Pioneering approach to bacterial cell biology & national leadership

To probe this issue, Shapiro scouted for a simple organism that might hold answers. To tackle the spatial element, she sought a creature that displays distinguishable structures at each end—and that produces distinct daughter cells. She landed on the bacterium Caulobacter crescentus. When it splits, one of its progeny possesses a stalk that secures it to a surface and the other carries a flagellum that propels it to a new location before it settles down to reproduce. Shapiro aimed to discern how this microbe’s genome governs this asymmetric division.

Shapiro’s approach caught the attention of leaders at Stanford University, who were looking for someone to head a new department of developmental biology. They recognized that she was grappling with the ultimate issue in that subject area: how a single cell and its genetic cache specifies instructions for cells that are programmed differently, an achievement that undergirds multicellular life. Shapiro was an unorthodox choice, given that multicellular animals such as flies and worms—not unicellular bacteria —undergo development. But Stanford appreciated her brilliance, charisma, and leadership qualities, and lured her from Columbia, where she had taken a faculty position several years earlier. At the helm, she recruited visionary investigators who were also opening research arenas. Stanford’s Department of Developmental Biology has flourished. Out of the 28 tenured faculty in this department since its inception in 1989, 14 have been elected to the National Academy of Sciences.

Space for new ideas

Conventional wisdom held that bacteria resemble scrambled bags of drifting enzymes and structural proteins that also harbor a floating chromosomal tangle. Yet, in 1993, Shapiro found that chemoreceptors, proteins that sense the external environment, cluster at the cell poles not only in C. crescentus, but in the laboratory workhorse, Escherichia coli.

Many years later, she identified a protein that not only homes to a particular spot, but does so at a specific point in the Caulobacter cell’s life cycle—right after it begins copying its DNA. This protein spurs a key regulator that Shapiro discovered, CtrA, to thwart the initiation of DNA replication. The system, she observed, ensures that the cell duplicates its genetic material only once per division.

She unearthed numerous other strategies by which the bacterium coordinates its tasks. For instance, as the DNA-copying machine moves along, it creates new, naked strands that initially lack chemical adornments called methyl groups. Consequently, recently made DNA is methylated on only one strand of its double helix, whereas the original, older DNA bears these embellishments on both strands. The methylation state influences the activity of several genes whose products play central roles in cell division and differentiation into stalked or swimmer cells, so an entire web of genes turns on and off—with precision—as the replication machinery travels. Sequential changes in the methylation state of the chromosome thus drive the cell cycle forward. This setup synchronizes DNA replication with genetic events that undergird subsequent steps, such as the physical separation of the two daughter cells.

Gradually, Shapiro filled in her picture of how Caulobacter integrates specific molecular movements and behaviors in space as well as time. For instance, the cell destroys CtrA in the half that is destined to become the stalked daughter, liberating it to begin DNA replication immediately upon starting its independent life. In the meantime, CtrA quells this process in its sister, which must swim to a new home before beginning to divide. This sharp segregation underscored the misconception that bacteria contain a chaotic soup of proteins.

Shapiro found that bacterial chromosomes, too, demonstrate exquisitely tuned physical choreography—and they adhere to a much higher degree of spatial organization than previously believed. Rather than wafting randomly here and there, they relocate with timed precision to designated spots in daughter cells before division even finishes. As soon as DNA is made, it harpoons across the cell to its new residence in the future swarmer cell. As replication continues, DNA spools out and homes to its destination, exactly opposite to where it came from.

Shapiro’s research upended conventional wisdom about bacteria.

Eventually, Shapiro would show—with Stanford colleague William E. Moerner (2014 Nobel Prize in Chemistry)—that membrane-less organelles foster some of Caulobacter’s methodical conduct. For example, rapid and selective entry and exit of particular molecules into and out of compartments at each pole gather distinct subsets of proteins such that each daughter inherits a set of regulatory molecules that dictates its developmental fate.

Since 1995, Shapiro has collaborated closely with physicist Harley McAdams (Emeritus, Stanford University School of Medicine). They began applying principles of electrical circuitry to complex genetic networks, noting that both types of systems must reliably operate under changing internal and external conditions. This advance stands as an early example of systems biology, which deploys computational tools to decipher how living systems function. Shapiro and McAdams integrated their labs to spark fruitful interactions and fresh insights among physicists, biochemists, electrical engineers, and geneticists, thus manifesting the power of cross-disciplinary research, which broke ground at the time.

Along the way, Shapiro has trained 71 graduate students and postdoctoral fellows, more than 30 of whom have become faculty members at research institutions around the world; two dozen of them are running Caulobacter labs.

Shapiro has taken her expertise outside of the lab to advise multiple presidential administrations on bioterrorism, antibiotic resistance, and emerging infectious diseases.

Applying expertise to benefit humanity

Shapiro has also applied her influence and experience in the broader world. By the late 1990s, she was growing increasingly concerned about threats from the microbial realm and, in 1998, President Clinton invited her to the White House to speak to his cabinet about biological warfare. The evening before the meeting, her presentation was vetted and she was reminded that she had five minutes—no more—to talk.

When her turn came, she decided that the next moments of her life presented an unprecedented opportunity, and she went off script. She told Clinton that Nature is a better genetic engineer than any bioterrorist. He asked for an example, so she gave an impromptu lesson on how a harmless strain of E. coli turned into the gastrointestinal pathogen E. coli 0157 by picking up a gene from a different disease-causing bacterium. Responding effectively to a germ, she emphasized, requires the same strategy regardless of whether it emerges from a garage or the environment. She lobbied Clinton and, later, the George W. Bush administration, for federal financing to fund basic research that would illuminate the natural processes that underpin the development of such scourges and deduce how best to protect ourselves from them.

Part of the solution relates to the rising tide of antibiotic resistance and the associated need for new classes of drugs—a situation that pharmaceutical companies are struggling to address. She and chemist Stephen Benkovic (Pennsylvania State University) teamed up to conceive an unconventional scheme with which to confront this challenge. They developed boron- rather than carbon-based compounds, which defied standard pharmaceutical thinking, as boron on its own is toxic. They established Anacor Pharmaceuticals in 2002, which has produced two FDA-approved, topical drugs, one of which subdues ectopic dermatitis and the other fights fungal infections. She and Benkovic have since pivoted to agriculture to co-found a second company, Boragen (now 5Metis), one of whose compounds attacks a fungus that devastates banana plants.

With confidence and ingenuity, Shapiro has sparkled as an investigator, an academic leader, an advocate for basic research, and an entrepreneur. Consistently ahead of her time on all fronts, she has made exceptional contributions to our understanding of cellular life and to the scientific community.

by Evelyn Strauss

Research Articles

Maddock JR and Shapiro L. (1993). Polar location of the chemoreceptor complex in the Escherichia coli cell. Science. 259, 1717-1723.

McAdams HH and Shapiro L. (1995). Circuit simulation of genetic networks. Science. 269, 650-656.

Domian IJ, Quon KC, and Shapiro L. (1997). Cell type-specific phosphorylation and proteolysis of a transcriptional regulator controls the G1-to-S transition in a bacterial cell cycle. Cell. 90, 415-424.

Laub MT, McAdams HH, Feldblyum T, Fraser CM, and Shapiro L. (2000). Global analysis of the genetic network controlling a bacterial cell cycle. Science. 290, 2144-2148.

Thanbichler M and Shapiro L. (2006). MipZ, a spatial regulator coordinating chromosome segregation with cell division in Caulobacter. Cell. 126, 147-162.

Wang J, Moerner WE, and Shapiro L. (2021). A localized adaptor protein performs distinct functions at the Caulobacter cell poles. Proc. Natl. Acad. Sci. USA. 118, e2024705118.

Biographical Articles

Shapiro L. (2012). Life in a three-dimensional grid. J. Biol. Chem. 287, 38289-38294.

Shapiro L. (2022). A half century defining the logic of cellular life. Annu. Rev. Genet. 56, 1-15.