The authors begin with the observation that, despite “remarkable progress” in synthesizing molecular switches, there have been only few and very rudimentary examples of harvesting useful work from such molecular switches. They then ask whether only incremental progress will be necessary for artificial molecular machines to achieve the levels of function so elegantly achieved by biological molecular machines, or whether some paradigm shift in thinking will be necessary (they believe the latter).

The fundamental theory of molecular machines is applied to two questions. (1) Can artificial molecular machines be developed to manipulate or chemically transform other molecular or nanoscale structures? (2) Can artificial molecular machines be assembled into integrated systems that work together to manipulate or fabricate structures at the meso- and macroscopic levels? The overall conclusion of these authors with respect to these two questions is optimistic:

Indeed, nanoscale-based machinery has been envisaged ever since the days of Feynman and today the Feynman’s Grand Prize offers a $250,000 reward to the first persons to create a nanoscale robotic arm, capable of precise positional control. While, in pursuit of this goal, the “top-down” fabrication strategies have so far failed rather dismally, we are convinced that a “bottom-up” approach, utilizing AMMs [artificial molecular machines], can deliver. Engineering a macromolecular architecture capable of robotic function will no doubt be a considerable synthetic challenge. We feel, however, that the time is ripe for such an undertaking—for instance, by combining AMMs with the DNA-origami materials, such that the former would provide the actuation within precisely folded DNA nanoscaffolds of the latter.

A major focus of this tutorial review is to describe the recently developed theoretical concepts “that distinguish simple molecular switches from fully fledged molecular machines.” Simple molecular switches differ from familiar macroscopic switches in that the switching between the states of the switch is driven by thermal noise. To advance from simple molecular switches to molecular machines, it must be possible to drive chemical reactions uphill, away from equilibrium, as do biological motor molecules. This can be accomplished by using molecular switches to alter the energy profile of the reaction by first lowering the energy of the intermediate to be less than the energy of the starting material, and then switching again to raise the energy of the intermediate above that of the product, and finally switching again to reset the system to the original energy profile. Switching makes each molecular transformation along the way spontaneous, but the end result is shifted way from the equilibrium without switching.

The authors give the example of doubly stable bistable rotaxanes—dumbbell-shaped molecules in which an electrochemical input can move reactants to different positions along the central part of the dumbbell to alter an energy profile and drive a reaction uphill. An example is given of a molecule that can be switched by an oxidation-reduction event between contracted and extended states. If such a molecule is attached to a molecular spring, then the extended form of the molecule could store energy in the spring molecule. If the architecture of the device as a whole allows the spring to be detached from the oxidation-reduction switch, then the energy stored in the spring can be harvested to do external work. Thus an oxidation-reduction switch becomes part of a simple molecular motor.

Having considered how to extract external work from externally switchable molecules, the authors consider how sufficient energy to perform macroscopic work could be harvested from mesoscopic arrays of AMMs. They note that in biological systems molecular motors are organized spatially and synchronized to act together, and consider approaches to fabricate such arrays through self-assembly. They cite metal oxide frameworks as one potentially promising type of scaffolding that might be used to array AMMs.

The brief roadmap presented in this tutorial review outlines the challenges and opportunities involved in transforming simple molecular switches into AMMs. The authors are optimistic:

On the horizon lie new types of “mechanized” enzyme-like mimicks, addressable nanomaterials, nanorobots, and possibly more into the bargain.

Physicist Richard Feynman in his famous 1959 talk, “Plenty of Room at the Bottom,” described the precise control at the atomic level promised by molecular machines of the future. More than 50 years later, synthetic molecular switches are a dime a dozen, but synthetically designed molecular machines are few and far between.

Northwestern University chemists recently teamed up with a University of Maine physicist to explore the question, “Can artificial molecular machines deliver on their promise?” Their provocative analysis provides a roadmap outlining future challenges that must be met before full realization of the extraordinary promise of synthetic molecular machines can be achieved.

The tutorial review is published by the journal Chemical Society Reviews.

The senior authors are Sir Fraser Stoddart, Board of Trustees Professor of Chemistry, and Bartosz A. Grzybowski, the K. Burgess Professor of Physical Chemistry, both in Northwestern’s Weinberg College of Arts and Sciences, and Dean Astumian, professor of physics at the University of Maine. (Grzybowski is also professor of chemical and biological engineering in the McCormick School of Engineering and Applied Science.)

One might ask, what is the difference between a switch and a machine at the level of a molecule? It all comes down to the molecule doing work.

“A simplistic analogy of an artificial molecular switch is the piston in a car engine while idling,” explains Ali Coskun, lead author of the paper and a postdoctoral fellow in Stoddart’s laboratory. “The piston continually switches between up and down, but the car doesn’t go anywhere. Until the pistons are connected to a crankshaft that, in turn, makes the car’s wheels turn, the switching of the pistons only wastes energy without doing useful work.”

Astumian points out that this analogy only takes us part of the way to understanding molecular machines. “All nanometer-scale machines are subject to continual bombardment by the molecules in their environment giving rise to what is called ‘thermal noise,’” he cautions. “Attempts to mimic macroscopic approaches to achieve precisely controlled machines by minimizing the effects of thermal noise have not been notably successful.”

Scientists currently are focused on a chemical approach where thermal noise is exploited for constructive purposes. Thermal “activation” is almost certainly at the heart of the mechanisms by which biomolecular machines in our cells carry out the essential tasks of metabolism. “At the nanometer scale of single molecules, harnessing energy is as much about preventing unwanted, backward motion as it is about causing forward motion,” Astumian says.

In order to fulfill their great promise, artificial molecular machines need to operate at all scales. A single molecular switch interfaced to its environment can do useful work only on its own tiny scale, perhaps by assembling small molecules into chemical products of great complexity. But what about performing tasks in the macroscopic world?

To achieve this goal, “there is a need to organize the molecular switches spatially and temporally, just as in nature,” Stoddart explains. He suggests that “metal-organic frameworks may hold the key to this particular challenge on account of their robust yet highly integrated architectures.”

What is really encouraging is the remarkable energy-conversion efficiency of artificial molecular machines to perform useful work that can be greater than 75 percent. This efficiency is quite spectacular when compared to the efficiency of typical car engines, which convert only 20 to 30 percent of the chemical energy of gasoline into mechanical work, or even of the most efficient diesel engines with efficiencies of 50 percent.

“The reason for this high efficiency is that chemical energy can be converted directly into mechanical work, without having to be first converted into heat,” Grzybowski says. “The possible uses of artificial molecular machines raise expectations expressed in the fact that the first person to create a nanoscale robotic arm, which shows precise positional control of matter at the nanoscale, can claim Feynman’s Grand Prize of $250,000.”

Scientists are reporting an advance in overcoming a major barrier to the use of the genetic material RNA in nanotechnology — the field that involves building machines thousands of times smaller than the width of a human hair. An area that is currently dominated by its cousin, DNA.

Their findings, which could speed the use of RNA nanotechnology for treating disease, appear in the monthly journal ACS Nano [Fabrication of Stable and RNase-Resistant RNA Nanoparticles Active in Gearing the Nanomotors for Viral DNA Packaging].

Peixuan Guo and colleagues point out that DNA, the double-stranded genetic blueprint of life, and RNA, its single-stranded cousin, share common chemical features that can serve as building blocks for making nanostructures and nanodevices. In some ways, RNA even has advantages over DNA. The field of DNA nanotechnology is already well-established, they note. The decade-old field of RNA nanotechnology shows great promise, with potential applications in the treatment of cancer, viral, and genetic diseases. However, the chemical instability of RNA and its tendency to breakdown in the presence of enzymes have slowed progress in the field

The scientists describe development of a highly stable RNA nanoparticle. …

The abstract of the ACS Nano paper concisely states why RNA offers several potential advantages compared to DNA, and what they have accomplished:

Both DNA and RNA can serve as powerful building blocks for bottom-up fabrication of nanostructures. A pioneering concept proposed by Ned Seeman 30 years ago has led to an explosion of knowledge in DNA nanotechnology. RNA can be manipulated with simplicity characteristic of DNA, while possessing noncanonical base-pairing, versatile function, and catalytic activity similar to proteins. However, standing in awe of the sensitivity of RNA to RNase degradation has made many scientists flinch away from RNA nanotechnology. Here we report the construction of stable RNA nanoparticles resistant to RNase digestion. The 2′-F (2′-fluoro) RNA retained its property for correct folding in dimer formation, appropriate structure in procapsid binding, and biological activity in gearing the phi29 nanomotor to package viral DNA and producing infectious viral particles. Our results demonstrate that it is practical to produce RNase-resistant, biologically active, and stable RNA for application in nanotechnology.

The potential advantages of RNA for making building blocks for advanced nanotechnology stem from its hypothesized primordial role in the pre-biotic evolution of life (see RNA world hypothesis). While RNA shares with DNA the molecular recognition properties essential for a role in replicating genetic information, its more versatile chemical nature also facilitates catalytic functions, like proteins. However, this chemical versatility also renders RNA much more susceptible to both chemical and enzymatic degradation (by enzymes called RNases), making RNA difficult to work with (a fact to which I can personally testify having spent most of my research career working with RNA) and presumably accounting for why evolution chose DNA as the genetic material for everything larger than some smaller viruses. Among the many biological roles that RNA molecules fill is the one Prof. Guo and his colleagues have worked with for many years—gearing a powerful nanomotor that packages viral DNA into the protein shells of a bacterial virus named phi29. By constructing the RNA building blocks for this gearing out of RNA subunits that have been chemically modified (substituting a fluorine atom for the 2′-hydroxyl group of the ribose sugar) to resist degradation, and showing that this RNA molecule still folds properly and still functions to make infectious virus particles, Guo and his colleagues have cleared a path for more thorough exploitation of the unique properties of RNA.

An open access review by Peixuan Guo of the potential of RNA Nanotechnology, published in 2005, can be found here. Another RNA nanotechnology pioneer, Luc Jaeger, published a paper in 2009 “Defining the syntax for self-assembling RNA tertiary architectures” (open access version) focused on “RNA architectonics” to decipher the code needed to “build new functional RNA shapes with self-assembly properties”. These studies “demonstrate that small structural motifs can potentially code for the precise topology of an almost infinite variety of large molecular architectures. Ultimately, it is anticipated that RNA particles with the structural complexity of the ribosome could be generated through RNA architectonics.” It will be interesting to watch over the next several years if this variety of 3D structures leads to useful structures and devices for the development of molecular machine systems and ultimately productive nanosystems.

…a current update and the most comprehensive summary so far of the many potential applications of advanced diamondoid medical nanorobotics to conventional and anti-aging medicine. Here’s the abstract:

Nanotechnology involves the engineering of molecularly precise structures and molecular machines, and nanomedicine is the application of nanotechnology to medicine, including the development of medical nanorobotics. Theoretical designs for diamondoid nanomachinery such as bearings, gears, motors, pumps, sensors, manipulators and even molecular computers already exist. Technologies required for the molecularly precise fabrication of diamondoid mechanical components and medical nanorobots, along with feasible strategies for the mass production of these devices, are the focus of active current research. This chapter describes a comprehensive solution to human morbidity and aging which will be attained when mankind has established control over all critical molecular events in the human body through the use of medical nanorobotics. Medical nanorobots can provide targeted treatments to individual organs, tissues, cells and even intracellular components, and can intervene in biological processes at the molecular level under direct supervision of the physician. Programmable micron-scale robotic devices will make possible comprehensive cures for human disease, the reversal of physical trauma, and individual cell repair. This leads to the complete control of human aging via nanomedically engineered negligible senescence (NENS) coupled with nanorobot-mediated rejuvenation that should extend the human healthspan at least tenfold beyond its current maximum length. The nanomedical solution is the final step in the roadmap to the control of human aging.

Best wishes,

Robert A. Freitas Jr. http://www.rfreitas.com
Author, Nanomedicine http://www.nanomedicine.com and http://www.MolecularAssembler.com
Senior Research Fellow, Institute for Molecular Manufacturing

Tad Hogg and I published a major paper on powering medical nanorobots earlier this year, which is now available online at:

Tad Hogg, Robert A. Freitas Jr.,”Chemical Power for Microscopic Robots in Capillaries,” Nanomedicine: Nanotech. Biol. Med. 6(April 2010):298-317. [PDF]

This paper represents the first detailed theoretical study of the actual power limitations of oxygen/glucose-powered in vivo medical nanorobots in human tissue capillaries. We look at nanorobots that are positioned in single or multiple circumferential rings along the interior surface of capillary blood vessels.

My personal web page is at http://www.rfreitas.com. Tad’s web page is at http://www.imm.org/about/hogg/.

ABSTRACT. The power available to microscopic robots (nanorobots) that oxidize bloodstream glucose while aggregated in circumferential rings on capillary walls is evaluated with a numerical model using axial symmetry and time-averaged release of oxygen from passing red blood cells. Robots about 1 µm in size can produce up to several tens of picowatts, in steady state, if they fully use oxygen reaching their surface from the blood plasma. Robots with pumps and tanks for onboard oxygen storage could collect oxygen to support burst power demands two to three orders of magnitude larger. We evaluate effects of oxygen depletion and local heating on surrounding tissue. These results give the power constraints when robots rely entirely on ambient available oxygen and identify aspects of the robot design significantly affecting available power. More generally, our numerical model provides an approach to evaluating robot design choices for nanomedicine treatments in and near capillaries.

Adam Keiper over at the New Atlantis reminds us it’s the 50th anniversary of Feynman’s Plenty of Room at the Bottom talk.

So what’s the next paradigm shift? From this list, probably nuclear power. After that, perhaps, a loosening of political correctness in climatology.

Nuclear power is moving slowly, but I had never expected a loosening of PC in climatology as fast as is evidenced by things like this interview with Judith Curry, chair of the School of Earth and Atmospheric Sciences at Georgia Tech:

Curry: We need climate glasnost: openness, transparency, and freedom of information. Scientists who engage in advocacy activities generate lack of confidence in their science, both from within the scientific community and from the public. The public should expect accountability from our major institutions, particularly the IPCC.

or this editorial on the CBC (Canada’s national public broadcaster):

http://www.youtube.com/watch?v=lgIEQqLokL8

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