Cell Biology, Systems Biology
University of California, San Francisco
Dr. Lim is also professor and chair of the Department of Cellular and Molecular Pharmacology at the University of California, San Francisco.
Design Principles of Cell Signaling Systems
When Wendell Lim looks at a cell, he sees an opportunity. A tweak here, an adjustment there, and cells could be redesigned to deliver therapeutic payloads, repair cancerous lesions, or attack microscopic pathogens.
Lim thinks scientists can achieve these goals if they have a detailed instruction manual—a sort of user's guide—that explains how biochemical circuits control a cell's function and ultimately its fate. Lim, a biochemist and cell biologist at the University of California, San Francisco (UCSF), is beginning to develop that guide, and the results of experiments in his lab are filling in the details of how these internal circuits control cells.
Lim views cells as biological versions of the tiny submarines in the 1966 film Fantastic Voyage that take scientists directly to the source of a medical problem. They are "complex mechanical and sensing devices that can carry out highly complex tasks," he says, such as secreting antibodies or forming repair structures like blood clots and bone. That's where he intends to take his research at HHMI.
"Biology is on the cusp of a new era," Lim says. "Biology has long been something that mankind has looked at for its beauty and elegance. But I think we need to get beyond that to understand its underlying logic. If we can understand the instruction manual, we can change cells and do things to help solve problems in biotechnology or health," he explains. "It will give us the ability to understand how to treat disease more rationally."
Though he's a biologist by training, Lim's view of the world is influenced by engineers—and he's borrowed a few pages from their playbook. He marvels at the remarkable signaling pathways inside living cells that take in and integrate vast amounts of information about the cells' environment. Cells process and use this information to make complex decisions about how to respond to changing environmental conditions. Lim sees opportunity here, and he's relying on an emerging paradigm in cell biology to help accomplish his aims.
Lim and others have shown that signaling pathways are actually built from modular components. These biological modules are reused in different cells and organisms to accomplish various tasks. An example of one such module is a scaffold protein that can simultaneously bind to many other proteins. Lim describes these molecules as the wiring that promotes efficient communication with the right partners and prevents crosstalk with the wrong ones. But little is known about these critical nodes, he notes, so his lab is trying to figure out how they direct the flow of information.
One way to tease out the contributions of each of biology's modular components, he says, is to build cell signaling systems from scratch. Lim is in the vanguard of the nascent field of synthetic biology, where scientists create new or precisely modified systems by cobbling together biological components. By linking these components into functional systems, this engineering approach offers a way to understand how the pieces fit together. Scientists can also see how new behaviors and capacities evolve if they change the order of the components.
In 2007, Lim's group published research in the journal Nature showing that they could direct cells to take on a desired shape by integrating designer proteins into a circuit that controls how cells form. Their work revealed that it is possible to reprogram cellular circuits with the same dexterity and diversity engineers use to build computer chips.
Building his own systems and tinkering with the components of cell communication pathways has a number of advantages. "We can ask, 'What are the aspects that are there that are really important?'" Lim says. "It allows you to really test what we have learned about natural signaling proteins and networks."
Lim, whose parents are both physician-scientists, has been immersed in science all his life. In high school, he was a finalist in the Westinghouse Science Talent Search, now sponsored by Intel. He says he is "driven by a deep curiosity about how things work." Now he is passing on that enthusiasm to a new generation of biologists.
In summer 2007, Lim opened his lab to a small team of high school seniors to prepare them to compete in the International Genetically Engineered Machine (iGEM) competition at the Massachusetts Institute of Technology (MIT). Teams in the competition are usually made up of undergraduates, who are directed by faculty advisers. UCSF does not have undergraduates, but Lim thought that, with proper training, high school students might represent UCSF and mount a competitive challenge. Lim and his research group worked closely with the students all summer and in early fall, as the team readied for the iGEM competition at MIT in November. The high school students used the tools of synthetic biology to create the beginnings of an artificial organelle inside a cell. Their project received many accolades and bested those from scores of universities, including Harvard, MIT, Caltech, and Princeton.
"I wouldn't be where I am if I hadn't had an opportunity to get into research at an early age," Lim explains. "One thing I am interested in trying to convey to young people is just how fun and interesting and creative science is."