viruses – Waiving Entropy

Take a Minute to Appreciate the Science Behind the Coronavirus Vaccines

Daniel Bastian — Sat, 23 Jan 2021 03:10:06 +0000

As more of us get the vaccine, particularly friends and family who work in health care — thank you for all that you do! — it’s worth reflecting on the genius, passion, and raft of hard-won scientific insight on which these vaccines rest. This post from evolutionary biologist Jerry Coyne dives into the technology and engineering behind BioNTech/Pfizer’s mRNA vaccine, the one that most people seem to have received so far (though Moderna’s works much the same way). Learning more about what went into this unprecedented endeavor can help crystallize the significance of this moment. It’s a lot more than a jab in the arm.

The New York Times, courtesy of one of my favorite science journalists Carl Zimmer, has already put out individualized breakdowns of each of these vaccines here and here (as well as several others approved for emergency use). But Coyne’s post goes into more detail, including how the genetic code used in the vaccine was initially entered into DNA printers (those exist) which then converted the bytes on disk to actual DNA molecules. You don’t need to understand the niceties of nucleotides to marvel at what our best and brightest managed to achieve this year. And taking a few minutes out of our day as an expert walks us through it helps us better appreciate how we arrived at this moment and the sheer complexity of the science involved.

Over at Science Magazine, Derek Lowe brings us up to speed on the spate of development research on mRNA vaccines in the years leading up to the pandemic. The immune system is obnoxiously intricate, so much so that a vaccine which triggers too strong of a response can be rendered ineffective as the body’s innate immunity quashes the viral proteins before they have a chance to make it into your cells. It’s a balancing act between the innate and adaptive immune systems, and we didn’t stumble upon the right formula by accident. These techniques, as Derek points out, have been carefully honed over decades of empirical study, and they essentially paid “off just in time for the current pandemic.”

This preparatory work in large part explains how scientists were able to churn out the initial batch of vaccines so quickly. Zooming out for a moment, many of us still haven’t quite fathomed the dizzying pace at which science operated over the last year. The typical lead time for a vaccine product is in the ballpark of ten to fifteen years. For SARS-CoV-2, we went from having the genome sequenced and uploaded to the internet on January 10th of last year to robust Phase 3 clinical trial data in 300 days. Moderna reportedly took just two days to finalize the design of their mRNA vaccine after the sequence data was posted online. Thanks to years of groundwork and the collective efforts of scientists around the world, we decoded a deadly virus, organized clinical trials, and began distribution of two promising vaccines — all inside of a year.

This stunning series of events was helped along by hard work, and a few lucky breaks, to be sure, but we were able to accomplish this feat because the science behind these vaccines is well established. Their formulation builds on previous depth of knowledge about genetic instructions, protein structure, DNA & RNA sequencing, and viral evolution, while their rapid rollout stems from advances in scalable technology and large-scale trial design. We also owe an enormous debt to Professor Zhang in China, who set a precedent for open data sharing when he bravely ignored threats from above by releasing the initial sequence of the coronavirus on that seminal day last January.

The Covid-19 pandemic has inflicted an incalculable toll on human life, but we’d be remiss not to acknowledge the reality of our scientific successes. We’ve faced down pandemics in the past, but never have we mobilized our scientific and technological arsenal the way we did in 2020. The quiet, steady toil of research that’s played out across generations, and the selfless actions of Chinese whistleblowers, represent “the perfect example of why we can see further by standing on the shoulders of giants.”

Further reading:

Feature image credit: Illustration by Andy Potts

What Do We Know About the New Variant of Coronavirus?

Daniel Bastian — Tue, 29 Dec 2020 23:17:38 +0000

The talk on everyone’s lips this week is the new Covid variant identified in the the UK. Concern surrounding the new strain has sapped some of the elation brought on by the first rollout of vaccines. While there’s no evidence so far that the UK variant — or any of the other known variants — has any impact on the efficacy of vaccines, early reports suggest the new kid on the block is well worth paying attention to, as its more contagious nature threatens to test our resolve over the next few months and push our already overburdened health care systems to their limit.

Here’s the original paper on the SARS-2 variant known as B.1.1.7 that emerged in the UK at least as early as September. One question that’s on a lot of people’s minds is: how did this happen? The received wisdom was that SARS-2, like its coronavirus kin, is relatively genetically stable in both humans and animals, certainly when compared to influenza and other RNA-based viruses. (It’s why we develop a new flu vax every year, but we don’t for measles.) For example, Carl Zimmer wrote the following on the 30th of April (emphasis mine):

“In fact, researchers have found that the coronavirus is mutating relatively slowly compared to some other RNA viruses, in part because virus proteins acting as proofreaders are able to fix some mistakes. Each month, a lineage of coronaviruses might acquire only two single-letter mutations.

In the future, the coronavirus may pick up some mutations that help it evade our immune systems. But the slow mutation rate of the coronavirus means that these changes will emerge over the course of years.”

Of course, this never meant that the novel SARS-CoV-2 wouldn’t defy our expectations (as it has in several other respects), or that science doesn’t change. More people getting sick means more replicating viruses. More replication means more mutations. And more mutations mean more opportunities for the coronavirus to change in significant, even dangerous ways. The longevity of the pandemic, and the fact that SARS-2 has managed to worm its way into nearly every corner of the globe, raised the prospect of new strains emerging, and here they are — if a bit sooner than expected.

What appears to have happened, according to the running hypothesis in the above paper, is that the UK strain originated from a prolonged infection in an immunocompromised host. Coronaviruses isolated from patients with prolonged or persistent bouts of Covid show an unusually high amount of genetic variation. These patients tend to be immunodeficient in some way or another, which biases them toward chronic infection as the virus is allowed to linger in the body for a much longer period of time compared to people with healthy immune systems.

And it’s precisely this combination that produced the unique evolutionary pressures that gave rise to the UK strain:

Weak selective pressure from the patient’s natural immune response

Unusually large and genetically diverse virus population that builds up over the course of the infection

Strong selective pressure after convalescent plasma or other forms of antibody therapy are introduced several weeks later

In short, hosts with a weakened immune system foster a higher degree of viral evolution compared to immunocompetent individuals due to some unique factors at play in such hosts.

The authors note that patients with this particular type of infection are a rarity, and that onward transmission from said patients should be rarer still. Patients who develop chronic infections are usually hospitalized and under the care and supervision of trained health care workers equipped with proper PPE. Thus forward transmission is unlikely, or at least far less likely compared to asymptomatic “silent spreaders” walking around with no clue they’re even carrying the virus. In this case, however, transmission did occur. It sounds like we may have just gotten unlucky. It may be that the new strain’s more contagious properties managed to crash through the normal impediments.

The researchers identified a total of 23 mutations present in the new variant, including 6 synonymous mutations, 14 non-synonymous mutations, and 3 deletions.

By Jonathan Corum | Source: Andrew Rambaut et al., Covid-19 Genomics Consortium U.K.

According to a preprint released by British scientists this past Wednesday, the cumulative effect of these various mutations is more rapid spread. While the variant is not currently linked to more severe illness or higher risk of hospitalization or death, initial estimates indicate B.1.1.7 is between 56 and 70 percent more infectious compared to others that have been circulating in most parts of the world. That’s alarming news for nations already seeing record high case counts and deaths as we settle in for the winter and outdoor activity wanes.

From the moment the new variant was announced, many experts suggested it was essentially a foregone conclusion that it wouldn’t stay confined to the UK for long, and likely had already escaped. Given the shamefully low rates of testing across the US in particular, the lack of a national program for genetic sequencing, and the reality of international travel, one could easily presume the mutant strain had been circulating here for weeks, if not months, without detection.

Sure enough, news came this morning that the first case of B.1.1.7 in the US has been confirmed in Colorado. More than a dozen other countries have also reported finding the new variant in samples isolated from patients. That the variant had been on hand but not accounted for was bolstered by the fact that the patient in Colorado had no travel history. Presumably, it was spreading among the community for quite some time.

One silver lining in all this is that most scientists doubt the new strains will undermine the vaccine effort. The CDC is currently tracking a number of SARS-2 variants or strains1 identified over the last few months, one from the UK (B.1.1.7) and one in South Africa (B.1.351). Under both, the agency emphasizes that there is no evidence either variant “has any impact on disease severity or vaccine efficacy.” Dr. Fauci appears optimistic as well. That said, we cannot yet rule out the possibility, and a number of countries and vaccine makers are hustling to secure more concrete answers to this very question.

The scientists behind the B.1.1.7 paper do close out on a hopeful note by reflecting on a strain that emerged in Singapore. That strain was discovered earlier this year and produced a milder form of Covid in patients. However, it died out shortly afterward thanks to the swift control measures enacted by the government. Singapore’s encounter with its own unique variant can serve as a hopeful lesson for Western nations by demonstrating that similar successes can be achieved if we act quickly and decisively.

The revelation of a new, faster-spreading variant comes at a most inopportune time. Just as the world begins to celebrate the influx of vaccines, a more formidable foe has arrived that threatens to complicate our ability to control the virus. But there is also an opportunity here. The emergence of new strains sharpens the urgency of vaccination programs around the world. We — from global health agencies to ordinary citizens — can respond to these new perils in the months ahead by stepping up surveillance and testing, and by redoubling our efforts to distribute the vaccines as quickly, as widely, and as safely as possible. First and foremost, these efforts must entail educating people about vaccine safety and the role we all play in minimizing transmission and bringing the virus to heel.

As it’s often said, vaccines don’t save lives, vaccination campaigns do.

Further reading:

Image credit: Shutterstock

Virology can be a notoriously confusing field both because the terminology used in the literature is often inconsistent, and because popular concepts within the field are still fiercely debated. (Welcome to academia.) As an example, terms like ‘isolate,’ ‘strain,’ ‘variant,’ ‘species,’ and ‘serotype’ are not always used the same way by different infectious disease researchers; while some associate these terms with different concepts, others may use them more or less interchangeably, or worse, inconsistently.

The CDC weighed in on this matter in their interim report on B.1.1.7: “The press often uses the terms “variant,” “strain,” “lineage,” and “mutant” interchangeably. For the time being in the context of this variant, the first three of these terms are generally being used interchangeably by the scientific community as well.”

Typically, the terms mentioned by the CDC above are reserved for versions with special changes that confer a new property to the virus. Since lineage B.1.1.7 appears to be up to 70% more transmissible thanks to a few key mutations, it’s acceptable to refer to it as a new ‘strain’ or ‘variant.’ Other viral genomes isolated from patients, which number in the hundreds of thousands at this point, have no new or discerning features or properties to write home about, and are merely considered ‘isolates.’

To be sure, virologists will not necessarily agree on this, just as many did not agree with referring to the Singapore virus as a ‘new strain.’ The conversation will go on.

Why You Should Still Wear a Mask—Even After Getting Vaccinated

Daniel Bastian — Wed, 23 Dec 2020 18:17:25 +0000

A few Covid-centric items to share today that I trust many will find useful. The first is a top-notch summary by Stat of the current state of knowledge about the coronavirus a year into the pandemic. Given the unprecedented global effort to understand this virus, I expect it’ll be outdated in six month’s time as science marches on, but it serves well enough for now.

“The single advantage that’s propelled SARS-2 on its around-the-world quest: People can pass it to others before they start feeling sick or even if they never show symptoms. Together, this accounts for more than 50% of new cases, according to the Centers for Disease Control and Prevention.

This is not the case with the two other coronaviruses, MERS and the original SARS, that in recent decades have spilled from animals into people and raised global alarms. Those infections are much deadlier than the one caused by SARS-2 — MERS in particular — but people are only contagious once they show symptoms. It’s much easier to stop a virus when you have a clear sign of who is infected.

Covid-19 is not just heterogeneous in presentation, but in severity. One in five people who get it never feel sick at all, while another one in five will get severely or critically ill. Experts say the fact that the vast majority of people will recover just fine has made it harder to get everyone to take it seriously — and in turn to take precautions to protect themselves, their communities, and health system capacities. Experts wonder if people might act differently if SARS-2 had a mortality rate like SARS of nearly 10%, as opposed to 1% or less.

“People are like, my cousin got it and he was fine,” said virologist Juliet Morrison of the University of California, Riverside. “Well, you might have a genetic propensity to develop more serious disease, or you might have an underlying risk factor you don’t know about. Seeing how it’s presented in one individual or even the majority of the population does not mean you’ll have the same disease presentation.”

It’s those one in five silent spreaders which brings us to the second item: a write-up in The New York Times on why continuing to wear a mask after getting a vaccine is a good idea. The main reason for this is because coronavirus transmission may still occur by a vaccinated person. This possibility arises from the fact that infection risk — and, by extension, transmission — isn’t something the clinical trials by Pfizer, Moderna, and other vaccine makers are designed to suss out. At least, it isn’t the primary goal behind such trials.

Clinical trials are designed to test the safety and efficacy of a particular treatment. And ‘efficacy‘ in the case of a vaccine typically means ‘ability to prevent illness’ (i.e. prevents an infection from establishing disease in the body). It does not necessarily mean that recipients can’t still be infected and spread the virus without developing symptoms. After all, our bodies are utterly teeming with viruses, most of which are benign, and we’re ‘infected’ by viruses all the time in the sense that they find their way into our cells and tissues. But the vast majority of these situations don’t result in our getting sick because the infection is subdued by our immune system before the pathogen’s replication process gets off the ground.

Like its predecessor, SARS-CoV-1, SARS-2 prefers to take up residence in the nose and throat, where it can pass to new hosts by hitching a ride on droplets ejected by coughs and sneezes. Ideally, a vaccine would produce antibodies that circulate to every area of the body in which the virus resides, and stop it from multiplying. But this often isn’t the case in practice; different types of vaccines with different methods of delivery tend to specialize at shutting down infection in certain parts of the body and can be somewhat less effective in other sectors. It’s why nasal vaccines and oral vaccines, for example, are considered the more optimal remedy for respiratory viruses like SARS-1 and -2.

In contrast, the first generation of vaccines from Moderna and Pfizer are, as with most vaccines throughout history, deep, intramuscular injections. The clinical trial data lend strong confidence they protect against illness, but how effective they are at muzzling the virus in the airways is unclear. It may be that these initial recipes are better suited for tamping down viral activity throughout the lungs and stomach, but prove moderately less effective at dispatching antibodies to the nose and throat area — the locus of transmission. If that turns out to be the case, then the virus could still take refuge in a vaccinated person’s nasal region or upper respiratory tract, ready and able to migrate to new hosts, despite not doing any material damage to its current host.

As The Times notes:

“The coronavirus vaccines have proved to be powerful shields against severe illness, but that is no guarantee of their efficacy in the nose. The lungs — the site of severe symptoms — are much more accessible to the circulating antibodies than the nose or throat, making them easier to safeguard.

“Preventing severe disease is easiest, preventing mild disease is harder, and preventing all infections is the hardest,” said Deepta Bhattacharya, an immunologist at the University of Arizona. “If it’s 95 percent effective at preventing symptomatic disease, it’s going to be something less than that in preventing all infections, for sure.”

The scientists contacted for the story do instill a bit of hope, however, by expressing a middle-ground possibility in which the first round of vaccines don’t arrest the virus entirely but do reduce the viral load in the mucosal tissues (i.e., those lining the nose, mouth, lungs, and digestive tract). Reducing viral load reduces risk of transmission.

“Still, he and other experts said they were optimistic that the vaccines would suppress the virus enough even in the nose and throat to prevent immunized people from spreading it to others.

“My feeling is that once you develop some form of immunity with the vaccine, your ability to get infected will also go down,” said Akiko Iwasaki, an immunologist at Yale University. “Even if you’re infected, the level of virus that you replicate in your nose should be reduced.”

In short, a vaccine may not always block an infection entirely, but it can prevent you from getting sick from it. What this ultimately means is that people who receive an approved vaccine will be protected against Covid, but could still contract/be infected by the virus and transmit it to unvaccinated persons. And if so, they would still represent a risk to others, thus necessitating the continued use of masks. In effect, vaccinated people would need to think of themselves going forward as asymptomatic carriers until we know more.

From a public health standpoint, vaccines that don’t stop transmission are less useful than those that do, but the fact is that we still don’t know enough about all the ways SARS-2 spreads or how the first batch of vaccines affect risk of infection and transmission. If it turns out that upper-arm injections ferry sufficient antibody counts to the nose and mouth, then those risks will be low. Alternatively, we may need to wait for mucosal vaccines to arrive that can generate the particularized immune response that blocks both illness and transmission. Or we may end up needing a combination of various delivery types to shore up comparable levels of immunity in the blood and mucosa alike.

These answers will come in time. Until then, wearing a mask and continuing to observe public safety guidelines even post-vaccination is the best way to protect others and end this pandemic as soon as possible.

Scientists also cannot yet say how long immunity (either natural or vaccine-induced) lasts, or SARS-2’s capacity to mutate around our medical arsenal. Based on these two facts alone, mask use is recommended well into the future.

Finally, for those wanting a deeper dive into the science behind this pandemic, this MIT lecture series a friend recently brought to my attention is super informative, albeit impossibly dense in spots (especially lectures 8 and 9, so caveat lector). Dr. Fauci is featured in lecture 4 and is a highlight.

Further reading and resources:

Image credit: MIKE REDDY FOR STAT

Debugging Our DNA: From Gene Therapy to CRISPR

Daniel Bastian — Mon, 23 Apr 2018 19:04:08 +0000

STAT recently released a phenomenal three-part video series on biomedicine in collaboration with Retro Report. The latter is known for their bite-sized documentaries that follow up on old stories and explore how they figure into today’s news. In this series they recount the hopes and aspirations associated with sequencing the human genome and precision medicine, and retrace the often tortuous history of biotechnologies past and present, from gene therapy to burgeoning gene editing tools like CRISPR.

In Part 2, we’re reminded of the discomfiting story of Jesse Gelsinger, whose death set the field of gene therapy back more than a decade. Gene therapy is one of our earliest attempts to correct for disorders arising from our DNA, with the first clinical trial conducted in May 1989 by the National Institutes of Health. At bottom, gene therapy tries to reverse the course of genetic disorders and other diseases, usually by inserting a working gene variant into the body to compensate for a faulty one.

Huntington’s disease, for example, is a rare neurodegenerative disorder caused by a mutation in the huntingtin gene on chromosome 4. (Naming genes by what goes wrong when they mutate is a popular convention in genetics.) Humans have two copies of this gene, one from each parent. If just one copy has the mutation that gives rise to the disease, the individual will inherit the disorder. We call this an autosomal dominant disorder, which according to the rules of inheritance, means that any child of an affected parent has a 50% chance of suffering the condition. Cystic fibrosis, on the other hand, is an autosomal recessive disorder, requiring two copies of the mutated gene to express the disease.

What gene therapy aims to do is supply the cells with a normal or non-mutated copy of the gene(s) responsible for these and other disorders. This was the goal behind Jesse Gelsinger’s treatment in 1999. The 18 year-old Gelsinger suffered from OTCD (ornithine transcarbamylase deficiency), a metabolic condition that impairs the body’s ability to process nitrogen in the blood. As with the others mentioned above, OTCD has a genetic explanation: it’s caused by a mutation in the OTC gene located on the X chromosome. Its inheritance is X-linked recessive, meaning men more commonly suffer from the condition than do women.

In a clinical trial overseen by James Wilson, founder of University of Pennsylvania’s former Institute for Human Gene Therapy, scientists used a viral vector to deliver an unmutated copy of the OTC gene into Gelsinger’s blood. The antigenic presence triggered a massive immune response, sparking a deadly high fever and lethal levels of blood clotting. Gelsinger did not survive.

Wilson and his research cohort quickly found themselves on the wrong end of political stilettos. The FDA, NIH, a Senate subcommittee, and his own university launched investigations and held hearings to probe the ethical, legal and scientific implications of gene therapy. Wilson, in addition to being sued by Gelsinger’s family and the Justice Department, was slapped with a five-year ban from human clinical trials. Around the same time, two others died in Europe from therapeutic DNA delivery, almost shuttering the field for good.

In the case of Gelsinger, his immune response and subsequent death were the result not of the insertion of the functioning allele but of the delivery mechanism — the viral vector. James Wilson’s team used what are called adenoviruses, specialized viruses that take up the functional DNA before being injected into the host. What we think happened is that Gelsinger had already been exposed to the particular adeno-associated virus used in the study. When the particles made it to his liver, his previously acquired antibodies induced the body-wide bout of inflammation that overwhelmed his immune system.

We still use viruses to deliver DNA in gene therapeutic trials. But Wilson and others have made great strides in the time since Gelsinger’s death, discovering a number of viral candidates far better suited for genetic treatments. The ones in use today are not only more efficient and provoke little to no immune response, they can also be tailored to specific types of human tissue, from muscle tissue to the liver and even the brain. Subjacent to a 2013 article by Carl Zimmer are a number of examples of disorders currently being treated by gene therapy interventions, including hemophilia, muscular dystrophy, blindness, and even nicotine addiction. To date, over 2,500 gene therapy treatments have been approved for clinical trials.

Gelsinger’s story underlines the at times tragic cost of clinical trials in exchange for future cures. As you’ll see in the videos below, many of the participants in these trials volunteer knowing that their decision could ultimately prevent others from suffering as they have. There are never guarantees in these arrangements, but the possibility of successful treatment of a debilitating disease often outweighs the risk for many patients.

Retro Report’s recap of the fall and rise of gene therapy helps set the stage for CRISPR, a genetic engineering tool that’s become a remarkably powerful way to edit DNA in any species. One key distinction to keep in mind when it comes to gene therapy and its successor, is that, unlike CRISPR, gene therapy doesn’t actually repair broken genes; it simply provides a working variant alongside the defective one. That is, the mutated one remains in place. With CRISPR, we are actually changing the DNA in living cells.

Because of this, it’s always been unclear how long gene therapy treatments, if successful, will last. In the case of one woman in the documentary who was treated for ADA deficiency at a young age, we learn that the therapeutic benefits subsided over time, and that she’s had to continually receive treatment over the course of her life. This is important because a successful gene therapy trial does not mean that the patients were cured or that the benefits they received from the treatment are persistent.

With CRISPR and other gene editing kits (there are several flavors), the mutated code is snipped out and replaced with healthy DNA. Rather than rely on viruses to deliver the DNA, CRISPR makes use of Cas9, an enzyme that can cut DNA directly. When the enzyme’s guide RNA finds a match within a selected strip of DNA, it deletes the matching portion, disabling it. A 3D illustration does wonders for understanding how this system works: Genome Editing with CRISPR-Cas9 by the McGovern Institute at MIT is still my favorite.

While CRISPR is currently being put to extraordinary use by humans, we didn’t invent this technology. We discovered it by studying bacteria, which have been using it as a defense against viruses and other foreign elements for hundreds of millions of years. Scientists have simply co-opted this natural mechanism by changing the guide RNA to match the specific DNA sequence we want to cut in an organism’s genome.

Where it gets interesting is what happens after the molecular scissors excise the target DNA. Normally, the cell’s repair mechanisms kick into gear and attempt to reconstitute the missing section of DNA. This process can introduce mutations that often end up disabling the gene altogether. Sometimes, knocking out the defective DNA is all that’s needed and we can stop there. In other cases we might want to replace the mutant gene with a healthy copy, effectively editing the DNA sequence. This is the step that’s proved a bit trickier in practice.

When Chinese researchers attempted this in human embryos, CRISPR managed to cut DNA in only a fraction of the 71 embryos that survived, out of a total of 86, and only in a fraction of those 71 did cells manage to take up the new DNA. In other words, 28/71 were successfully spliced, but only a few of the 28 ended up with the intended DNA. (Note that the Chinese team used non-viable zygotes only — i.e., the zygotes were fertilized by two sperm, so they had an extra set of chromosomes.) The ability of cells to take up a desired sequence of DNA without introducing off-target effects is where the rubber meets the road right now in genetic engineering.

CRISPR and other high-profile biotech have undoubted potential and are amazingly cool. But we still have a long way to go before we’ll be rewriting the DNA underlying SNP-related diseases like cystic fibrosis, sickle-cell anemia, Tay-Sachs disease, or breast cancer, or curing neurological disorders such as Alzheimer’s and Parkinson’s, to say nothing of enhancing or regulating traits controlled by multiple genes (see polygenic trait). The time required to refine our understanding of gene-based treatment, moreover, will provide us the necessary opportunity to assess these technologies at the level of ethics and define the boundaries of permissible application and misuse.

The hope is that one day these more precise molecular techniques now at our disposal will eliminate common genetic diseases entirely. But comparing today’s headlines with those of yesterday suggest that, in some ways, we’ve been here before. The under-delivered promises made alongside advancements in gene therapy and the $2.7 billion Human Genome Project should remind us of the untold complexity that awaits us as we delve ever deeper into the labyrinthine realm of biomedicine.

Enjoy STAT’s series The Code below.

External link: ‘The Code’: roots of today’s most promising genetic technologies

Further reading:

Early Mutation Exacerbated Ebola Outbreak

Daniel Bastian — Fri, 11 Nov 2016 15:49:40 +0000

Zika may have elbowed Ebola out of the headlines, but research continues to move forward on the West African epidemic that concluded earlier this year. We’re beginning to learn more about how Ebola works, its capabilities and limitations, how it has evolved over time, and what made the 2014 strain the most ruinous on record.

Ebola has darted in and out of the wild since it first appeared in 1976, periodically testing the integrity of our immune systems in the process. But in none of the previous outbreaks did the virus manage to secure a lasting foothold in human populations. Earlier flare-ups tended to peter out after a few hundred cases at most. There is no question, both in terms of body count and geographic spread, that our latest encounter was different.

After emerging in southern Guinea in late 2013, Ebola raced south to Liberia and Sierra Leone, eventually leaving footprints in a total of ten countries and claiming a total of 11,310 lives. This past January the WHO officially called an end to the Ebola crisis after three years of containment struggles requiring immense doses of cooperation between international and local communities.

Exactly how the West African strain achieved what its predecessors could not has been an ongoing discussion among health authorities and epidemiologists. Many have pointed to regional deficits in public healthcare, which resulted in lower quality care and limited resources available to treat growing populations of infected. At least 20 percent of cases, the WHO estimates, were caused by unsafe burial customs. And as the crisis unfolded, eradication efforts were repeatedly harried by local superstitions that viewed Ebola as a curse rather than a disease and created a growing distrust of foreign medical staff.

These primarily sociological factors threw up challenges in the fight against Ebola, but many wondered whether a change to its genetic profile could also account for its unusual savagery this time around. There was a lot of speculation — and misinformation — at the time that Ebola was now an airborne virus, that like influenza and SARS, it could remain in the air for long durations by hitching a ride on fine aerosols after being ejected from the body with a cough or a sneeze. Those fears were laid to rest, and there is still no evidence that Ebola can be transmitted any way other than through direct physical contact with an infected person’s fluids (e.g., blood, vomit, feces, urine, sperm), which contain high enough concentrations of the virus to transmit to a new host.

But just because Ebola didn’t sprout wings doesn’t discount other genetic changes that might have eased transmission. We now have some pretty major news to share on that front. Research released this month by two independent teams shows that Ebola did in fact change in an important way during the course of the outbreak. Both studies found a mutation that conferred a number of advantages and enabled the virus to outcompete its earlier form.

Researchers believe this mutation, labeled GP-A82V, may largely have fueled the heightened virulence of the West African epidemic. Not only did it allow the contagion to spread at a much faster rate compared with previously circulating strains, it also made it more deadly; patients infected with this new strain were significantly more likely to die compared to spillover events of the past.

The first study analyzed 1,489 Ebola genomes from samples taken from infected patients across West Africa. By plotting the sequences on an evolutionary tree known as a phylogeny, the team observed how the virus developed over time, along with its geographic distribution. In the early months of the epidemic, they discovered, the virus diverged into two distinct strains, one of which quickly predominated and nearly replaced the original strain. Though naturally many mutations arose as the crisis progressed, it picked up one in particular that altered Ebola’s surface proteins, known as glycoproteins (GP).

Before a virus can begin pumping out copies of itself, it first must gain access to the host’s DNA. Think of the proteins comprising the surface of a human cell as differently shaped locks and the proteins studding a virus’ outer shell as sets of keys. If the contact points interlock in just the right way, the virus can maneuver its way inside the host cell. Just one matching combination is enough to jimmy its way in, as typically a virus will target a single host protein.

Could GP-A82V have improved Ebola’s ability to latch onto and enter human cells? To test this hypothesis, Dr Jeremy Luban and his colleagues created a hybrid virus by inserting the Ebola gene responsible for GP production into HIV. (This delicate process is streamlined by the fact that both are single-stranded RNA viruses, with Ebola containing seven genes and HIV consisting of nine.) They ran an experiment with two groups of hybrid viruses. One group contained GP-A82V, and the other group — the control group — contained the original gene. The results were conclusive: GP-A82V improved HIV’s ability to infect human and other primate cells fourfold.

This also appears to explain why Ebola’s already high mortality rate reached 90% in some regions during the West African epidemic. Due to the lower cost of entry, the virus keyed its way through more cells, building up the viral load in the blood and overwhelming the system before immune defenses had time to respond.

Virologist Jonathan K. Ball and his team confirmed these conclusions in a separate study, with some surprising results along the way. Their tree, derived from 1,610 Ebola genomes, returned the same basic patterns: Ebola mutated early and spiraled out of control thanks to a structural change in its surface proteins.

Rather than HIV, Dr. Ball’s group created their hybrids from mouse retroviruses known as murine leukemia virus. Experiments demonstrated that strains with GP-A82V doubled the rate of infection for human cells, consistent with the parallel study. But the most illuminating result of all came when they then ran the same experiment on cells from different species of fruit bats, widely thought to be Ebola’s natural host. Remarkably, GP-A82V had the opposite effect: the same mutation that enhanced uptake in human cells decreased infectivity in bat cells. This finding points to adaptation to a new host — us.

GP-A82V first showed up in the cells of a patient in Guinea back on 31 March 2014, just before the spread intensified. Absent this mutation, it’s likely the number of infected would have dwindled as Ebola followed the example of earlier incarnations and retreated to the wild as it struggled to find suitable hosts.

This latest evidence strongly suggests that Ebola has adapted in unprecedented ways to the human vessel, and may serve as a harbinger of greater unpleasantness to come. Its extended stay during the West African event has cleared the path across the species barrier and helped pave the way for its inevitable reemergence. In the event this latest research leads to new vaccines, we may be better prepared to thwart the next shock to the system, provided we also learn from the mistakes and echo the successes of these past three years.

Further reading:

Review: Whiteout

Daniel Bastian — Sun, 03 May 2015 17:01:11 +0000

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.

The Vaccine that Rescued a Generation

Daniel Bastian — Sat, 18 Apr 2015 18:18:20 +0000

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:

“Word that the Salk vaccine was successful set off one of the greatest celebrations in modern American history,” Oshinsky remembers. “The date was April 12, 1955 — the announcement came from Ann Arbor, Mich. Church bells tolled, factory whistles blew. People ran into the streets weeping. President Eisenhower invited Jonas Salk to the White House, where he choked up while thanking Salk for saving the world’s children — an iconic moment, the height of America’s faith in research and science. Vaccines became a natural part of pediatric care.”

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

Review: The Hot Zone

Daniel Bastian — Tue, 18 Nov 2014 23:38:23 +0000

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.

New Study Sheds Much-Needed Light on Norovirus

Daniel Bastian — Sat, 08 Nov 2014 17:14:22 +0000

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

Review: A Planet of Viruses

Daniel Bastian — Thu, 07 Feb 2013 00:11:06 +0000

“[Viruses are] biology’s living matrix.”

We share little in common with our forebears’ understanding of the universe. In ancient times the earth was ensconced by a dome or firmament which held back rain and other effusions from above. Drought and wetness were tangible indicators of the pantheon’s impression of earthly behavior, with a blue sky betokening the rain that lay just beyond the earth’s protective shell. For many of our ancestors, the stars influenced the health of those on earth; for others, calamity and human hardship could be ascribed to nothing more than the shifting dispositions of the local deities. Maladies of the skin and throat and other physiological dysfunction were regarded as plagues, or instances of pestilential terror cast down as punishment. It was not until our discovery of the virus that these superordinary affiliations were shorn in favor of the vanishingly tiny world thriving right under our noses.

Viruses have been invading other life forms for billions of years with nary an invitation, yet our knowledge of this relatively young science is still fairly limited. Helming this microcosmic thrill ride in A Planet of Viruses is Carl Zimmer, first-place recipient of the 2012 AAAS Kavli Science Journalism competition and one of the most illustrious science reporters of our time. Author of Microcosm and Parasite Rex, pathogen science has long been his forte. In his latest and most abbreviated work, Zimmer marshals his treasure of insights and provides us a sweeping introduction to this fascinating, if ineluctably unnerving world.

The book is organized as a compilation of well-connected short essays, a format that suits the material well. Each of the chapters spotlights a specific strain or type of virus which has wreaked considerable chaos on human welfare–from rhinovirus, smallpox, and influenza to HIV and West Nile–and Zimmer’s characteristic story-centric style makes each vignette as rousing as the last. As you progress, Zimmer slowly raises the curtain on virus ingenuity, weaving accessible tales and the latest research and statistics throughout.

The Infiltrator

Since viruses first breached the scientific periphery in the 19th century, over 5,000 separate strains have been identified, with possibly tens of thousands more harboring in the oceans and lining the guts of every species on earth. While they can vary broadly in physical size, shape, number of genes, and mobility within and between hosts, they all borrow from the same playbook. At the first, a virus requires a host to survive, unlike bacteria, so its blinkered priority is to gain access to the cellular machinery of other life forms. Whether it’s animals and plants or bacteria and archaea, a virus does not discriminate.

I like to think of them as the world’s smallest stealth agent, as resourceful as they are deadly. In what makes Ethan Hunt look like an amateur, a virus has the ability to infiltrate a host’s cells in a variety of ways, a skill which amplifies as evolution takes its course. Once the virus descends upon the host’s genetic structure, it can really begin its work. With full access to the genetic database the virus begins installing its own DNA onto the cells of its host, overriding the host’s DNA. At this point, the virus is replicated by the host’s hijacked DNA at a prodigious rate until many thousands of identical copies line the inside of the host’s cells. Depending on the genetic mixture, this assimilation can disrupt a host gene’s ability to make proteins, unleashing havoc on the unwitting custodian, or the virus presence can trigger the release of antibodies which scramble to shut down the intruders, subjecting the host to nasty symptoms in the process.

There is ongoing debate over whether viruses qualify as a form of life. They cannot survive outside of a host cell and are absent any kind of cellular architecture, rendering them little more than small, self-assembling clusters of nucleic acids. Even so, Zimmer is quick to point out their indispensable role in shaping and sustaining life over the aeons. “We humans are an inextricable blend of mammal and virus. Remove our virus-derived genes, and we would be unable to reproduce.” (p. 93)

Viruses have also been implicated in the origin of life, as their capacity for self-replication may hold the keys to how precellular material jumpstarted the chain of life on earth.1 The uninvited stowaways have been shuffling genes among different host species ever since, comprising as much as 8% of the human genome.2 Thus not only have viruses been a tremendous force in the evolution of life on this planet, they are essential to our survival.

Zimmer also discloses plainly just how near are viruses and other infectious agents. Each of our trillions of cells can contain hundreds of viruses and bacteria.3 Human papillomavirus (HPV), most known for inflicting cervical cancer and killing over 270,000 women every year, is actually quite common and can be found nestled in your skin cells.4 We constantly shed our outermost layer of skin after cell death, depositing the virus-laden DNA all around us. That means that right now you likely have more than a few HPV viruses on the desk and laptop in front of you. Not the cheeriest thought perhaps, but you will find solace in the fact that the majority of HPV strains are benign and pose no immediate risk.

Cat, Meet Mouse

It is true that the lion’s share of known viruses introduce no changes to infected cells or simply lie dormant within our DNA. But it is also true that pathogens evolve more quickly than any known form of life. For this reason microbe trajectories always lie one step ahead of us and are difficult, if not impossible, to predict. Zimmer relates this chilling reality by describing why scientists are urging against the over-use of antibiotics. Not only do antibacterials have a null effect on viruses, they upset the delicate ecosystem inside our bodies and ‘incentivize’ bacteria to evolve countermeasures, potentially resulting in more noxious versions of both benign and harmful strains.

In response to this dilemma, many medical biologists now have their eyes on an alternative approach to fighting bacteria: phage therapy, an area in which precious little research has been conducted. Somewhat confusingly, a bacteriophage is a virus used to combat resilient bacteria. Essentially, pitting pathogen against pathogen. Zimmer tells of a lab-engineered phage (pictured below) developed by a team from Boston University and MIT that can wipe out 99.997% of E. coli strains. More impressively, “scientists at the Eliava Institute have developed a dressing for wounds that is impregnated with half a dozen different phages, capable of killing the six most common kinds of bacteria that infect skin wounds.” (p. 38) Among many microbiologists, this approach to resistant bacteria is a heavily favored alternative to antibiotics. But until a wider body of research is explored, such precision warfare is confined to the lab.

A coliphage, courtesy of GrahamColm

Exit: Stage Left

By all accounts, the most uplifting installment is that of smallpox, which Zimmer recounts in a coda entitled “The Long Goodbye.” When this dark scourge first started replicating inside of human hosts remains an open question. Telltale signs can be seen in the 3,000 year old mummified corpse of Pharaoh Ramses V, while other scientists date its emergence as early as 10,000 BC. Based on extant medical records and fatality rates, it’s been estimated that smallpox caused 400,000 European deaths each year during the 18th century and another 300-500 million deaths in the 20th century alone, bringing down three empires in the process. Its final death toll across human history and its legacy in shaping civilization may never be fully realized, but it met a worthy competitor in one Edward Jenner.

Among the venerated elite in science history, Jenner used cowpox, a member of the same viral family as smallpox, to inoculate potential smallpox victims. It worked, and while Jenner did not discover the antigenic properties activated by vaccination, it was his “trial by fire” testing and scrupulous documentation of his findings that led to its widespread adoption against smallpox. In 1979, the World Health Organization declared smallpox an eradicated disease. The unflinching bravura of those who risked their lives in the global eradication effort functions as a testament to human possibility. WHO’s vaccination campaigns, which achieved success largely by isolating the infected from the non-infected and administering vaccines to quarantined communities, is perhaps the greatest success story in all of medicine and lends hope for the outcome of future travails.

Closing Thoughts

Thanks to one of the finest science communicators today, the remaining essays assembled in A Planet of Viruses are every bit as informative and accessible. As stepladder to the scientific community, Zimmer has a knack for engaging readers of all stripes, from the layperson to the armchair scientist to anyone who simply likes reading good stories. His way is precise, not overly simplified, choosing just the right level of linguistic precision to divulge this teeming underworld to his readers. While certainly not as detailed as some of his earlier expositions, this brilliant anthology serves as a perfect preamble to the bustling field of microlife. Clocking in at just under 100 pages, I highly recommend you target this one for your next free weekend, preferably before, and not after, having eaten.

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

Feature image credit: rost9 — 3D illustration pathogenic viruses causing infection in host organism.

“Virus self-assembly within host cells has implications for the study of the origin of life, as it lends further credence to the hypothesis that life could have started as self-assembling organic molecules.” (Koonin et al 2006)
“To put that figure in perspective, consider that the 20,000 protein-coding genes in the human genome make up only 1.2 percent of our DNA”. (p. 52) Zimmer offers that our identity is tied up more in ancient virus than in anything we can call “us”.
Viruses are the most abundant form of microorganism on the planet. There are an estimated 10^31 viruses (read: not distinct strains or species) currently flourishing within the cells of unwitting hosts. Written out, that number looks like:

10,000,000,000,000,000,000,000,000,000,000

Parenthetically, there are also 10^30 bacteria on earth, so naturally they’re the most abundant hosts for viruses. It could in fact be said that biology is 99% micro.
Cervical cancer is the third leading cause of death in women, just behind breast cancer and lung cancer.