chapter 10 Bioelectronics Contents

Introduction ...... 253 Biosensors...... 253 Biochips...... 254 Priorities for Future Research ...... 256 Chapter IO References ...... 256

Figure Figure No. Page 29.The Use of Proteins in Constructing Circuit ...... , ...... 255 —

Chapter 10 Bioelectronics .—— .—

Introduction --—----- ———

The potential for the use of proteins in elec- used for several years, but design problems have tronic dmices has received attention recently with limited their acceptance. Biotechnology is ex- the advent of recombinant DNA (rDNA) technol- pected to increase the variety, stability, and sen- ogy}’ and the potential for computer-aided design sitivity of these devices. Biochips (biologically of proteins (I ,2,3 5 ,6,7, 11, 13,14,15,19,2 1 ). Work based microchips) capable of logic and memory is focused in two areas: biosensors and biochips. are still only speculative, and their development Biosensors (biological}’ based sensors) have been is many years away.

Biosensors -——-- –—- —— .——.

A potential application of biotechnology is in the not only could obviate the need for enzymes but development of improved sensing devices. Be- also could substantially broaden the applications cause of their high specificity. for given sub- of biosensors. A longer term solution to the lack of stances, enzymes and monocIonal antibodies particular enzymes might be to have computers (hlAbs) are particularly suited for use as sensors. design enzymes with particular catalytic func- Sensors using these biological molecules have the tions. Finally, features of proteins that determine potential to be smaller and more sensitive than temperature stability could be incorporated into traditional sensors. the genes that code for important sensing en- zymes. Biosensors using enzymes have been used to detect the presence of various organic compounds A new approach to fabrication is yielding bio- for many years (12). Most of them have used a sensors with greater speed, sensitivity, and ease free or immobilized enzyme and an ion-sensitive of operation [4). The new biosensors use a field- electrode that measures indirectly (e.g., by tem- effect transistor that translates a chemical reac- perature or color changes produced during an tion, such as that catalyzed by an enzyme, into enzymatic reaction) the presence of a product the an electronic signal. Because the electronic re- formation of which is catalyzed by the enzyme. sponse is a direct measure of the chemical reac- Because of the proximity of the enzyme and elec- tion, the sensitivity and speed of the device is in- trode, these biosensors are rapid and sensitive. creased. (It is postulated that these sensors could They have not had wide application, however, use MAbs as specific detection agents.) The British because of the high cost of many enzymes, lack Government has one of these new biosensors on of particular enzymes, and temperature instabil- the market; it detects a particular nerve gas (4). ity. There are many potential applications for im- The use of rDNA and MAb technology and com- proved biosensors in the medical, industrial, en- puter-aided design of enzymes and other proteins vironmental, and defense fields (2, 12). These are may allow the problems associated with existing discussed in turn, biosensors to be overcome. The cloning in bac- teria of genes coding for useful enzymes, for ex- In medical diagnostics, many substances need ample, could allow the enzymes to be made in to be measured accurately and rapidly, but the large amounts cost effectively. The use of MAbs, sensors now available are often expensive, slow, which can be made for virtually any molecule, and insensitive. Improved biosensors could poten-

253 254* Commercial Biotechnology: An International Analysis —. -— —. — —— -——. — —— tially solve many or all of these problems. Such Better biosensors might circumvent these prob- biosensors could detect, for example: lems. other environmental biosensors could be developed to detect exposure of workers to haz- . antigens associated with infectious disease, ardous substances and to monitor indoor air pol- ● hormonal levels to examine endocrine func- lution in the office or at home. tion, and . serum protein levels indicative of disease. The U.S. Department of Defense (DOD), in the near future, will be the major supporter of bio- One particularly important medical application of sensing research in the United States ($8 million improved biosensors could be in the treatment over the next 4 years). DOD’s aim is to develop of diabetic patients for whom proper levels of in- biosensors for the detection of chemical and bio- sulin and glucose must be maintained. Small, im - logical warfare agents that are small, have high plantable devices that sample blood for glucose sensitivity, quick response times, and no false and regulate the delivery of insulin could be de- alarms (18). If such devices were developed, they veloped. would have broad civilian applications such as As mentioned in Chapter 3: The Technologies, those just mentioned. Companies funding re- one of the hindrances to effective bioprocess mon- search on biosensors for a number of uses include itoring and control is the need for a wide range IBM, IT&T, and Johnson & Johnson in the United of sterilizable sensors. Biosensors could be devel- States and Cambridge Life Sciences in the United oped to measure levels of key reaction substances, Kingdom (4,9,16). such as reactants, intermediates, nutrients, and Many technical barriers to developing highly products. Continuous monitoring of several sub- reliable biosensors remain (8,17). Operating limita- stances with biosensors interfaced to a computer tions (e.g., a narrow temperature range) and fab- would allow better control over the reaction proc- rication problems have yet to be overcome. Re- ess and thus increase productivity. The use of search is needed to identify which proteins are thermotolerant enzymes could potentially allow most appropriate for this technology. Moreover, these sensors to be sterilized in place. sensors implanted in animals or used to monitor A potential environmental application of im- bioprocesses must be sterilized prior to implan- proved biosensors would be to monitor water and tation or use, and research is needed to develop air quality. However, cost considerations limit the biosensors that are not destroyed by sterilization use of the extremely sensitive sensors now avail- methods. Over the next 5 to 10 years, many of able. Additionally, very few measuring systems these generic problems inherent in the develop- are portable enough for monitoring in the field. ment of biosensors will probably be solved (2,18).

Biochips

Probably the most novel potential application Two small entrepreneurial firms in the United of biotechnology is in the production of a bimol- States are doing research on biological micro- ecular electronic device. Such a device would chips, or biochips: Gentronix (Rockville, Md.) and contain a specially designed organic molecule that Ean-Tech (San Francisco, Calif.). Furthermore, would act as a semiconductor surrounded and DOD will be funding biochip research beginning stabilized by specially designed proteins, as shown in fiscal year 1984 at $3 million to $4 million for in figure 29. Researchers have studied the use of 5 years. A few large electronics companies in the proteins as a matrix for semiconductors since the United States (Westinghouse, General Electric, early 1970’s, but the possibility of designing pro- and IBM) have small inhouse programs in this teins aided by computers and producing the pro- area. Japan, France, the United Kingdom, and the teins with rDNA technology has sparked more in- U.S.S.R. have indicated interest in bimolecular tense interest. computers (10,20). Ch. 10—Bioelectronics 255 —— —.—

Figure 29.—The Use of Proteins in width of molecules, the resulting devices would Constructing a Circuit be very small and should find use in areas where A semiconducting small size is essential (e.g., in missile guidance). organic molecule Furthermore, because of the nonmetallic nature / Protein of biochips, it is thought that they would be im- ffl‘a me mune to ‘(electromagnetic pulse,” the extraordi- nary electrical charge that results from a nuclear explosion and renders useless all metallic devices in a large area. In spite of the potential uses, how- ever, it is likely to be many years before any com- plex biochip wiIl be developed. A conventional silicon chip contains a set of op- tically imprinted circuits on a wafer of silicon. Four factors limit the number of circuits con- tained on a chip, First, the lower limit of the width of a circuit is determined by the wavelength of light used for imprinting. The current limit is 1 to 10 microns; it has been postulated that by 1990 the width could be 100 times narrower (2). Sec- ‘ monolayer lattice ond, the distance between circuits is limited by SOURCE Otflce of Technology Assessment the nature of the silicon circuit construction itself. When circuits are too close together, electrons can “tunnel” between circuits. This tunneling Bioelectronics research is in its infancy. Al- decreases the reliability of the electronic device. though most potential applications of proteins in The lower limit for the distance between circuits this field are only speculative, the successful is rapidly being approached for silicon chips. The development of these applications could have a third limiting factor for conventional chips is heat substantial effect on the electronics industry. dissipation. As circuits are packed more closely Computers using protein-based biochips, for ex- together, the chip becomes too hot to function ample, would be smaller, faster, more energy ef - effectively. Lastly, as the amount of information ficient, and possibly more reliable than computers processing ability per chip increases, the prob- using silicon chips. * The impact of such biochips lems with fabrication and quality control increase. would be as broad as that of present computers, from hand-held calculators to robotics. Biological and chemically synthesized molecules conceivably could solve these problems associated The biological nature of biochips also raises the with conventional silicon chips as well as provide possibility of some exciting medical applications– additional advantages in design. Because the mol- they could be implanted in the body to interface ecules themselves would be the conductors, the with the living system. Some possibilities include: lower limit of the circuit width would be the brain implants to circumvent damage that width of molecules, which is several orders of has caused blindness and deafness, magnitude narrower than silicon circuits used (or even postulated) at present. Molecular circuits ● cardiac implants to regulate heart beat, could be placed very close to one another without ● blood implants to regulate drug delivery (e.g., insulin for diabetics), and tunneling effects, because the proposed molecules ● implants to control artificial limbs. conduct current without losing electrons. Fur- thermore, since almost no energy is required for DOD considers biochip technology potentially molecules to conduct current, very little heat very useful. Because the circuits would be the would be generated even when the circuits were *Mutations that occur at a certain low level during growth of close together. The specificity of complex inter- micro-organisms could affect the reliability of the final product. actions among proteins and the self-assembling .

256 Commercial Biotechnology: An International Analysis — -— -— —.. . —.- .— —..

processes characteristic of biological systems There are many problems to be solved before would facilitate the fabrication of very reliable a threedimensional biochip will become available. biochips. Biological equivalents of capacitors, transistors, and resistors are yet to be developed. Switching The fabrication of complex three-dimensional devices, necessary for use with the computer bi- biochips with the fabrication technology now nary system, are only theorized. No one has deter- used in the electronics industry is probably im- mined how a three-dimensional biological struc- possible. An essential feature of the use of a pro- ture will do logic functions or store memory. The tein matrix is that the proteins direct their own problem of interfacing biochips so they can be assembly and the appropriate positioning of the programed or can assimilate other input has not semiconductor molecules. There are numerous been addressed. And, because the chips would examples of self-assembling protein structures, use complex molecules, research needs to be done including virus particles, and these are being on their environmental stability, studied intensely for potential applications to biochip technology. Biochips will not be possible without computer- designed proteins and rDNA technology. Yet it Several proteins, including MAbs, have been will probably be several years before rDNA tech- suggested for constructing a biochip in three di- nology will be able to contribute substantially to mensions. The movement of microelectronics biochip research, because it is first necessary to from two- to threedimensional structures would understand more about the relationship between allow not only for increased complexity but also protein structure and function, the biological self- for greatly reduced size. The use of a three-di- assembly processes, and the mechanisms by mensional protein matrix necessitates the design which molecules could do logic functions and of proteins that will interact with other proteins store memory. at correct and unique angles. The construction of these proteins will rely on computer-aided de- sign and rDNA technology.

Priorities for future research

Increased funding for research in the follow- ● field-effect transistors, ing areas could speed the development of bioelec- ● miniaturization of sensors, tronics: ● biological self-assembly processes, and ● molecular-switching mechanisms for elec- ● computer-aided design of proteins, tronic signal propagation. ● temperature stability of proteins,

Chapter 10 references*

*1. Angier, N., “The Organic Computer, ” Discover, 4. Economist, “Sensing Devices: A New Breed)” June May 1982, pp. 76-79. 25, 1983, p. 92. 2. Clerman, R. J., “State-of-the-Art Survey: Biochips 5. Fox, J. L., “Molecular Electronic Devices Offer Technology” (McLean, Va.: MITRE Corp., 1982). Challenging Goal, ” Chem. & Eng. News, May 23, 3. Economist, “Putting Organic Molecules to Work,” 1983, PP. 27-29. June 4, 1983, pp. 87-88, 6. Freidman, S., “Molecular Electronics Promises ‘Biochips’, But Research Proceeds Behind ‘Silicon Wall’,” Genetic Engineering Ne~ts,September/C) c- ● References of general interest are marked with asterisks. tober 1982, p. 1. Ch. 10—Bioelectronics ● 257

*- (. * 14. Peterson, I., “The Incredible Shrinking Compu-

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