Formidable sexual promiscuity. That’s not the teaser for a pornographic video but a serious health threat that humans face. It’s the term microbiologists use to describe bacterial sex, the ancient process that contributes to the very modern scourge of antibiotic resistance, which could account for 10 million deaths a year by 2050.
Bacteria and fungi created natural antibiotics eons before drug companies turned them into medicines. To counter these natural microbe killers, bacteria and other microbes also created fiendishly effective antibiotic-resistance mechanisms long before humans started pumping antibiotics into humans and livestock. While overuse of antibiotics has been fingered as the driver of resistance to these drugs, the contribution of bacterial sex plays an underappreciated role, one that could bedevil efforts to fight antimicrobial resistance.
I’m a microbiologist by training, and I continue to be fascinated by all things microbial. For the past four years, I have been working on a biography of Esther Lederberg. With her husband, Joshua Lederberg, and their colleagues, she turned the light on bacterial sex 70 years ago, work that continues to inform our understanding of bacterial genetics and antimicrobial resistance today.
Before going further, a brief lesson from Genetics 101 may be helpful. In humans and other multicellular organisms, genes are largely confined to chromosomes which, in turn, are confined to the nucleus of each cell. Bacteria are different. They have no nucleus and their genes reside in two places: Most are located on the single, main chromosome; others sit outside the chromosome in small genetic elements called plasmids. These are cleverly designed to be shared with other bacteria.
Since the 1800s, scientists have known that bacteria reproduced by fission: A cell simply splits in two, resulting in two genetically identical daughter cells.
In 1946, Joshua Lederberg and Edward Tatum astonished the genetics world with their discovery that bacteria could exchange genes through a process now known as conjugation. It’s really a form of bacterial sex which, oddly enough, is entirely separate from bacterial reproduction.
Conjugation occurs when two bacteria — a donor and a recipient — sidle up to each other. The donor creates a tube, called a pilus, that attaches to the recipient and pulls the two cells together. A plasmid from the donor passes to the recipient, providing the recipient with new genetic information. This process, also known as horizontal gene transfer, won Joshua Lederberg a share of the 1958 Nobel Prize in physiology or medicine.
A year after the initial discovery of bacterial conjugation, Joshua Lederberg married Esther Zimmer, who had just earned a master’s degree in genetics from Stanford University while working in Tatum’s lab. The young Lederberg team — Joshua was 22 and Esther 24 — moved to the University of Wisconsin, where they began to explore the strange world of bacteria sex.
Esther Lederberg was an exceptionally talented bench scientist. Her remarkable powers of observation and creativity helped put bacterial genetics at the center of DNA research in the 1950s. One of her important findings led to the discovery of the fertility factor, which she called the F-factor. Its presence makes a bacterium a donor cell. F-factor was the first plasmid identified. Others soon followed, including the R-factor (R for resistance), which combines the F-factor and antibiotic resistance genes.
Esther Lederberg also discovered how viruses spread bacterial genes. One day in 1950, she observed that something seemed to have been nibbling at the edges of some of her bacterial colonies. She eventually identified the culprit: viruses hiding inside the chromosomes of their bacterial hosts. This kind of virus, known as a bacteriophage, is usually dormant. But when activated by some environmental stress, it emerges from dormancy, multiplies inside the bacterium, then erupts, killing its host and spewing copies of itself — along with some of the bacterial genes it had been hiding between — into the environment. These copies then infect nearby bacteria, and the cycle begins again. This process, known as specialized transduction, is another type of horizontal gene transfer.
The identification of F-factor and bacteriophages suggested a dynamic dimension to bacterial genetics.
Since the discovery of penicillin in 1928, more than 100 antimicrobial drugs have been developed. These drugs have saved countless lives. But they also have a dark side. The overuse of antibiotics has encouraged the emergence of terrifying, drug-resistant organisms, such as methicillin-resistant Staphylococcus aureus (MRSA) and other so-called superbugs.
An early indication that bacteria could develop resistance to antibiotics was seen in the aftermath of dysentery epidemics in Japan following World War II. Scientists assumed that the appearance of drug-resistant bacteria “was the result of a predictable process,” wrote Tsutomu Watanabe, who communicated the Japanese findings to Western researchers in the 1960s.
The predictable process he was referring to is natural selection: Spontaneous genetic mutation conferring drug resistance occurs in a bacterium, and the resistant strain multiplies in the presence of the drug. But Watanabe and his colleagues uncovered another phenomenon at work. They demonstrated that the genes for antibiotic resistance were all transferred together and “at one stroke.” They also concluded that the transfer of the resistance genes occurred within a patient’s own intestinal tract, from harmless E. coli bacteria to Shigella, the pathogen that causes dysentery.
This finding indicated that, in the strange world of bacterial sex, there is no species barrier. To make matters worse, a bacterium that acquires resistance genes also acquires the F-factor, meaning it can turn around and spread those genes to others.
In my former life, I taught biology to high school students. The unit on genetics was a favorite because many students were curious to learn about heritable traits they got from their parents. But imagine an alternate reality in which human genetics was like bacterial genetics. Instead of being able to pass your genes only to your offspring, you could share them with family members or friends — or birds, for that matter — and acquire genes from them. This is the world bacteria live in. “They can exchange DNA as easily as we might exchange phone numbers, money, or ideas,” wrote Ed Yong in his book, “I Contain Multitudes.”
The discovery of bacterial sex provided useful tools for cloning genes and sequencing genomes. The recombinant DNA revolution represents the culmination of technological development that began with the Lederbergs’ bacterial mating experiments. It was only later that researchers appreciated the natural role of bacterial sex in the dissemination of antibiotic resistance.
A modern outgrowth of the Lederbergs’ legacy is the field of metagenomics, the study of microbial populations in their natural habitats. By applying new combinations of powerful DNA-based technologies, scientists can sample, sequence, and study entire microbial ecosystems at the genetic level. Recent studies have uncovered a vast reserve of antibiotic resistance genes throughout domestic and wild habitats. These studies suggest that antibiotic resistance genes are ancient and can be readily accessed by modern pathogens through bacterial sex.
To fight antimicrobial resistance, researchers are exploring strategies to inhibit bacterial conjugation. Some are looking at ways to block the enzymes needed to transfer plasmids. Some are trying to find ways to interfere with the construction of the pilis. Still others are trying to exploit natural mechanisms, such as restriction-modifying enzymes or CRISPR-Cas gene-editing systems, that bacteria use to defend against invading genomes.
Despite discoveries by the Lederbergs and others that bacteria have sophisticated ways to transfer genes and obtain new ones, clinical medicine and the pharmaceutical industry have only recently begun to appreciate the remarkable adaptability and genetic innovation that bacteria possess. As University of Chicago microbiologist James Shapiro once put it, “Bacteria do not have fixed specific genomes, but instead share a vast genome distributed across multiple cells and virus particles.” In other words, beyond the threat of individual pathogenic, antimicrobial-resistant species lies a World Wide Web of sharable genetic information.
That’s likely to complicate the fight against antimicrobial resistance. But it may also offer strategies for preventing the emergence of new superbugs.
T.E. Schindler is a science writer with a background in microbiology research, biotechnology, and education.