The Cell’s Integrated Circuit: A Profile of Lucy Shapiro

Relishing her fine arts courses and focusing on painting in high school, Shapiro was also influenced by her biology teacher, so much so that she double majored in fine arts and biology when she entered Brooklyn College in 1958. After graduating in 1962, she met Theodore Shedlovsky, a physical chemist at Rockefeller University in New York, at a group art show that included Shapiro’s work. “His avocation was finding young people in the arts who he thought had potential in science and convincing them to give science a chance,” Shapiro says.

Shedlovsky convinced Shapiro to enroll in an organic chemistry course back at Brooklyn College. Shapiro went to the chemistry department chair’s office to ask for permission to take the course. The chair’s assistant told her that only honors organic chemistry was available that semester. The chair of the department overheard the conversation, came out of his office, and asked why Shapiro thought she should be allowed to take the honors course when she had had no prior college chemistry. Unfazed, Shapiro replied: “Well, I am smart.” Reflecting on the incident, she now says, “I think he took that as a challenge.”

During the class, Shapiro says, she fell in love with the spatial properties of organic molecules, and she found she had a knack for visualizing them in three dimensions—in part, she says, because of her training as a painter. “That course changed my whole life,” Shapiro says. “I thought that organic chemistry was simply beautiful, and it was the impetus for my becoming a scientist.”

The confidence and poise Shapiro showed in her encounter with the chemistry department chair is something she says she’s always possessed. It’s part of what drove her to take on her first faculty position, just months after completing her PhD at the age of 27, and later to build a new department of developmental biology at Stanford University.  

“If you are confident in what you are talking about, and your science is excellent, there is no need to be intimidated by anyone,” says Shapiro. “This is particularly important for women in science.”

Shapiro was a unique thinker from the start of her scientific career: she saw the cell as an integrated system in which biochemistry and genetics are completely interconnected with a living, three-dimensional structure. Over a span of 50 years, she has continued to conduct research that has revealed how the genetics of a cell dictates its spatial dynamics and how this relationship feeds back to modulate genetic regulatory pathways. She was among the researchers who established the field of systems biology, and she brought Caulobacter crescentus, a quirky single-celled bacterium with a flagellum at one end and a stalk at the other, into the limelight as an important model system for studying cell biology and regulatory networks in more-complex cell types. Her work led her to launch a company that developed a successful antifungal drug and a novel eczema treatment. And then, in 1998, she became a scientific advisor to the White House.

High expectations

Shapiro was born in Brooklyn in 1940, the eldest of three daughters. Her mother, Yetta Cohen, was also born in New York, to Russian immigrants. Cohen had a master’s degree in teaching and taught music and reading in the city’s public schools. Shapiro’s father, Philip Cohen, was an immigrant from Ukraine, a self-educated salesman who had never had any formal schooling. Yet Shapiro’s parents had high academic expectations for her. “It was assumed that education was going to be the most important part of my life,” she says. She also learned early on to deal with adversity. Shapiro’s sister, Enid, younger by just 17 months, was born with brain damage. Shapiro was tasked with helping to raise her.

“When you are in the midst of something like that, you don't really see the challenge, it’s just what life is like.” 

After that first organic chemistry course where Shapiro realized that science was her calling, she returned to Shedlovsky for advice. He suggested she apply to work in a few biology labs as a research assistant, and she ended up in Thomas August’s microbiology lab at New York University. It was 1962, and researchers in Norton Zinder’s Rockefeller University lab had recently discovered the first RNA-containing bacteriophage. Tasked with understanding the functions of RNA polymerase, Shapiro and colleagues discovered, in 1963, that Zinder’s phage, F2, used an RNA-dependent RNA polymerase to copy its own RNA genome. Two other labs characterized similar activity in bacteria infected with other RNA phages around the same time.

Shapiro had worked in the lab as an assistant for just six months when Jerard Hurwitz, then a molecular biologist at NYU, asked her if she would like to pursue a PhD. Shapiro was a hard worker in the lab—which later moved to the Albert Einstein College of Medicine—and she was dedicated to catching up to her graduate student peers. She took courses in math, chemistry, biochemistry, and physical chemistry at universities throughout New York City. “Biochemistry opened up the world of the living cell to me, its foundation being exquisite chemistry,” Shapiro says.

She then studied a reovirus with postdoc Richard Bellamy, now an emeritus professor at the University of Auckland in New Zealand. The duo characterized the virus’s oddly behaving RNA and found it to be double stranded—but not before they contracted a serious respiratory infection from the copious virus particles they were generating in the lab for the experiments. It took Shapiro and Bellamy three weeks to recover from the infection.

Shapiro was now fully within the burgeoning molecular biology community, spending summers with her colleagues at Cold Spring Harbor Lab and counting geneticist Barbara McClintock among her most influential mentors.

A new model organism

Almost as soon as Shapiro received her PhD in 1966, Bernard Horecker, the chair of the department of molecular biology at Albert Einstein College of Medicine, asked her to return as a faculty member—and told her that she could work on whatever she liked. “He told me to take three months to read and think. That does not happen today! It was a gift,” she says. Shapiro pored over the literature and concluded that researchers were either busting open cells and performing in-vitro assays to understand the biochemistry of isolated cellular components, or they were conducting genetics experiments to infer the inner workings of the cell. Shapiro saw the limits of both approaches; neither completely satisfied her curiosity about how cells worked.

Molecular biologist Joe Sambrook

Lucy Shapiro

She saw the cell as a dynamic, three-dimensional entity with spatial features that were as important as its genetics and biochemistry. So she formulated two questions that continue to drive her research: How is information on the spatial positioning of the cell’s molecules encoded, and how are the events inside a cell coordinated to yield an integrated system?

To answer these questions, Shapiro first needed to find a suitable model system. She wanted to study a simple cell that had polarity and that engaged in asymmetric cell division—the type of mitosis where two daughter cells differ from each other. She found all of these criteria in the little-studied bacterium Caulobacter crescentus. At that time, Caulobacter could not be easily cultured in the lab, and its genetics and biochemistry were a black box. While many of her mentors tried to dissuade her from starting from scratch with an uncharacterized organism, Shapiro’s self-assurance shone through, and she also had support from McClintock. “She was instrumental in my having the courage to work with Caulobacter,” Shapiro says.

At the time, microbiologist Roger Stanier’s students, working at his University of California, Berkeley lab, had developed a technique to synchronize Caulobacter cultures, which Shapiro took advantage of to study the genes that regulate the bacteria’s cell cycle. She got some help from then Johns Hopkins graduate student Bert Ely, who generated Caulobacter mutants and created the first detailed genetic map of the species. Shapiro spent much of the 1970s and 1980s creating the tools she needed to study the bacterium. In a lab “the size of a broom closet,” she and her lab members cultured and characterized it. They determined the cell cycle control of phospholipid membrane biosynthesis and the synthesis of the polar flagellum and the machinery that moved the cell, which gave clues to how the bacterium’s inherent polarity formed.

Everything is connected—in the cell

In 1986, Shapiro moved to Columbia University to chair the microbiology department. Three years later, she moved again, to build Stanford’s new department of developmental biology from scratch—even though she was essentially a bacterial geneticist.            

Starting in the 1990s, she and her colleagues announced a series of breakthroughs. Two postdocs in her lab, Janine Maddock and Dickon Alley, demonstrated that bacterial cells are highly organized. They showed that both in Caulobacter and in E. coli, the chemoreceptor proteins involved in chemotaxis—the movement of the bacterium in response to particular substances in its environment—are localized to one pole of the cell. The dogma in the field had been that bacterial cells were swimming pools of free-floating proteins with DNA, like an unorganized “ball of spaghetti,” Shapiro says. “It took the community five years to really believe our work that the cell’s proteins and other molecules are dynamically and highly regulated into subcellular domains.” Later, Shapiro and colleagues showed that a similar localization occurs with chromosomal loci on the single circular chromosome.

In 1996, Shapiro’s graduate student, Kim Quon, was looking for mutations that prevented flagellum formation and discovered a master transcription factor, called CtrA, that controls an array of Caulobacter genes necessary to coordinate the cell cycle. “We knew this was big when we all swapped notes in the lab and realized that those working on chemoreceptor genes, flagella genes, DNA replication initiation, and other gene functions all had the same promoter sequence to which this transcription factor, CtrA, bound,” Shapiro explains. The discovery of a master gene regulator was among the first pieces of evidence showing that cells possess integrated genetic circuits, which orchestrate the complex set of cascading events that drive the cell cycle. The lab’s later work uncovered a hierarchical circuit in which one regulatory gene would turn on another set of genes, complete with feedback loops, and so on.

Listening to Shapiro discuss the bacterial cell as a controlled circuit swayed her physicist husband, Harley McAdams, to join her in her research. Shapiro and McAdams opened a joint multidisciplinary lab in which biology students worked alongside engineering and physics students to address how the bacterial cell works as a complete system of genetic and spatial controls.

Their collaborative efforts helped to launch the field of systems biology. In 1995, the pair proposed a model in which the genetic circuitry of the bacterial virus phage lambda parallels an electrical circuit. Five years later, Shapiro’s graduate student Mike Laub completed the first microarray experiment on the bacterial cell cycle, providing a comprehensive view of how all Caulobacter genes are transcriptionally controlled throughout the cycle. “That work told us that the bacterial cell doesn’t just turn genes on or off in response to its environment, but rather that there are hard-wired gene sets that are turned on in a temporal order as the bacterium progresses through the cell cycle,” Shapiro says.  

Her lab may be on the verge of yet another breakthrough. She and her students, along with collaborators, are among the first to study cytoplasm phase separations—non-membrane-bound cytoplasm regions that provide functional organization within the cell—in bacteria. “We’ve all missed this for years, thinking that membranous organelles provide the only structure within the cell,” Shapiro says. Instead, it appears that there are distinct and dynamic membraneless sections that carry out specific biochemical functions.

Such work, Shapiro notes, wouldn’t be possible without exceptionally supportive mentors and students. Mentoring the young women and men graduate students and postdocs that have come through her lab to help them become successful scientists has been among her most important roles, she says. One testament to her mentorship skills is that more than 40 of her mentees are now leading academic labs of their own.

Beyond the lab

In addition to her basic biological work in the lab, Shapiro has also ventured into translational research. Recognizing an increase in infectious diseases around the world and the need for new antibiotics and antifungal agents, Shapiro paired up with Penn State chemist Stephen Benkovic in 1999 to create a new class of antimicrobial compounds using boron—rather than carbon—at the active site of molecules, despite being advised by pharmaceutical chemists that the idea would never work. The two founded Anacor Pharmaceuticals, now owned by Pfizer; one of their compounds is now a Food and Drug Administration–approved antifungal agent, and another is a nontoxic topical treatment for eczema in children and adults.

Sitting in a movie theater recently, Shapiro saw a commercial for the eczema drug. “It was such an incredible and surreal feeling to see our boron-containing drug being touted on the big screen,” she says. “‘If only my mother was here to see this,’ I thought.”

Shapiro served as a scientific advisor to President Bill Clinton, and also to former Secretary of Homeland Security Tom Ridge and former Secretary of State Condoleezza Rice on bioterrorism threats during George W. Bush’s presidency. In 2012, she received the National Medal of Science from then-President Barack Obama. The National Science Foundation made a video, which included her four grandchildren. Her advice to them and others: “Follow your passion, and you’ll have a rich and worthwhile life.”

Heeding her own advice, Shapiro still finds time to paint—mostly when she travels. Her works have been shown in multiple exhibitions, and her portrait of molecular biologist Joe Sambrook will soon become part of the Cold Spring Harbor Lab’s permanent collection.