Health and Medicine: Challenges for the Chemical Sciences in the 21st Century

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Overview

The report assesses the current state of chemistry and chemical engineering within the context of drug discovery, disease diagnosis, and disease prevention. Also addressed are chemical and chemical engineering challenges in pharmaceutical synthesis, delivery, and manufacture.
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Product Details

  • ISBN-13: 9780309087209
  • Publisher: National Academies Press
  • Publication date: 2/6/2004
  • Pages: 76
  • Product dimensions: 5.90 (w) x 8.80 (h) x 0.30 (d)

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HEALTH AND MEDICINE

CHALLENGES FOR THE CHEMICAL SCIENCES IN THE 21ST CENTURY


NATIONAL ACADEMIES PRESS

Copyright © 2004 National Academy of Sciences
All right reserved.

ISBN: 978-0-309-08720-9



Chapter One

Executive Summary

The Challenges for the Chemical Sciences in the 21st Century Workshop on Health and Medicine was held on December 2-4, 2002, at the Arnold and Mabel Beckman Center in Irvine, California. The goal of the workshop was to identify and discuss new tools and approaches, new methods in synthesis and development, new directions in manufacturing and delivery, and major accomplishments and challenges in the chemical sciences relating to health and medicine. There were 12 speakers tasked to address their research areas and how they pertain to the workshop themes. The workshop presentations were as follows:

"Systems Biology and Global Analytical Techniques," Leroy Hood, The Institute for Systems Biology

"Structural Proteomics and Drug Discovery," Stephen W. Kaldor, Syrrx, Inc.

"Challenges in Nucleic Acid Chemistry," Gerald F. Joyce, The Scripps Research Institute

"Biochemical Complexity," Barbara Imperiali, Massachusetts Institute of Technology

"Chemical Biology," Peter B. Dervan, California Institute of Technology

"Biotechnology," Peter G. Schultz, The Scripps Research Institute

"Synthetic Challenges," Samuel Danishefsky,Columbia University and Memorial Sloan-Kettering Cancer Center

"Cell/Tissue Engineering," Linda G. Griffith, Massachusetts Institute of Technology

"Bioinformatics," Sangtae Kim, Eli Lilly and Company

"Drug Delivery," W. Mark Saltzman, Yale University

"Medicinal Chemistry," Paul S. Anderson, Bristol-Myers Squibb Company

"Bioprocessing," James R. Swartz, Stanford University

There were also breakout sessions in which participants in the workshop expressed their views about the various topics. The following report is a compilation of participant views and speaker presentations and is not intended to be a comprehensive review of research efforts in the area of health and medicine. Additionally, the report is a meeting summary and not a consensus report.

NEW TOOLS AND APPROACHES FOR DISCOVERY, DIAGNOSTICS, AND PREVENTION

The advancement of science in the health and medicine arena has brought about many new tools and approaches for drug discovery, diagnostics, and prevention of disease. There are a number of efforts underway to increase the throughput of DNA sequencers, which would allow for multiple genome comparisons. This technology could eventually give rise to predictive, preventative medicine based on an individual's genetic makeup. DNA is also being exploited for its informational and chemical properties to create nanoscale machines that will lead to powerful new approaches to chemical and biological problems. Although oligonucleotide drugs have been in existence for a number of years, it was only recently that viable drug candidates emerged to successfully treat disease. The increased understanding of their mechanism of action (e.g., role of antisense RNA and RNA interference in disease treatment) has led to new therapeutic candidates and better methods to minimize the unwanted side effects of these drugs.

High-throughput approaches, such as combinatorial chemistry, proteomics, and informatics, are now at the forefront of scientific discovery. These advances are a direct result of the development of new synthetic strategies and deciphering of entire genomes. The ability to effectively screen thousands of compounds in search of a lead target molecule has given rise to many new therapeutic agents. The highly automated nature of this approach has dramatically decreased the amount of time required to synthesize, purify, and characterize a compound. This has enabled researchers to pursue rational drug design. Parallel processing and miniaturization has also played a large role in decreasing the time needed to express and purify proteins. This, coupled with high-throughput microcrystallization techniques, has led to large-scale structure determination. In addition, recent advances in tandem mass spectrometry have allowed scientists to analyze protein expression from entire genomes, which has aided in identification of proteins expressed in response to various cellular stressors. There have also been advances in co-expression techniques aimed at deciphering intracellular localization and protein-protein interactions.

NEW METHODS IN SYNTHESIS AND DEVELOPMENT FOR PHARMACEUTICALS

Since the market for leading therapeutic drug classes is over $350 billion per year, there is a great demand to pursue new methods in synthesis and development. This demand must take into account the fierce competition in an industry that is experiencing considerable cost pressures. In the face of this challenge the ultimate goal of the pharmaceutical industry is to find safe, effective medicines. The traditional approach of the pharmaceutical industry is to identify a therapeutic target, link the chosen target to a defined biological mechanism, discover a lead compound that works by this mechanism, and optimize the lead for potency and selectivity of the biological activity. The increased use of outcome studies to establish the therapeutic value of new medicines prior to choosing a target has raised this process to a new level of sophistication. Once the target has been selected, linking this to a specific biological mechanism provides focus for the discovery effort. Identification of the lead compound has benefited from the advent of high-throughput screening methods that enable a large number of compounds to be screened in a relatively short time. Recent advances in stereo-selective synthetic chemistry have better facilitated the making of lead analogs. These lead compounds can then be subject to a variety of substrate binding and toxicological tests to ensure the efficacy of the drug.

There have been many drug discoveries that illustrate how focusing on the action of a drug has facilitated the discovery process. This has been made easier by rapid structural analysis of target macromolecules by X-ray crystallography, NMR spectroscopy, and mass spectrometry.

On a macromolecular scale, research in tissue engineering has focused on the development of nonimmunogenic materials to serve as scaffolds for regeneration in damaged tissues. This technology is also being applied to generate skin for severe burn victims. There is current research in the development of synthetic bone grafts, which interact with cells in the body in a manner that attracts those required for healing. At present, polymer scaffolds can be used to grow bone and cartilage. The ultimate vision in the field of tissue engineering is to create artificial organs that can viably replace damaged organs and can be used in drug testing. A more tractable possibility is the development of tissue chips that can serve as a medium for tissue-specific drug testing. These chips comprise polymer-supported human cells that retain the functions normally associated with intact organs. The success of this technology would greatly enhance the efficiency of drug testing for therapeutics when sufficient animal models are unavailable. This could also eliminate the need for animal testing altogether, which would solve the long time ethical debates about using animal models for testing purposes.

NEW DIRECTIONS IN MANUFACTURING AND DELIVERY

With the rapid increase in the availability of biological information in the post-genomic era, there is an increased need to produce and deliver new pharmaceuticals and diagnostic systems. As new, complex chemicals are identified, challenges arise in the large-scale manufacturing and precise delivery of pharmaceuticals to the desired site of action. This challenge is further increased by the intense federal regulation of pharmaceutical manufacturing. The Food and Drug Administration not only must approve a drug but also the process by which it is made. A small change in manufacturing could lead to a reevaluation of the entire synthetic process, thus requiring further costly and time-consuming clinical trials. This is especially true for such biological compounds as proteins, since minute changes in manufacturing can lead to variations in post-translational modifications as well as possible tertiary structure modifications.

In response to the demand for decreased cost and increased efficiency of pharmaceutical manufacturing and delivery, many new advances have been made. Some of these include large-scale controlled cultivation of animal and plant cells, production of therapeutic proteins and first generation systems for their controlled release, development of more effective delivery methods of complex pharmaceuticals, and the development of improved membrane and chromatographic methods used in separation. There have also been considerable developments in theoretical, experimental, and computational techniques designed to increase drug yields.

There are a variety of new manufacturing processes that may provide promise in surmounting the obstacles present in modern pharmaceutical manufacturing. Hybrid manufacturing processes that utilize chemical synthesis as well as biocatalysis are being developed to remove potentially harmful forms of a pharmaceutical that are not therapeutically active. The directed evolution of proteins is facilitating the use of catalytic enzymes in nonaqueous environments. These processes are increasingly being developed simultaneously with discovery to reduce the time it takes for a product to reach the market.

ACCOMPLISHMENTS

In recent years there have been tremendous accomplishments by chemists and chemical engineers in the area of health and medicine. The discovery of safe and effective medicines in both the pharmaceutical and biotechnology industries is a testament to this. Some of these include angiotensin-converting enzyme inhibitors for hypertension and cholesterol biosynthesis inhibitors for the control of cholesterol levels. These advances would not have been possible without the application of biochemical and bioprocess science approaches. The design of scalable protein separation processes that are reproducible across many clinical trials has been critical to success in the biotechnology sector. In addition, advances in diversity-oriented synthesis methodologies have produced both small focused libraries and very large libraries for screening new disease targets. Optimization of these combinatorial methods may aid in developing effective new therapeutics.

The chemical sciences have not only played a major role in drug discovery but also in drug delivery and disease pathophysiology. Novel controlled release devices fabricated from synthetic polymers have been instrumental in delivering organic and protein therapeutics to patients. Quantitative analysis of the cellular mechanisms of drug delivery, uptake, and degradation has led to significant advances. The modeling of these molecular processes in cells has aided drug delivery and provided insight into the mechanism of disease states.

The emergence of new molecular technology has provided a gateway to seemingly limitless exploration of chemical biology and biomolecular engineering, which are the fusion of chemistry and chemical engineering with the field of biology. The most prominent example of this is the decoding of the three billion DNA base pairs of the human genome. These new technological advances have changed much of the chemical sciences from hypothesis-driven science to discovery science. The enormous amount of biological information now available has enabled scientists to implement a systems approach to biological problems. It is now possible to employ a top-down approach when looking at biological processes. Chemical biology applies chemical-scale molecular approaches to elucidate biological processes. Small molecule inhibitors have been used in conjunction with protein engineering to investigate the biological role of a particular protein. These approaches offer promise for dissecting biological pathways, which may lead to future therapeutics.

CHALLENGES

Although there have been significant advances in chemistry and chemical engineering with respect to health and medicine, the ever increasing wealth of information in this area has posed significant future challenges for scientists. There are a myriad of complex biological processes that scientists have yet to understand. These processes will most likely become more complicated as science reveals more pieces of the puzzle. The committee has highlighted some of the challenges that were discussed in the workshop.

There is a continued need in health and medicine for advances in synthetic techniques.

Advances in measurement and imaging that improve understanding of biological function at the molecular level will aid progress in chemical biology.

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.

Research in nanotechnology shows promise for impact in health and medicine.

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.

Innovation requires the sharing of information across novel technologies and chemistry and biological efforts. Therefore, improvements in data access, data management, and data manipulation are critical for future successes in health and medicine.

Perhaps one of the greatest challenges to the increasingly interdisciplinary fields of chemistry and chemical engineering is the development of a curriculum that can adequately provide the education needed to do research across the chemistry-biology divide. It is unclear whether current programs provide the background knowledge necessary to do interdisciplinary research. Scientists are required to know a tremendous amount of information to understand both chemical and cellular processes. There must be balance between the breadth and depth of knowledge between these fields. In addition to the education of scientists, there must be continued efforts to educate the general public about the importance and relevance of science at the interface of chemistry and biology. Educating the public about the significance of this work will aid in bolstering continued federal support for research in this area.

The pharmaceutical and biotechnology industries must continue to evolve to meet the ever increasing demand for safe, effective therapeutics. However, they must accomplish this goal while finding cheaper R&D alternatives and increasing their success rate, which must be accomplished in part by developing further advances in bioprocessing techniques that will provide faster time-to-market capabilities. More efficient processes must be created to decrease costs while maintaining new drug discovery.

(Continues...)



Excerpted from HEALTH AND MEDICINE Copyright © 2004 by National Academy of Sciences. Excerpted by permission.
All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
Excerpts are provided by Dial-A-Book Inc. solely for the personal use of visitors to this web site.

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Table of Contents

Contents

EXECUTIVE SUMMARY....................1
1 NEW TOOLS AND APPROACHES FOR DISCOVERY, DIAGNOSTICS, AND PREVENTION....................7
2 NEW METHODS IN SYNTHESIS AND DEVELOPMENT FOR PHARMACEUTICALS....................13
3 NEW DIRECTIONS IN MANUFACTURING AND DELIVERY....................21
4 ACCOMPLISHMENTS AND CHALLENGES IN HEALTH AND MEDICINE FOR CHEMISTRY AND CHEMICAL ENGINEERING....................27
APPENDIXES A STATEMENT OF TASK....................37
B BIOGRAPHIES OF THE ORGANIZING COMMITTEE MEMBERS....................38
C WORKSHOP AGENDA....................41
D PARTICIPANTS....................44
E REPORTS FROM THE BREAKOUT SESSION GROUPS....................46

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