The Skaggs Institute for
Chemical Biology

The Skaggs Institute for Chemical Biology at TSRI was established in 1996 by Aline and Sam Skaggs with a commitment of $100 million through the Skaggs Institute for Research and through their family foundation, the ALSAM Foundation.

The Skaggs Institute's mission is to improve human health with cures for diseases, and to do so by supporting research at the interface of chemistry and biology. In its first six years, more than a dozen principal investigators were recruited from leading academic institutions from around the world. The Skaggs Institute now includes two Nobel laureates, and more than a thousand research papers have been published by scientists affiliated with it.

Skaggs investigators have determined the structures and functions of many proteins and nucleic acids, particularly those involved in cancer and diseases of the immune system. For instance, one lab uses x-ray crystallography to determine the structures of molecules involved in diabetes, anemia, and HIV disease. Another uses nuclear magnetic resonance to study protein-protein and protein-nucleic acid interactions in solution. Targets for therapeutic intervention include macromolecules involved in leukemia, cancer, and mental retardation.

Other investigators are looking at the structural details and folding pathways of RNA molecules, including RNA enzymes, the ribozymes, and the complex machinery of the ribosome, the site where proteins are manufactured inside living cells.

Proteins are of particular interest to several investigators who work in the new field of proteomics, which extends the information we learned from the human genome by studying how the genes are actually expressed in various tissues under normal conditions or in disease states. For instance, what are the genes that are expressed in particular regions of the brain during waking and after sleep deprivation? What are the genes that are expressed in cancer cells? In sleep, pain sensitivity, and thermoregulation? Moreover, two Skaggs investigators are developing probes to analyze which proteins are active in particular tissues and disease states.

Skaggs investigators have discovered new catalysts for chemical reactions of interest to medicinal chemistry, and several of the groups at Skaggs are using antibodies to carry out chemical catalysis. They have developed efficient systems for the synthesis of antibodies, discovered new antibodies that release proven anticancer drugs from the drug precursors within living organisms, and found that all antibodies can convert oxygen into hydrogen peroxide, which may be important in understanding how antibodies evolved.

The actual connectivity of proteins is being scrutinized by a Skaggs team that uses chemical ligation to tie the polypeptide chain into knots. Another team approaches cancer therapeutics by studying nucleic acid repair enzymes. And a third has determined the solid-state structures of human enzymes involved in the processing of nitric oxide, a biological messenger of blood pressure regulation, blood clotting, and neurotransmission.

Living systems and their properties are also investigated by a number of Skaggs researchers. One group has made progress on purely synthetic molecules that indicate how molecular information and nonlinear catalysis can lead to self-organization and emergent properties generally associated with living systems. Another investigates the origins of nucleic acid structure and has discovered an alternative nucleic acid based on threose that can base pair and share information with RNA and DNA. And another uses directed molecular evolution to create nucleic acid enzymes, including ones that can cleave RNA or DNA molecules involved in multiple sclerosis.

Two laboratories have paved the way toward an expanded genetic code by designing separate methods for engineering bacteria to encode unusual amino acids into proteins. These techniques can be used to design completely novel proteins to probe the basic biology of various molecules and organisms.

The fundamentals of how molecules fit together and how they recognize each other is being pursued by another research group, which is synthesizing self-complementary molecules that assemble completely surrounding small targets. These assemblies are used to accelerate reactions, stabilize reactive intermediates, and probe weak intermolecular forces.

Another investigation produces structure-based small molecules for intervention in neurodegenerative diseases, especially those involving the build-up of amyloid plaques in the brain.

Two Skaggs research groups successfully completed the total synthesis of vancomycin, which acts as the last line of defense against life-threatening antibiotic-resistant infections. The last decade has seen the emergence of a strain of Staphylococcus aureus that is resistant to vancomycin's mode of action, in which the molecule binds to the cell wall of a bacteria and arrests its growth. Staphylococcus aureus's resistance involves a subtle, single-atom change in the components of the growing cell wall. The resistance is encoded in the DNA of the organism and this DNA is mobile—it can be passed from one bacterial cell to another, similar to the way in which penicillin resistance spreads.

One research group at The Skaggs Institute is positioned to overcome this resistance by making complementary changes on the synthetic vancomycin, hoping to restore the binding to the bacterial cell wall and overcome the resistant bacteria's defense. Another is using the methods known as combinatorial chemistry to prepare and screen a large number of vancomycin-like molecules for antibiotic activity in a short time. A number of potent antibiotics have already been discovered using this approach.

A completely different approach to the problem of antibiotic resistance is being pursued by another laboratory, which is devising programmable, automated syntheses of libraries of oligosaccharides, which are sugar molecules involved in cell-surface recognition. These libraries can then be screened for new antibiotics, like ones that target bacterial RNA, for example.

The Skaggs Institute for Chemical Biology also seeks to provide a nurturing environment for the next generation of research scientists. Each year it supports more than 200 postdoctoral researchers and an average of 40 graduate students—The Skaggs Institute's most important assets.