© 1999 Robert A. Freitas Jr. All Rights Reserved.

Robert A. Freitas Jr., Nanomedicine, Volume I: Basic Capabilities, Landes Bioscience, Georgetown, TX, 1999

7.4.5.4 Cell Message Modification

Properly configured in cyto nanorobots can modify natural intracellular message traffic according to preprogrammed rules or by following external commands issued by the attending physician. In the case of steroids and thyroid hormones, this may involve the direct manipulation of the signaling molecules themselves (after they have passed through the cell membrane) or their bound receptor complexes. However, most signaling molecules are absorbed at the cell surface, initiating a signal cascade which must be modulated by manipulating the second-messenger molecules or other components of the signal cascade. A complete analysis of the modifications that nanorobots may impose upon normal intracellular message traffic is beyond the scope of this book. However, a few basic examples of modifying action may be illustrated using the familiar cyclic AMP (cAMP; C₁₀H₁₁N₅O₆P, MW = 328 daltons) messaging system.

A. Amplification -- A single epinephrine molecule received by a b-adrenergic receptor at a cell surface transduces the activation of dozens of G-protein a subunits, each of which in turn activates a single adenylate cyclase enzyme which cyclizes hundreds of ATP molecules into cAMP molecules. The intracellular population of cAMP (in muscle or liver target cells) is normally <~10^-6 M or ~5 million molecules for a typical (20 micron)³ tissue cell. Stimulation by epinephrine raises the cAMP population to ~25 million molecules in a few seconds. Upon detecting this rising tide of cAMP in a few millisec, a single in cyto nanorobot could amplify this existing chemical signal by instantly releasing 20 million cAMP molecules (occupying ~0.01 micron³) from onboard inventories -- decreasing cellular response time by several orders of magnitude.*

* From a practical standpoint, R. Bradbury notes that designers should have knowledge of the biochemical pathways that are most critical in the response to a signal, hence nanorobots may be able to skip the intermediate steps required in the biological system. In the present example, the cascade is typically intended to increase the glucose available for muscles, so it might make more sense to skip the cAMP step and simply commence disassembly of glycogen (in the liver and muscles) and accelerate the pumping of glucose into the bloodstream (from the liver).

B. Suppression -- Similarly, upon detection of rising cAMP levels in target cells, resident nanorobots could use molecular rotors to rapidly remove cAMP from the cytosol as quickly as it is formed, even under maximum adrenal stimulation. From Eqn. 3.4 the diffusion-limited intake current at the basal concentration (~6 x 10^-7 molecules/nm³) for a cAMP-absorbing spherical nanodevice 1 micron in radius is ~4 million molecules/sec, so a single such device could probably keep up with natural cAMP production rates and thus completely extinguish the response by preserving a flat basal concentration. (As a practical matter, it may be more efficient to simply control epinephrine generation at its glandular source unless it is desired to interface with just a single tissue type.) Simultaneously, the cAMP-absorbing nanorobot may hydrolyze the stored cAMP (hydrolysis energy is ~11.1 Kcal/mole or ~77.1 zJ/molecule)³²⁹⁸ in the manner of the cAMP phosphodiesterases (c.f. nanofactories, Chapter 19), then excrete these deactivated AMP messenger molecules back into the cytosol. Similar methods might be useful in ligand-gated ion channel desensitization or in disease symptom suppression (Chapter 24) -- as for example, in suppressing the prolonged elevation of cAMP in intestinal epithelial cells associated with the cholera toxin, that produces severe diarrhea by causing a large influx of water into the gut.

C. Replacement -- Combining suppression and amplification, an existing chemical signal may be eliminated and replaced by a different -- even an opposite -- message pathway using nanorobot mediators. Alternative pathways may be natural or wholly synthetic. Novel responses to existing signals may be established within the cell to enhance functionality or to improve stability or controllability. For example, detection of one species of cytokine by a nanorobot could trigger rapid specific absorption of that cytokine and a simultaneous fast release of another (different) species of cytokine in its place. Such procedures must take into account the redundant signaling pathways and backup systems (e.g., developmental signals, immune system, blood clotting). Medical nanorobotics will allow the replacement of many redundant pathways with more refined and specific responses.

D. Linkage -- Previously unlinked signal cascades may be artificially linked using in cyto nanodevices. As a fanciful example, the receipt of epinephrine by nanorobots located in the capillaries of the brain could trigger these devices to suppress the adrenalin response while simultaneously releasing chemical messengers producing message cascades that stimulate production of enkephalins or other opioids, thus encouraging a state of psychological relaxation rather than the "fight or flight" response to certain stressful conditions.

Last updated on 16 April 2004