The Chemical Biology Institute at Yale’s West Campus

The Science Institutes at Yale’s West Campus Chemical Biology Cancer Biology Energy Sciences Microbial Diversity Nanobiology Systems Biology

Understanding the power of molecules in living systems

hemical biology is the science of molecules in the context of living systems. At the Yale Chemical Biology Institute, our brightest molecular scientists work to synthesize, build, and manipulate molecules and molecular assem- blies, large and small, to address challenging problems in health, energy, Cand the environment. The Institute provides support for a cadre of Yale researchers who develop and apply the tools of chemistry to understand, control, and discover biology, asking questions both fundamental and applied. At the same time, the Institute o≠ers a training ground for physician-scientists who seek to reinvent drug discovery from the ground floor upwards. Part of a larger, collaborative research community on Yale’s West Campus, the Institute draws scholars from across the life sciences.

Donor support has an important part to play in this mission. The challenge of understanding molecules and manipulating their interactions with living systems is extraordinary, uniting top minds not just in chemistry and biology but also engineering, physics, and medicine. It requires a continuing investment in advanced laboratories, equipment, and specialized support sta≠. Giving in all these areas can help to sustain the Chemical Biology Institute among the nation’s research centers at the very forefront of discovery. Building chemical The Chemical Biology Institute was Synthetic biology is concerned with established on Yale’s West Campus in programming cells and organisms with tools for the problems 2011 under the leadership of Alanna new functions. This work can involve Schepartz, the Milton Harris ’29 ph.d. “cutting and pasting” genetic elements to of biology Professor of Chemistry and professor alter RNA sequences; at Yale, scientists of molecular, cellular, and develop- are taking a broader view to use pro- mental biology. When fully sta≠ed, teins and portions of DNA as well, in an it will bring together twelve principal e≠ort to re-program the genetic code. investigators and a supporting team Natural products biosynthesis explores the of 120 post-doctoral fellows, gradu- machinery cells use to make molecules ate students, and specialists. These and then exploits this understanding to scientists will focus on advancing the make new compounds. By using com- very frontiers of chemical biology to pounds both natural and man-made, discover the science of molecules scientists can alter, perturb, and predict as they relate to living systems and biological interactions. the application of these discoveries to problems in biology and medicine. Next-generation therapeutics, which uses these and other molecular discoveries to The Chemical Biology Institute will fight or prevent disease. expand Yale’s e≠orts in three core subfields:

2 The power of inter- Yale’s institute model supports teams The West Campus, a former pharma- of researchers who bring the perspec- ceutical facility with 434,000 square disciplinary science tives and tools of diverse disciplines to feet of laboratory space, is designed bear on key scientific questions. Open to connect faculty and students across laboratories, flexible workspaces, and the life sciences to benefit both fun- shared instrumentation foster interac- damental and translational research. tion and innovation, and scientists Funding to maintain and update these use state-of-the-art equipment not exceptional facilities—as well as to always available in typical academic hire knowledgeable experts to operate laboratories. To study chemical them—is essential to advancing biology, for example, faculty members the Institute’s work. and students can employ mass spec- trometry, a sophisticated technique that helps to determine the structure and interactions of molecules isolated from cells, tissues, or organisms. They can also call on a support sta≠ of laboratory technicians and comput- ing and instrumentation specialists to manage the massive volumes of data that modern science produces.

3 Yale innovators in chemical biology research Fighting disease not be possible without the West with man-made Campus infrastructure and interdisci- molecules plinary environment,” Schepartz says. One of the biggest Using nature’s arsenal challenges facing the pharmaceuti- When the first map of the human cal industry, explains Institute director genome was published in 2003, scien- Alanna Schepartz, is that it has been tists focused on the protein-coding TEMP-need hi-res very difficult to identify synthetic small regions responsible for genetic traits molecules that influence the activities and basic cellular functions. Vast of proteins whose function depends stretches not coding for proteins were on binding, not catalysis. Natural small labeled as “junk DNA.” Today, research- molecules such as peptides are better ers believe that these non-coding suited for this task, but they are not regions play a key role in regulating able to traffic to the cell interior, where gene expression. They also represent most of these binding proteins are a largely untapped opportunity for “Yale is in a privileged position, intervening in human disease. located. “We want to teach the world with space and opportunity how to use peptides and small proteins Andrew Phillips is deeply interested in as drugs—inside the cell,” she says of to build a visionary organiza- undruggable targets represented by her pioneering work. protein-binding interactions and junk tional model.” —Andrew Phillips DNA. “When it comes to drug develop- Recently, Schepartz’s team discovered a is enthusiastic about the outcome. unique chemical signal that helps small ment, there is no shortage of targets,” proteins exit the vesicle that transports he says. “We just haven’t found the Some of Phillips’ novel compounds are them inside the cell. Now that they’ve molecules that work against them.” already licensed to drug companies found that signal, they can study how for development, but he notes that With the tools of chemical biology, it works and use that knowledge to in a traditional setting, it takes about Phillips is confident this situation design new molecules that enter a cell fifteen years to get from a laboratory will change. His lab looks at biologi- and disrupt so-called “undruggable” discovery to an approved drug—a long cally active natural products—that targets. and financially risky process. is, chemical substances produced by At West Campus, alongside fellow living things, like a snake’s venom or a “Yale is in a privileged position, with chemist Andrew Phillips, Schepartz is tobacco plant’s nicotine—that might space and opportunity to build a vision- furthering this work by developing mol- have structures and functions useful in ary organizational model,” he says. ecules that can enter cells and activate drug discovery. He then works to trans- “The Chemical Biology Institute is well or inhibit genes dependent on a partic- late his findings into “small molecule suited to explore ideas that won’t be ular protein called p53—often referred strategies” to provide the next genera- funded by the pharmaceutical compa- to as the “guardian of the genome,” as tion of anti-cancer therapeutics. At nies. This is bleeding-edge research, but it helps prevent cells from becoming Yale, Phillips is targeting a transcription in five or ten years, it will be maistream. cancerous. “These two projects would factor implicated in lymphoma, and he We are truly defining the future here.”

5 A case of “who all the players are” in chromatin mistaken regulation. “Knowing this is important for understanding healthy cells, but identity it also gives us clues as to what goes Biochemist wrong in conditions like cancer or Matthew Simon autism,” he says. wants to know why cells go rogue. “Many develop- “The regulation of chromatin is a prob- mental disorders and diseases such as lem you can’t study within a single cancer have the property where cells field,” Simon adds. “If you’re serious a path to drug discovery no longer know what type they are,” about answering these questions, Today, the vast majority of drugs he says. “They act out in ways that are you need to work e≠ectively across a available in the clinic target just 20 damaging to the organism.” The secret, number of disciplines, and Yale’s West percent of the proteins involved in he suspects, might lie in chromatin, a Campus o≠ers a great opportunity to disease—often proteins that perform combination of DNA and proteins that do that.” or catalyze a key chemical reaction. forms the nucleus of cells and, among But the remaining 80 percent have other things, helps specify cell type. The role of different jobs, binding to other pro- small molecules This line of inquiry has led Simon to teins, DNA, or RNA. The functions of study the non-coding RNAs thought to in cellular com- these binding proteins are difficult to regulate chromatin. He has developed munication alter with small molecules, so much a chemical technique to make methyl- A chemist who so that proteins in this class have ated histones in a test tube, providing joined the Chemi- been described as “undruggable.” a ready model of what chromatin looks cal Biology Institute in 2012, Jason But recent breakthroughs in chemi- like in the cell. By testing the action Crawford uses genomic information to cal biology are enabling scientists on of non-coding RNAs in this artificial decode how small molecules and their Yale’s West Campus to focus on these environment, Simon hopes to map actions contribute to host-bacteria targets, decoding their functions and creating novel chemical compounds that can work against developmental disorders, cancer, and neurodegen- erative disease.

Our desire is to apply chemistry in a productive way to help society” — Jonathan Ellman

6 interactions. “Bacteria communicate Chemistry in through the exchange of small mol- service to an integrated approach ecules in cellular pathways,” Crawford society to science research explains. “We study these pathways to determine precisely what molecules Jonathan Ellman develops novel they make and how these molecules Chemical Cancer can start or inhibit important processes chemical tools Biology Biology in the cell.” that may well be the forebears of Microbial Core tomorrow’s drugs. “Our desire is to Nanobiology Diversity Facilities For example, a species of roundworm apply chemistry in a productive way is known to carry the bacterium to help society,” he says. Photorhabdus luminescens. When it Systems Energy Biology Sciences hunts and penetrates insect larvae, Ellman is the Eugene Higgins Professor the roundworm regurgitates the bac- of Chemistry at Yale and a professor of teria into its prey, killing the larvae and pharmacology. In the Chemical Biology providing a meal for both. For Crawford, Institute, he designs and synthesizes The 136-acre West Campus is home this is where things get interesting. chemical structures that interact with to an integrated cluster of research biological systems, with the goal of institutes in the areas of chemical Using molecular communications, creating precise tools to make research biology, cancer, nanobiology, systems P. luminescens and related bacteria pro- and discovery more efficient—tools biology, microbial diversity, and en- duce novel antibiotics repelling other that might be applied to new drugs, ergy sciences. Supporting this work competing microorganisms that might diagnostics, or energy storage. are four core facilities shared by Yale’s want to share the meal. Then, with a science faculty: food source secured, it signals its host For example, he recently developed a to begin its reproductive cycle, develop- small compound that blocks an over- • Yale Center for Molecular Discovery ing more roundworms. activated enzyme from functioning • Yale Center for Genome Analysis inside the cell—an action implicated • High Performance Computing While Crawford is focused on the in rheumatoid arthritis, among other Center fundamental actions that underlie diseases. The work demonstrates a disease—“You have to know how it new approach to discovering such “in- • West Campus Analytical works before you can figure out how hibitors,” and the resulting compound Chemistry Core to stop it”—he is encouraged by the is now being used as a starting point These interrelated institutes and core potential for medical applications. in drug discovery. facilities sustain a multidisciplinary “This is a great model to investigate the approach to today’s most pressing Ellman notes that he is particularly action of cellular pathways that may questions of human sustainability— excited to welcome his younger be biomedically relevant,” he explains. health, the environment, and energy colleagues at the Chemical Biology “As we identify the small molecules —and advance Yale University as Institute, such as Crawford and Simon. that drive these processes, we can lay a national leader in scientific teach- “We are creating a nucleus for young, the groundwork for directing similar ing and research. interventions in a therapeutic way, enthusiastic scientists, and West delivering antibiotics or triggering Campus gives them a particular free- key cellular processes against human dom they might not find in a traditional disease.” department,” he says. “We have an opportunity to build something really special here.”

7 To learn more For more information about Yale’s West Campus, please visit: www.yale.edu/westcampus

Photo Credits All photos by Denton Hoyer unless otherwise noted.

Peptide graphic courtesy of ChemBioChem (Volume 12, Issue 7, page 973, May 2, 2011, © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim): cover (middle)

lisegagne/iStockphoto: page 4

Faculty photos courtesy of the Chemical Biology Institute: pages 5–7

smartstock/iStockphoto: page 6 (top left)

04/13 .5 M Printed on 30% recycled, postconsumer-waste paper 8