Lucy Shapiro

Lucy Shapiro began playing the piano at age four. When the time came to think about high school, her parents suggested that she audition for a public institution in Manhattan, the High School of Music and Art. Family resources were limited and her local school was academically weak, so this possibility seemed like an excellent solution for the brainy teenager. Convinced that she was a mediocre musician, Shapiro taught herself how to draw during the year before her entrance exam. Unbeknownst to her parents, she checked the “art” rather than the “music” box during the application process. To their surprise, Shapiro’s painting portfolio provided her admittance ticket.

That incident illustrates Shapiro’s independent vision, and it taught her that she could influence her life’s trajectory. She has pioneered a novel approach to studying development and has spawned a new field. Her work has revealed how a particular bacterium coordinates its activities in time and space to generate two distinct offspring, a process that parallels stem cell division. In 1989, Stanford University recruited Shapiro to build its new Department of Developmental Biology.

As an undergraduate at Brooklyn College, Shapiro majored in fine arts and biology; given her passion for drawing, she planned a career in medical illustration. Around graduation time, she was showing her paintings, and Rockefeller University physical chemist Ted Shedlovsky sought her out at the exhibition. A friend thought he might want to meet her, as he had a history of encouraging young artists to explore science.

Shedlovsky gave Shapiro word puzzles and decided that she was sharp. He convinced her to take an organic chemistry course. Although she had not completed the prerequisites, she dove in.

The class introduced her to an invisible world that followed logical rules. In her senior paper, Shapiro had explored why Dante Alighieri wrote the Divine Comedy in the vernacular rather than Latin. Although the topic interested her, she found it intellectually soft, as her conclusions were subjective and untestable. Organic chemistry offered a welcome contrast. Furthermore, it was visual. In her mind, she could see three-dimensional molecules and picture their reactions, which somehow combined to create life’s activities. Rather than looking back and recapturing history, she decided to discover the unknown. She embarked on a Ph.D. in molecular biology.

Throughout her graduate training, Shapiro wondered whether her findings from test-tube studies of cell contents reflect behavior inside cells. The bacterial cell resembles a factory, with many components and activities that influence one another in complicated ways. Pulling the cell apart and studying each piece separately, she reasoned, would not illuminate how the entire system operates. Furthermore, cell extracts lack the three-dimensional structure of their living counterparts. When she established her own lab, she set out to understand how the cell functions as an integrated network, including how the genetic circuitry coordinates its activities in time and space.

Shapiro wanted to start by probing how cells allocate their contents during cell division, when each daughter must receive the appropriate components. She decided that she should identify a single-celled organism that divides asymmetrically so she could map molecules and structures relative to a known position—such as an appendage that can easily be seen through a microscope.

Shapiro hunted in the scientific literature for a creature that would lend itself to her studies and pinpointed the bacterium Caulobacter crescentus. When it splits, one daughter—the swarmer cell—carries at one of its poles a flagellum, a tail-like apparatus that helps it swim; the other daughter carries at one of its poles a stalk, which tethers it to a surface. After cell division, the stalked cell begins the cell cycle again, whereas the swarmer’s cell-division activities are blocked until after it propels itself to a new location and replaces its flagellum with a stalk.

At each point in the cell cycle, specific machinery performs required tasks in a controlled fashion. For instance, a particular group of molecules copies DNA, once per cycle—and different equipment constricts the cell’s middle to pinch off into two daughters, but only after a single DNA copy has been placed in each half. These activities and many others must respect temporal rules to ensure efficiency and avoid chaos.

By the late 1990s, new techniques allowed genome-wide analysis that revealed the genetic underpinnings of this process. Shapiro and graduate student Michael Laub showed that a large subset of C. crescentus genes turn on and off at specific times during the cell cycle.

Shapiro discovered that three regulatory proteins—DnaA, GcrA, and CtrA—run the show, acting consecutively to spur activity of numerous genes. The cascade unfolds properly in part because generation of dnaA and ctrA messenger RNAs—the templates for the DnaA and CtrA proteins, respectively—is influenced by whether chemical decorations called methyl groups adorn one or both strands of their DNA. At the beginning of the cell cycle, both strands carry methyl groups; in contrast, newly synthesized DNA has not yet acquired the embellishments. The methylation state of any stretch of DNA therefore depends on how recently the copying machinery has passed. Consequently, activity from the dnaA and ctrA genes rises and falls as they are duplicated. Shapiro showed that sequential changes in the chromosomal methylation state couple the progression of DNA replication to cell-cycle events that are conducted by the many genes that are regulated by DnaA, GcrA, and CtrA.

Moreover, this system displays further complexity and sophistication. For example, in addition to governing other genes’ activities, CtrA suppresses DNA replication until the appropriate time, and DnaA enables DNA replication to begin.

As she was establishing crucial features by which temporal control of molecular machinery drives the cell cycle forward, Shapiro was investigating the spatial dimension. In the early 1990s, she contributed significantly to a major shakeup in how scientists view bacterial cells. According to conventional wisdom, most bacterial proteins disperse themselves evenly inside cells and their surrounding membranes. In this scenario, bacteria are like swimming pools: Proteins float everywhere.

Shapiro and two postdoctoral fellows, Dickon Alley and Janine Maddock discovered that proteins called chemoreceptors sit near the flagellum in C. crescentus and at the cell’s poles in the laboratory workhorse, Escherichia coli. As the latter organism produces identical daughter cells, the observations established the principle that sequestration of proteins to particular sites is not a Caulobacter quirk.

A few years later, Shapiro showed that some of Caulobacter’s geographically picky proteins exhibit this feature only at certain points of the cell cycle. One of them activates CtrA, the regulator protein that also quashes the initiation of DNA replication. By being in the right place at the right time, the CtrA activator ensures that the cell copies its DNA only once per cell cycle. These findings and others from Shapiro’s lab bolstered the realization that bacteria are not tiny sacs of jumbled molecules. Rather, the microbes place their components in specific locations at specific times.

Shapiro uncovered many other layers of cell cycle choreography. By the turn of the 21st century, scientists had known for decades that genes reside at particular addresses on chromosomes, but like proteins, the genetic material was thought to drift freely within bacteria. A few regions of chromosomes—the spots where DNA replication begins and ends, for example—were known to occupy specific spots inside the cell, but information about other chromosomal sites was scarce.

With time-lapse microscopy and fluorescent tags, Shapiro showed in 2004 that each chromosomal region moves in an orderly fashion—as it is duplicated—to a set location in the new daughter cell. DNA that is copied early sits near the cell’s stalked pole and that which is copied later lies close to the plane of cell division. Shapiro thus established that bacterial genomes adhere to a much higher degree of spatial organization than previously thought.

She then delved into the details by which cellular equipment facilitates movement of Caulobacter chromosomes. The portion that is replicated first travels rapidly to the other pole. The subsequent series of highly orchestrated events ensures that the cell division apparatus does not start to form until chromosomes have begun to segregate to the daughter cells.

These findings and a multitude of others have unveiled the process by which a simple organism deploys complex strategies and integrates them in time and space to display hallmark morphological and biochemical features at different times. Shapiro has conducted much of her work since 1995 with her husband, physicist Harley McAdams. They teamed up scientifically after her constant exuberance about the intricacies of Caulobacter biology seeded in him the idea that strong analogies exist between control of biological and electrical systems. Together, they began validating this hypothesis with a cross-disciplinary approach. In the lab, they literally put physicists next to bacterial geneticists, and electrical engineers next to biochemists. Much of their subsequent work would not have happened without the resulting collaborations, Shapiro says.

Insights into the Caulobacter cell cycle resonate beyond the bacterial world; in particular, the process shares similarities with stem cell division. In both cases, two distinct cells arise, one of which is identical to the parent and one of which is not. Shapiro is providing a detailed description of how a single genome is read to produce two different outcomes, a phenomenon that underlies multicellular life.

In addition to providing information about basic biology that might eventually foster medical innovations, Shapiro has collaborated with Stephen Benkovic (Penn State) to design new drugs that combat microbes. They have constructed a novel class of small molecules, unusual in their possession of a Boron atom. This work has produced one of the two new antifungal agents in 25 years.

Shapiro credits much of her success to her roles as a mother and grandmother. Her children anchored her and provided a stable core and richness to her life.

In 2011, Shapiro won the National Medal of Science. In a video to mark the occasion, she gives advice to the next generation that she clearly has followed herself: “Do whatever is your passion and love it very deeply. Have a rich, worthwhile life that you can look back on with great joy and with pride.”

Author: Evelyn Strauss, Ph.D.