STMFMs and Biomedical Applications

Nondestructive STM interactions with biological material have immense potential, assuming certain technical obstacles are overcome. Potential problems include the following:

1. Biomolecules, cells, and tissues are not conductors. Electron tunneling through these materials, if it occurs, may be damaging. Nevertheless, several groups including IBM Zurich have succeeded in imaging biomaterials in air such as protein coated DNA and virus structures. The tunneling is thought to occur from tip onto biomolecular surface followed by "low resistance electron transport to the conducting substrate" (Travaglini, Rohrer, Amrein and Gross, 1986). Simultaneous optical microscopy, as can occur with the nanotech workstation, may help this situation since photons can lower tunneling barriers. Appropriate choice of optical microscopy wavelengths may thus facilitate STM imaging by permitting non damaging tunneling currents.

An alternative approach is to utilize an atomic force microscope (AFM) mode of operation for biological materials. In this case a lever arrangement adapted to, and mounted on, an STM which trails along the surface, or is held steady to observe mechanical dynamics of the material (i.e. protein conformational change). The movement of the lever is monitored by the STM, so that mapping and dynamics can be observed without direct tunneling through the biomaterial.

Nanoscale thermocouple and pipette STM tips as described by IBM's Pohl (1987) may also be useful for biological materials.

2. Biomaterials should be studied in a stable environment as much like the aqueous medium within cytoplasm as possible. Temperature, pH, ionic concentrations, availability of high energy phosphate groups and numerous other parameters need to be closely regulated. Researchers at University of California-Santa Barbara have demonstrated that STM imaging can occur at ionic liquidsolid interfaces. By insulating STM probes to very near their tips, significant leakage of current to the ionic aqueous environment is apparently avoided (Sonnenfeld and Hansma, 1986). Thus STM should be applicable to characterization of living biomolecules under stable physiological conditions.

Figure 10.19: STM tunneling switches modulated at optical frequencies with lasers. By Conrad Schneiker (Schneiker, 1986).

3. A third problem has been the "near sightedness" of the STM. Hansma's Santa Barbara group and the IBM-Zurich team had difficulty in locating DNA molecules on the background substrate with the STM. This "needle in a haystack" problem is potentially solved by a nanotechnology workstation configuration in which the coarse approach of the STM is made simpler by visual observation. Further, immunofluorescence techniques may be utilized to identify specific biomolecular targets and the STM probes themselves. Electophoretic fields applied to the sample stage may attract and immobilize charged biomolecules rendering them easier to locate and study (Lindsay, 1987).

Potential applications of STM to biology and medicine include repetitive imaging and structural mapping of living material, nondestructive study of dynamical structural changes such as protein receptors (via alterations in the AFM mode), detection of possible propagating phonons or solitons (using the multiple STM configurations, one tip can perturb and another detect perturbation at a second position on a macromolecule or polymer), spectroscopic analysis (i.e. DNA base pair reading, cytoskeletal lattice communication), and real time imaging (via high speed scanning) of living structures can expand the horizons of experimental biosciences. Further, a capability for nanoscale manipulation of biomaterials and organelles offers a host of imaginative possibilities. For instance, a few dozen multitip STM/FMs might be developed to directly extract, manipulate, analyze, and modify DNA or other cellular components, thereby greatly assisting some subfields of genetic engineering and medical research. Synthesis or modulation of important biological molecules which are "topologically complex" (e.g. receptors, enzymes, antibodies, cytoskeleton) which may be difficult and relatively expensive using present day synthetic chemistry, could ultimately be feasible with STM/FMs. Feynman (1961) commented that great progress may be expected in biology when "you can simply look at, and work with individual molecules." STM/FMs could help materialize some even grander biomedical applications when used in combination with genetic engineering: to create, modify, or program micro-organisms for therapeutic uses.

Ettinger (1972):

If we can design sufficiently complex behavior patterns into microscopically small organisms, there are obvious and endless possibilities, some of the most important in the medical area. Perhaps we can create guardian and scavenger organisms in the blood, superior to the leukocytes and other agents of our human heritage, that will efficiently hunt down and clean out a wide variety of hostile or damaging invaders.

Asimov (1981) suggests that we:

Consider the bacteria. These are tiny living things made up of single cells far smaller than the cells in plants and animals ... . [We] can, by properly designing these tiniest slaves of ours, use them to reshape the world itself and build it close to our hearts' desire ... .

White (1969) proposed a similar notion for programmable cell repair machines:

appropriate genetic information can be introduced by means of artificially constructed virus particles into a congenitally defective cell for remedy (and) ... repair. The repair program must use (the cells own protein synthesis and metabolic pathways to diagnose and repair any damage.

Approaches to biomedical nanotechnology relying solely on genetic/protein engineering and self assembly (Asimov, 1981; Aridane, 1983; Drexler, 1981, 1986) are severely constrained by the lack of direct control and observation: the potential attributes of STM/FMs. Hybrids and components of organisms, cytoskeletal structures, viruses, and synthetic structures may evolve, facilitated by STM/FM capabilities, to fabricate, examine, and modify nanostructures. Ettinger

(1972) anticipated "nanominiaturized robots to serve us." Feynman (1961) reported that a friend, Albert R. Hibbs suggested:

a very interesting possibility for relatively small machines. He says that, although it is a very wild idea, it would be interesting in surgery if you could swallow the surgeon. You put the mechanical surgeon inside the blood vessel ... . Other small machines might be permanently incorporated inside the body ... .

Feinberg (1985) sees

... the construction of nanosensors that could be implanted into the human body. They could ... [monitor] various physiological functions from subcellular molecules up through tissues and organs ... essential in determining some of the mechanisms involved in growth and aging.

Feinberg (1985) also proposed the use of laser energy to power and communicate with implanted sensors, and to direct activities of nanorobots.

... using coherent, short-wavelength radiation, we too will be able to match the accomplishments of the cells that compose us, and do molecular engineering.

These molecular structures will be much more complex than anything that human technology has thus far achieved ... . It may be possible to extend some of the methods using ... shortwavelength coherent radiation ... to nanofabrication as well as to seeing what we are doing in the nanoworld, since microholography can be used to demagnify patterns as well as magnify them.

There exist rationale and applicability for mobile nanodevices whose missions might be to stalk and destroy lethal viruses or malignancies, excavate clogged blood vessels, correct genetic expression and differentiation, repair or remove the processes of ageing including senile tangles of cytoskeletal proteins, and perhaps augment natural capabilities. Virtually every disease might be amenable to intracellular house calls by such structures, if they ever exist. Such nanodevices might be patterned after, or directly utilize, cytoskeletal elements (centrioles, microtubules, etc.), viruses (bacteriophages) programmed by specifically engineered genes, and/or controlled by telemetry. Synthetic materials including nano STM/FMs composed of piezo-materials may be incorporated.

Ellis (1962) discussed the possibility of microteleoperators (and suggested that protein enzymes may function in this manner). Nanoantennas have been proposed by Marks (1985) who described two orthogonal layers (about 200 nanometers in length) of metallic dipole antenna arrays which can convert photons to direct current with 75 percent efficiency. Javan (1985, 1986) has studied metal whiskers which can form tunnel junctions and may be suitable as nanoantennas. Feinberg's (1985) notion of communication by short wavelength coherent radiation, and Pohl's nanoaperture concept could be utilized for remote nanovision feedback and observation of nanoscale activities (Schneiker, 1986).

STM/FMs combined with genetic engineering and immunological techniques could be used to create, observe, and evaluate such mobile nanodevices whose capabilities would be optimized as replicating automata.

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