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4 Accomplishments and Challenges in Health and Medicine for Chemistry and Chemical Engineering ACCOMPLISHMENTS IN CHEMISTRY Chemists work on molecular-scale phenomena, meaning they discover mol- ecules that exist in nature and invent both new molecules and new materials. The molecular perspective of chemistry is fundamental to explaining complex behav- iors of biological systems. Therapeutic molecules, generally small organic mol- ecules, are the medicines that change the course and progression of many human diseases. Some of the recent contributions of chemical science to advances in health and medicine were discussed at this workshop and are summarized below. The discovery and development of safe and effective medicines by teams of medicinal chemists in the pharmaceutical and biotechnology sectors have pro- gressed rapidly in recent years. Some of these medicines include angiotensin- converting enzyme inhibitors for hypertension and rate-lim~ting enzyme inhibi- tors in cholesterol biosynthesis by the statin class of drugs for the control of cholesterol levels. There have also been improved therapeutics for depression and schizophrenia by receptor subtype specific ligands, as well as the HIV pro- tease inhibitors and non-nucleoside reverse transcriptase inhibitors for the treat- ment of AIDS. New medicines require new molecules, which emerge from chemical syn- thesis of natural products, synthetic chemical libraries, and rational design. Mol- ecules that arise from nature teach architectural complexity and functional group density, which has evolved into a valid utility in biological systems. Some ex- amples include lactams, stating, macrolides, taxanes, and anthracyclines. The advances in diversity-oriented synthesis methodologies have produced both small focused libraries of specific scaffolds and large libraries numbering mol- 27

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28 HEALTH AND MEDICINE ecules in the millions as sources for screening new disease targets for therapeu- tic leads. The rational design of new compounds has given rise to breakthrough products such as Gleevec, which is the first rationally designed molecule to do specifically what is was designed to do (inhibit Abl-family kineses). The contin- ued advances in synthetic organic chemistry of both natural products and com- plex libraries have provided many advances in the treatment of numerous dis- eases and ailments. New molecular technology, such as the invention of polymerase chain reac- tion (PCR) and DNA sequencers that cart decode millions of DNA bases per day, has revolutionized the context of biology. This has enabled the decoding of the three billion DNA base pairs of the human genome. Additionally, multiple paral- lel signature sequencing analysis (MPSS) has allowed for the observation of the entire transcriptome of a particular type of cell. Chemical biology, a fusion of the two sciences, has come to the forefront in the last decade. This is reflected, among other things, in the name change of several academic chemistry departments to departments of chemistry and chemi- cal biology. Chemical biology applies chemical-scale molecular approaches to elucidate problems in biology and often involves the interaction of small organic molecules with biological macromolecules (DNA, RNA, proteins, membranes, and organelles). A few noteworthy discoveries discussed at the workshop include small molecules that dimerize and activate target receptor proteins, the biosyn- thetic incorporation of unnatural amino acids into proteins at specific sites, com- binatorial biosynthesis of new antibiotics, biosensors to monitor calcium ions in cells and to localize proteins in subcellular locales, the directed evolution of pro- teins to create novel or improved properties, and in vitro selection of nucleic acids with specific binding or catalytic activities. Advances in protein semi-syn- thesis (native chemical ligation and expressed protein ligation) have also led to the creation of proteins with novel properties. Much of the work at the biology and chemistry interface has changed from hypothesis-driven science to discovery science. Human biology is evolving from an information-poor arena to an information-rich science amenable to a systems approach, which will revolutionize medicine from being reactive to predictive to preventive. ACCOMPLISHMENTS IN CHEMICAL ENGINEERING Chemical engineers emphasize a quantitative analysis and design approach to the operation of molecular systems, pursuing advances in chemistry-based products and chemistry-based processes. The application of chemical engineer- ing principles and tools to biological systems, primarily in regard to biomolecular products and biomolecular processes, including those involving cells and tissues, has contributed greatly to a number of advances in health and medicine in the last

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ACCOMPLISHMENTS AND CHALLENGES 29 decade. Some of these accomplishments highlighted in the workshop are dis- cussed below. The development of bacterial, yeast, and animal cell bioreactor technologies for production of therapeutic proteins, including monoclonal antibodies from re- combinant DNA methods, has enabled this powerful new class of drugs to emerge alongside classical small molecule organics. Protein drugs are often capable of focused stimulation of desired cell functions for treatment of disease. This activ- ity is generally not possible with small molecule organic drugs. Proteins are much more challenging to manufacture. Application of biochemical reactor analysis and design approaches, including quantitative kinetics, mass and heat transfer, and fluid mechanics, has led to a series of highly effective protein therapeutics that are presently in clinical use. Examples of these are the protein erythropoietin used for anemia, GCSF for neutropenia, interleukin-2 for boosting the immune system, TNFR for arthritis, and lo-interferon for multiple sclerosis. The design of scalable protein separation processes has been necessary to purify and concentrate these high-value products for therapeutic use. Achieving well-characterized and exceedingly pure moieties in substantial amounts in a re- liable manner and across many trials is critical to clinical effectiveness and gov- ernment agency approval of biological therapeutics. These separation processes are diverse in nature, in accord with the complex characteristics of biological macromolecules and cells, and typically make use of molecular recognition inter- actions employing additional biomolecules specifically generated for targeting particular proteins in solution or on cell surfaces. Novel controlled-release devices derived from synthetic polymers have per- mitted a crucial means to deliver protein and organic therapeutics to patients. Proteins are typically rapidly cleared from the bloodstream and tissues through both relatively nonspecific and specific mechanisms, involving physiochemical transport, enzymatic degradation, and cellular uptake. Quantitative analysis of these dynamic systems of in viva barriers, in terms of chemical engineering pro- cess models, has indicated how proteins might be more effectively introduced into the patient (i.e., in what locations and with what rates). Polymer microspheres containing proteins have been demonstrated to possess the capability for releas- ing the drugs in appropriate locations and with appropriate rates, resulting in improved pharmacokinetic profiles and physiological effects. However, these products generally suffer from problems of initial burst, in which a large portion of the dose is released in the first few hours. Cell therapies have also begun to demonstrate impact in clinical medicine, requiring purification, expansion, or metabolic functions of blood and tissue cell populations in vivo or ex viva. Applications already in practice include immune white blood cell replacement in bone marrow transplantation and extracorporeal liver cell bioreactors for enhancement of metabolic tissue function to counteract liver disease.

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30 HEALTH AND MEDICINE Determination of the most useful candidates for drugs, whether proteins or small molecules, along with how to best deliver them and diagnose conditions indicating their use, benefits from a fundamental understanding of how biomolecular mechanisms govern cell and tissue functions. In collaboration with basic biological sciences, chemical engineering approaches that model molecular processes in cells, tissues, and organs have been successfully applied to yield significant insights into pathophysiology. Prominent examples include analysis of transport phenomena that critically affect tumor diagnosis and therapy, kinet- ics of receptor and ligand processes regulating cell proliferation and migration, and dynamics of cell and substratum interactions involved in biomaterials coloni- zation and immune and inflammatory system responses to host insult and injury. CHALLENGES FOR CHEMISTRY AND CHEMICAL ENGINEERING The scope and pace of accomplishments in chemistry at the health and medi- cine interfaces serve as starting points for deconvoluting the multilayered sys- tems that make up both the normal physiology of human biology and the patho- physiology of disease. There are grand challenges at the interface of chemistry, biology, and medicine that are baffling in their complexity, such as understanding the chemical bases of thought, memory, and cognition; and how to elucidate mul- tigenic contributions to diseases such as diabetes, obesity, schizophrenia, and degenerative diseases. The timeline of discoveries is not clear, but there is opti- mism that personalized and regenerative medicine will be hastened by meeting several of the short-term challenges that exist at the interface of chemistry and . . met 1clne. Chemical engineering tools and principles, including chemical reaction ki- netics, thermodynamics, fluid mechanics, and heat and mass transfer, ought to provide powerful approaches to a number of important challenges in health and medicine in the coming decade. Significant progress toward overcoming these challenges should lead to useful new products from the pharmaceutical and bio- technology industries. We highlight here some challenges that were apparent from the workshop discussion. The name of the presenter who discussed the topic is shown parenthetically after each heading. There is a continued need in health and medicine for advances in syn- thetic techniques. Chemical Synthesis (Joyce) The synthesis of smart nanoscale materials for diagnosis by biosensing and controlled, programmable drug delivery is a current challenge for both chemists and chemical engineers. The power of chemical synthesis will need to be imple- mented for synthesis of molecules at the nanoscale range in order to match spe-

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ACCOMPLISHMENTS AND CHALLENGES 31 cific target structures. The design of self-assembling and template-mediated syn- thetic systems is a current frontier in synthetic chemistry. The synthesis of com- pounds that target specific cell types and specific regions of the cell is also an important frontier for achieving enhanced specificity with regard to mechanism of action. Molecular Design (Danishefsky) New advances in chemistry can lead to the generation of new compounds that can block interactions that are not commonly targeted by current drugs. These include protein-protein interactions, protein-oligonucleotide interactions, and protein-carbohydrate interactions. While genomics can identify potential drug targets, compounds that block or activate these targets will come from chemistry. In addition to continuing to develop new synthetic chemistry, there must be further advances in molecular design methodology. These are required to develop effective inhibitors of some of the attractive targets identified by advances in genomics and proteomics. Because it is known that the assembly of multiprotein complexes is required for many biological processes, the synthesis of compounds that can assemble systems of interacting proteins would be ad- vantageous. Such compounds could be useful for controlling responses due to multiprotein assemblies in applications like vaccine development and control of cellular differentiation. Advances in measurement and imaging that improve understanding of biological function at the molecular level will aid progress in chemical biology. Analytical Chemistry (Hood) Analytical chemistry challenges will continue and will drive the measure- ment sciences at the interfaces of chemistry, biology, and medicine. Advances in analytical chemistry will spur advances in systems biology by enabling the col- lection of information across a wide range of time regimes in cells, tissues, or- gans and individuals. Challenges for analytical chemistry will involve modular- ity, scalability, and dynamic range of techniques, and multisystem computational models for analysis. Advances that reduce the cost of bringing new drugs to market and lengthen the profitable lifetime of existing drugs are vital in providing the benefits of new developments to the public.

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32 Chemical Discovery (Anderson) HEALTH AND MEDICINE The pharmaceutical and biotechnology industries must continue to evolve to meet needs for new blockbuster medicines in an era of market consolidations, tight capital markets, and rising costs. Chemical discovery and development must increase the success rate from the current 10 percent for drug candidates in clini- cal trials, lower the costs (estimated at $250-$800 million per drug developed to FDA approval), and shorten the 10- to 12-year average development cycle. Bioprocessing (Swartz) Further advances in bioprocessing are required to lower the cost of drug manufacturing and provide for faster time-to-market capabilities in order to reap swifter benefits from new discoveries. Directions offering promise include (a) improved methods and devices for global, molecular-level analytical measure- ment of biochemical properties in sensitive, small-scale, high-throughput modes; (b) bioreactor scale-down to facilitate high-throughput analytics; (c) enhanced understanding of cell functions across a spectrum of organisms to increase pro- duction efficiencies of therapeutic biomacromolecules and cells; and (d) cell-free production of biochemicals to reduce capital expenses and obtain increased flex- ibility for process changes. Human Organ Physiology and Pathology (Griffith) New experimental models of human organ physiology arid pathology could offer quantum leaps forward in drug discovery and development. Tissue-engi- neered in vitro organ surrogates could provide an ability to identify the most useful drug targets for affecting human cell function and permit true pharmacogenomic analysis by creating surrogates from a spectrum of human sub- population genetic backgrounds. This same approach could allow toxicogenomic studies in similar manner, for off-target effects of drugs in human tissues; replac- ing animal studies would be a tremendous benefit for multiple reasons. Indeed, it can be projected that the impact of tissue engineering on human health care will ultimately be far greater for drug discovery and development than for patient implants. Research in nanotechnology shows promise for impact In health and ~ met lame. Nanotechnology (Joyce) Chemists could build on the DNA-based nanofabrication technologies that have led to controlled cubic architectures, informational objects based on DNA structures, DNA-fueled tweezers, and other mechanical devices. Nucleic acid

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ACCOMPLISHMENTS AND CHALLENGES 33 chemistry has had notable reach-through polymerase chain reaction (PCR) tech- nology, which has revolutionized forensic science and medical diagnostics. Fur- ther advances in diagnostics using biosensors and gene amplification are in the offing and will be required to enable real-time medicine, including biodefense applications. Oligonucleotide therapeutic candidates are advancing and it is likely that RNA interference (RNAi) will have tremendous reach in the coming decade. Biosensor arrays may evolve from dumb arrays to smart arrays, using smart RNA aptamers. The development of an appropriate chemistry and chemical engineering curriculum is a challenge that must be met to adequately provide the education needed to do interdisciplinary research across the chemistry and biology divide. Incorporating Chemistry into Biology (Dervan) Chemists are becoming increasingly involved in biological research. With the emergence of such interdisciplinary fields as chemical biology and systems biology, chemists are actively working on solving biological problems with chemical approaches. This requires expansive knowledge of both chemistry and biology, which may not be adequately addressed in a chemistry or biochemistry curriculum. There is, therefore, a pressing need for a revised curriculum that stresses the use of chemical approaches to address biological issues. Chemical biology offers many challenges, among them use of chemical-scale thinking for proteomics and ligand arrays. Small molecules are being developed as regulators of gene expression, targeted, for example, at the histone acetylation and methylation enzymes, and as ligands for multisubunit complexes such as the proteasome or the spliceosome. Charting the small molecule inventory of cells, the metabolome, in a time-dependent way has predictive utility and will be an analytical chemistry challenge. The evolution of macromolecules as specific, po- tent therapeutic agents will require many approaches, which may range from DNA shuffling and selection to site-specific incorporation of unnatural amino acids and their subsequent selective modification. Innovation requires the sharing of information across novel technolo- gies and chemistry and biological efforts. Therefore, improvements in data access, data management, and data manipulation are critical for future successes in health and medicine. Computational Models of Cell Function (breakout sessions) Computational models of cell function emphasizing a dynamic, multivari- able understanding of intracellular regulatory networks could lead to unprec-

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34 HEALTH AND MEDICINE edented work in silica drug discovery and design capability derived from mo- lecular processes. However, a cell-level integrative-systems perspective rather than a reductionist perspective would be involved. These kinds of models could then be coupled with those at higher level in physiological hierarchy (tissue, or- gan, systemic) to aid in elucidating more effective delivery principles and mo- dalities, with both pharmacokinetic and pharmacodynamic analyses becoming much more mechanism-based than empirical. Innovative techniques for targeting therapeutics (small molecule, protein, nucleic acid, and cell) to specific, localized sites of action in the patient should bring substantial benefits in therapeutic index, enhancing effectiveness, and re- ducing toxicity. These techniques might comprise biochemistry-derived cell se- lectivity along with physical approaches for discerning and reaching particular tissue regions with minimal invasiveness.