Paul Ahlquist: Working to beat the virology numbers game

“Doing more with less” may be a common term these days in the workplace. But apply the same phrase to health-threatening viruses, and it gets to the heart of their elusive danger.

“From a genetic standpoint, you have something that is little more than a scrap of instructions scrawled on a Post-it note, but is capable of bringing the world to its knees,” says Paul Ahlquist, director of the Morgridge Institute Virology focus. “One has to ask, how is this possible?”

That question, once answered, will have major implications for human health, Ahlquist says, by providing better ways to disrupt the ability of viruses to hijack healthy cells. Viruses have a remarkable capacity to appropriate a cell’s own functions, much like guerilla warfare, and get it to carry out scores of subroutines that keep the virus thriving and changing in the body.

That simplicity is especially on display with a virus like HIV, which has a genomic makeup of roughly 9,000 DNA base pairs. That compares to about 4.6 million base pairs for the E. coli bacteria. While small, viruses are diverse and mutate with often-deadly speed.

“If you took everything to date that has been published about HIV — just trying to understand it — you would fill libraries,” Ahlquist says. “But the fact is, we have the HIV instruction manual. It’s one page long and written in a four-letter alphabet. It’s more like a grocery list than an encyclopedia.”

Ahlquist’s team at the Morgridge Institute for Research is focusing on that paradox – complexity masquerading within simplicity. The lab is focusing on virus-host interactions over a variety of viruses, including HIV, human papillomavirus (HPV), influenza and Epstein-Barr virus.

Specific projects include investigating the link between the HPV virus and cervical cancer. The team is working to identify the changes that take cells from normalcy to intermediate stages to cancer, and strategies to quickly identify viral-linked patterns that pose the highest danger of leading to cancer. Work on HIV includes investigating how the virus uses host functions at multiple stages of its growth process, from early steps at establishing itself in the host chromosome to later stages of assembling and transmitting infectious viruses to new cells.

Across all work, the team is working to understand the molecular mechanisms that underpin these events — a key to having a rational basis for interfering with the transmission of the virus.

This is an important and exciting time to be studying virology, Ahlquist says, thanks to the new perspective provided by genomics and advanced computation. Prior to this time, incremental advances in knowledge often lacked the larger context, how these puzzle pieces all fit together.

“It’s like landing on a new world — you see lots of interesting things but have no idea where it ends,” he says. “But if you suddenly have a satellite view of the land, and you see the boundaries and what’s inside the borders, that’s a very different game.”

That’s where systems biology has so much potential, Ahlquist says, as a way of enabling scientists to develop wire-frame diagrams of how all things interact to create a complex — but finite — biological machine. It provides the biological equivalent of the periodic table of the elements.

“That is the power we want to have to make our understanding of biology and medicine more rational and productive,” he says.

These more robust tools will be more important during a time of heightened threats for new outbreaks. All of the major human viral diseases are a product of zoonosis, or transfer from animals, and they all have sprung from long-recognized viruses not considered a threat to humans, until they mutate.

“You can’t say this class of viruses is dangerous and that one isn’t, because the ones we formerly knew as innocuous keep turning out deadly cousins,” he says.

Recent advances in treatment of HIV, which employ a variety of drugs that work to continually suppress rather than eliminate the virus, have implications not only for treating other deadly viruses, but could be a game-shifting approach to treating cancers.

Like viruses, cancers work in a very similar manner within the body, continually mutating and creating resistant strains. It explains the all-too-common cases of cancer therapy, where a patient appears to be 100 percent cancer-free, only to have the disease come charging back. Those resistant “deadly cousins” were already in the body, waiting to take over.

The idea of using a “cocktail” of three or four anti-cancer drugs at a time, to continually suppress cancer, may in the end offer a better shot at providing patients reasonably healthy lives than trying to eliminate the cancer altogether, Ahlquist says.

The Morgridge team’s work underscores the importance of early detection of viruses, when there is the least amount of genetic variability. “It’s a numbers game in terms of whether there is enough diversity to allow the pathogens to escape the control measures you’ve chosen. If you hit it early enough, you can cure it.”

Ahlquist’s work takes place across many research partners, including the Graduate School, the School of Medicine and Public Health, the College of Agricultural and Life Sciences, the McArdle Cancer Center and Howard Hughes Medical Institute. The Morgridge Institute impact has been dramatic in providing a platform to interact productively with a wider range of researchers and to make contributions back to campus.

“The viruses evolve and we must evolve, too,” Ahlquist says. “Things like the Morgridge Institute and joint appointments have been really important contributions to our evolution by creating a mixing of ideas and providing a degree of flexibility that allows us to go in new directions.”