Drug resistance: Can targeting evolution be the solution?

Science has given doctors more and more powerful drugs to deploy against infectious diseases and cancers in recent decades, and yet many new therapies have failed to live up to their promise. Andrew Read has some ideas about how to change that.

As an evolutionary biologist, Read views much drug therapy as an impossible game of “whack-a-mole,” where microorganisms and cancer cells evolve and change to resist drugs and survive. Speaking to writers at the New Horizons in Science briefings presented by the Council for the Advancement of Science Writing during the ScienceWriters2019 conference in State College, Pa., on Oct. 27, Read suggested that more and powerful drugs may not be the solution. Instead, he called for managing evolution to prevent the emergence of drug resistance in the first place.

Each year, Read said, 650,000 Americans die from evolution—40,000 from drug-resistant infections and 610,000 from drug-resistant tumors. Pressure from drugs creates populations of microbes and cancer cells that survive because of genetic mutations that protect them from the drugs designed to eliminate them. Read, a professor of biology, entomology, and biotechnology at Penn State University, believes that researchers should look for ways to slow or stop the evolution of resistant cells. He hopes new strategies can clear the way for common drugs to ultimately wipe out the enemy army before it has a chance to develop its evolutionary weapons.

Antibiotic resistance in bacteria has been widely reported, but Read noted that evolution is a challenge across the spectrum of disease. The influenza virus tends to mutate just enough to disguise itself from last year’s vaccine, so that a new flu vaccine must be released each year to keep up. And like bacteria, cancer cells—which are mutated normal cells—can undergo further mutations that make them drug-resistant. When drug-sensitive cells are killed and resistant cells have free rein to replicate, the result is often the start of a relapse.

Resisting the resistance

Instead of targeting the enemy with new weapons, Read asked, what if medicine could prevent the enemy from forming in the first place? He described two approaches.

The first would take a cue from two types of therapy that have more or less beaten evolution already: vaccines and combination therapies. Unlike antimicrobial and antiviral drugs and standard cancer chemotherapy, vaccines remain effective even as a disease mutates and evolves. Timing and targeting make the difference. Vaccines are given as preventive measures when pathogen populations are low, mutations are few, and transmission is unlikely. Drugs are given after a disease has already progressed.

And unlike drugs, which are aimed at specific parts of a pathogen, vaccines are multi-targeted packages of weaponry designed to equip the patient with a broad immunity. Combination therapy, treatment with two or more drugs, has likewise been successful with HIV, tuberculosis, and acute lymphoblastic leukemia (ALL). Read called for broader use of combination therapies to prevent evolution and reduce the need for new drugs.

As a second approach, Read said there is a need for anti-evolution drugs to wipe out resistance itself so that other drugs can do their job. In a 2017 article published in the Proceedings of the National Academy of Sciences, Read and several colleagues examined competition-enhancing drugs in mice. The mice were infected with malaria parasites, some sensitive to a drug and others drug-resistant.

The scientists manipulated the supply of a nutrient to create conditions where the two populations had to compete for limited resources. The emergence of drug resistance was prevented by the competition. Cancers also develop populations of drug-sensitive and drug-resistant cells, he noted, and it might be possible to change drug timing and doses to use competition to manage resistance evolution.

Read also had some radical thoughts about prescribing practices. Health care providers routinely stress the importance of always finishing a prescribed course of antibiotics. The concern is that if you don’t kill all the bacteria in your body, any left over are more likely to be resistant. Read said the length of a prescription can be arbitrary, not adjusted to take account of evolutionary dynamics. Is it better to treat with a slow, progressive therapy or a single aggressive one? Where is the line between under-treatment and the evolution of resistance? These questions are the subject of continuing studies.