Nanomedicine, Volume I: Basic Capabilities
© 1999 Robert A. Freitas Jr. All Rights Reserved.
Robert A. Freitas Jr., Nanomedicine, Volume I: Basic Capabilities, Landes Bioscience, Georgetown, TX, 1999
1.3.3 Biotechnology and Molecular Nanotechnology
Some pragmatic readers may be wondering what is so special about molecular nanotechnology, that existing or anticipated biotechnology could not accomplish just as well? After all, biotechnology is already an established medical capability. It has real applications and real products already on the market. Reflecting upon the future possibility of sophisticated mechanical medical nanorobots equipped with powerful nanocomputers, in 1989, one well-known cryobiologist215 mused that "what is not clear is just what need we would have for such devices." The simplest answer, suggested by Figure 1.5, is that each of the three contemporary branches of "nanotechnology" offers something of unique value to the practice of medicine.
Nanoscale materials technology3221,3222,3262 has already found widespread use in medicine, including biocompatible materials and analytical techniques,341 surgical and dental practice, nerve cell research using intracellular electrodes, biostructures research and biomolecular research using near-field optical microscopy, scanning-probe microscopy and optical tweezers, and vaccine design,570 and also many 20th century bulk chemical and biochemical manufacturing techniques along with much of classical pharmacology.
As for "biotechnology," the original meaning of this word contemplated "the application of biological systems and organisms to technical and industrial processes".2223 In recent times, the field has expanded to include genetic engineering and now takes as its ultimate goal no less than the engineering of all biological systems, even completely artificial organic living systems, using biological instrumentalities.
The third branch, molecular nanotechnology, takes as its purview the engineering of all complex mechanical systems constructed from the molecular level -- potentially offering new tools for medical practice, the principal subject of this book. Observes G.M. Fahy,2271 "the difference between nanotechnologists and biotechnologists is that the former do not restrict themselves to the biological limitations of the latter, and they are much more ambitious about the kinds of accomplishments that they want to achieve."
Doctors can utilize solutions to medical problems from all three approaches. As noted earlier, 80-90% of medical complaints resolve themselves via natural homeostatic processes, or without the necessary involvement of active biotechnological or molecular-nanotechnological agents. But by employing biotechnology, the range and efficacy of treatment options greatly increases. With molecular nanotechnology, the range, efficacy, comfort and speed of possible medical treatments again expands enormously. Molecular nanotechnology is essential when the damage to the human body is extremely subtle, highly selective, or time-critical (as in head traumas, burns, or fast-spreading diseases), or when the damage is very massive, overwhelming the body's natural defenses and repair mechanisms.
Table 1.4, inspired by an earlier discussion from G.M. Fahy,215 makes these options more explicit. At every difficulty level, most classes of medical problems may be resolved with varying efficacy within the homeostatic/nanomaterials, biotechnological, or molecular-nanotechnological approaches. As the chosen technology becomes more precise, active, and controllable, the range of options broadens and the quality of the options improves. Thus the question is not whether molecular nanotechnology is required to accomplish a given medical objective. In many cases, it is not -- though of course there are some things that only biotechnology and molecular nanotechnology can do, and some other things that only molecular nanotechnology can do. Rather, the important question is which approach offers a superior solution to a given medical problem, using any reasonable metric of treatment efficacy. For virtually every class of medical challenge, a mature molecular nanotechnology offers a wider and more effective range of treatment options than any other approach.
It is quite possible to imagine an advanced biotechnology that uses an engineered white cell, fibroblast, or macrophage chassis, energized by native oxygen and glucose (Section 6.3.4) and modified mitochondrial powerplants, driven by pseudopodia, cilia or flagella (Section 9.4), communicating and navigating via biochemical signals (Sections 7.2.1 and 8.4.3), and even incorporating onboard digital biocomputers (Section 10.2.3) to make microscopic biorobots. Principal arguments favoring the biotechnology approach for medical purposes are: (1) that we are already somewhat familiar with such systems, after half a century of intensive molecular biology research; (2) that we have already "built" precursor systems, such as a whole living amoeba constructed from five distinct parts,159 bioengineered viruses3003 and bacteria2018,3038 as DNA insertion devices, and natural replication stimulated in genetically engineered starter microbes; (3) that biocompatibility will not be a major issue since fibroblasts (which express no HLA Class II antigens, hence stimulate no rejection response; Section 188.8.131.52) could be used as the starter material; (4) that both engineered viruses2326,2327 and bacteria are already in wide commercial and research use; and (5) the greater complexity of self-repair in mechanical systems, should it be needed. Many believe that the development pathway to early biorobots may be considerably shorter than for the mechanical nanorobots of the molecular nanotechnology approach, for which in 1998 not a single working prototype yet existed, even in research laboratories.
It is also possible to imagine a molecular nanotechnology that uses mechanical nanorobotic systems. Such systems will have many constitutional differences from biological-based systems. For instance, mechanical systems will transport parts, materials, energy and instructions via fixed channels, whereas most (but not all) biological systems operate by diffusion.2244 Mechanical systems will have structures constrained by specific geometries, whereas biological systems have structures defined by patterns of containment and interconnection -- the shape of a membrane compartment in a cell matters less than its continuity and the contents of the volume it defines.2244 Mechanical systems will be deterministically manufactured by operations analogous to manual construction, whereas engineered ribosomes will self-assemble via diffusion and stochastic matching of complementary parts;2244 in other words, biology uses recipes, while mechanical systems use blueprints.2022 Cells grow, with their parts adapting to one another; mechanical nanorobots may be constructed from parts of fixed structure.2244 Biology uses self-repair; mechanical systems generally do not2022 -- largely because self-repair (by component exchange) will not be needed in molecular mechanical systems, whose designs may be made more simple by relying upon high component redundancy10 (Chapter 13). These and other differences imply a number of important advantages that mechanical-based medical systems will enjoy over biological-based medical systems, which, taken together, strongly suggest that predominantly mechanical nanosystems may be the approach of choice for a mature medical nanotechnology. The advantages of molecular nanotechnology (e.g. the mechanical tradition) are many:
1. Speed of Medical Treatment. Doctors may be surprised by the incredible quickness of nanorobotic action when compared to the speeds available from fibroblasts or leukocytes. Normal homeostatic processes such as dermal wound repair via natural fibroblasts may require weeks to run to completion. Typical fibroblast movements occur at 0.1-1 microns/sec (Section 9.4), but mechanical nanomanipulators can operate at 1-10 cm/sec speeds (Section 9.3.1) or faster, a speed advantage of 4-5 orders of magnitude. Even the strongest biological fibers (e.g. intermediate filaments) have a failure strength 3 orders of magnitude below the strongest mechanical fibers (e.g. fullerene nanotubes; Table 9.3). Biological cilia beat at ~30 Hz while mechanical nanocilia may cycle up to ~20 MHz, though practical power restrictions and other considerations may limit them to the ~10 KHz range for most of the time (Section 9.3.1). Flexible mechanical surfaces can complete a morphing motion in ~0.1 millisec, compared to the ~100 millisec snapback time for pinched red cell membrane (Section 184.108.40.206), again a thousandfold advantage in speed. Thus we expect that mechanical therapeutic systems can reach their targets up to ~10,000 times faster, all else equal, and treatments which require ~105 sec for a biological system may need only ~102 sec for a mechanical system;3233 tachyiatria improves both patient and physician comfort. In either biological or mechanical systems, large numbers of devices of comparable physical size (e.g. ~microns) may be employed to do the work, so numbers alone cannot offset the mechanical speed advantage.
2. Power Density and Transduction. Biological cells typically employ power densities of 103-104 W/m3, with maximum densities of ~106 W/m3 in honeybee flight muscle cells and bacterial flagellar motors (Table 6.8). By contrast, nanomechanical power systems can produce power densities of 109-1012 W/m3 (Section 6.3), an advantage of 103-108 for mechanical over biological systems. By 1998, conducting polymer-based actuators generated 20-100 times the force for a given cross-sectional area as mammalian skeletal muscle.2388 Additionally, amoebic locomotion in motile cells requires diffusion-limited cytoskeletal disassembly and reassembly to achieve movement; mechanical motility systems may employ simple cable-pulling, winches, or ratchets, which are faster and more direct. Some biological energy transducers are reversible, but muscle contraction is irreversible -- not only cannot muscle actively re-expand, but stretching it doesn't make it produce much useful chemical energy. In contrast, electric motors can be run backwards to generate electricity, forcing pistons makes them pump, and loudspeakers can be used as microphones.2022
3. Superior Building Materials. Typical biological materials have tensile failure strengths in the 106-107 N/m2 range, with the strongest biological materials such as wet compact bone having a failure strength of ~108 N/m2, all of which compare poorly to ~109 N/m2 for good steel, ~1010 N/m2 for sapphire, and ~1011 N/m2 for diamond and carbon fullerenes (Table 9.3), again showing a 103-105 advantage for mechanical systems that use nonbiological materials. Nonbiological materials can be much stiffer, permitting the application of higher forces with greater precision of movement, and they also tend to remain stable over a larger range of temperature, pressure, salinity and pH. Proteins are heat sensitive in part because much of the functionality of their structure is due to noncovalent bonds involved in folding, which are broken more easily at higher temperatures; in diamond, sapphire, and many other rigid materials, structural shape is covalently fixed, hence is far more temperature-stable. Most proteins tend to become dysfunctional at cryogenic temperatures, unlike diamond-based mechanical structures (Section 10.5). Biomaterials are not ruled out for all nanomechanical systems, but represent only a small subset of the materials that can be used in nanorobots. Mechanical systems can employ a wider variety of atoms and molecular structures in their design and construction, with novel functional forms that might be difficult to implement in a biological system such as steam engines (Section 6.3.1) or nuclear power (Section 6.3.7). As another example, an application requiring the most effective bulk thermal conduction possible should use diamond, the best conductor available, not some biomaterial with inferior thermal performance.
4. Nondegradation of Treatment Agents. Diagnostic and therapeutic agents constructed of biomaterials generally are biodegradable in vivo, although there is a major branch of pharmacology devoted to designing drugs that are moderately non-biodegradable -- anti-sense DNA analogues with unusual backbone linkages and peptide nucleic acids (PNAs) are difficult to break down. However, suitably designed nanorobotic agents constructed of nonbiological materials are not biodegradable. An engineered fibroblast may not stimulate an immune response when transplanted into a foreign host, but its biomolecules are subject to chemical attack in vivo by free radicals, acids, and enzymes. Even "mirror" biomolecules or "Doppelganger proteins"2285 comprised exclusively of unnatural D-amino acids have a lifetime of only ~5 days inside the human body.2286 Nonbiological materials such as diamond and sapphire are highly resistant to chemical breakdown or leukocytic degradation in vivo, and pathogenic biological entities cannot easily evolve useful attack strategies against these materials (Section 220.127.116.11.6).
5. Control of Nanomedical Treatment. Present-day biotechnological entities are not programmable and cannot be switched on and off conditionally during task execution. A digital biocomputer, while possible in theory, represents a considerable conceptual departure from the usual biological paradigm. Even assuming that a digital biocomputer could be installed in a fibroblast, and that appropriate effector mechanisms could be attached, such a system would necessarily have slower clock cycles, less capacious memory per unit volume, and longer data access times, implying less diversity of action, poorer control, and less complex executable programs than would be available in nanoscale electromechanical computer systems (Section 10.2). The mechanical approach emphasizes precise control of action, including control of physical placement, timing, strength, structure, and interactions with other (especially biological) entities. The biological approach emphasizes the use of poorly controlled natural structures, needlessly sacrificing huge blocks of the available functionality and design space.
6. Nanodevice Versatility. Mechanical systems can readily incorporate biological elements if necessary, but artificial biological systems can incorporate nonbiological materials such as carbon nanotubes or diamond/sapphire structural elements only with difficulty, in part because biology has a more limited repertoire of "effector" mechanisms. Artificial biological systems cannot easily incorporate nonbiological materials where desired because natural biological assembly methods make no provisions for these materials either in the coded instructions in DNA or in the attachment chemistries. Rebuilding or reconstructing the human body with nonbiological components (e.g. fullerene encabled bone for bone damaged in an accident; Chapters 24 and 30), or augmentation of human body function with unnatural abilities or features (e.g. autogenous paracrine control; Chapter 12), will be very difficult or impossible to achieve using purely biotechnological means.
7. Avoiding Overspecialization. M. Krummenacker notes that one of the most glaring shortcomings of bacteria and other naturally occurring molecular machinery -- when viewed as systems subject to further engineering -- is the rather limited range of molecular substrates they can utilize. For example, bacterial enzymes are highly specialized devices, with very narrow substrate specificities. Thousands of different enzymes are needed in each organism, and the substance classes capable of digestion are limited to some sugars, various amino acids including proteins that can be degraded by excreted proteases, lipids, and a few other smallish oxygen-functionalized carbon molecules such as glycerol and ethanol. Some bacteria can metabolize CO2 and a handful of aromatic compounds, but there is a vast range of organic chemicals that most bacteria cannot degrade or manufacture. A much smaller set of substantially more general molecular tools can probably be designed using the mechanical approach; mechanosynthesis can fabricate and assemble, or disassemble, a far wider range of molecular structures than are available to the cellular machinery of life.
8. Faster and More Precise Diagnosis. The analytic function of medical diagnosis requires rapid communication between the injected devices and the attending physician. If limited to chemical messaging, biotechnology devices will require minutes or hours to complete each diagnostic loop. Nanomachines, with their more diverse set of input-output mechanisms (Chapter 7), can outmessage the results of in vivo reconnaissance or testing literally in seconds. Such nanomachines can also run more tests of greater variety in less time. Mechanical nanoinstruments, including molecule-by-molecule disassemblers (Chapter 19), will make comprehensive cell mapping and cell interaction analysis possible. Bacterial resistance can be assayed at the molecular level, allowing new treatment agents to more easily be composed, manufactured and immediately deployed (Chapter 19).
9. More Sensitive Response Threshold for High-Speed Action. Unlike natural systems, an entire population of nanobiotic devices can be triggered globally by just a single local detection of the target antigen or pathogen. The natural immune system takes >105 sec to become fully engaged after exposure to a systemic pathogen or other antigen-presenting intruder. A biotechnologically enhanced immune system that can employ the fastest natural unit replication time (~103 sec for some bacteria) will require ~104 sec for full deployment post-exposure. By contrast, a nanobiotic immune system (Chapter 19) can probably be fully engaged (though not finished) in at most two blood circulation times, or ~102 sec.3233
10. More Reliable Operation. Engineered macrophages would probably individually operate less reliably than mechanical nanorobots. Many pathogens, such as Listeria monocytogenes and Trypanosoma cruzi, are known to be able to escape from phagocytic vacuoles into the cytoplasm;2165 while biotech drugs or cell manufactured proteins could be developed to prevent this (e.g. cold therapy drugs are entry-point blockers), nanorobotic trapping mechanisms can be more secure (Section 10.4.2). Proteins assembled by natural ribosomes typically incorporate one error per ~104 amino acids placed; current gene and protein synthesizing machines utilizing biotechnological processes have similar error rates. A molecular nanotechnology approach will improve error rates by at least a millionfold10 (Chapter 20). Mechanical systems can also incorporate sensors to determine if and when a particular task needs to be done, or when a task has been completed. Finally, it is unlikely that natural organisms will be able to infiltrate mechanical nanorobots or to co-opt their functions. By contrast, a biological-based robot could be diverted or defeated by microbes that can piggyback on its metabolism, interfere with its normal workings, or even incorporate the device wholesale into their own structures, causing the engineered biomachine to perform some new or different function than was originally intended. There are many examples of such co-option among natural biological systems, including the protozoan mixotrichs found in the termite gut that have assimilated bacteria into their bodies for use as motive engines,2025-2027 and the nudibranch mollusks (marine snails without shells) that steal nematocysts (stinging cells) away from coelenterates such as jellyfish (i.e. a Portuguese man-of-war) and incorporate the stingers as defensive armaments in their own skins,2295 a process which S. Vogel2022 has called "stealing loaded guns from the army."
11. Verification of Progress and Treatment. Using a variety of communication modalities, nanorobots can report back to the attending physician, with digital precision, a summary of diagnostically- or therapeutically-relevant data describing exactly what was found, and what was done, and what problems were encountered, in every cell visited. A biological-based approach relying upon chemical messaging is necessarily slow with limited signaling capacity. Also unlike mechanical nanorobots, biotechnological systems generally cannot monitor their own functions while working, and, except for a few highly specialized DNA proofreading systems, cannot directly inspect their work while it is in progress or after it is finished.
12. Minimum Side Effects. Almost all drugs have side effects, such as conventional cancer chemotherapy which causes hair loss and vomiting, although computer-designed drugs (Chapter 18) have high specificity and relatively few side effects. Carefully tailored cancer vaccines under development in the late 1990s were expected unavoidably to affect some healthy cells. Even well-targeted drugs are distributed to unintended tissues and organs in low concentrations,1492 although some bacteria can target certain organs fairly reliably without being able to distinguish individual cells. By contrast, mechanical nanorobots may be targeted with virtually 100% accuracy to specific organs, tissues, or even individual cellular addresses within the human body (Chapter 8). Such nanorobots should have few if any side effects, and will remain safe even in large dosages because their actions can be digitally self-regulated using rigorous control protocols (Chapter 12) that affirmatively prohibit device activation unless all necessary preconditions have been, and continuously remain, satisfied. G.M. Fahy2271 has noted that these possibilities could transform "drugs" into "programmable machines with a range of sensory, decision-making, and effector capabilities [that] might avoid side effects and allergic reactions...attaining almost complete specificity of action....Designed smart pharmaceuticals might activate themselves only when, where, and if needed." Additionally, nanorobots may be programmed to excuse themselves from the site of action, or even from the body, after a treatment is completed; by contrast, spent biorobotic elements containing ingested foreign materials may have more limited post-treatment mobility, thus lingering at the worksite causing inflammation when naturally degraded or removed.*
* R. Bradbury notes that artificial eukaryotic biorobots may possess an apoptotic pathway (Section 10.4.1.1) which could be activated to permit clean and natural self-destruction that avoids inflammation in surrounding tissues. Artificial prokaryotic biorobots could also be designed for human biocompatibility; by replacing bacterial genes with generic human genes, such a device may be undetectable to the immune system.
13. Reduced Replicator Danger. Drexler2244 points out that living systems are evolved systems, while nanomechanical replicators would be designed: "The former are shaped to serve the goal of their own survival and replication in a natural environment, whereas the latter will be shaped (whether well or poorly) to serve human goals, perhaps in an artificial environment." Genetic engineering involves not design of replicators from scratch, but tinkering with the molecular machinery of existing bioreplicators. Since bioreplicators were not designed, they are not necessarily structured in ways that lend themselves to complete understanding, and processes based on diffusion and matching allow complex nonlocal interactions that can be hard to trace. Bioreplicators can be crippled, but having evolved in nature, they resemble systems that can survive in nature. Typically, they are able to exchange genetic information with wild organisms, raising the possibility of the introduction of new, unconstrained replicators in the natural environment. Having evolved to evolve, they have a capacity for further evolution -- to serve their own survival, not human goals.2244 For example, even when stripped of key pieces of DNA to interfere with its replication powers, a live attenuated AIDS vaccine can slowly recover its virulence and can attack immune cells.2939 R. Bradbury suggests that artificial biorobots could incorporate multiple fail-safe mechanisms including required external essential nutrients or suicide suppressors, self-destruct triggers, countdown timers like telomeres, and engineering to reject foreign DNA (the basis for restriction enzymes), but it remains logically easier for a system with inchoate capacity to evolve to resume doing so, than for a system which has never had this capability to spontaneously develop it.
In contrast, nanomechanical replicators (e.g. assemblers; Section 2.4.2) will be designed from scratch and thus will differ fundamentally from biological systems. The parts and structures of designed mechanical systems will be known, and the relationships among their parts will also be designed and fixed. More important, nanoreplicators will be fundamentally alien to the biosphere, unrelated to anything that has evolved to survive in nature. Certainly the capacity to fail can appear by accident, and emergent capabilities cannot be completely ruled out, but engineering experience shows that the ability to perform complex organized activities (such as replication in a natural environment) does not normally appear spontaneously.2244 Also, and purely as a geometrical consideration, adding a new part inside a densely organized geometric structure (as would be found in a nanomachine) typically requires changes in the relative positions of many other parts, and hence corresponding adjustments in design. Adding a part inside a densely organized topological structure (as found in living systems) typically leaves topologies unchanged -- room can be made by stretching and shifting other parts, with no change in their essential design,2244 hence permitting easier modification to biological structures by exogenous agencies.
Note that mechanical medical nanodevices need not be capable of replication. There is no requirement for replication in vivo; such replication would be needlessly dangerous, and adding this capability would reduce effectiveness in carrying out the primary medical task. Analogously, viral vectors employed in genetic therapies are modified to be "incapable" of replication.
14. Assured Patentability. Microscopic biorobots, unavoidably derived from natural biological material, may someday be deemed unpatentable under a general prohibition on "genetic colonialism" or other emerging legal doctrines.2323 In contrast, mechanical nanorobots, being fully-artificial and designed machines, should always be patentable provided they satisfy the customary legal criteria.
Last updated on 5 February 2003