Chemical Biology of the Cell

"Cells are the reaction vessels of biology, and chemical biologists and cell biologists are probing many similar questions about cells from complementary perspectives." So said Nature Chemical Biology Editor Terry L. Sheppard last month to introduce the first in a series of annual symposia sponsored by the journal. The purpose of the series is to provide chemists and biologists "with a forum for exchange of ideas," Sheppard said.

Nature Chemical Biology is about a year-and-a-half old, having published its first issue in June 2005. Its first symposium was held in the Boston Museum of Science's meeting room, which featured a distractingly spectacular panoramic view of the city.

The meeting focused on several aspects of the chemical biology of cells. In an opening session on the nucleus and cell division, for example, assistant professor of biological chemistry and molecular pharmacology Antoine M. van Oijen of Harvard Medical School discussed some of his group's recent work on DNA replication.

Van Oijen "showed how one can use single-molecule approaches to learn new things about processes that we thought we understood in a broad sense" but about which important details still have not been worked out, said session chair Ulrike S. Eggert, assistant professor of biological chemistry and molecular pharmacology at Harvard and the Dana-Farber Cancer Institute. Van Oijen and coworkers recently achieved a more detailed understanding of DNA replication by using "new technology that now allows us to make movies of molecules as they function in real time—an exciting and very promising new area of chemical biology," Eggert said.

Van Oijen's group was trying to answer a long-standing question about the mechanism of DNA replication: How do the two DNA polymerase enzymes that work together to copy each of the two individual strands of double-stranded DNA manage to coordinate their separate movements? If the movements weren't coordinated, the two polymerases would drift apart. That could be a bit inconvenient, seeing as they're both components of the same replication complex.

Replication of one of the strands of DNA, called the leading strand, is continuous and progresses much more quickly than that of the other strand, the lagging strand, which has to be copied discontinuously, one fragment at a time. By using bead immobilization, a flow cell, and microscopy to watch the DNA-copying process at a single-molecule level in real time, van Oijen and coworkers were able to confirm that the leading-strand DNA polymerase minds its manners; it pauses periodically to wait for replication on the lagging strand to catch up (Nature 2006, 439, 621; C&EN, March 27, page 40).

Professor of microbiology and immunology Garry Nolan of Stanford University and coworkers also use advanced research tools for single-cell chemical biology studies, in their case to study signaling processes. They employ techniques such as flow cytometry and fluorescence-activated cell sorting to analyze phosphorylated proteins and other molecular markers of interest in populations of single cells. Their goals include studying processes like immune signaling in specific cell subpopulations and determining relationships between cell signaling components.

"This technology has already proven its worth and will continue to facilitate discoveries in two primary arenas": characterizing biological phenomena on a single-cell level and identifying biomarkers to diagnose disease and establish optimal therapies, commented Nathanael Gray, an assistant professor of biological chemistry and molecular pharmacology at Harvard and the Dana-Farber Cancer Institute. Gray chaired the session on cytoplasmic processes at which Nolan spoke.

Professor Akihiro Kusumi of the Institute for Frontier Medical Sciences at Kyoto University focuses not on the cytoplasm but on the cell membranes that encase cells and control their communication with the outside world. "I was very impressed by his creative combination of single-molecule measurements of the diffusional motions of individual membrane proteins with electron tomography data on the 3-D structure of the inner membrane surface," said membranes session chair Adrian Whitty, head of physical biochemistry at Biogen Idec, in Cambridge, Mass. Work by Kusumi's group "provides a particularly powerful demonstration of how integrating experimental techniques that probe the biological world at very different scales can lead to new functional insights," he said.

A chemical biology study of a somewhat slimier nature was described by Joseph P. Noel, a Howard Hughes Medical Institute investigator and professor of chemical biology and proteomics at the Salk Institute for Biological Studies, in La Jolla, Calif. Through bioinformatics, biochemical experiments, and other tools, Noel and coworkers showed how slime mold "uses a unique hybrid polyketide/fatty acid synthase enzyme to make a natural product that has a profound impact on cellular differentiation," said assistant professor of chemistry Sarah E. O'Connor of Massachusetts Institute of Technology, who chaired the session on metal ions and metabolites at which Noel spoke. "This is a wonderful example of how a so-called secondary metabolite can play a crucial role in developmental biology," she added.

Noel's study reveals the molecular mechanism by which the slime mold, which usually exists as an amoeboid single cell, converts itself into a multicellular tower when its bacterial food supply becomes insufficient. The tower consists of a stalk with a spore at the top. The spore is better able to tolerate a dearth of the bacteria the slime mold usually ingests, enabling the microorganism to survive lean times.

The new type of hybrid multienzyme complex that Noel and coworkers discovered is called Steely2. It catalyzes biosynthesis of the core structure of differentiation-inducing factor, a hormone that sparks tower formation by inducing slime mold cells to differentiate into dedicated stalk or spore cells (Nat. Chem. Biol. 2006, 2, 495). Noel believes the new multienzyme complex could be used as a model to design a variety of related enzyme systems for metabolic engineering applications.

Another highlight of the metal ions and metabolites session was a presentation by professor of biological chemistry Jeremy Nicholson of Imperial College London, in which he "beautifully demonstrated how state-of-the-art NMR spectroscopy and mass spectrometry can be used to create metabolic profiles from human tissue samples and biofluids," O'Connor said. These profiles provide a basis for pharmaco-metabonomics studies—the use of "predose" (baseline) metabolic data to predict responses to different drugs and disease treatments in individuals—an important contribution to personalized health care. Nicholson "went on to show how spectroscopic data can be used to both diagnose and better understand the molecular basis of metabolic diseases such as diabetes in human populations," O'Connor said.

In a concluding session, chemistry professor Carolyn R. Bertozzi of the University of California, Berkeley, and professor of physiology and cellular biophysics James E. Rothman of Columbia University were asked by meeting organizers to philosophize a bit about the current status and future directions of chemical biology.

"Twenty years ago, chemistry and biology were still considered separate disciplines," Bertozzi said. "But times have changed for the better, and now we're much more intermingled." Bertozzi noted that studies like those discussed at the symposium point out the benefits of joining chemistry with biology.

But in plainspoken, provocative comments, Rothman cast doubt on exactly how useful biologists consider chemists' contributions. "There's an essential difference between biologists and chemists," he said. According to Rothman, the former have the burden of determining exactly how biological systems work. But apart from discovering new principles of biochemical reactivity, of which there are fewer and fewer, he said, chemists often simply focus on engineering new aspects into cells and tissues by combining technologies in novel ways. Such engineering studies rarely fail, he noted, whereas "if biological experiments are successful 1% of the time, that's pretty good."

For example, he said, "chemists develop probes and give them to biologists with a hope and a prayer that they might make a difference. But what fraction of those truly prove to be useful is something I don't know."

"Sorry to pour cold water on your conference," Rothman added. "Some of the technologies chemists develop will be useful to biologists, but many others won't. I think many biologists have this point of view."