Zone. And when you combine the low science literacy rates in America with its media’s penchant for doom-mongering and narcissistic over-commentary, some version of collective psychosis is all but inevitable. Then again, the recent outbreak has sparked renewed interest in the book, and its infidelity to fact doesn’t help the situation.

In an effort to defuse some of this noise, let’s get to know the real Ebola virus, at least what we’ve gleaned so far. First, some perspective. Yes, Ebola is deadly, and international aid groups should be throwing everything they’ve got at curbing this latest and greatest outbreak. As of 14 November 2014, there have been more than 14,000 reported cases and over 5,000 confirmed deaths (WHO updates this page weekly) since it emerged in Guinea one year ago. But as a matter of pure numbers, Ebola is a minor player on the pathogen roster.

Compare those figures with seasonal flu — the reason many of your coworkers have been calling in sick recently — which infects hundreds of millions and causes 250-500,000 deaths every year (including 20,000 in the U.S. alone). Or norovirus, which infects 267 million people and kills 200,000 annually. Hepatitis C is a virus that currently infects 150 million people worldwide, while malaria kills more than 600,000 a year, or about 68 people per hour. Even rabies accounts for a steady 69,000 deaths per year. Any fear you might have of Ebola should be calibrated against the numbers, which tell us that we’re far more likely to die from lightning, a car accident or a plane crash than we are from Ebola.

Much of that has to do with Ebola’s method of transmission. Contrary to what Preston repeatedly suggests in The Hot Zone, Ebola is not transmitted through the air or by respiratory secretions (i.e., coughing or sneezing), unlike influenza or SARS. Ebola can only be transmitted by direct physical contact with the blood, vomit or feces of an infected person. A cough or a sneeze from an Ebola host doesn’t contain high enough concentrations of the virus to infect someone nearby because Ebola doesn’t aerosolize in the way its airborne counterparts do. This explains why the reports keep flowing in of infected healthcare workers; they are at the highest risk of infection because they’re the ones working with the patients after the incubation period is over and symptoms have surfaced. So unless you find yourself in contact with any of these three fluids of an Ebola victim, you have little to worry about.

Many have frowned on science for not having a vaccine ready by the truckloads. This may sound brusque, but given the differential threat of the other viruses mentioned above, Ebola isn’t a top priority. We’ve seen a total of 32 outbreaks over the last 40 years, and yet none have secured a lasting foothold in humans. In contrast, flu and malaria are perennial killers of titanic proportions. Moreover, vaccines and antivirals (like the experimental ZMapp, which co-opts tobacco plants to clone antibodies derived from mice) are painstakingly difficult and costly to produce and must be adapted to the rapid pace of evolution. In the triage of epidemiological exigency, Ebola’s sporadic presence and short-fused temperament simply rank lower next to many other human scourges.

Its tendency to play hopscotch with the human race is also why there is much we still don’t know about Ebola. As Level 4 contagions go, it is deceptively simple. Were you to ogle it under a microscope, you’d see a single strand of RNA that codes for a mere seven proteins, one of which — VP24 — has been identified as the key facilitator for disrupting the cell signaling processes involved in immune response. With the key communication lines cut, Ebola is allowed free rein and overwhelms the host system before antiviral reinforcements have time to interfere.

The biochemistry is less opaque than Ebola’s origins, however. One of the finer points we’ve yet to work out is zoonotic provenance: in which species did Ebola first arise, and from which host population did it make the jump to us? Was it in the direction of apes-to-humans like HIV, or did it spill over from some other creature whose environment overlaps with ours? The favored culprit is Egyptian fruit bats, which are known to carry not only the sister virus Marburg but antibodies to Ebola. Even so, it could lurk elsewhere in the wild, biding its time until local conditions pave the way for its reemergence. Learning how pathogens jump from one species to another is vitally important to preventing future outbreaks and is a hot topic among research communities today.

Closing Thoughts

Much like this review, the central character of Preston’s fan favorite is the omnipresent virus. The human characters in the book are poorly developed and ultimately forgettable backdrops which fade in and out as Preston heightens the drama around his lurid replicator — that “nonhuman other” for which he prowls in Kitum Cave. You’ll get a few interesting bits about life inside a biosafety facility, but for the most part any factual profile on Ebola is swallowed whole by the embroidery and myriad grotesqueries sprinkled in at the expense of navigating a more careful line between fiction and reality. Take The Hot Zone for what it is: a high-speed medical-mystery thriller meant to make you tremble at the raw power of nature.
 

In a sense, the earth is mounting an immune response against the human species. It is beginning to react to the human parasite, the flooding infection of people, the dead spots of concrete all over the planet, the cancerous rot-outs in Europe, Japan, and the United States, thick with replicating primates, the colonies enlarging and spreading and threatening to shock the biosphere with mass extinctions. Perhaps the biosphere does not “like” the idea of five billion humans. Or it could also be said that the extreme amplification of the human race…has suddenly produced a very large quantity of meat, which is sitting everywhere in the biosphere and may not be able to defend itself against a life form that might want to consume it. Nature has interesting ways of balancing itself.” (pp. 310-311)

 
For an accessible take on the real “true story” of Ebola virus, you’ll want to check out David Quammen’s Ebola: The Natural and Human History of a Deadly Virus, which is an expanded extract from his larger book Spillover: Animal Infections and the Next Human Pandemic. It’s top-notch. If you prefer an even snappier overview you can load up during your morning commute, Quammen also appeared in a recently updated Radiolab podcast to discuss the current outbreak.

Note: This review is mirrored over at Goodreads and at Amazon.

UPDATE 4.5.2015: Since my review last November, the number of deaths from Ebola have more than doubled, and the case count has increased by 75%. (Situation reports published weekly.) Liberia has been inching toward disease-free status with new cases slowing to a trickle, but two new cases on 25 March have delayed that declaration for now. Meanwhile, a half dozen vaccine candidates are in development, a few of which have progressed to Phase I clinical trials. The longer this epidemic is allowed to proceed, the more familiar the pathogen will become with our biology, and the easier it will be to make the jump to our species in the future.

 
 
On The Loom, Carl Zimmer discusses some fascinating new research into norovirus. As the most common cause of infectious diarrhea in humans, norovirus infects 267 million people and kills 200,000 annually. For such a high-profile killer, far too little is known about it.

This is mostly because we haven’t figured out how to rear human norovirus cells in culture. Instead, we’re stuck with using the cells of other animal hosts that can, like mice. Mice and other rodents are often good proxies for human trials, but there is no guarantee that rodent biology follows the same antigenic protocols as that of humans, and in many cases it doesn’t.

Indeed, it was in vitro tinkering with HeLa (human cells infected with a cancerous virus) that helped researchers develop a vaccine for polio and effective drug treatments for other scourges like HPV, herpes, leukemia, influenza, hemophilia and Parkinson’s disease. Absent test tube studies with human DNA, our success in producing a norovirus vaccine or antiviral has been tepid at best.

Another reason for the lack of progress is our poor understanding of its basic virology. Until now we weren’t even sure which cells it targets (there are over 200 types of cells in the human body). It made sense that this pathogen attacked the epithelial tissue lining the intestines, which caused inflammation, hence the awful vomiting and diarrhea of its infected hosts.

But thanks to a new study by a team of scientists at the University of Florida, we’ve now learned that in fact it targets B cells—the white blood cells in charge of producing antibodies. They discovered this by using mice which lacked the ability to make B cells. As counterintuitive as it sounds, without B cells the virus was benign; the mice were almost completely resistant to norovirus. When they combined mouse cells infected with norovirus with mouse B cells, the virus resumed its invasion and began replicating as predicted.

They then reproduced this result in humans with a stool sample from an infected patient. Once again, the virus immediately latched onto human B cells, but was powerless without B cells present. Of course, we need our antibodies, so removing them from humans is out of the question.

The team did encounter one puzzling twist, however. Recall Asimov’s famous line: “The most exciting brand of discovery is not when a scientist exclaims ‘Eureka!’ but rather ‘Huh, that’s odd’.” When they used a thin filter to separate out bacteria, the virus-infected cells were no longer able to infect the B cells. The conclusion was near at hand: bacteria were assisting the norovirus in its assault.

Finding the culprit or culprits would have been a herculean task were it not for the ever-growing databases that catalog the bacteria we’ve found in our gut. It turns out that one of the more common strains—Enterobacter cloacae—has already been implicated in virus behavior. And norovirus can bind to it.

To complete the chain of reasoning and test their hypothesis, the team added just this one bacterium back into the stool sample. As expected, norovirus was able to infect the human B cells once again. The virus has an ally, and it turns out they’re an incredibly successful pair. It’s not clear how Enterobacter cloacae aids the virus in this way, but this will surely be the focus of future research.

If only we could look past the norovirus and knock out its accomplice. One surefire method is of course antibiotics. When the team pumped some into the mice, their sterilized guts were no longer able to usher the virus into the B cells. This is a poor option for any immune system, however. Low-res remedies like antibiotics are akin to grenades, killing off both good and bad bacteria, which can rupture an immune system and lead to much worse problems down the road. (Antibiotics also have a null effect on viruses and should be reserved for especially harmful bacterial infections, something scientists have been advising for decades.) We need bacteria, and they need us.

Unfortunately, the state of medicine and knowledge of the microbiome haven’t reached the point where we can produce a drug custom-tailored to wipe out specific bacterial species while leaving the neighbors intact. Inside of us is a delicate ecosystem we are just beginning to flesh out. And research like this helps light the way.

External Link: Norovirus: The Perfect Pathogen Emerges From the Shadows

Source study: Enteric bacteria promote human and mouse norovirus infection of B cells

 
 
Faced with questions of personhood and human identity, there is perhaps nothing more unequivocal you could point to than your genome — your personal genetic signature. But what if there isn’t just one genetic signature to which you play host? And what if one or more of those signatures is from another person entirely?

A series of recent studies promises to pile additional layers of complexity onto the already heavily ramified field of genomics. In the NY Times, Carl Zimmer introduces us to evidence that will change how we think about the human genome.

We often think of our cells as specialized entities serving different functions but all housing the same genetic information. It may come as a surprise, then, to know that a cell swabbed from our cheek can have an entirely different genetic code from that of a plucked hair, for example, or from a neuron in the brain. In fact, if you were to sequence a random sample of cells from the same host, you might find a potpourri of genomes, with some even belonging to another person.

The pair of phenomena associated with these intra-organism variations are formally known as mosaicism and chimerism. We’ve known about the former since the 1930s when American geneticist Curt Stern demonstrated the occurrence through mitosis, a natural cell process utilized by every eukaryotic organism.

© Garland Science

When a female egg is fertilized, a single genome — a marital blend of the two parent genomes — emerges. At this stage, there is just one cell with one genome, called a zygote. That cell then divides to form an embryo, but mitosis is an imperfect and infrequently sloppy process. The replicants are often not perfect clones of their parent cells, and genetic dissimilarities can arise. The mutant cells of course also divide, thus birthing the embryo and resulting organism with different sets of genetic instructions. One set may grow into the tissue that forms the lungs, while another may develop into a vital organ.

This scenario is known to occur not only during embryogenesis, but at any stage of a species’ life. Put simply, these mosaic derivatives can pop up at any time as a function of the disorder inherent in various stages of cell division.

Chimerism, by contrast, also occurs in utero but is the result of two or more zygotes swapping cells back and forth in the womb on their way to becoming an embryo. If these cells make mitotic headway in certain locations in the body, twins may share certain cells in common.

Another manner in which a foreign genome can be introduced and spread is from an organ transplant. One study at Innsbruck Medical University found that 74 percent of patients contained the genome of the donor in addition to their own, a full nine years after the transplants were performed.

While initially received with little skepticism, the idea that any cell taken from anywhere in the body will have identical DNA is now just too simplistic a view of biology. Until recently there simply hasn’t been enough original research into this area to conclude how widespread mosaicism and its cognates are.
 

We have also found that many women harbor cells that contain Y chromosomes. How is this possible? It turns out that genetic material can be passed from fetus to mother. The placenta — nature’s all-in-one life support system — allows for bidirectional exchange of various nutrients and fluids. Embryonic cells can also be left behind after the birth of a child, which can then multiply and assimilate into neighboring tissues.

“It’s pretty likely that any woman who has been pregnant is a chimera,” Dr. Randolph said.”

Indeed, these are not fringe cases which demand unique explanations, but evidenced by several focused studies to date. Zimmer recounts one such study conducted last year.

“In 2012, Canadian scientists performed autopsies on the brains of 59 women. They found neurons with Y chromosomes in 63 percent of them. The neurons likely developed from cells originating in their sons.”

What about blood type? Is it possible to have not one but two different blood types? Indeed it is. Mothers and fetuses can intermingle red blood cells during and after gestation. That means if you’re a mother you may have some Type A cells and some Type O cells, for example. While women who carry fetuses with incongruous blood types normally develop antibodies to suppress them, the mismatched type often lingers in the blood stream long after the baby is born.1

Challenges Ahead

Our newfound view of cellular nonconformity is certain to have rippling import for everyone from geneticists and oncologists to forensic investigators. To be sure, multiple DNA sequences deflate some of the confidence services like 23andMe and other genetic counseling and personal genomics services can provide. Sequencing the genome of a single group of cells with one suite of medical predispositions and physiological baselines doesn’t tell you anything about cells with a different genetic manual.

Medical practitioners will need to work out how the presence of multiple genomes impacts the host. Specifically, we need a better understanding of how isolated blotches of a “foreign” or mutant genome fit into the overall genetic canvas. Is genetic diversity spread across different sites of the body something that promotes proper health, or is this cause for concern?

As you can imagine, such a situation can also create headaches for forensic scientists working to establish identity of victims and criminals.

“Last year, for example, forensic scientists at the Washington State Patrol Crime Laboratory Division described how a saliva sample and a sperm sample from the same suspect in a sexual assault case didn’t match.”

With this and other research into the microbiome, it’s clear that speaking of our genome in the singular is no longer tenable. We are curator to a mosaic of genetic programming, and the implications and links to medical science will take time to fully dissect. If this latest research has shown us anything, it’s that no neat and tidy schema for reality is immune to being ruptured by new evidence.

External link: DNA Double Take

Further reading: You can actually have two sets of DNA

1. In rare cases, it is even possible for your blood type to change. As mentioned, an organ transplant can alter the genetic makeup of the recipient, but certain kinds of transplantation can even overwrite the patient’s blood type over time, such as bone marrow transplants. To prevent body-wide rejection, doctors will ideally use a donor that is a match in blood type and other biomarkers, especially human leukocyte antigens (HLA), but once the recipient’s marrow is replaced, it will begin pumping out the donor’s blood cells. It may take several weeks or months for the original blood type to be replaced entirely, but eventually it will.

 
 
In 1951 doctors at Johns Hopkins in Baltimore diagnosed an unusually extreme case of cervical cancer. The breakneck growth rate and resistance to common remedies were unlike anything previously seen. Without informed consent, the doctor scraped a clump of cells from the cancerous tumor during one of the 30 year-old woman’s visits and deposited them with a nearby cell culture lab operated by George Gey. There, in the air-controlled space of Gey’s facility, something happened that researchers had long suspected out of reach.

Where countless other cells before them had died, hers survived, and multiplied indefinitely. The immortality of this one cell line would prove instrumental in treating a number of the world’s most heavy-hitting diseases and set the stage for an all new era in cell research, medical diagnosis, drug development, and bioethics. But this is a story not just about bundles of cells, but about the humanity behind them, and in particular the family to which they will forever be tied.

That woman was Henrietta Lacks. Henrietta passed away just nine months after her diagnosis, but it would be more than two decades before her family received word of the namesake cell line which survived her — HeLa. Its value as a scientific and commercial commodity was paramount, getting bogged down in the thicket of rights and privacy less so. Once researchers discovered that Henrietta’s cells did not die but instead bred a new generation every twenty-four hours, HeLa quickly became the tireless workhorse of the culture community. Vials were trucked to research facilities around the world, where they were regularly exposed to a pavilion of infectious diseases, merged with non-human DNA, and even shot into space in an effort to study the influence of zero gravity.

Over time, details about the parent of the eponymous cells funneled out of view. Henrietta’s own kin were oblivious to the fact that her cells still lived, were being actively studied and tested in dozens of countries, and were even being exchanged at great profit.1 Once the unwitting donor’s official name was released, journalists descended in full fervor, leading to a lifetime of turmoil and unrest for the Lacks household. Set against the rich legacy of the family’s cells, their life of poverty and unpaid medical bills seemed untoward, and this sense of injustice only mounted as more details filtered in from the press.

Rebecca Skloot’s segue into this lush narrative was by and large a product of serendipitous circumstance, having first heard of HeLa in an intro to biology course at her local community college. After learning that these cells had lived outside of their host’s body for the better part of a century, and about the remarkable advances they have gifted to science, Skloot shot up her hand and innocently asked, “Who was she?” The professor’s reply proved unsatisfying: “An African American woman.” The seed of curiosity had been planted. By the time Skloot graduated she’d decided to write a book to recover this disremembered woman whose cells had won so many posthumous victories for science and society.

Who Was Henrietta Lacks?

For more than a decade, Skloot layered herself into the Lacks’ story, befriending and forming deep bonds with Henrietta’s children and cousinry. She forges an especially strong connection with Deborah Lacks, Henrietta’s youngest daughter, who was unfortunately too young to remember much about her mother. With a mix of patience and persistence the two work together to dig up Henrietta’s heritage and bring to light her hitherto uncelebrated legacy. It is Skloot’s at times unstable relationship and camaraderie with Deborah that gives the narrative its steam, as the two probe ever deeper into the mystery surrounding her mother.

Tracing the family’s roots fixes Henrietta’s childhood at the tail end of the Jim Crow era, a time when segregation meant a great deal more than which bathroom and water fountain one was required to use. Rampant legal disadvantages in the South bred systemic, institutionalized deprivations for Blacks, and this included limited access to medical care. Having spent her youth on a slave plantation in Clover, Virginia, Henrietta joined in the Great Migration at the ripened age of twenty-one, exchanging her familiarity with tobacco fields for a new life in Baltimore. Nine years later, she would be diagnosed with the malignancy that led to her iconic cell line. And it would be another fifty years before Deborah, with the help of Skloot, laid eyes on her mother’s original medical records.

Johns Hopkins Hospital was founded for the express purpose of treating Baltimore’s poor and, unlike today, informed consent upon providing blood or tissue samples was neither required by law nor common practice (the term did not even appear in a court document until 1957). Like everyone at the time, Henrietta hadn’t a clue about what would become of her excised genetic material and the boons it would — or could — lavish upon the scientific community. This became a flashpoint issue in the years that followed as the occasional patient attempted to turn a gray area into a lucrative venture. While we learned more about DNA and transmissible disease, Henrietta’s resilient cells inaugurated an international conversation on the commercialization of biological materials and where exactly donors fit within that ecosystem. In many ways, the conversation is ongoing.2

The HeLa Legacy

To properly gauge the vastitude of the legacy tied up in Henrietta’s cells, it’s important to understand twentieth century cell culture. Until Henrietta came along, cell immortality was a pipe dream. While standard, non-cancerous cells had been grown in vitro since 1907, none of them survived long enough to endure important testing, petering out after 50 divisions on average.3 Even cancer cells, like those common to cervical cancers, died shortly after relocation to the culture environment. This meant not only was there a brief window for experimentation but that a continuous supply of fresh cells was needed to sustain research. Many in the field yearned for a better way.

HeLa keynoted a paradigm shift. They were robust enough to survive in the bricolage of materials used in Dr. Gey’s culture medium, and they were susceptible to the same range of infectious diseases as were normal cells. This allowed researchers to inject the lively DNA with diseases as well as cures. Much more than a newfound convenience, this revolutionized the medical and biological sciences, so much so that one of the researchers Skloot interviews in the book, when asked what would happen if HeLa was pulled from research use, replied, “Restricting HeLa cell use would be disastrous. The impact that would have on science is inconceivable.” (p. 328)

Thanks to Dr. Gey’s partnering efforts with labs around the globe, the benefits of HeLa manifested seemingly overnight. One year after HeLa’s discovery, Jonas Salk and his team were able to derive a vaccine for polio by infecting HeLa cells, followed shortly by drug treatments for HPV, herpes, leukemia, influenza, hemophilia, and Parkinson’s disease. In 1953 HeLa became the first cells to be cloned successfully. In total, some 60,000 papers have been published on HeLa, and cell culturists still use her cancer cells as a model for human biology.

Just what was it that gave HeLa cells their added dose of moxie? Even today, we can only speculate. We now know that Henrietta was infected with both HPV and syphilis, so one theory is that this virulent combination may have helped suppress PCD. A rival theory suggests she had highly atypical genes to begin with, perhaps a rare mutation, that enabled the cancer to spiral in unspecified directions. A good deal of uncertainty remains. HeLa has also been a source of much frustration over the years from regularly contaminating other cell lines, often halting research until the botch-up is sorted.

Closing Thoughts

Rebecca Skloot’s ten-year effort is a literary and cultural marvel balanced between unsheathing the humanity behind one of the richest stories in all of science and laying bare the bioethical implications to which it is attached. It succeeds on both fronts. Skloot is at her most exhilarating when channeling the lens of Deborah Lacks as they band together to reach some much-needed closure to the saga thrust upon the Lacks family. With her first book, Skloot has demonstrated in equal measure her facility for conveying scientific nuance while weaving meaning and poetic force into a cohesive whole. While this is first and foremost a work of nonfiction, its pages are emblazoned with enough touches of novel-like charisma to beckon both crowds. The Immortal Life of Henrietta Lacks is a timeless narrative delivered by a gifted writer and the definitive presentation of the legacy Henrietta never lived to see. Highly recommended.

Skloot also founded The Henrietta Lacks Foundation – click here for more – to provide support for the Lacks as well as assistance to African Americans pursuing education in science and medicine. A portion of her book’s proceeds are donated to the Foundation.

Note: This review is mirrored over at Goodreads and at Amazon.

Further reading: 5 important ways Henrietta Lacks changed medical science

1. The biotech outfit Microbiological Associates began selling HeLa for profit as early as 1952.

2. Skloot includes a superb summary in the afterword which draws together the various threads of this nuanced debate. The clinic-patient relationship is somewhat different today, though still more opaque than some regulators call for. As of this writing, there is no law requiring informed consent (i.e., signed permission) before submitting to any DNA sample. Nor is there any law stipulating that patients be informed of their tissue’s commercial potential. There have been a few high profile court cases, but “no law enacted to enforce the ruling, so it remains only case law.” (p. 326) Most medical institutions today do provide consent forms, but the loose regulation means the language employed is inconsistent and often vague.

3. Otherwise known as the Hayflick limit.

 
 
As we seek to master our microbial stowaways, it has become increasingly clear our dominion will be hard-fought. Bacteria continue to evolve around our medical salvos with frightening proficiency and at a rate faster than we can munition new countermeasures.

And we are almost entirely to blame. Our medical professionals have over-prescribed; patients have under-dosed; agriculturalists have embraced the profit-generating potential of antibiotics for livestock. All without proper consideration of both the small-scale and macro-societal impacts of such practices.

The net result of this ratcheted microbial warfare is that the drugs we’ve depended on for so long have stopped working. Resistance through overuse. And what might happen when antibiotic resistance (AR) crescendos to a critical risk? What would a world look like absent antibiotic remedies?

i09 cites just a few of the consequences we might face:

•Transplant surgery becomes virtually impossible. Organ recipients have to take immune-suppressing drugs for life to stop rejection of a new heart or kidney. Their immune systems cannot fight off life-threatening infections without antibiotics.

• Removing a burst appendix becomes a dangerous operation once again. Patients are routinely given antibiotics after surgery to prevent the wound becoming infected by bacteria. If bacteria get into the bloodstream, they can cause life-threatening septicaemia.

• Pneumonia becomes once more “the old man’s friend”. Antibiotics have stopped it being the mass-killer it once was, particularly among the old and frail, who would lapse into unconsciousness and often slip away in their sleep. Other diseases of old age, such as cancer, have taken over.

• Gonorrhea becomes hard to treat. Resistant strains are already on the rise. Without treatment, the sexually transmitted disease causes pelvic inflammatory disease, infertility and ectopic pregnancies.

• Tuberculosis becomes incurable – first we had TB, then multi-drug-resistant TB (MDR-TB) and now there is XDR-TB (extremely drug resistant TB). TB requires very long courses (six months or more) of antibiotics. The very human tendency to stop taking or forget to take the drugs has contributed to the spread of resistance.

These concerns, multiplied by our own carelessness, have now ushered in the post-antibiotic era, where fresh approaches to combating life’s tiniest killers will be required. Phage therapy has been an enticing option for years, but there haven’t been nearly enough trials for commercial feasibility.

Vaccines are another option, but experts estimate that vaccination preparations for some of the hardest-hitting bacteria are at least a decade away.

Even bespoke derivations of antibiotics hold some promise, but will demand hordes of funding and research.

The silver lining of course lies in our biology. As products of selection, we have the capacity to adapt along with our symbiotic foes. And thanks to our neural resources and innovative spirit, we have a great deal more weaponry at our disposal.

“Yes, the post-antibiotic era is nearly upon us, but as always, we’ll continue to fight and find new ways to combat the most efficient and prolific organism this planet has ever seen.”

 
 
External link: Can We Avoid an Antibiotic Apocalypse?

Feature image credit: Photos by Courto

 
 
Here on earth, life has evolved multicellularity dozens of times since the first proto-biological forms took shape — at least 25 times according to Grosberg and Strahmann. There is no need to teleport to the past, however, as we can now observe directly this metamorphosis by experiment alone.

In the past month two separate trials with single-celled yeast have shown how yeast respond in the face of different selection pressures. Instead of separating from the mother cell into two distinct daughter cells (mitosis), or untethering itself from the parent cell after maturity (budding), new yeast cells globbed together in both of the experiments, creating an amorphous blob geared to outcompete its neighbors. That is, the transition from unicellularity to multicellularity has now been observed and monitored in the lab.
 

This increase in mass provides various functional benefits, such as conforming to a sucrose-based diet in the case of the trial at Harvard.
 

This latest experiment at Harvard (and various others like it) illustrates elegantly the degree to which biology is shaped by its environment. Changing up food sources or food scarcity can dramatically reshape populations as natural selection determines which individuals are better suited to the latest pressures operating in their habitat. This bottom-up process of “design by adaptation” is a one of great ingenuity and flexibility.
 

 
 
External link: Another Path For Evolving Bodies

Feature image credit: Wikimedia Commons

 
 
Life on earth is symbiotic. We are deeply interconnected with and inseparable from the rest of the biosphere. This deep alliance manifests in our genetic distance from other animals and plants, and by the vast array of microbes for which we serve as worthy hosts.

As many as 1¹² microbes are at this very moment foraging and scuttling about inside each and every one of us, some providing beneficial aid, some promoting harm, and some just along for the ride. Our ties run deeper, however. Advanced sequencing methods show that a whopping 8% of our genome is inherited viral DNA. Moreover, 37% of human genes have homologs in bacteria and 28% are traceable to unicellular eukaryotes.

This tangled web of co-dependency suggests that studying humans and other animals in isolation no longer makes sense. Instead of viewing ourselves as freestanding individuals, we are perhaps best thought of as integrated biological ecosystems. Bacterial colonies with legs.

A recent piece on i09 probes this connectedness by asking a question indissociable from Darwin’s great theory: is every living thing on earth related? After all, to talk about Darwinian evolution is to talk about universal common ancestry (UCA), the idea that all of life on earth is genetically linked to a single progenitive forerunner. Dogs, corvids, cetaceans, worms – if you follow the chain far enough back in time, you’d eventually converge upon a primordial bundle of life which gave rise to the biodiversity witnessed today.

We still can only speculate on the specific characteristics of this last universal ancestor (LUA), but recent statistical analysis provides further support for this key pillar of Darwin’s theory. Douglas Theobald, a research professor at Brandeis University in Massachusetts, now lends compelling mathematical evidence toward UCA and against multiple ancestry.

Theobald and his team started with twenty-three proteins common to twelve different organisms alive today. The twelve chosen are distributed evenly (four a piece) among the three basic domains of life: Archaea, Bacteria and Eukarya. Using model selection theory, the team then ran the genetic sequences to determine whether single or multiple ancestry was more likely.
 

Various patterns of descent can be grouped according to how much commonality organisms share in terms of their DNA. This can easily be done for specific phyla, but the statistical work done at Brandeis integrates all three of life’s branches, concluding that the overlap in gene relationships points to a genetic center, existing most likely 3.5 to 3.8 billion years ago. A number of variables were fed into their model, choosing to rely on more than just sequence similarity. The results strongly favor single ancestry over a multiply threaded origin scenario.

Various attempts have been made to distill and visualize earth’s great chain of being. The collaborative, peer-reviewed Tree of Life Web Project, which began back in 1995, is a superb rendering of relatedness and perhaps the best source freely available. Go ahead. Meet the family below.

Courtesy of the Tree of Life Web Project

The image (click here for a larger view) collates all major phyla and locates them according to the best available molecular and cladistic data. It’s a tidy picture of the history of life on earth.

While we have much to learn about the details, the results are in: we are intertwined with an imponderably vast chain of life reaching back to precellular material and to the interstellar maelstroms from whence it derived. We share kinship, however distant, with every form of life on earth – with those that once paced and stalked the steppes of Europe, with those that paddle and float in the chemosynthetic depths of the Pacific, with those that soar, swoop and sail the skies above us, and with those that have yet to come.
 

External link: Is every living thing on Earth related?

Feature image: “Redwood Extreme” by colindub.com