Peg Riley Wants a New Drug

For more than half a century, humans have been using antibiotics to kill bacteria. The bad news, says biology professor Peg Riley, is that we were too good at it. Since the start of antibiotic mass production during World War II, we’ve been able to save countless lives using these drugs to combat gangrene, pneumonia, syphilis, and many other previously incurable infections. But our medical triumphs have been accompanied by significant problems. ( http://www.bio.umass.edu/biology/faculty/riley.phtml )

Antibiotics are often non-specific, killing off beneficial bacteria along with their disease-causing brethren. Some powerful antibiotics cure and kill at the same time, wiping out harmful microorganisms and also destroying human organs and tissues. Worst of all, the microbes responsible for many infections have been busily evolving resistance to the drugs we use against them. ( http://www.tufts.edu/med/apua/ )

“One of our biggest health crises is this antibiotic resistance,” says Riley, who has devoted most of her scientific career to the study of bacterial evolution. She recently received a $900,000 National Institutes of Health (NIH) grant to study the problem of resistance to antibiotic drugs. “If you have kids, you know that they get ear infections you can’t cure,” she says. “You have conjunctivitis happening all the time. You have patients who go into the hospital and get staph infections and die.”

Other medical research professionals share Riley’s concern. “Health practitioners around the world can no longer expect their choice of antibiotic to work,” wrote Stuart B. Levy, professor at Tufts University School of Medicine, in his introduction to the World Health Organization’s comprehensive 2001 report on the subject. “Multi-drug resistance has become common in clinical settings.”

As bacteria increase their antibiotic resistance in the coming years, Riley and other experts warn, the problem is only going to escalate. “We have this huge crisis that’s going to explode in the next 20 years because we don’t have any replacements for those existing antibiotics,” says Riley.

The Alliance for the Prudent Use of Antibiotics (APUA), headed by Levy, has been monitoring the worldwide emergence of resistant bacterial strains since 1981. According to APUA research, the cost of treating antibiotic resistant infections already amounts to billions of dollars per year. Some experts predict that as resistance to antibiotics increases at a faster pace than it can be controlled, the future will resemble the pre-antibiotic era. Others are more optimistic that global research efforts and careful drug management can reverse the trend.

One key to solving this health care crisis, Riley believes, lies in taking some cues from creatures that have four billion years of bacteria-killing experience. It turns out that we are amateurs when it comes to slaying microbes; the real pros are other microbes. Over the course of hundreds of millions of years of competing for ecological niches in water, soil, and the bodies of plants and animals, bacteria have evolved extremely effective chemical weapons to help them eliminate rival bacteria. And the toxins that these microorganisms produce to kill other microorganisms do their work without promoting resistance in the target populations. While the relatively new antibiotics created in human laboratories have lost much of their usefulness in just a few decades, the ancient antibiotic chemicals that microbes deploy against one another are still going strong.

“What we’re doing is not working,” Riley says. “What they’re doing has worked and worked, and still works, so why not look at what they’re doing and adopt their approach? One of my research goals right now is to illustrate for pharmaceutical companies and for medical doctors that we should be thinking in an entirely different way about how to make drugs and how to use drugs.”

When Riley refers to pharmaceutical companies she is, to a certain extent, talking about herself: She recently co-founded a company that aims to turn her microbial research into drugs that offer a radical new solution to the problem of antibiotic resistance. And when she mentions medical doctors, she is talking about what she almost became: In 1980 she arrived on the UMass Amherst campus with visions of med school. She credits this university with helping her discover her true vocation as a research biologist.

Riley grew up in Walpole, the daughter of a computer salesman and a stay-at-home mom who raised six children. (Her mother, Jo Ann Sprague, enrolled at UMass Boston in her forties as an undergraduate, and went on to a career in state politics. She recently retired after 12 years in the state legislature.) Although he raised his family in Massachusetts, Riley’s father is a Midwest native and an alumnus of Michigan State University. Peg spent her first two years of college living with an aunt in East Lansing and attending her dad’s alma mater, then transferred to UMass Amherst. That started a relationship that finally brought her back to this campus last year as a full professor and director of the acclaimed graduate program in organismic and evolutionary biology.

Riley says she was always more interested in outstanding professors than in any particular subject matter. She abandoned plans for a medical career when she met the late zoology professor David Klingener and felt his intellectual charisma steering her imagination in a new direction. “I took his course on comparative vertebrate anatomy,” she says, “and by the second lecture I knew that this man was special. I didn’t care about the topic so much, but listening to him I just thought, ‘This is an extraordinary educator.’ From that day on I never wanted to be anything but a research scientist in biology.”

She completed her bachelor’s degree, with Klingener as her honors thesis advisor, and stayed on to earn a master’s. Having concentrated on mammal biology as an undergrad, she began exploring the evolution of microscopic single-cell organisms as a graduate research assistant in the laboratory of geneticist Bruce Levin (now at Emory University in Atlanta). That was the beginning of her involvement in the microbial research that has since become central to her career.

After earning her PhD at Harvard, Riley returned to Levin’s laboratory on a postdoctoral research fellowship. “Bruce taught me the power of using microbes to answer questions that couldn’t be addressed with mammals,” she says. “With microbes, you could actually run experiments in the lab that were evolution experiments. You had a sort of hands-on tool to get at some really big questions in evolution.”

Bacteria reproduce so quickly, she explains, that the evolutionary process of natural selection becomes something scientists can observe in action in the lab, not just piece together from the fossil record. In the case of antibiotic resistance, for example, researchers can watch a drug kill off maybe 99,999 out of 100,000 bacteria in a given colony, or even 999,999 out of a million, then watch the few survivors multiply overnight into a population of millions of drug-resistant microbes.

At the conclusion of her postdoctoral fellowship, Riley landed a job at Yale. She taught there for 15 years until UMass Amherst hired her back in 2004, putting her in charge of her own research laboratory in the Morrill Science Center. “My lab at Yale was probably twice as big, four times more expensive, and yet this one feels like home in a way that Yale never did,” she says. “So I’m really thrilled.”

In her campus laboratory, Riley will be using her four-year NIH grant to study the genes that confer antibiotic resistance on strains of bacteria in the wild. She has studied microbes that evolved deep in the Australian Outback, far from hospitals, sewage treatment plants, and other sites where humans use antibiotic chemicals, and has found that some of those wild microorganisms already possess genes that would enable them to resist the chemical weapons in humanity’s medical arsenal. By comparing the bacteria that have evolved this resistance in the wild with those that have developed resistance in response to human use of antibiotic medications, she hopes to expand the knowledge that medical researchers can bring to bear on the problem of drug-resistant disease organisms.

Meanwhile, at her off-campus pharmaceutical company, which she co-founded with Smith College biology professor Rob Dorit, she pursues the development of new drugs based on bacteria’s own bacteria-killing expertise. Riley and Dorit met as grad students at Harvard and later were colleagues on the Yale faculty. Since they both lived in the Pioneer Valley while working in New Haven, Dorit explains, they carpooled for the long commute. They spent hours on I-91 talking about their mutual interest in the biochemistry of bacteria, and finally decided to pool their efforts in the form of a small but ambitious drug research company.

Riley brings to the partnership an expertise in the genetics behind bacteriocins, the toxins that bacteria use against one another. Dorit brings long experience with what he describes as “experimental manipulation of molecules.” In this case, that might mean snipping off key molecules from two or more bacteriocins and grafting them together to create an enhanced biochemical weapon. One molecule might help the toxin attach to a specific cell surface receptor, while another might provide especially effective killing power once the lethal compound has penetrated to the cell’s interior.

To explain what makes bacteriocins preferable to the antibiotics now in use, Riley likens warfare in the microbe realm to the childhood game of rock-paper-scissors—a constant cycle featuring three combatants each of whom wins in competition with one of its rivals and loses in competition with the other.

“Rock beats scissors, scissors beats paper, paper beats rock,” Riley concludes. “That’s how they’ve won the resistance game. They’ve created a system that continually moves through this dynamic, which means that the population will always have the ability to either resist something or kill something or be sensitive to something.”

A crucial aspect of this bacterial rock-paper-scissors cycle is the fact that the toxin involved is lethal just to one strain of bacteria, so it does not massively disrupt the body’s ecosystem as do the antibiotics produced by today’s pharmaceutical industry. As Riley sees it, one of the biggest challenges she faces will be persuading industry to change its thinking and embrace the “entirely new paradigm” suggested by her research. “We have to get pharmaceutical companies to understand that making 50 different drugs is better than making one drug that will lose its efficacy in 10 to 20 years.”

So far, Riley says, she and Dorit have experimented successfully with bacteriocins that work against the microbes responsible for urinary tract infections. If they meet with continued success, Dorit ventures to predict, they might be able to bring their first new-generation drug to market in the next three to five years. “If we concentrate on getting the science done well,” he says, “all the rest will happen.”

Riley agrees, with guarded optimism. “I see good things ahead. But it’s the transition of basic science into practical science, and you never know.”

The Microbiology of Antibiotic Resistance

Often, antibiotic resistance is conferred by a change in some existing gene, a random mutation, that either allows the bacteria to pump the offending toxin out of the cell, limits its entry into the cell, or renders it inactive by cellular enzymes. However, these mutations, which save the bacteria when it is exposed to a drug, tend to impose burdens that make it difficult for an organism to perform necessary biological functions. In a nontoxic environment, a cell with normal receptors can nourish itself better than the mutant and therefore enjoys a competitive advantage. A Kevlar vest furnishes a rough analogy. In certain environments, where bullets are flying, the vest provides a distinct survival advantage. In the absence of gunfire, however, it puts the wearer at a disadvantage by impeding speed and agility. But since antibiotic drugs attack microbes through their cell surface receptors, a cell with an abnormal receptor, a proverbial Kevlar vest, enjoys a natural defense when a microbe colony comes under antibiotic attack. Surrounding bacteria succumb to the drug, die off, and do not pass on their genes to subsequent generations, while the mutant survives and reproduces so that its genetic resistance to the drug quickly becomes the norm in that colony.

A Microbial Game of Rock-Paper-Scissors (R-P-S)

Utilizing bacteria’s natural cycle of resistance and dominance offers a more targeted means of treating infections, versus antibiotics’ “buckshot” method.

1. A colony of E. coli resides in your gut (S). When a rival E. coli (P) raids in an effort to take over that niche, the invaders produce a toxin specifically designed to kill off the resident bacteria that currently occupy the contested piece of intestinal real estate.

2. A small number of the invaders commit suicide as they produce potent toxins that kill the resident strain. The outcome is a rapid displacement of the resident with the rival strain of E. coli. Although some cells die in the production of toxin, the outcome is their closest relatives’ taking over the valuable niche. The original occupants (S) are dead. A minority of original cells has mutations that make them resistant to the toxin (R), but are vastly outnumbered for the time being by the successful invaders (P).

3. Once the sensitive residents are killed, the process of producing toxin becomes too costly and the resistant strains (R) begin to outgrow the producers. The second stage is the transition between the producers and resistant cells. The resistants can feed themselves and reproduce more efficiently for two reasons. They are not diverting any of their energy to produce toxin and they are not dying from the presence of the toxin. Aided by these advantages, they soon reproduce themselves in such numbers that they become the dominant presence (R).

4. As the resistant bacteria increase their numbers and crowd out the toxin-producers, a few cells have mutations that recreate the sensitive state (S). These newly created sensitive strains have an advantage over their resistant relatives: they can exploit the local nutritional resources more efficiently and reproduce in numbers that quickly return them to dominance. It’s a continuous cycle. The sensitive strain of bacteria loses to the toxin producers (P); they in turn lose to the resistant strain (R); then the resistants lose to the sensitives (S).

By Chris O'Carroll

http://www.umassmag.com/Fall_2005/Peg_Riley_Wants_a_New_Drug_936.html

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