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A Battle on Many Fronts

A Battle on Many Fronts
For every one of the researchers at The University of Texas at Austin involved in the study of infectious diseases, the challenge is a never-ending one.

It’s a race to stay one step ahead of the mutations and transmission of the pathogenic microorganisms they’re analyzing in their labs, modeling on their laptops, and tracking around the world. Science grows more global, and so do diseases.

There’s hope and fear in perhaps equal measure. Chemical engineer Jennifer Maynard, for instance, envisions developing an effective antiviral treatment for pertussis (whooping cough) that could help save the lives of thousands of babies too young to be vaccinated.

For biologist Robert Krug, however, the future is scarier. If the avian flu, which he’s been studying, adapts to where it can jump quickly from human to human, it may prove harder to contain than was the 1918 influenza virus that killed tens of millions of people worldwide.

Maynard and Krug are two of a number of professors at the university looking to understand not only the fundamental science of infectious diseases like whooping cough, avian flu, cholera, HIV and SARS, but the social, geographical and political aspects of them as well. They’re examining the way they disperse throughout communities and landscapes, the way they’re understood by the public and the way they might be contained.

infectious_krugRobert Krug: Fighting Off the Flu

Robert Krug, a professor of molecular genetics and microbiology, has for many years been working to understand and develop treatments for the influenza virus, one of history’s greatest killers (the 1918 influenza pandemic killed between 20 and 40 million people worldwide). More recently, Krug has been focusing on the H5N1 strain of influenza—“bird flu”—which threatens to turn into one of the future’s greatest killers as well.

“This new avian flu, if it’s anything like the 1918 virus, is extremely dangerous,” says Krug.

Not only is it highly virulent, he explains, but its proteins are unfamiliar to the human immune system, which makes it difficult for the body to manufacture antibodies and for scientists to develop effective vaccines. It’s also very prone to mutation

“Right now the H5N1 virus isn’t efficient in transmitting from humans to other humans,” says Krug, “but if we don’t stop transmission from birds to humans, then we may be in trouble, because transmission to humans will afford the virus the potential to adapt to humans.”

Krug recently received a $5 million grant from the National Institutes of Health to develop drugs that target the NS1 protein, without which neither the avian flu strain, nor the seasonal flu viruses that kill some 36,000 Americans a year, can replicate and spread.

Working with small, non-pathogenic pieces of flu viruses, Krug has already found features of the NS1 protein that can be exploited for drug development. He and his colleagues at Rutgers University and in other labs at The University of Texas at Austin now hope to develop small molecules that will inhibit NS1 function and thereby inhibit the virus.

The researchers’ ultimate goal is to develop not only effective antivirals to contain outbreaks, but also vaccines against H5N1 to prevent them. Both will be necessary, Krug believes, in order for us to stay ahead of the virulence and mutating capacity of avian flu.

infectious_maynard2Jennifer Maynard: Walloping Whooping Cough

There’s a simple reason, says chemical engineering professor Jennifer Maynard, that the television screens and billboards of Texas have recently become populated with warnings about the dangers of pertussis (whooping cough). The infection rate has been creeping up throughout the industrialized world, and small outbreaks like the one this year in the neo-natal unit at Seton Medical Center in Austin are becoming more common.

“Doctors are not absolutely sure why the infection rate is going up,” says Maynard. “It’s probably a result of strains surviving in adults, who until recently did not receive booster immunizations and whose immunity has waned. In fact, anyone who has had a cough lasting at least two weeks probably has pertussis. It’s unpleasant, but not usually dangerous in adults.”

In contrast, infants who become ill, like those at Seton, are often very sick, coughing hard enough to cause brain hemorrhages. Even more alarming for parents is that the only available therapies are supportive care.

In order to develop a specific therapy for pertussis, Maynard is working to engineer an antibody to neutralize the major toxin produced by the bacteria and thus limit the disease. The antibody has previously been proven effective in reversing disease in mice, but has not been developed for humans by a pharmaceutical company, says Maynard, because there hasn’t been sufficient motivation (the immunization program in the industrialized world has been very effective in keeping the number of cases low).

“Vaccination is the most important part of prevention,” she says, “but for the few babies who do get whooping cough, it is very traumatic. It would be nice if there’s something we can do for them apart from putting an oxygen mask on their face and sticking an IV in their arm.”

Maynard, who plans to move her engineered antibodies into mouse trials soon, and then into human clinical trials, is also hoping that what she’s learned about the pertussis bacteria may prove to be a boon in developing drugs for other diseases.

“It’s an incredibly interesting bacteria,” she says. “If you could take what this bacteria does, and transplant it to other bacteria, you could do some amazing things in biotechnology.”

infectious_payneShelley Payne: Battling Bacteria

There’s a simple, but rather sinister, illustration that biology Professor Shelley Payne uses to demonstrate how Shigella bacteria—which causes dysentery, a severe intestinal infection—invade and destroy a host cell. In the first stage, “Attachment,” we see a few ant-like Shigella bacteria clinging to the outside of the cell. Then follows “Invasion” (the shigellae now cling to the inside of the cell membrane), “Intracellular Multiplication,” (the bacteria multiply, fill the cell and move into adjacent cells) and then, finally, the “Cell Lysis and Death” stage, where an explosion of the bacteria burst the cell open.

Payne’s research is dedicated to understanding, and ultimately inhibiting, the virulence factors of both the Shigella bacteria and the cholera-causing Vibrio cholerae bacteria. In particular, Payne and her colleagues look at the numerous ways the invasive bacteria extract from host cells the iron they need in order to replicate.

“In response to the low iron environment of the host, these pathogens produce iron-binding compounds and proteins that help them acquire iron from their host,” says Payne. “Low iron also triggers the expression of virulence factors, including toxins. We are studying the iron acquisition systems and the mechanisms by which low iron signals pathogens to produce these factors. If we can find ways to interrupt this process, we may be able to control the infections and reduce the severity of the diseases.”

Both shigellosis and cholera, which are transmitted predominantly through contaminated food and water, have been largely eliminated in the developed world, but they persist as serious health problems in nations which don’t have well-managed water and sewage systems. Cholera has been on the rise in recent years, particularly in Africa, where some 235,000 cases and more than 6,000 deaths were reported in 2006, and shigellosis is a vastly greater problem—there are an estimated 165 million cases, and 1.5 million deaths, every year.

Although there is a vaccine that’s proven somewhat effective in preventing cholera, there’s no vaccine for shigellosis. For people who contract shigellosis and cholera the treatment options are very limited, consisting primarily of efforts to keep them well hydrated until the infection runs its course and antibiotics to reduce the duration of infection.

“These are devastating diseases, particularly in areas of poverty and overcrowding,” says Payne. “It is critical to find more effective methods to control these pathogens and prevent the infections.”

infectious_geislerGary Geisler: Building a Digital Disease Library

For Gary Geisler, an expert in the design and development of digital libraries and multimedia interfaces, the challenge is to more efficiently disseminate information that’s out there in the world but not always accessible. An assistant professor in the School of Information, Geisler is working with a team of doctors from Harvard Medical School to develop “eMicrobes,” a Web site and digital curriculum for medical students, instructors and field practitioners involved in the global fight against the spread of infectious diseases.

“We’re using a medical textbook as a conceptual metaphor,” says Geisler. “The site won’t look like a textbook—that’s something that was tried in the early days of the Web, but didn’t work very well—but it’s going to combine a microbiology atlas with a case-based approach, presenting patients with a collection of symptoms, taking users through prospective diagnoses, giving images of test results, arriving at a final diagnosis.

eMicrobes is being funded by a three-year, $413,087 grant from the National Library of Medicine, and will roll out its three primary applications in successive years of the grant period. At the end of the first year, says Geisler, the Web site should be available to the medical community. By the end of the second year, the site will include features that automatically update the relevant entries with the latest articles and studies catalogued in the massive PubMed database. By the third year, the content will be formatted so that users in the field can access the information through handheld devices (like phones and PDAs) and whole portions of the library can be downloaded to computers so that they’re available off-line for users without reliable Internet access.

“There are other sites out there that have some of this information,” says Geisler, “but nothing with the goals of eMicrobes, that’s targeted so specifically to infectious diseases. So we believe it has the potential to be very useful in confronting infectious disease, particularly in the developing world, where they have the least resources to do so.”

infectious_ancel_meyersLauren Ancel Meyers: Tipping Points

To Lauren Ancel Meyers, assistant professor of integrative biology, the secret to understanding and limiting the spread of infectious diseases lies not so much in the drugs we develop to combat them, nor in the body of scientific knowledge we’ve amassed about their pathology. It’s in the lives of the people who contract and transmit the diseases.

In 2003, for instance, in response to a number of small outbreaks of severe acute respiratory syndrome (SARS) in Canadian cities, Meyers and her colleagues used census and demographic data to create a mathematical model of the city of Vancouver. Taking into account such variables as age, population distribution, likely points of transmission, family size and frequency of hospital visits, they were able not only to understand why SARS had spread much less quickly than had been anticipated, but to offer suggestions about the kinds of context-dependent interventions that should diminish even further the spread of the disease in future outbreaks.

Among the common-sense insights emerging from Meyers’ models, which draw heavily on work that physicists have done in percolation theory, is that not everyone is equal when it comes to spreading disease. Her methods—which are part of the emerging field of contact network epidemiology—are able to represent much more accurately than older methods the diversity of human behavior. She takes particular notice of both “superspreaders,” people like bartenders or healthcare providers who come into contact with large numbers of other people, and “supershedders,” who are unusually effective at emitting the virus into the environment they share with others.

When dealing with the flu virus, for instance, she’s concluded that for less contagious strains of the flu the best way to protect the elderly from the flu will often involve focusing vaccination efforts not on the elderly—who don’t derive as much immunity from the vaccine—but on school children. Children not only contract and transmit the flu easily but tend to have the density of contacts (in schools) that aids a lot of transmission in a short time. If the transmission chain can be severed early, says Meyers, you can provide “herd immunity.”

In her most recent work, Meyers is adapting her models to the complexities of sexually transmitted infections (STIs) like HIV, which tend to spread much more slowly than respiratory diseases and which are much more variable in their transmission patterns across different populations. With a grant from the Santa Fe Institute, Meyers is working with public health experts to analyze eight large-scale sets of epidemiological and sociological data (comparing, for instance, rural communities with a low rate of HIV infection to populations of prostitutes and IV drug users, where the HIV rates go as high as 15 percent).

“The first question is what is the structure of the networks through which sexually transmitted diseases spread?” says Meyers. “Once we understand what the common features are, and what the different features are of these networks, we will then ask, using the kinds of mathematical models I’ve developed—how does disease typically spread through these populations, which individuals are very important in making disease spread, and thus which individuals are going to be important for targeting intervention?”

infectious_ellingtonAndy Ellington: Evolving Defenses

The basic tools with which biochemistry Professor Andy Ellington approaches the study of infectious disease are aptamers—small, customized pieces of RNA that he engineers, through the process of “directed evolution,” so they bind extraordinarily well to bacteria like Bacillus anthracis (anthrax) and viral proteins like those found in HIV.

The process begins with robots that synthesize billions of random DNA sequences. Those sequences are used as patterns to create aptamers of RNA (the molecule that helps make proteins from DNA), and the population of aptamers is then tested in a solution with a target molecule. Those that bind best with the target are kept and the others are removed. This selection process is repeated many times until an almost perfect population of RNA aptamers has evolved that interacts best with the target.

“We throw things at bacteria,” says Ellington. “We see what sticks—literally what sticks—then we amplify it, make more of it, and go through Darwinian cycles of selection and amplification in order to find the best reagents for a given bacteria.”

The result are aptamers that not only are extremely good at binding to their selected targets, but that can also serve as the building blocks of technologies and therapeutics that can help contain or inhibit the spread of disease.

Ellington and his lab are working, for instance, with an Austin-based biotechnology company to develop a biosensor that fluoresces in the presence of particular bacteria.

“Think of it as a long train,” he says. “We’re the beginning of the train. We actually touch the bacteria, which initiates an amplification reaction, which leads to the accumulation of hundreds or thousands of copies of a DNA sequence. Once those copies have been created, we can readily detect them. From touching the bacteria, which may be too sparse to detect on its own, we’ve generated a nucleic acid product—one much easier to detect—that’s symbolic or representative of the bacteria.”

Ellington is also using aptamers to develop therapeutics for HIV, evolving reagents that can penetrate to the insides of infected cells and, once inside, recognize particular viral proteins and inhibit the proteins from executing the virus’s own replication program. The challenge, he says, is less the evolution of the targeted aptamers than it is getting them to deliver themselves to the right cells.

“If we could do that,” he says, “it would be like if your immune system could not just make antibodies but could make antibodies that get inside your cells rather than just course around your bloodstream.”

The goal, says Ellington, is to develop specific diagnostic and therapeutic technologies.

“I want them to move out of my lab, into the companies and then out into the marketplace,” he says.

Photo of Dr. Krug: Matt Lankes
Photos of Drs. Maynard, Payne, Geisler and Ellington: Christina Murrey
Photo of Dr. Ancel Meyers: Marsha Miller
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Tuesday, 07 February 2023

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