Path to Better Health New approaches to life-saving antivirals

Broad-spectrum approaches could tip the balance against virus threats

by Paul Ahlquist

Investigator

  • Paul Ahlquist, Morgridge Investigator in the John W. and Jeanne M. Rowe Center for Research in Virology and HHMI Investigator

About the Project:

In the game against an essentially unlimited pool of virus threats, humanity is seriously outmatched. In order to shift the balance, scientists need to change the game. Paul Ahlquist and his lab are working to develop broad-spectrum antivirals, solutions that will target many viruses at once.

John W. and Jeanne M. Rowe Center for Research in Virology:

The Rowe Center works to unlock the secrets of virus-host interactions to better protect human health.

Humanity faces an essentially unlimited pool of virus threats. The emergence of new viruses like HIV, Ebola, or Zika is only going to increase as humans encroach further into the wild environment. The question is, what are we going to do about it? The major problem is that to develop a new drug or vaccine typically takes 10 years and costs on the order of a billion dollars, and the ones we do have only act on a highly specific target.

People are not nearly as safe against disease as they would like to think they are. This serious imbalance — unlimited threats and limited responses — is not a winning game for humanity. We need to change this game.

At the Morgridge Institute, one of our highest priorities is to develop what we are calling broad-spectrum antivirals. That is, to use the limited capacity and resources available to produce agents that will target many viruses at once and thereby get more bang for our investment in each case.

Broad-spectrum agents already exist to battle against bacteria. If your child scrapes a knee, you go into the medicine cabinet and pull out a general antibiotic ointment that is typically a mixture of several things to protect your child. You don’t have to start a gene-sequencing experiment to figure out what kind of bacteria might be in that scrape.

We simply don’t have that now for viruses. We need something that might work against a great many different viruses at once.

One approach we are excited to pursue is to target the functions of the host cell, rather than the functions of the virus directly. We’ve already identified over a hundred specific host genes that are involved in different steps of virus replication, as well as the pathways that a virus follows to deposit its infectious payload.

More importantly, as we analyze those pathways, we’re finding that often many different viruses depend on a common pathway. Viruses whose fundamental molecular biology are quite different can have a common vulnerability from this angle. We just need to figure out how to shut that street down.

It’s fascinating to see how these systems operate their beautiful little machines that our work is just beginning to reveal in their complexity.

As our technologies have become more powerful, we are also going after all pathways in the cell to simply catalog the major needs of large numbers of viruses. We can do experiments now on the scale of tens of thousands of genes, something that was not possible when I started doing this work. These are extremely valuable experiments that don’t involve a pre-designed hypothesis.

This kind of discovery research is powerful because of its ability to reveal new connections that can be so substantial we’re often left gasping and grasping to try to understand what they mean.  Fortunately, other powerful emerging technologies are coming to our rescue. We often combine the output of these kinds of discovery experiments with substantial computational exercises.

The Morgridge Institute is deliberately building a culture of support for this type of science: to ask big questions and not being deterred by not immediately knowing what the answer is going to be. It is thoughtfully assembling multidisciplinary capabilities that combine well together to support these activities, such as computational biology and cutting-edge imaging at both the light and electron microscopy level to see what is happening inside the cells. We have people working together and talking from highly different backgrounds now.

The viruses are winning, but in an environment that values fundamental research, we have a much better chance of shifting the balance in our direction.

Investigator

  • Paul Ahlquist, Morgridge Investigator in the John W. and Jeanne M. Rowe Center for Research in Virology and HHMI Investigator

About the Project:

In the game against an essentially unlimited pool of virus threats, humanity is seriously outmatched. In order to shift the balance, scientists need to change the game. Paul Ahlquist and his lab are working to develop broad-spectrum antivirals, solutions that will target many viruses at once.

John W. and Jeanne M. Rowe Center for Research in Virology:

The Rowe Center works to unlock the secrets of virus-host interactions to better protect human health.

Path to Better Health

Path to Better Health

The series explores the tremendous stakes involved in biomedical research and why a fundamental understanding of biology is needed to improve human health. Learn more about the challenges of predicting preterm births, developing protections against viruses, fighting a devastating tropical disease, and keeping babies safe under anesthesia.

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