{"id":13782,"date":"2020-01-08T20:38:09","date_gmt":"2020-01-09T01:38:09","guid":{"rendered":"https:\/\/biology.mit.edu\/?p=13782"},"modified":"2020-10-28T20:43:58","modified_gmt":"2020-10-29T00:43:58","slug":"pushing-the-field-of-chemical-biology-in-a-new-direction","status":"publish","type":"post","link":"https:\/\/biology.mit.edu\/pushing-the-field-of-chemical-biology-in-a-new-direction\/","title":{"rendered":"Pushing the field of chemical biology in a new direction"},"content":{"rendered":"
\n

n 1996, Virginia Cornish had the idea that would define her career in synthetic biology. She had been working in chemistry labs that were trying to imitate, in test tubes, the complex chemistry that occurs in living organisms. Inside a cell, genes code for hundreds of enzymes that are produced to catalyze different chemical reactions. But what if a cell\u2019s natural machinery could be co-opted to do new chemistry, even chemistry that doesn\u2019t occur in nature? She saw the potential for living cells to become tools.<\/p>\n

Stuart Schreiber, now at the Broad Institute of MIT and Harvard, discovered early in his career that a certain immunosuppressant drug worked by allowing proteins in the cell to dimerize, or link together, with proteins they wouldn\u2019t normally interact with strongly. These new protein-protein interactions led to new reactions in the cell. He suggested that other small molecules, or \u201cchemical dimerizers,\u201d could be synthesized that would cause other novel protein-protein interactions, with therapeutic potential to trigger a range of biological functions in the cell, such as gene expression, protein degradation, and apoptosis. But it struck Cornish that chemical dimzerizers could instead be used to screen for specific enzymes in a cell\u2019s genetic library, by dimerizing transcription factors so that they would only activate gene expression in the presence of a specific enzyme. Paired with molecular engineering, this could guide directed evolution in the lab. \u201cI called this chemical complementation,\u201d she says.<\/p>\n

She brought the idea to professor\u00a0Bob Sauer<\/a>, who had just admitted her as a postdoc to his lab in MIT\u2019s Department of Biology. Only three months after she\u2019d begun working with him, Cornish received an unexpected invitation to interview for an assistant professorship in the Department of Chemistry at Columbia University, where she\u2019d gotten her undergraduate degree in biochemistry. She bused down to New York with the plans for chemical complementation in her pocket. By the end of the day she\u2019d been offered her own laboratory.<\/p>\n

The offer was tempting, but Cornish asked Columbia if they\u2019d wait for her to finish her postdoc, and ended up staying in the Sauer lab for two years. Those years turned out to be vital, she says. \u201cI had a lot of biology to learn.\u201d<\/p>\n

A Changing Field<\/strong><\/p>\n

Cornish came to Columbia from Savannah, Georgia in 1987, and joined the lab of Ronald Breslow, who had been chair of the committee that had urged the university to begin admitting female students in 1983. Columbia was renowned for organic chemistry, and Breslow\u2019s work in biomimetic chemistry \u2014 synthesizing molecules in round-bottomed flasks that resemble molecules found in living systems \u2014 was laying the groundwork for the nascent field of chemical biology.<\/p>\n

After graduating from Columbia, Cornish took her rigorous training in organic chemistry West to do her PhD in the lab of Peter Schultz at the University of California, Berkeley. Schultz\u2019s lab had just succeeded in synthesizing unnatural amino acids that could be encoded into a cell\u2019s DNA and fed into its translational machinery to create novel proteins. This was an unconventional project for a chemistry lab, but Schultz was interested in bringing together organic chemistry and molecular biology to manipulate large molecules, even ones as large and complex as those of the ribosome.<\/p>\n

Cornish\u2019s thesis used Schultz\u2019s method of unnatural amino acid mutagenesis to introduce a chemical group called a ketone, rather than an amino acid, into the cell. The ketone could then be tagged with a fluorescent label, and serve as a biosensor for certain chemicals. This was early work in what would later become the field of bio-orthogonal chemistry.<\/p>\n

Excited by the molecular engineering she\u2019d learned in the Schultz lab, Cornish wanted to explore it further in living cells. That meant joining a biology laboratory. She\u2019d heard that MIT\u2019s Department of Biology was a great place to be a postdoc, and was drawn to the molecular engineering Bob Sauer\u2019s lab was doing with bacteria. Then the idea for chemical complementation came to her as she was getting coffee with a friend from the Schreiber lab, and she knew exactly what she wanted to do with her postdoc.<\/p>\n

\u201cThe main thing I remember about Virginia is that she was just fearless,\u201d Sauer recalls. Cornish\u2019s project, to synthesize a small molecule that could be easily adapted to dimerize a large variety of proteins, was a problem the Sauer lab had never taken on before. \u201cAs biochemists, we were interested in protein-protein interactions, and how those mediated networks of genetic regulation, because a lot of the proteins that bind DNA specifically do so as dimers or tetramers,\u201d says Sauer. \u201cShe took it to a different level by thinking about how you can use chemical biology to actually dimerize things.\u201d<\/p>\n

\"\"Cornish remembers the \u201cintellectually vibrant environment\u201d at MIT and the cross-fertilization between labs in the department, and learned as much from other postdocs as from faculty. Petra Levin, a postdoc in professor\u00a0Alan Grossman<\/a>\u2019s lab, spent hours patiently teaching her genetics. At that time, Sauer\u2019s lab held joint group meetings to discuss their research in protein folding and transcription with two other labs in the department at that time, headed by Peter Kim and Carl Pabo. It was the genesis of a larger collaboration, informally known as \u201cthe structural biology supergroup.\u201d<\/p>\n

\u201cI still remember the first time I presented my idea of chemical complementation to this group,\u201d Cornish says. \u201cPeter Kim grilled me for a good fifteen to twenty minutes, going so far as to ask me what my transcription factor was.\u201d<\/p>\n

Sauer\u2019s lab works with\u00a0Escherichia coli<\/em>, but Cornish decided that her model organism of choice chemical complementation wasn\u2019t a bacterium. It was a yeast,\u00a0Saccharomyces cerevisiae<\/em>. Researchers at Johns Hopkins had just found a method for chemically dimerizing proteins in yeast, and it had \u201call the right parts and pieces\u201d that Cornish needed for her own experiment. She began spending more and more time in\u00a0Chris Kaiser<\/a>\u2019s lab next door, borrowing their media to culture yeast. She was introduced to a postdoc in\u00a0Gerald Fink\u2019s<\/a>\u00a0lab, Hiten Madhani, who taught her the fundamentals of yeast genetics. She still has the pieces of paper from their meetings, where Madhani sketched out the yeast plasmids and genetic markers.<\/p>\n

\u201cShe was down the hall learning stuff from the Kaiser lab, over in the Chemistry Department learning stuff from them,\u201d says Sauer. \u201cI provided a bench for her.\u201d<\/p>\n

Synthetic Solutions<\/strong><\/p>\n

When Cornish finished her postdoc and finally took her position at Columbia in 1999, chemical complementation became the foundation for the research in\u00a0her lab<\/a>. Working in yeast distinguished Cornish from other scientists who came out of MIT and were doing similar experiments in bacteria in the early 2000s, synthesizing molecules to work together in living cells \u2014 the first forays in what is now known as synthetic biology.<\/p>\n

Cornish is now the Helena Rubinstein Professor in the departments of Chemistry and Systems Biology at Columbia. She has become a leader in her field, serving on the executive committee of\u00a0Genome Project-Write<\/a>, a group of synthetic biologists that has come together to establish ethical standards and self-regulation of new technologies to edit and synthesize genetic information.<\/p>\n

She stays focused on how synthetic biology can advance medicine and make products that solve real problems. In 2017, the Cornish Group engineered baker\u2019s yeast to detect fungal pathogens and react by turning red, creating a cheap biosensor with the potential to save lives in regions without medical access. Synthetic biologists have, up until now, focused on engineering individual cells, but Cornish\u2019s next project is to engineer entire communities of yeast cells to work together, like our microbiome does, by taking advantage of the complex communication networks between them. Cornish says that in the lab, \u201cthe most exciting moment really is when you\u2019re doing something that you can\u2019t quite articulate.\u201d<\/p>\n

She credits her mentors \u2014 Breslow, Schultz, and Sauer \u2014 with instilling that creative drive in her. All of them were \u201cpushing the field in a new direction,\u201d as she puts it. She pays that mentorship forward to her students. \u201cSometimes there\u2019s a sense that great science and mentorship are at odds with one another,\u201d she says, but she\u2019s found that the opposite is true. \u201cI think the best way to do great science is just to enable your students to be everything that they can be. And then it really becomes an exciting collaboration.\u201d<\/p>\n

Images courtesy of Virginia Cornish<\/h5>\n<\/div>\n","protected":false},"excerpt":{"rendered":"

n 1996, Virginia Cornish had the idea that would define her career in synthetic biology. She had been working in chemistry labs that were trying to imitate, in test tubes, the complex chemistry that occurs in living organisms. Inside a cell, genes code for hundreds of enzymes that are produced to catalyze different chemical reactions. 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