Trip Wire: Q&A with Epidemiologist Stephen Morse

Stephen Morse is in the vanguard of an effort to predict the next pandemic — but says prevention is an elusive goal.

By Gemma Tarlach|Friday, November 01, 2013
stephen-morse
stephen-morse
Yana Paskova

Quick with a smile and even faster with a pun, native New Yorker Stephen Morse doesn’t seem like a man preoccupied with mass killers. 

As a boy he toyed with the idea of becoming an Egyptologist or herpetologist — “I spent a lot of time trying to catch snakes in the Pine Barrens of New Jersey” — but eventually he chose microbiology. A lifelong lover of solving puzzles, Morse gravitated toward some of the most mysterious microbes: killer viruses that seemed to strike from out of nowhere, sometimes reaching pandemic levels.

“I like intellectual challenges — that’s probably my greatest weakness,” jokes Morse, sitting in his office at Columbia University’s Mailman School of Public Health, where books, often two or three rows deep, are crammed floor to ceiling.

Morse is credited with creating the term emerging infectious diseases in the late 1980s to explain viruses that can exist for years in an animal host without causing illness. The virus “emerges” when human activity, such as habitat destruction, causes host-human contact. With the right conditions — including transmissibility — the virus infects and spreads through our species, sometimes globally.

More than 20 years after he began trying to solve one of epidemiology’s biggest challenges — understanding why pandemics happen and how we can stop them — Morse serves as the director of the U.S. Agency for International Development’s worldwide PREDICT project, which has been part of the organization’s Emerging Pandemic Threat (EPT) initiative since 2009. The program is multidimensional, from cutting-edge mathematical virus modeling to field educators teaching hunters how to reduce risk of infection from contaminated game.

On a humid New York summer day, in between fielding calls from the State Department and other eminent virologists about expanding PREDICT’s efforts into new countries, Morse explained to Discover why preventing pandemic remains an elusive goal.


Discover: Influenza is the biggest pandemic threat we face. Does the threat come from known strains evolving to be more virulent or from the emergence of a strain that’s never been seen before?

Stephen Morse: When I suggested influenza in 1990 as a paradigm of an emerging infection, (Nobel laureate) Howard Temin, a mentor of mine, disagreed. He believed it was a question of evolution, as did most microbiologists. But I think it’s a prototype in many ways. It’s fooled us every single time. It’s very complex. It has multiple hosts and can evolve by mutation but also reassortment (when two closely related strains infect the same host and exchange gene segments, producing new strains — a process distinct from mutation, when the RNA of a virus is miscoded during replication). We’re often unaware of what it’s doing in nature. 

What is the mechanism for the critical step between evolving in nature and spilling over into humans, causing infection? Take us through, for example, H5N1, avian influenza A, commonly known as bird flu, which has been a problem particularly in Asia for the past decade.

SM: With H5N1, in the late ’90s there was a small outbreak of 18 cases with six deaths in Hong Kong. That’s a high mortality rate, but no one paid much attention; it was not a big deal at the time. They cleared out the markets and the wild birds and the parks, and nothing more was heard. 

But the virus didn’t go away. It simply went underground, continuing to evolve in its natural host, wild waterfowl. Then it came back in 2003 and it was nasty, so evolved that a lot of people didn’t recognize it. It was far more virulent. It had been evolving during that period in its natural hosts.

It was certainly taking its toll on the poultry population. But we weren’t seeing a lot of human-to-human transmission, so we didn’t see much occasion for H5N1 to go further and take wing, pardon the pun.

Why do China and other parts of East Asia seem to be such an epicenter of influenza? Pigs are considered an ideal influenza “mixing vessel” because they are susceptible to both mammalian- and avian-based strains of influenza. And wild waterfowl, particularly migratory species, often host multiple strains of avian influenza. Is the prevalence of outbreak in Asia due to the number of animals on the continent or something else?

SM: Lewis Thomas, in Lives of a Cell, has an essay on germs that says something to the effect that all of these events are an unfinished negotiation over boundaries between the host and the pathogen. That’s really what it is. The boundaries have been set over many years, many generations with the pathogen’s natural host. We haven’t reached that degree of armistice.

When you put several species together, quail and ducks or chickens and ducks, there are opportunities for species that never get together in nature to suddenly be in close proximity and share their viruses. In its natural hosts, influenza appears to be relatively static, but when it gets into a new host, many of those constraints are lifted. It’s a renegotiation. Why do these pandemics come from China? Because China has integrated farming systems. They put two of influenza’s favorite hosts, waterfowl and pigs, together. 

Is H7N9, identified earlier this year, a virus with real pandemic potential?

SM: I’m more concerned about H7N9 than I was about H5N1. H7N9 is very recently evolved. H7 has been around a while — people get conjunctivitis with it but don’t even know they had influenza. But N9 is new. It’s very rare in nature. N9 seems to have come from a wild bird, probably around Korea somewhere, although there’s evidence for rare N9s in other birds in Mongolia and Siberia, where these migratory wildfowl tend to congregate. H7N9 has to get deep into the lungs, which is why it’s not that transmissible.

If it’s not very transmissible, why does it worry you? Granted, a virus could always become more transmissible either through appropriating a piece of genetic code from a more easily spread strain (reassortment) or through its own genetic code mutating. But that risk exists for any virus. Why is H7N9 such a threat? 

SM: In humans, the normal influenza receptors we have in the upper respiratory tract are not like the avian receptors H7N9 needs. It has to go deeper down, into our lower respiratory tract, to find the receptors it needs. Because it has to go deeper, once it does infect, the prognosis is not good — the risk of mortality would be high. Unlike H5N1, H7N9 could be as bad as the 1918 influenza pandemic if it were to become as transmissible because it’s unfamiliar to humans — we’ve never seen it before — and because of how deep down our receptors for it are. 

The track record for predicting a pandemic is, well, zero. Why?

SM: It’s true we’ve never predicted pandemic successfully. That’s been our biggest failure. We have a very bad handle on how it adapts to humans. We have very poor ability to predict transmissibility.

H5N1 can bind to human receptors, for example, but H5N1 proved receptor specificity is not enough to be highly transmissible. It’s a necessary but not sufficient condition. The question is what are the sufficient conditions to transmit person-to-person. The answer is we still cannot predict that. We can get the complete genetic sequence of a virus, but nobody can tell you whether it’s going to be able to transmit. They can tell you, possibly, whether it has the capability of infecting humans, but that’s not the whole story.

Why do viruses cause severe disease in us? It’s very likely the hyperinflammatory response, the overabundance of what people call the cytokine storm, which causes many of the symptoms. They’re the same symptoms you see in septic shock and other types of severe inflammatory reaction, an over-exuberant response from our own protective mechanisms. We know some of the molecular features that cause these reactions, but we don’t know all of them.

Since its start in 2009, PREDICT has been working with its partners to map hot spots where pathogens are most likely to emerge in human populations and cause infections, with the potential to escalate to a pandemic. These kinds of maps have been attempted before, but how does this type of predictive mapping inform our understanding of, say, a particular strain of influenza?

SM: We need to add to our knowledge of disease ecology, of knowing what’s out there. Looking back, I don’t think if we saw the precursor, the ancestor, of HIV, we would have recognized the threat it posed until it reached the human population. I don’t have any illusions that finding something in nature will predict the next pandemic. But we need to build our database. We don’t have any way to do a reasonable risk assessment.

You make an interesting point that, even if we’d had the surveillance in place, we might not have appreciated the threat HIV or its precursor posed. Why?

SM: You wouldn’t think HIV would have succeeded because it’s so inefficient at transmission. But HIV took advantage of contaminated injection equipment, of sexual activity. Transmissibility depends on our behavior. HIV might not have happened 100 years ago.

Another big part of PREDICT’s mission is, in fact, to address human behavior that might give a virus an advantage. Is public health education more important than the cutting-edge pathogen detection done in labs to prevent pandemic?

SM: The lab is very important. Certainly it’s an essential part of what we do as scientists. But if we want to do anything about emerging infections, we have to do it as a public health and policy issue. There are a lot of ways to do it. They may not all be economically feasible. But a lot of it is appropriate behavior change, such as safe hunting: The original cases of infection of what is now HIV obviously got into somebody’s bloodstream. You see people cutting the game up, having cuts on their hands. Eventually, something’s going to happen. 

Do you think we’ll ever be successful in predicting a pandemic?

SM: I’m an optimist in that I see movement. The fact that we can have a USAID program like Emerging Pandemic Threats, and that the Centers for Disease Control and Prevention is strengthening its global surveillance efforts and field epidemiology training programs, these are very important, as are communications — when I was starting out in this field, who would have believed you could reach almost anywhere in the world with a cell phone?

Having global surveillance is the first step and a necessary step, but it’s not sufficient. What we would like to do is find the rules for these emerging infections, the rules for viral traffic. We already know something about those, how they get into human population. But now we need to know the proclivity of a virus or other pathogen to get into the human population.

The One Health Initiative (a global partnership between physicians, veterinarians and public health officials) is also an important part of it. People are beginning to realize all of the species on this Earth have something in common. Everything has a common thread. You know, I like the idea of finding commonalities, of order in what seems to be a chaotic system. A virus is not just an animal problem, and it’s not just a human problem. 

As someone who’s been at the forefront of unraveling emerging infectious diseases and the mechanisms of pandemics, what keeps you up at night?

SM: Most of all, the one we’re not expecting. Because none of these pandemics have been predicted. I worry about H7N9. I worry about the new coronavirus. But what I really worry about is the one that’s out there that we’re not aware of, and we’re not looking for.

flu-image
flu-image
Alison Mackey/Discover

The Name Game: Figuring Out Flu

Keeping track of influenza’s many names (and many strains) sometimes seems as tricky as predicting a pandemic. Here’s what you need to know.

ABC, easy as 1-2-3

Influenza viruses belong to the Orthomyxoviridae family and are divided into A, B and C types based on their antigen (antibody-producing) protein type. Types B and C are found in humans and, occasionally, seals and pigs, and are not divided into subtypes. Type A shows up in birds and mammals like us, and is the only type of influenza that has caused pandemics. It’s influenza A subtypes that typically pose a health threat. 

What subtype surfaces

Influenza A is further divided into subtypes based on how it binds to the cell of its host. A glycoprotein on the virus’s surface called hemagglutinin, which has 17 identified types (H1-H17), determines how the virus sticks to and enters the host cell. 

Another glycoprotein, neuraminidase, with 10 known types (N1-N10), affects how efficiently the virus spreads through an infected individual. It is the specific combination of glycoproteins that distinguishes one subtype from the next (H7N9 versus H5N1, for example). Not all potential host species are equally susceptible to all glycoproteins, so some subtypes infect one species, such as chickens, but not others.

For the birds

The term bird flu is imprecise. More than 100 species of wild waterfowl have been identified as natural, usually asymptomatic hosts of a variety of avian influenza A (bird flu) subtypes. Influenza A subtypes H5N1 and H7N9, for example, are both called bird flu, though the viruses have different paths of infection,
or receptors, and different degrees of transmissibility.

When flu piggybacks

Swine flu applies to any type or subtype of influenza for which pigs are natural hosts. It is most often associated with the H1N1 subtype, which was behind the 1976 swine flu scare. In 2009, a new strain of H1N1 caused what the Centers for Disease Control and Prevention called “the first influenza pandemic in more than 40 years,” testament to a long-known influenza subtype evolving into a new threat.

No flu for you

Other pathogens with pandemic potential are sometimes mistakenly called “flu,” including SARS and MERS, two coronaviruses that emerged in 2003 and 2012, respectively. Both coronaviruses cause respiratory symptoms similar to influenza.

evolution-of-h7n9
evolution-of-h7n9

H7N9 is an example of a virus making proteins from “borrowed” RNA segments acquired during reassortment with other influenza subtypes that are found in different host species.

Alison Mackey/Discover based on illustrations courtesy of the CDC/Dan Higgins
respiratory-system
respiratory-system


Science Source

The 3 R’s of Influenza Pandemic

There are several steps between an influenza strain’s emergence from its natural animal host and a large-scale human outbreak. Here are three important links in the possible chain of events.

Step 1: Rapid evolution 

Influenza has a high rate of mutation because enzymes involved in RNA replication lack a proofreading function, leading to frequent errors. Some of the mutations increase a strain’s pandemic potential. For example, the infamous 1918 influenza may have been the second wave of a strain that appeared in 1917. The 1917 virus had infection and mortality rates typical of seasonal flu, but a single mutation in the proteins affecting how the virus binds to a host cell may have led to the deadly 1918 wave, which killed more than 50 million people worldwide.

Step 2: Reassortment

When multiple influenza subtypes come into close contact in an environment such as a farm, the viruses can exchange pieces of genetic code. This viral swap meet, called reassortment, can increase transmissibility and virulence. The 2009 H1N1 strain, which killed more than 4,000 people worldwide, incorporated pieces of avian, human and swine flu subtypes through reassortment.

Step 3: Receptor specificity

Like different picks in a locksmith’s tool, the 17 known subtypes of hemagglutinin, a surface protein on influenza strains, match different sialic acid receptors on a host cell. Without the right receptor, the virus cannot attach tightly enough to invade the cell and co-opt it for replication. 

Generally speaking, humans have upper and lower respiratory receptors. Some influenza viruses attach to upper respiratory receptors. These generally are more transmissible human-to-human because the virus doesn’t have that far to travel along the respiratory tract to find the cell it needs for replication. Other influenza subtypes must travel to the lower respiratory tract to find their receptors; while this generally makes a subtype less transmissible, infection via these receptors often is associated with higher mortality.

The Rogues’ Gallery of Potential Pandemics

The most dangerous virus is the one we haven’t yet encountered, but epidemiologists already have their eyes on several ne’er-do-well pathogens.
H7N9
H7N9
CDC/Cynthia Goldsmith and Thomas Rowe

H7N9

Known associates: Similar influenza H7 subtypes, some of which cause conjunctivitis (pinkeye) but not typical flu symptoms; N9 subtypes are novel to humans.

Aliases: avian influenza A, bird flu

First offense: Identified in April, H7N9 appears to have spread from wild waterfowl host to poultry in China and, from there, to humans.

Favorite hangouts: Flourishes among birds in crowded farm and market environments.

Modus operandi: About a third of the 130 people infected with H7N9 earlier this year died; the pace of new cases fell sharply after the Chinese government took steps to reduce bird-to-human transmission opportunities. 

Threat level: HIGH. H7 subtypes in general can become more transmissible to humans, but the N9 element of H7N9 is newly evolved, and, if it became more transmissible, humans would have no pre-existing immunity to it. In addition, H7N9 may have rapidly acquired resistance to existing antiviral medication.

MERS
MERS
CDC/Maureen Metcalfe and Azaibi Tamin

MERS-CoV

Known associates: Fellow coronavirus SARS-CoV (see below) and other members of the Coronaviridae family.

Aliases: Middle East Respiratory Syndrome

First offense: Identified in humans in 2012 in Saudi Arabia; other cases found in the Arabian Peninsula or in individuals with connections to the region.

Favorite hangouts: Earlier this year, researchers found an Egyptian tomb bat in Saudi Arabia with a strain of the virus identical to that of the first human patient; another team discovered that 50 camels from the area all tested positive for MERS-CoV antibodies, suggesting camels may be intermediary hosts.

Modus operandi: Like SARS, MERS-CoV causes difficulty breathing, coughing and fever, and can progress to pneumonia and respiratory failure.

Threat level: MODERATE. As of September, 132 cases of MERS-CoV had been confirmed, with 58 deaths, suggesting high virulence. Milder cases may have gone unreported, increasing the number of infections but lowering the mortality rate. In July, after an Emergency Committee meeting, WHO declared MERS-CoV was not an imminent public health crisis.

SARS-CoV02
SARS-CoV02
CDC/Dr. Mary Ng Mah Lee

SARS-CoV

Known associates: A member of the Coronaviridae family, which includes pathogens behind the common cold and a highly contagious intestinal disease that infects dogs. 

Aliases: SARS-associated coronavirus, severe acute respiratory syndrome

First offense: Identified in 2003 in China, it likely emerged from an as-yet-unidentified small mammal.

Favorite hangouts: The virus appears to have retreated to its natural reservoir, laying low, in effect, until another human-host interaction allows it to re-emerge.

Modus operandi: Symptoms such as coughing and difficulty breathing begin two to 10 days after infection, though individuals may be contagious before or after showing symptoms. The general mortality rate is roughly 10 percent, but climbs to 50 percent in individuals with other health problems.

Threat level: MODERATE-HIGH. It’s been 10 years since the outbreak that infected an estimated 8,000 people worldwide and killed at least 750. Due to its high transmissibility and moderately high mortality rate, in 2012 SARS-CoV was designated a potential “severe threat” by the CDC’s National Select Agent Registry.

H5N1
H5N1
CDC/Cynthia Goldsmith and Jackie Katz

H5N1

Aliases: Avian influenza A, bird flu, Highly Pathogenic Avian Influenza H5N1 (HPAI H5N1)

First offense: A small outbreak in Hong Kong in 1997. Returned in a deadlier form in 2003, infecting more than 600 people, mostly in East Asia. 

Favorite hangouts: H5N1, which evolved in wild waterfowl, has devastated domestic poultry with a 90 to 100 percent mortality rate.

Modus operandi: WHO estimates that 60 percent of individuals infected with the virus will die, a rate on par with the Black Death and other public health catastrophes. (The 1918 Influenza Pandemic had an estimated mortality rate of less than 5 percent.)

Threat level: MODERATE-HIGH. Although it has a high mortality rate, H5N1 is not easily transmissible between humans. Scientists are watching closely for signs of mutation or reassortment — a process in which various strains can mix and match their genetic material — that may make it spread more efficiently. 

H1N1
H1N1
CDC/Cynthia Goldsmith and D. Rollin

H1N1

Known associates: Other influenza A subtypes that naturally reside in pigs.

Aliases: Swine flu, swine influenza A

First offense: H1N1 made headlines in the ‘70s; a new and more deadly strain of the virus subtype emerged in 2009. Lab-confirmed H1N1 deaths during the 2009-’10 pandemic were roughly 18,500 worldwide, though some theorize the mortality rate was substantially higher. 

Favorite hangouts: H1N1’s evolution is a classic example of its natural reservoir, the pig, serving as a mixing vessel. Pigs have multiple influenza receptors and can harbor human and avian strains of the virus in addition to their own, leading to reassortment. The 2009 strain of H1N1 is, in fact, a hodgepodge of swine, human and avian strains of the virus.

Modus operandi: The 2009 H1N1 strain is worrisome because, like the 1918 influenza, it appeared to be more lethal in young adults than most influenza strains.

Threat level: MODERATE-HIGH. The 2009 H1N1 strain is expected to remain in worldwide circulation; because it is no longer a novel strain, however, many individuals will have some immunity to it.

H3N2v
H3N2v
CDC/ Dr. Michael Shaw and Doug Jordan, M.A.

H3N2v

Known associates: Other subtypes of swine flu

Aliases: Swine flu variant (the word variant applies to influenza A subtypes that usually only infect pigs if they go on to infect humans.)

First offense: Identified in pigs in 2010, H3N2v began infecting humans in the American Midwest a year later.

Favorite hangouts: Farms and agricultural shows and fairs

Modus operandi: Since 2011, more than 300 people have been infected with H3N2v, with one documented case of human-to-human transmission.

Threat level: LOW. Although outbreaks have been sporadic and almost entirely limited to individuals in close contact with swine, H3N2v is considered enough of a potential threat to be targeted in the development of this season’s flu shot. 

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