Smallpox: Could a vanquished foe return?

ASU research monitors virus that could cause threat

August 29, 2018

Smallpox, one of the most devastating diseases in human history, has ancient roots. Detected in mummified remains dating to the Egyptian dynasties, the disease would eventually claim hundreds of millions of victims in the 20th century alone. As recently as 1967, smallpox was still killing around 15 million people annually.

In 1980, however, the World Health Assembly declared smallpox officially eradicated, thanks to aggressive global vaccination efforts. This triumph is often cited as one of the greatest success stories in modern medicine. A timeline of significant events in smallpox's history. Smallpox was declared eradicated by the World Health Assembly in 1980, but new concerns about the virus have scientists re-examining it. Download Full Image

But while naturally-occurring smallpox may be a thing of the past, humanity could nevertheless experience a new outbreak of this dreaded disease. Samples of variola, the virus responsible for causing smallpox, still lurk in laboratory freezers in the U.S. and Russia. Despite elaborate security measures, some threat remains of the virus escaping to wreak havoc.

More ominously, technical advances in synthetic biology could permit variola or related sequences to be duplicated from scratch in a laboratory, raising the possibility of accidental spread or use of the pathogen as a bioweapon.

Monitoring a menace

In new research, PLuS Alliance student Dillon Adam, supervised by Arizona State University Associate Professor Matthew Scotch and Raina MacIntyre of UNSW’s Kirby Institute, investigates methods for rapidly identifying the incidence and global migration routes of variola, using techniques known as phylogenetics and phylogeography.

The methods described offer powerful tools that could be used in the field to pinpoint and arrest a future outbreak of smallpox at the earliest phase of an epidemic.

Further, the new study uses phylogenetics and phylogeography to chart historic migration patterns of smallpox.

Matthew Scotch is the co-director of the Biodesign Center for Environmental Health Engineering.

Matthew Scotch, assistant director of the Biodesign Center for Environmental Health Engineering.

Scotch is the assistant director of ASU's Biodesign Center for Environmental Health Engineering. He and MacIntyre co-authored the new paper, led by Adam. Adam and MacIntyre are researchers at UNSW’s Kirby Institute, where most of the work was carried out.

The group’s research findings recently appeared in the Oxford journal Molecular Biology and Evolution.

“Phylogeography is a discipline that can inform public health surveillance,” Scotch said. “We show that in this work by focusing on select smallpox genes. This virus still represents a serious concern among epidemiologists and hopefully, this work will help us in a response, if ever needed.”

Preparing for the worst

A follow-up simulation conducted by the researchers underscored the urgency of developing reliable, rapid response strategies for dealing with a future bioterror attack using smallpox or a related pathogen.

Researchers joined forces with stakeholders in health, foreign affairs and trade, defense, police and key nongovernmental agencies to conduct the bioterror exercise. Their aim was to model the effects of a smallpox attack that begins in Fiji, followed shortly by a much larger event occurring in a bigger country in Asia.

The exercise was conducted by The NHMRC Centre for Research Excellence, Integrated Systems for Epidemic Response (ISER), led by UNSW, which conducts applied systems research on epidemic control.

The results are alarming. The simulation suggests that an epidemic of smallpox could — within weeks — spread like a wildfire across the globe. Stores of vaccine would quickly be depleted. The patient load would overwhelm hospitals and health care systems, and severe impacts on travel and trade would occur. Further, as health care workers, military and police were affected by the disease, they would be left unable to cope with increasingly dire conditions. Organized society would begin to unravel.  

A variety of factors conspire to make this scenario particularly destructive. These include a world population that has either never been vaccinated or has waning immunity to smallpox; delayed diagnosis due to unfamiliarity with symptoms of smallpox by most of today’s physicians and rapid transit between all points on the globe, permitting brisk dissemination of the virus.

The simulation suggests that a lightning-fast response by health care officials would be critical for avoiding catastrophe. Aggressive, coordinated action against a smallpox outbreak will have to occur within one week of the first infectious case or the epidemic will spiral out of control.

Time is the enemy

Until now, however, positive laboratory diagnosis for variola has been cumbersome, time-consuming and costly. In the new study, researchers use just three genes from the virus, instead of the entire genome, to identify it. Studying sequence alterations in different isolates of variola can help establish where an epidemic began, track its rate of spread and establish its routes of migration. Sequencing minimal genetic material to identify a future re-emergence of smallpox could radically accelerate the mobilization of health care resources, improving outcomes.

The study results show that examination of 3 critical diagnostic genes, knows as hemagglutinin (HA), cytokine response modifier B (CrmB) and A-type inclusion protein (ATI) can not only identify variola, but distinguish between the two leading strains of the virus: Variola Minor and the significantly more lethal Variola Major.

Once the diagnostic viral genes have been sequenced, researchers apply sophisticated statistical methods, known as Bayesian analysis, in order to evaluate the most likely disease epicenter, rates of viral spread and geographical distribution over time. Health care workers can apply this information to formulate the best approach to containing and eradicating the disease, before an epidemic rages out of control.

Phylogenetics uses the appearance of a pathogen (or its morphology), combined with molecular data — typically DNA sequence. Through careful analysis of these factors, phylogenetic researchers can build family histories of organisms that reveal their degree of relatedness.

The technique depends in part on the fact that pathogens develop mutations at different rates over time. RNA viruses mutate quickly, DNA viruses (including smallpox), less rapidly and bacteria, comparatively slowly. Molecular clocks of mutation rate have been established for most known pathogens and are used to build and calibrate phylogenetic trees.

The integration of evolutionary frameworks with epidemiological data from a given outbreak can be used to produce phylogeographic models tracking disease source, speed of diffusion and extent of spread. The combined techniques of phylogenetics and phylogeography offer potent tools for health agencies confronted with a contagious outbreak.

Phylogeography has already been used to investigate viral dispersal for diseases including dengue fever, rabies, influenza and HIV. It is also poised to significantly improve viral mapping of origin and spread for avian influenza, though it has yet to be applied in the case of an active disease epidemic. The increasing availability of rapid, low-cost sequencing technologies will lead to more widespread application of phylogenetics and phylogeography for infectious disease monitoring.

Profile of a killer

In addition to providing techniques to pinpoint a future outbreak of smallpox, the study uses the most complete dataset currently available of whole genome and partially sequenced variola isolates to show how waves of destruction in past outbreaks of the disease spread across the continents.

Using reduced genetic datasets of variola sequence information, sampled from 1654 to 1977, and Bayesian phylogeogeaphy, the group was able to map, for the first time, 10 statistically likely routes of historic smallpox transmission between 8 discrete regions: Latin America, Europe, Western Africa, Eastern Africa and the Middle East, Southern Africa, Southern Asia, Asia Pacific and East Asia.

The methods outlined are the first to empirically describe global transmission of historic variola isolates through the use of phylogeography, revealing two discrete lineages of Variola Major circulating between East Asia and Europe following WWII.

Renewed threat

Could smallpox really rise from the dead to cause a new and terrifying pandemic? In addition to 571 known samples of variola hibernating in laboratories, an additional threat exists. Advances in the manipulation of the molecules of life through techniques of synthetic biology have enabled the construction of smallpox or a similarly deadly pathogen.

In 2017, Canadian researchers synthesized another form of poxvirus extinct in nature, establishing the frightening potential of fast-paced genetic innovations.

According to MacIntyre, who leads the Biosecurity Program at the Kirby Institute: “Biowarfare has been used since recorded history. Certain terror groups have openly called for biological attacks in July this year. The capability for attacks is increased by publicly available methods for making synthetic viruses, so we have both intent and capability. This means such threats must be taken seriously.”

In addition to heightened vigilance, techniques like those described in the current research offer the best hope of averting a large-scale smallpox catastrophe in the future and fulfilling the World Health Organization’s mandate for improved smallpox preparedness.

MacIntyre is also an adjunct professor at ASU and a fellow (along with Scotch) in the PLuS Alliance, a collaborative effort by ASU, King’s College London and UNSW Sydney aimed at addressing global challenges in health, social justice, sustainability, technology and innovation.

Assistant science writer, Biodesign Institute

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ASU Art Museum showcases permanent collection in exhibit of Warhol works

ASU Art Museum showcases Andy Warhol pieces from the permanent collection.
August 29, 2018

'Pop/Funk' also highlights museum's pieces by ceramic artist Viola Frey

The new exhibit at the Arizona State University Art Museum features two artists — one wildly famous and one less well-known — who were both important in the socially tumultuous mid-20th century.

“Pop/Funk: Warhol and Frey” is actually two solo exhibitions that celebrate art movements noted for elevating pop culture — a fitting theme because nearly all of the works are drawn from the museum’s permanent collection, which belongs to the public.

“Andy Warhol is one of the most well-known figures in modern art, and Viola Frey is less well-known so we’re hoping that people will come for Warhol and stay for Viola,” said Brittany Corrales, the curatorial coordinator for the ASU Art Museum. The Warhol show opened last week and the Frey exhibit opens Saturday.

Corrales said that building a show from among the museum’s 12,000 works was the idea of the director, Miki Garcia, who started in late 2017.

“She is really interested in showcasing our permanent collection, so she charged the curators with curating more exhibitions utilizing the breadth and depth of the objects that we already have,” she said. The show was curated by Heather Lineberry, the museum's senior curator.

Warhol, one of the most famous artists in pop art, and Frey, well known in funk art, both grew up in working-class families and were contemporaries on opposite coasts.

“Funk art grew out of the Bay Area in the 1960s, the same time pop art grew out of New York,” Corrales said.

“Warhol is working on paper and Frey in ceramics. So they have different media but there are actually quite a few similarities between the two movements and the two artists as individuals.”

Frey, who grew up in rural Lodi, California, on her family’s vineyard, was surrounded by strong working women.

“She drew a lot of inspiration from them and you really see that in her work," Corrales said.

“In the work here, she’s playing a lot with gender roles. She has these really great reclining figures that are often in the tradition of art history, but rather than being women, they’re men. So she flipped the script on that.”

Frey didn’t embrace the “funk art” label, dismissing it as “boys’ club," but she's an important artist in the movement.

The show includes 14 ceramic objectsThe ASU Art Museum owns 12 of the Frey works and two are on loan for the exhibition, one from Stéphane Janssen and R. Michael Johns, and one from Lynn and Herb Rigberg. by Frey ranging from 1963 to 1996, some of which were previously exhibited outdoors on the museum terrace.

“With our Ceramics Research Center, we have one of the strongest collections of ceramic art in the 20th century, and that includes a large collection of funk art ceramic objects,” Corrales said.

“She trained as a painter and you see a lot of painterly aspects to her ceramics — broad brushstrokes and primary colors, so they’re a little bit cartoonish with a lot of humor.”

The Warhol show includes 128 works ranging from 1972 to 1986, including 84 Polaroids, 37 black-and-white photographs and seven large screen prints.

“He would use the Polaroids as studies for screen prints, so you’ll see him moving the figure in different poses until he found the one he wanted,” she said.

The Polaroids include studies of the actress Tracee Ellis Ross as a serene 9-year-old and a very young Andre Leon Talley, the onetime editor-at-large of Vogue magazine.

The museum owns more Warhol Polaroids but must limit their public display because of potential damage by light, Corrales said.

“We had a Farrah Fawcett Polaroid that was in an exhibit last semester, and as much as we would have liked to include it, we had to put it away.”

The black-and-white photographs are from Warhol’s everyday life.

“He would carry around a film camera. Those were his nightlife photos and you can see the parties he would go to and the weddings and the street life,” she said. “Those are more casual and you can see the cast of characters he surrounded himself with.”

Those photos show New York scenes like people smoking in bars and nuns in party hats.

The screen prints include one of the cathedral in Cologne, Germany, that sparkles because it incorporates real diamond dust.

Corrales said that the ASU Art Museum always incorporates works from the permanent collection into exhibitions.

“But it took Miki looking at what we had and seeing that these are big-name artists that we need to give floor space to.

“She believes the collection belongs to the public so we want to bring it out as much as possible.”

"Pop/Funk: Warhol and Frey" runs through Dec. 29.

Top photo: The "Pop/Funk: Warhol and Frey" exhibit includes the piece "Reclining Red Man" by Viola Frey. Photo by Deanna Dent/ASU Now

Mary Beth Faller

Reporter , ASU News