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Biotechnology in the 21st century
FEATURES
Biotechnology in the 21st century Charles R. Cantor Although the future is unpredictable, it is highly likely that biotechnology will play a much more visible and significant role in the 21st century than it did in the 20th century. The number and kinds of drugs provided by biotechnology will expand markedly and biotechnology will stand at the center of the oncoming revolution in bioinformatics.
ttempts to predict the future are certain to contain serious errors of omission. However, as long as the basic laws of physics remain intact, it is relatively safe to envisage certain short-term trends. A wise soul, in 1900, might have predicted the current explosion of the use of cellular telephones, but who could have predicted the power of today’s laptop computers? In this article, I will separate notions that I consider to be relatively safe bets from those that strike me as plausible but totally speculative. Some of the techniques that fueled the development of biotechnology in the 20th century will continue to be important in the foreseeable future. These have brought us several protein-based therapeutics produced by recombinant-DNA methods and more are likely to follow. Combinatorial chemistry and automated tools for high-throughput screening have improved the prospects for finding novel drugs; it is likely that these methods will be further developed and more-generally applied. The human genome sequence will appear at the beginning of the 21st century and this will provide a plethora of drug targets. Intelligent use of the sequence is encompassed in a newly named field, functional genomics, which will narrow the choice of therapeutic targets to a practical range. There will also be a vast acceleration in the rate of protein-structure determination, by a method known as structural genomics1. This will lead to the knowledge of all protein folds, and so structural modeling by homology will provide an instant view of the likely structure of any protein sequence. The availability of such encyclopedic structural information will greatly facilitate rational drug design because it will enable screening not just for good ligands but also for ligands without unwanted targets.
A
Personalized medicine It seems certain that a major focus of biotechnology over the next two decades will be on the area of pharmacogenetics and pharmacogenomics, or ‘individualized medicine’. The notion is simple. Normal genetic variations in genes responsible for drug metabolism or receptors of various ligands become medically significant when drugs are applied. By determining the particular variations carried by each individual, a more rational choice can be made of particular drugs to be used and the levels to be administered. Even though the task of screening for potentially thousands of variations in the global population seems daunting with C.R. Cantor ([email protected]) is at Sequenom, San Diego, CA 92121, USA.
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current technology, industry is rushing to fulfill this large, unmet need. Various chip-based2,3 or mass-spectrometric (http:// www.sequenom.com) approaches are likely to be scaleable and ready when needed. This will produce a win–win situation for all the participants: patients will receive better care; pharmaceutical companies will see the costs of clinical trials reduced; the success rates of clinical trials will be increased because the trial population can be segmented intelligently; diagnostic companies will vastly increase their business; and medicalcare insurers will see lower medical-care costs because they will not have to pay for medication that is either ineffective or has adverse side effects. Keeping up appearances The concept of medication will expand during the 21st century and this will increase the types of target and product that industry will focus on. Already, we can see a trend towards a concern with wellbeing rather than sickness. These factors will become much more pervasive and will include the control of weight and body fat, the reduction of stress and compensation for, or control of, unwanted environmental effects, even jet lag. It is easy to think of attractive commercial targets. A drug enabling the rapid removal of all blood alcohol on demand would please many. Viagra is surely just the beginning of drugs that address lifestyle, rather than conventional views of illness. There is hardly a soul who is not concerned with aging. The young would like to speed it up; the old would like to retard it or, at least, hide its effects. This poorly understood area of biology may take on major prominence. What some have called ‘vanity genetics’ will thrive and we will see therapy for wrinkles, adipose deposits, male-pattern baldness, bad breath and perhaps even monotony or decreased pheromone output. Nutraceuticals The notion of what a drug is and how it is delivered will change. Genetically engineered plants and other foodstuffs, termed nutraceuticals, will become the norm. Already, a canola oil has been developed with vastly increased levels of beneficial antioxidants 4, and this may be just the tip of the iceberg. As the genomics tidal wave expands to plants and animals of commercial importance, it will become much easier to use the tools of genetic engineering to create the desired modifications. Consumer resistance to such notions will evaporate as consumers become educated about the benefits and as they begin to taste products with improved flavors.
0167-7799/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S0167-7799(99)01394-3
TIBTECH JANUARY 2000 (Vol. 18)
FEATURES
Disadvantages of biotechnology As Wally Lamb so poignantly said, ‘I know this much is true’5. What follows is much more uncertain. Biotechnology can do good, but it also has the potential to do great harm. In the wrong hands, genetic engineering could be used to create an increasingly complex set of pathogens targeted at humans, plants or animals. The popular press is full of such stories and Richard Preston’s The Cobra Event is particularly compelling6. Although we cannot predict the exact course that biotechnology will take, we can predict that some people will try to use any future advances malevolently. Thus, an unceasing effort has been mandated to develop defensive tools or preventative measures against the use of biotechnology in the making of weapons. In the USA, this issue is already the target of a major research program, ‘Unconventional Pathogen Countermeasures’, which is funded by the Defense Advanced Research Projects Agency (http://www.darpa.mil/dso/ rd.upc). Directed evolution Another area that is destined to play a major role in 21st-century biotechnology is directed evolution. I discuss it here in the ‘blue sky’ category because I feel that it has an almost limitless perspective. Macromolecular combinatorics (e.g. shuffling7, RNA aptamers8 or mRNA–protein fusions9) when combined with either high-throughput screening methods or, better yet, intelligent selection schemes, will allow proteins and nucleic acids with a vast array of novel properties to be produced. Whole organisms can be subjected to similar rapid evolution. Where this will ultimately take us might surpass our imagination. It also raises a number of important ethical and legal issues. The more I reflect on it, the more I am forced to conclude that the next step in humankind’s evolution is our acquisition of the power to control the evolution of our own species and all others on this planet. I can only hope we use this power wisely. If it is not impossible, for some reason I cannot fathom, we should be able to use directed evolution to create plants that walk, animals that can carry out photosynthesis and other unlikely chimeras. Computer communication The area of computational biology or bioinformatics is already an active component of biotechnology, as reflected by the successes of companies such as Incyte and LION. Its placement in the ‘blue sky’ category occurs because the upside is almost too vast to contemplate. The power of available computation continues to expand exponentially. The next revolution, a dramatic increase in user-friendliness, is just beginning. Soon, we will use sound rather than fingertips for most computer communication. Thus, we will be able to maintain contact with the network whatever else we may be doing. Is it only a matter of time before the barrier between our brain and the computer is bridged directly? Although the detailed path this will take is not predictable, I would be astounded if, by the end of the 21st century, the distinction between organisms and computers was not blurred. This will require some kind of interface whether it be electronic or chemical, but TIBTECH JANUARY 2000 (Vol. 18)
it will happen, and it will change our way of life more dramatically than the current computers have changed life in the 20th century. Developing improved interfaces between organisms and computers may come about by a generalization of the DNA and protein chips already in production. Such chips, although capable of parallel processing, are actually rather unintelligent devices because they require cumbersome readout. Integration of the readout directly with computer-readable electronics has been achieved, but apparently not with the sensitivity or reliability needed for general use. This will come, and the readout might be coupled through the electronic, mechanical or chemical properties of the biological targets themselves, whether these are molecules, cells or organisms. Nathan Lewis et al.10 have described a remarkably effective chemical nose, based on very simple hardware analysed by very sophisticated software. As we learn more about our own sensory systems, the principles used by nature to design these, sharpened by eons of evolution, may be used to improve the specificity of such communication. As our ability to speed up evolution matures, we should be able to go beyond, in human–computer communication, anything we can remotely conceive of at present. Suffice to say for certain that, in 2099, biotechnologists will not be reading hard-copy journals as some of the readers of this article have just done. References 1 Pennisi, E. (1998) Taking a structured approach to understanding proteins. Science 279, 978–979 2 Cargill, M. et al. (1999) Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat. Genet. 22, 231–238 3 Halushka, M.K. et al. (1999) Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis. Nat. Genet. 22, 239–247 4 Kishore, G.M. and Shewmaker, C. (1999) Biotechnology: enhancing human nutrition in developing and developed worlds. Proc. Natl. Acad. Sci. U. S. A. 96(11), 5968–5972 5 Lamb, W. (1998) I Know This Much is True, Harper Collins 6 Preston, R. (1997) The Cobra Event, Random House 7 Crameri, A. et al. (1998) DNA shuffling of a family of genes from diverse species accelerates directed evolution. Nature 391, 288–291 8 Gold, L. et al. (1995) Diversity of oligonucleotide functions. Annu. Rev. Biochem. 64, 763–797 9 Roberts, R.W. and Szostak, J.W. (1997) RNA-peptide fusions for the in vitro selection of peptides and proteins. Proc. Natl. Acad. Sci. U. S. A. 94, 12297–12302 10 Lonergan, M.C. et al. (1996) Array-based sensing using chemically sensitive, carbon black-polymer resistors. Chem. Mater. 8, 9, 2298
TIBTECH encourages comment on all published articles. Letters to the Editor should be addressed to: Dr Meran Owen, Trends in Biotechnology, Elsevier Science London, 84 Theobald’s Road, London, UK WC1X 8RR. Please mark clearly whether or not the letter is intended for publication.
7
Biotechnology in the 21st century Charles R. Cantor Although the future is unpredictable, it is highly likely that biotechnology will play a much more visible and significant role in the 21st century than it did in the 20th century. The number and kinds of drugs provided by biotechnology will expand markedly and biotechnology will stand at the center of the oncoming revolution in bioinformatics.
ttempts to predict the future are certain to contain serious errors of omission. However, as long as the basic laws of physics remain intact, it is relatively safe to envisage certain short-term trends. A wise soul, in 1900, might have predicted the current explosion of the use of cellular telephones, but who could have predicted the power of today’s laptop computers? In this article, I will separate notions that I consider to be relatively safe bets from those that strike me as plausible but totally speculative. Some of the techniques that fueled the development of biotechnology in the 20th century will continue to be important in the foreseeable future. These have brought us several protein-based therapeutics produced by recombinant-DNA methods and more are likely to follow. Combinatorial chemistry and automated tools for high-throughput screening have improved the prospects for finding novel drugs; it is likely that these methods will be further developed and more-generally applied. The human genome sequence will appear at the beginning of the 21st century and this will provide a plethora of drug targets. Intelligent use of the sequence is encompassed in a newly named field, functional genomics, which will narrow the choice of therapeutic targets to a practical range. There will also be a vast acceleration in the rate of protein-structure determination, by a method known as structural genomics1. This will lead to the knowledge of all protein folds, and so structural modeling by homology will provide an instant view of the likely structure of any protein sequence. The availability of such encyclopedic structural information will greatly facilitate rational drug design because it will enable screening not just for good ligands but also for ligands without unwanted targets.
A
Personalized medicine It seems certain that a major focus of biotechnology over the next two decades will be on the area of pharmacogenetics and pharmacogenomics, or ‘individualized medicine’. The notion is simple. Normal genetic variations in genes responsible for drug metabolism or receptors of various ligands become medically significant when drugs are applied. By determining the particular variations carried by each individual, a more rational choice can be made of particular drugs to be used and the levels to be administered. Even though the task of screening for potentially thousands of variations in the global population seems daunting with C.R. Cantor ([email protected]) is at Sequenom, San Diego, CA 92121, USA.
6
current technology, industry is rushing to fulfill this large, unmet need. Various chip-based2,3 or mass-spectrometric (http:// www.sequenom.com) approaches are likely to be scaleable and ready when needed. This will produce a win–win situation for all the participants: patients will receive better care; pharmaceutical companies will see the costs of clinical trials reduced; the success rates of clinical trials will be increased because the trial population can be segmented intelligently; diagnostic companies will vastly increase their business; and medicalcare insurers will see lower medical-care costs because they will not have to pay for medication that is either ineffective or has adverse side effects. Keeping up appearances The concept of medication will expand during the 21st century and this will increase the types of target and product that industry will focus on. Already, we can see a trend towards a concern with wellbeing rather than sickness. These factors will become much more pervasive and will include the control of weight and body fat, the reduction of stress and compensation for, or control of, unwanted environmental effects, even jet lag. It is easy to think of attractive commercial targets. A drug enabling the rapid removal of all blood alcohol on demand would please many. Viagra is surely just the beginning of drugs that address lifestyle, rather than conventional views of illness. There is hardly a soul who is not concerned with aging. The young would like to speed it up; the old would like to retard it or, at least, hide its effects. This poorly understood area of biology may take on major prominence. What some have called ‘vanity genetics’ will thrive and we will see therapy for wrinkles, adipose deposits, male-pattern baldness, bad breath and perhaps even monotony or decreased pheromone output. Nutraceuticals The notion of what a drug is and how it is delivered will change. Genetically engineered plants and other foodstuffs, termed nutraceuticals, will become the norm. Already, a canola oil has been developed with vastly increased levels of beneficial antioxidants 4, and this may be just the tip of the iceberg. As the genomics tidal wave expands to plants and animals of commercial importance, it will become much easier to use the tools of genetic engineering to create the desired modifications. Consumer resistance to such notions will evaporate as consumers become educated about the benefits and as they begin to taste products with improved flavors.
0167-7799/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S0167-7799(99)01394-3
TIBTECH JANUARY 2000 (Vol. 18)
FEATURES
Disadvantages of biotechnology As Wally Lamb so poignantly said, ‘I know this much is true’5. What follows is much more uncertain. Biotechnology can do good, but it also has the potential to do great harm. In the wrong hands, genetic engineering could be used to create an increasingly complex set of pathogens targeted at humans, plants or animals. The popular press is full of such stories and Richard Preston’s The Cobra Event is particularly compelling6. Although we cannot predict the exact course that biotechnology will take, we can predict that some people will try to use any future advances malevolently. Thus, an unceasing effort has been mandated to develop defensive tools or preventative measures against the use of biotechnology in the making of weapons. In the USA, this issue is already the target of a major research program, ‘Unconventional Pathogen Countermeasures’, which is funded by the Defense Advanced Research Projects Agency (http://www.darpa.mil/dso/ rd.upc). Directed evolution Another area that is destined to play a major role in 21st-century biotechnology is directed evolution. I discuss it here in the ‘blue sky’ category because I feel that it has an almost limitless perspective. Macromolecular combinatorics (e.g. shuffling7, RNA aptamers8 or mRNA–protein fusions9) when combined with either high-throughput screening methods or, better yet, intelligent selection schemes, will allow proteins and nucleic acids with a vast array of novel properties to be produced. Whole organisms can be subjected to similar rapid evolution. Where this will ultimately take us might surpass our imagination. It also raises a number of important ethical and legal issues. The more I reflect on it, the more I am forced to conclude that the next step in humankind’s evolution is our acquisition of the power to control the evolution of our own species and all others on this planet. I can only hope we use this power wisely. If it is not impossible, for some reason I cannot fathom, we should be able to use directed evolution to create plants that walk, animals that can carry out photosynthesis and other unlikely chimeras. Computer communication The area of computational biology or bioinformatics is already an active component of biotechnology, as reflected by the successes of companies such as Incyte and LION. Its placement in the ‘blue sky’ category occurs because the upside is almost too vast to contemplate. The power of available computation continues to expand exponentially. The next revolution, a dramatic increase in user-friendliness, is just beginning. Soon, we will use sound rather than fingertips for most computer communication. Thus, we will be able to maintain contact with the network whatever else we may be doing. Is it only a matter of time before the barrier between our brain and the computer is bridged directly? Although the detailed path this will take is not predictable, I would be astounded if, by the end of the 21st century, the distinction between organisms and computers was not blurred. This will require some kind of interface whether it be electronic or chemical, but TIBTECH JANUARY 2000 (Vol. 18)
it will happen, and it will change our way of life more dramatically than the current computers have changed life in the 20th century. Developing improved interfaces between organisms and computers may come about by a generalization of the DNA and protein chips already in production. Such chips, although capable of parallel processing, are actually rather unintelligent devices because they require cumbersome readout. Integration of the readout directly with computer-readable electronics has been achieved, but apparently not with the sensitivity or reliability needed for general use. This will come, and the readout might be coupled through the electronic, mechanical or chemical properties of the biological targets themselves, whether these are molecules, cells or organisms. Nathan Lewis et al.10 have described a remarkably effective chemical nose, based on very simple hardware analysed by very sophisticated software. As we learn more about our own sensory systems, the principles used by nature to design these, sharpened by eons of evolution, may be used to improve the specificity of such communication. As our ability to speed up evolution matures, we should be able to go beyond, in human–computer communication, anything we can remotely conceive of at present. Suffice to say for certain that, in 2099, biotechnologists will not be reading hard-copy journals as some of the readers of this article have just done. References 1 Pennisi, E. (1998) Taking a structured approach to understanding proteins. Science 279, 978–979 2 Cargill, M. et al. (1999) Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat. Genet. 22, 231–238 3 Halushka, M.K. et al. (1999) Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis. Nat. Genet. 22, 239–247 4 Kishore, G.M. and Shewmaker, C. (1999) Biotechnology: enhancing human nutrition in developing and developed worlds. Proc. Natl. Acad. Sci. U. S. A. 96(11), 5968–5972 5 Lamb, W. (1998) I Know This Much is True, Harper Collins 6 Preston, R. (1997) The Cobra Event, Random House 7 Crameri, A. et al. (1998) DNA shuffling of a family of genes from diverse species accelerates directed evolution. Nature 391, 288–291 8 Gold, L. et al. (1995) Diversity of oligonucleotide functions. Annu. Rev. Biochem. 64, 763–797 9 Roberts, R.W. and Szostak, J.W. (1997) RNA-peptide fusions for the in vitro selection of peptides and proteins. Proc. Natl. Acad. Sci. U. S. A. 94, 12297–12302 10 Lonergan, M.C. et al. (1996) Array-based sensing using chemically sensitive, carbon black-polymer resistors. Chem. Mater. 8, 9, 2298
TIBTECH encourages comment on all published articles. Letters to the Editor should be addressed to: Dr Meran Owen, Trends in Biotechnology, Elsevier Science London, 84 Theobald’s Road, London, UK WC1X 8RR. Please mark clearly whether or not the letter is intended for publication.
7