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Combining biology and electronics
systems The microchiphas already changed our work and lifestyles. The next revolutionwill come from biotechnology
Combiningbiology and electronics by ROBERT
J CLERMAN
T
wo fields of technology, microelectronics and biotechnology, are prime candidates to dominate industrial innovation over the remainder of this century. After more than 20 years of rapid growth, semiconductor technology is now incorporated in common household appliances as well as the most advanced electronics, such as high-speed computers and industrial robots. Biotechnology, by harnessing the power of the gene through recombinant DNA techniques, is likely to have an equally significant impact on industry and the quality of life. Biotechnology is younger (just over ten years old), and the first commercial products are now entering the marketplace. Bioelectronics, the term coined to describe the convergence of biotechnology and microelectronics, if successful, will open the way for the design and fabrication of microelectronic devices through the use of biological materials and processes. Biology offers a solution to what is Abstract: Bioelectronics involves the design of microelectronicdevices through the use of biological materials and processes. Biological systemshave many characteristicsthat are desirable in microelectronicsincluding small size, complex function, nondissipative conduction, 10211 power requirements, pattern recognition, and intelligence. This article describes the current state-of-the-art in bioelectronicsand the prospectsfor commercial devices in the near future. Keywords: bioelectronics, molecular-scale logic, molecular-scale memoy devices, biological self-assembly. Robert J Clerman is with the Mitre Corporation, USA.
~0126 no 2
march 1984
becoming an increasingly difficult problem for developers of microelectronic devices: how to continue the twenty-year trend of nearly annual doublings of circuit density without reversing the parallel trend of reductions in cost. This progression toward smaller and smaller device components is indicated in Table 1. Using current photolithographic methods of device fabrication, fundamental physical limits will be reached after only a few more doublings in circuit density. Biomolecular systems, with their inherent capacity to transport electrons at a molecular scale, may provide the key to developing subsequent generations of microelectronic devices. At a molecular scale, biological systems have many characteristics that are desirable in microelectronic including small size, components, complex function, nondissipative conand low power requireduction, At the scale of cells and ments. organisms, living systems exhibit desirable features such as parallel processing, pattern recognition, and intelligence. The goal of those involved in bioelectronics research is to exploit these desirable properties of biological systems in order to produce electronic logic and memory devices that will exceed today’s very large-scale inte-
grated circuit (VLSI) technology by as much as nine orders of magnitude in size and performance. This article will provide a brief overview of the current state of the art in bioelectronics and the prospects for development of commercially viable devices.
Component
disciplines
The skills necessary for the development of bioelectronics are too diverse to be drawn from any one discipline or industry. As the term bioelectronits indicates, first and foremost a combination of biology and microelectronics is required. Those involved in the early stages of bioelectronics include biologists and electrical engineers as well as chemists, physicists, and computer scientists. Representatives of these different disciplines have focused on different Four critical research problems. groupings of these researchers are:
l
molecular biologists working on the biological building blocks for device fabrication theoretical chemists seeking to synthesize chemical analogues for the circuits and switches of conventional devices
l
computer
l
and
information
scien-
Table 1. Scales of integration in microelectronics Scale of integration
SSI (small-scale integration) MS1 (medium-scale integration) Early LSI (large-scale integration) Current LSI Near-future VLSI (very large-scale integration) Proposed molecular scale bioelectronics
0011-684X/84/020025-04$03.00 @ 1984 Butterworth & Co (Publishers) Ltd.
Feature size (microns) 25 10 5 2 1 0.01
25
tists developing new device architectures that mimic biological information processing e physicists and electrical engineers working on problems of signal processing and ~pu~output at a molecular scale There is some overlap between the above groups and an increasing amount of communication is taking place. The research efforts of each must be successful if the goal of a new generation of biologically derived devices is to be met. The pivotal contribution of the biological approach adopted by the first group above is the opportunity it offers to reverse the classical engineering approach of microelectronics: building down from the macro to the micro through miniaturization of electronic components. Biological systems build up from the micro to the macro through self-assembly, the natural organization of atoms and molecules in particular three dimensional structures which can then ‘sub-
~~oZo~ca1systems b&d up from the micro to the macrcl through self-assembly.
assemble’ into more complex arrays to perform particular functions. Examples of this process can be found in the capacity of viruses or cellular organelles to self-assemble from their predissociated components. The most applicable form of subassembly for bioelectronics is the three dimensional folding of amino acid sequences into complex proteins. Using computer graphics to repro-
26
duce these protein structures, researchers hope to be able to design macromolecular structures which could function as the components of ultr~icrocircuits. However, the protein molecules that would subassemble in this fashion do not exist in nature. This is where techniques of recombinant DNA and monoclonal antibody production come in. Recombinant DNA technology, a form of genetic engineering, offers the possibility to program microorganisms to produce the desired proteins. Antibodies, proteins which bind with a very specific geometry to other proteins, could also be used in the fabrication of macromolecular devices. Newly developed techniques of monoclonal antibody production involve engineering the cells of the immunological system to produce particular antibodies in quantity. Researchers who subscribe to the ‘biological building block’ approach are, therefore, focusing on the question of how to exploit the subassembly capacity of biological systems in order to fabricate molecular-scale devices. One important step toward this goal is the patenting of a technique of depositing monomolecular protein layers in array structures which might provide the foundation upon which molecular logic could be built’. Researchers in the ‘theoretical chemistry’ group seek to discover chemical analogues for the switching elements and circuits that comprise all digital computers. As early as 1974, researchers at IBM’s Thomas J Watson Research Center in New York proposed that hemiquinones, a family of organic ring-shaped molecules, could function as information storage elements2. These structures can exist in two states which can be switched by application of an electric field and the status of the switch read out by the presence or absence of a current. Such switches could then be arrayed in logic circuits which function as the familiar boolean operators (‘and’, ‘or’, ‘nor’, etc.).
Although molecules such as the hemiquinones are theoretically suitable as switching analogues, there are a number of technical hurdles to be overcome before they can be used in the construction of molecular devices. The prospects for synthesizing such complex structures with conventional organic synthesis techniques is not good. This is where genetic engineering could be used to ‘program’ microorganisms to produce the desired structures. The other major problem is how to read in and write out from devices of molecular dimensions. Potential solutions to this problem include using light energy to excite the molecular switch and the development of ‘molecular wires’ in the form of long chain molecules which could transport the signal to a chemical substance which changes its light absorption properties based on the status of the switch3. A new approach to computation It is interesting to note that much of the above research is aimed at producing binary switches. The presumption is that bioelectronic devices will be used to do digital computations. There is a group of computer and information scientists who are questioning this presumption and suggesting that new computer architectures that are not composed solely of binary switches will be required to fully exploit the potential of bioelectronics. One model for study is information processing in the nervous systems of higher organisms. The idea that neurons act as switching elements, analogous to the switching elements of a computer, was popularized in the 1950s with the demonstration that networks of neurons could implement the computing functions of a digital computer. This concept is being reevaluated based on recent research suggesting that information processing in the brain, for example, may be a function of molecular scale processes within the neuron, as well as
data processing
systems the relatively macroscale processes of neuron firing4. As this group advances our understanding of biological information processing, including the processes that lead to pattern recognition and intelligence, their findings should help to guide bioelectronics in the development of radically different approaches to computation.
Cross-talk
Future outlook The future determined l
The fourth research group in bioelectronics is comprised of physicists and electrical engineers working on problems associated with smaller and smaller dimensions in device components. As feature sizes of current VLSI devices progressively shrink to submicron size and the number of devices packed onto a single integrated circuit increases to 500000 and more, problems with reliability are increasing. One problem is shielding such devices from radiation which might disrupt switching processes. Of particular concern is a phenomenon termed ‘cross-talk’ in which electrical signals are transferred between closely packed circuits in a seemingly unpredictable fashion. Given the prospect of bioelectronic devices with feature sizes of 0.01-0.02 microns or less and packing densities approaching 1018 switches per cubic centimeter, such cross-talk is a critical problem. Solid state physicists are tackling this problem, and. one group at Warwick University in England hopes to exploit the cross-talk phenomenon by predicting the pattern of signal crossovers and establishing ‘cooperative networks’ for parallel processing5. The contributions of biologists, chemists, computer and information scientists, Iphysicists and electrical engineers are necessary to address the fundamental research questions that surround bioelectronics. This research is currently at an early, mostly conceptual stage. No working devices exist today, and, with the exception of the patents assigned to McAlear and Wehrung, even the earliest prototypes are still on. the drawing board. What
~0126 no 2
follows is a discussion of the future prospects for this basic research bearing fruit in the form of a commercially viable technology.
march 1984
l
of bioelectronics by a combination
will be of:
the rate of scientific and technical advance in the four areas outlined above the demand for electronic circuitry of diminishing size and increasing complexity, reliability and speed
As mentioned earlier, this demand has existed since the advent of the integrated circuit in the 196Os, and the microelectronics industry has responded with a doubling of circuit density, with a parallel decrease in unit memory cost, on a nearly annual basis. Future increases in circuit density are likely to come at greater expense due to the costly procedures necessary to assure defect-free devices. Since the computing industry is likely to remain the driving force for miniaturization in microelectronics, it is useful to examine the needs of that industry to determine the future demand for bioelectronics. These needs include increased packing density, reduced fabrication cost, increased computation speed, and improved heat dissipation in closely packed circuits. With the technology to mass produce chips containing tens of thousands of circuit elements, it now costs more to assemble these chips onto printed circuit boards, to test and then combine these boards into a computer than to produce the chips. Constrained by two dimensional architectures, speed in today’s computers is limited by the length of wiring needed to connect these individual chips. Solutions to these problems are being sought with: research on new materials, e.g., superconducting
switching elements such as Josephson junctions; new fabrication methods, electron and ion beam lithoe.g., graphy; and three dimensional system design e.g., fifth generation, parallel processing computers. The biological approach to the same problems is attractive since it capitalizes on the inherent advantages of biological systems: small feature size, nondissipative conduction, and the ability to self-assemble in three dimensional arrays. When the computing industry and other users of microelectronics will be able to exploit this technology depends on the first of the determining factors mentioned above: the rate of scientific and technical advance.
Funding of research There is a familiar paradox in predicting future advances in research efforts as ambitious as that in bioelectronics: significant funding is required in order to make major advances, yet researchers often have difficulty in attracting these funds until such advances are demonstrated. Early bioelectronics researchers are coping with this situation by devoting much of their time to demonstrating the feasibility of their concepts through laboratory experiments designed to illustrate ‘chemical switching’ or the self-assembly of three dimensional protein arrays. These efforts continue, and, although no working devices have been constructed, interest in bioelectronics in the United States has been increasing recently. This has translated into more research funding, mostly from Department of Defense agencies. The electronics industry in the USA is also becoming increasingly involved; most major firms have designated ‘bioelectronics watchers’ and some have initiated research programs. However, even with the increasing participation of the government and private sector research establishworking prototype devices ments, Continued on page 30
37
Combiningbiology and electronics by ROBERT
J CLERMAN
T
wo fields of technology, microelectronics and biotechnology, are prime candidates to dominate industrial innovation over the remainder of this century. After more than 20 years of rapid growth, semiconductor technology is now incorporated in common household appliances as well as the most advanced electronics, such as high-speed computers and industrial robots. Biotechnology, by harnessing the power of the gene through recombinant DNA techniques, is likely to have an equally significant impact on industry and the quality of life. Biotechnology is younger (just over ten years old), and the first commercial products are now entering the marketplace. Bioelectronics, the term coined to describe the convergence of biotechnology and microelectronics, if successful, will open the way for the design and fabrication of microelectronic devices through the use of biological materials and processes. Biology offers a solution to what is Abstract: Bioelectronics involves the design of microelectronicdevices through the use of biological materials and processes. Biological systemshave many characteristicsthat are desirable in microelectronicsincluding small size, complex function, nondissipative conduction, 10211 power requirements, pattern recognition, and intelligence. This article describes the current state-of-the-art in bioelectronicsand the prospectsfor commercial devices in the near future. Keywords: bioelectronics, molecular-scale logic, molecular-scale memoy devices, biological self-assembly. Robert J Clerman is with the Mitre Corporation, USA.
~0126 no 2
march 1984
becoming an increasingly difficult problem for developers of microelectronic devices: how to continue the twenty-year trend of nearly annual doublings of circuit density without reversing the parallel trend of reductions in cost. This progression toward smaller and smaller device components is indicated in Table 1. Using current photolithographic methods of device fabrication, fundamental physical limits will be reached after only a few more doublings in circuit density. Biomolecular systems, with their inherent capacity to transport electrons at a molecular scale, may provide the key to developing subsequent generations of microelectronic devices. At a molecular scale, biological systems have many characteristics that are desirable in microelectronic including small size, components, complex function, nondissipative conand low power requireduction, At the scale of cells and ments. organisms, living systems exhibit desirable features such as parallel processing, pattern recognition, and intelligence. The goal of those involved in bioelectronics research is to exploit these desirable properties of biological systems in order to produce electronic logic and memory devices that will exceed today’s very large-scale inte-
grated circuit (VLSI) technology by as much as nine orders of magnitude in size and performance. This article will provide a brief overview of the current state of the art in bioelectronics and the prospects for development of commercially viable devices.
Component
disciplines
The skills necessary for the development of bioelectronics are too diverse to be drawn from any one discipline or industry. As the term bioelectronits indicates, first and foremost a combination of biology and microelectronics is required. Those involved in the early stages of bioelectronics include biologists and electrical engineers as well as chemists, physicists, and computer scientists. Representatives of these different disciplines have focused on different Four critical research problems. groupings of these researchers are:
l
molecular biologists working on the biological building blocks for device fabrication theoretical chemists seeking to synthesize chemical analogues for the circuits and switches of conventional devices
l
computer
l
and
information
scien-
Table 1. Scales of integration in microelectronics Scale of integration
SSI (small-scale integration) MS1 (medium-scale integration) Early LSI (large-scale integration) Current LSI Near-future VLSI (very large-scale integration) Proposed molecular scale bioelectronics
0011-684X/84/020025-04$03.00 @ 1984 Butterworth & Co (Publishers) Ltd.
Feature size (microns) 25 10 5 2 1 0.01
25
tists developing new device architectures that mimic biological information processing e physicists and electrical engineers working on problems of signal processing and ~pu~output at a molecular scale There is some overlap between the above groups and an increasing amount of communication is taking place. The research efforts of each must be successful if the goal of a new generation of biologically derived devices is to be met. The pivotal contribution of the biological approach adopted by the first group above is the opportunity it offers to reverse the classical engineering approach of microelectronics: building down from the macro to the micro through miniaturization of electronic components. Biological systems build up from the micro to the macro through self-assembly, the natural organization of atoms and molecules in particular three dimensional structures which can then ‘sub-
~~oZo~ca1systems b&d up from the micro to the macrcl through self-assembly.
assemble’ into more complex arrays to perform particular functions. Examples of this process can be found in the capacity of viruses or cellular organelles to self-assemble from their predissociated components. The most applicable form of subassembly for bioelectronics is the three dimensional folding of amino acid sequences into complex proteins. Using computer graphics to repro-
26
duce these protein structures, researchers hope to be able to design macromolecular structures which could function as the components of ultr~icrocircuits. However, the protein molecules that would subassemble in this fashion do not exist in nature. This is where techniques of recombinant DNA and monoclonal antibody production come in. Recombinant DNA technology, a form of genetic engineering, offers the possibility to program microorganisms to produce the desired proteins. Antibodies, proteins which bind with a very specific geometry to other proteins, could also be used in the fabrication of macromolecular devices. Newly developed techniques of monoclonal antibody production involve engineering the cells of the immunological system to produce particular antibodies in quantity. Researchers who subscribe to the ‘biological building block’ approach are, therefore, focusing on the question of how to exploit the subassembly capacity of biological systems in order to fabricate molecular-scale devices. One important step toward this goal is the patenting of a technique of depositing monomolecular protein layers in array structures which might provide the foundation upon which molecular logic could be built’. Researchers in the ‘theoretical chemistry’ group seek to discover chemical analogues for the switching elements and circuits that comprise all digital computers. As early as 1974, researchers at IBM’s Thomas J Watson Research Center in New York proposed that hemiquinones, a family of organic ring-shaped molecules, could function as information storage elements2. These structures can exist in two states which can be switched by application of an electric field and the status of the switch read out by the presence or absence of a current. Such switches could then be arrayed in logic circuits which function as the familiar boolean operators (‘and’, ‘or’, ‘nor’, etc.).
Although molecules such as the hemiquinones are theoretically suitable as switching analogues, there are a number of technical hurdles to be overcome before they can be used in the construction of molecular devices. The prospects for synthesizing such complex structures with conventional organic synthesis techniques is not good. This is where genetic engineering could be used to ‘program’ microorganisms to produce the desired structures. The other major problem is how to read in and write out from devices of molecular dimensions. Potential solutions to this problem include using light energy to excite the molecular switch and the development of ‘molecular wires’ in the form of long chain molecules which could transport the signal to a chemical substance which changes its light absorption properties based on the status of the switch3. A new approach to computation It is interesting to note that much of the above research is aimed at producing binary switches. The presumption is that bioelectronic devices will be used to do digital computations. There is a group of computer and information scientists who are questioning this presumption and suggesting that new computer architectures that are not composed solely of binary switches will be required to fully exploit the potential of bioelectronics. One model for study is information processing in the nervous systems of higher organisms. The idea that neurons act as switching elements, analogous to the switching elements of a computer, was popularized in the 1950s with the demonstration that networks of neurons could implement the computing functions of a digital computer. This concept is being reevaluated based on recent research suggesting that information processing in the brain, for example, may be a function of molecular scale processes within the neuron, as well as
data processing
systems the relatively macroscale processes of neuron firing4. As this group advances our understanding of biological information processing, including the processes that lead to pattern recognition and intelligence, their findings should help to guide bioelectronics in the development of radically different approaches to computation.
Cross-talk
Future outlook The future determined l
The fourth research group in bioelectronics is comprised of physicists and electrical engineers working on problems associated with smaller and smaller dimensions in device components. As feature sizes of current VLSI devices progressively shrink to submicron size and the number of devices packed onto a single integrated circuit increases to 500000 and more, problems with reliability are increasing. One problem is shielding such devices from radiation which might disrupt switching processes. Of particular concern is a phenomenon termed ‘cross-talk’ in which electrical signals are transferred between closely packed circuits in a seemingly unpredictable fashion. Given the prospect of bioelectronic devices with feature sizes of 0.01-0.02 microns or less and packing densities approaching 1018 switches per cubic centimeter, such cross-talk is a critical problem. Solid state physicists are tackling this problem, and. one group at Warwick University in England hopes to exploit the cross-talk phenomenon by predicting the pattern of signal crossovers and establishing ‘cooperative networks’ for parallel processing5. The contributions of biologists, chemists, computer and information scientists, Iphysicists and electrical engineers are necessary to address the fundamental research questions that surround bioelectronics. This research is currently at an early, mostly conceptual stage. No working devices exist today, and, with the exception of the patents assigned to McAlear and Wehrung, even the earliest prototypes are still on. the drawing board. What
~0126 no 2
follows is a discussion of the future prospects for this basic research bearing fruit in the form of a commercially viable technology.
march 1984
l
of bioelectronics by a combination
will be of:
the rate of scientific and technical advance in the four areas outlined above the demand for electronic circuitry of diminishing size and increasing complexity, reliability and speed
As mentioned earlier, this demand has existed since the advent of the integrated circuit in the 196Os, and the microelectronics industry has responded with a doubling of circuit density, with a parallel decrease in unit memory cost, on a nearly annual basis. Future increases in circuit density are likely to come at greater expense due to the costly procedures necessary to assure defect-free devices. Since the computing industry is likely to remain the driving force for miniaturization in microelectronics, it is useful to examine the needs of that industry to determine the future demand for bioelectronics. These needs include increased packing density, reduced fabrication cost, increased computation speed, and improved heat dissipation in closely packed circuits. With the technology to mass produce chips containing tens of thousands of circuit elements, it now costs more to assemble these chips onto printed circuit boards, to test and then combine these boards into a computer than to produce the chips. Constrained by two dimensional architectures, speed in today’s computers is limited by the length of wiring needed to connect these individual chips. Solutions to these problems are being sought with: research on new materials, e.g., superconducting
switching elements such as Josephson junctions; new fabrication methods, electron and ion beam lithoe.g., graphy; and three dimensional system design e.g., fifth generation, parallel processing computers. The biological approach to the same problems is attractive since it capitalizes on the inherent advantages of biological systems: small feature size, nondissipative conduction, and the ability to self-assemble in three dimensional arrays. When the computing industry and other users of microelectronics will be able to exploit this technology depends on the first of the determining factors mentioned above: the rate of scientific and technical advance.
Funding of research There is a familiar paradox in predicting future advances in research efforts as ambitious as that in bioelectronics: significant funding is required in order to make major advances, yet researchers often have difficulty in attracting these funds until such advances are demonstrated. Early bioelectronics researchers are coping with this situation by devoting much of their time to demonstrating the feasibility of their concepts through laboratory experiments designed to illustrate ‘chemical switching’ or the self-assembly of three dimensional protein arrays. These efforts continue, and, although no working devices have been constructed, interest in bioelectronics in the United States has been increasing recently. This has translated into more research funding, mostly from Department of Defense agencies. The electronics industry in the USA is also becoming increasingly involved; most major firms have designated ‘bioelectronics watchers’ and some have initiated research programs. However, even with the increasing participation of the government and private sector research establishworking prototype devices ments, Continued on page 30
37