Christine Peterson on current state and future potential of nanotechnology

Foresight Co-Founder and Past President: Christine L. Peterson was interviewed in the magazine “Future by Semcon“, published by Semcon, “a global technology company active in the areas of engineering services and product information.” The four-page article “Infinite nanotech possibilities” begins on page 34 of the current issue, which is available online. (The issue is presented as it appears in print, so in the “Browse the publication” box click on the “Table of contents”, then the article title, and then the “Go to page” button.) The interview presents a very succinct and easy overview of the current state and future potential of nanotechnology. Christine focuses on the potential of advanced nanotechnology to eliminate chemical pollution through complete control of atomic trajectories during the manufacturing process. She summarizes the progress of nanotechnology as near the end of the first stage of development, the use of nanostructured materials in a variety of applications, and the beginning of the second, the construction of nanodevices and more advanced products. The latter include medical applications, like (much) better detection and treatment of cancer. As Foresight members and Nanodot readers are well aware, however, the real excitement will come when these first two evolutionary stages give way to the third, truly revolutionary stage, the development of advanced nanomachinery for atomically precise manufacturing:

I think in the longer term it will be the way we make our products. It will mean that they incorporate computation, they incorporate the ability to change their shape, they are perhaps multipurpose products. At some point it starts to sound like science fiction, and there is a reason for that. When you look ahead two or three decades, if what you see at that stage does not look like science fiction, then you’re not trying, you’re not thinking ambitiously enough. …

The interview ends with two interesting questions. (1) When can we expect advanced nanomachinery to be commercialized? After acknowledging the range from optimistic to pessimistic predictions: “… let’s say that in 25 years maybe we will see some really dramatic stuff happening.” (2) Will any technologies not be affected in some way by advanced nanotechnology? “… I personally don’t see a technology area that will not be impacted by nanotechnology.” Do these two answers seem on target?

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Mechanical pressure produces atomically-precise, multifunctional 2D sheets

A few months ago the use of designed peptides to build supramolecular structures on surfaces was reported. Another group has now reported making two-dimensional atomically precise sheets using peptoids, a class of peptide mimetics in which the side chain is attached to the backbone nitrogen atom instead of to the alpha carbon atom. Such sheets might be useful as templates for assembling other nanostructures. A hat tip to Science Daily for reprinting this news release from the Lawrence Berkeley National Laboratory (Berkeley Lab) “Shaken, not stirred: Berkeley Lab scientists spy molecular maneuvers“:

Stir this clear liquid in a glass vial and nothing happens. Shake this liquid, and free-floating sheets of protein-like structures emerge, ready to detect molecules or catalyze a reaction. This isn’t the latest gadget from James Bond’s arsenal—rather, the latest research from the U. S. Department of Energy (DOE)’s Lawrence Berkeley National Laboratory (Berkeley Lab) scientists unveiling how slim sheets of protein-like structures self-assemble. This “shaken, not stirred” mechanism provides a way to scale up production of these two-dimensional nanosheets for a wide range of applications, such as platforms for sensing, filtration and templating growth of other nanostructures.

“Our findings tell us how to engineer two-dimensional, biomimetic materials with atomic precision in water,” said Ron Zuckermann, Director of the Biological Nanostructures Facility at the Molecular Foundry, a DOE nanoscience user facility at Berkeley Lab. “What’s more, we can produce these materials for specific applications, such as a platform for sensing molecules or a membrane for filtration.”

Zuckermann, who is also a senior scientist at Berkeley Lab, is a pioneer in the development of peptoids, synthetic polymers that behave like naturally occurring proteins without degrading. His group previously discovered peptoids capable of self-assembling into nanoscale ropes, sheets and jaws, accelerating mineral growth and serving as a platform for detecting misfolded proteins.

In this latest study, the team employed a Langmuir-Blodgett trough — a bath of water with Teflon-coated paddles at either end — to study how peptoid nanosheets assemble at the surface of the bath, called the air-water interface. By compressing a single layer of peptoid molecules on the surface of water with these paddles, said Babak Sanii, a post-doctoral researcher working with Zuckermann, “we can squeeze this layer to a critical pressure and watch it collapse into a sheet.”

“Knowing the mechanism of sheet formation gives us a set of design rules for making these nanomaterials on a much larger scale,” added Sanii. …

The research was published in the Journal of the American Chemical Society (JACS) [abstract]. It will be interesting to see if these peptoid nanosheets can be developed to provide atomically precise surfaces on which other components can be assembled in a defined atomically precise arrangement, as can be done with DNA origami.

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RNA CAD tool for synthetic biology may facilitate RNA nanotechnology

New computer assisted design (CAD) tools for engineering RNA components have been developed for the growing field of synthetic biology. The knowledge of RNA folding and RNA catalytic and binding functions incorporated into these CAD tools may also prove useful for RNA nanotechnology. A hat tip to Science Daily for reprinting this news release from the Lawrence Berkeley National Laboratory (Berkeley Lab) “CAD for RNA“:

The computer assisted design (CAD) tools that made it possible to fabricate integrated circuits with millions of transistors may soon be coming to the biological sciences. Researchers at the U.S. Department of Energy (DOE)’s Joint BioEnergy Institute (JBEI) have developed CAD-type models and simulations for RNA molecules that make it possible to engineer biological components or “RNA devices” for controlling genetic expression in microbes. This holds enormous potential for microbial-based sustainable production of advanced biofuels, biodegradable plastics, therapeutic drugs and a host of other goods now derived from petrochemicals.

“Because biological systems exhibit functional complexity at multiple scales, a big question has been whether effective design tools can be created to increase the sizes and complexities of the microbial systems we engineer to meet specific needs,” says Jay Keasling, director of JBEI and a world authority on synthetic biology and metabolic engineering. “Our work establishes a foundation for developing CAD platforms to engineer complex RNA-based control systems that can process cellular information and program the expression of very large numbers of genes. Perhaps even more importantly, we have provided a framework for studying RNA functions and demonstrated the potential of using biochemical and biophysical modeling to develop rigorous design-driven engineering strategies for biology.” …

The ressearch was published in Science [abstract]. To test their CAD tools, the researchers engineered 28 molecular devices to regulate metabolic pathways in bacteria via RNA-controlled gene expression, and verified that expected levels of expression were obtained. From the abstract, “… More broadly, we provide a framework for studying RNA functions and illustrate the potential for the use of biochemical and biophysical modeling to develop biological design methods.”

The news release continues:

… As with other engineering disciplines, CAD tools for simulating and designing global functions based upon local component behaviors are essential for constructing complex biological devices and systems. However, until this work, CAD-type models and simulation tools for biology have been very limited.

Identifying the relevant design parameters and defining the domains over which expected component behaviors are exerted have been key steps in the development of CAD tools for other engineering disciplines,” says Carothers, a bioengineer and lead author of the Science paper who is a member of Keasling’s research groups with both JBEI and the California Institute for Quantitative Biosciences. “We’ve applied generalizable engineering strategies for managing functional complexity to develop CAD-type simulation and modeling tools for designing RNA-based genetic control systems. Ultimately we’d like to develop CAD platforms for synthetic biology that rival the tools found in more established engineering disciplines, and we see this work as an important technical and conceptual step in that direction.” …

RNA nanotechnology has a unique set of advantages as a pathway technology toward atomically precise productive nanosystems that reflect its central role in biological systems. Unlike the simple Watson-Crick base-pair molecular recognition code that underlies DNA nanotechnology, the more complex rules of base-pairing involved in RNA folding allow RNA to fold into compact complex three-dimensional shapes. These shapes are somewhat reminiscent of the complex folds of protein structures, yet the folding rules are considerably simpler than those of proteins. These RNA CAD tools may be an important step toward powerful design tools for folded polymer paths toward molecular machine systems.

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Arrays of artificial molecular machines could lead to atomically precise nanotechnology

A few weeks ago we noted the publication of a tutorial review that asks whether artificial molecular machines can deliver the performance that visionaries expect. Upon learning that the full text is available after a free registration, I downloaded the review to learn what the authors think about the prospects of eventually doing atomically precise manufacturing with artificial molecular machine systems.

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.

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Artificial molecular motor controls molecular transformation

An important milestone in the development of nanotechnology leading to atomically precise manufacturing (molecular manufacturing) is the development of artificial molecular machines that can control molecular transformations. Two scientists from the University of Groningen, Netherlands, published a paper in Science [abstract] earlier this year demonstrating control of a chemical reaction by an artificial molecular machine. They constructed a light-driven molecular motor that catalyses different chemical reactions as the motor is stepped through its rotary cycle. The researchers’ institute has made the full text of “Dynamic Control of Chiral Space in a Catalytic Asymmetric Reaction Using a Molecular Motor” available here.

The authors constructed a rotary motor molecule in which the rotor and stator halves of the molecule rotate about an axle consisting of a carbon-carbon double bond. Rotation occurs in only one direction in a four-stage cycle driven by light absorption and by temperature change. Because the molecule is helical in shape, it is chiral, that is, it exists in two different conformations (shapes) that are mirror images of each other.

The rotor and stator halves of the molecule are each attached to a different chemical function so that when rotation about the axle brings the two functional groups spatially close to each other, they catalyze a chemical reaction. At the four different stages of the rotary cycle, the two groups are either widely separated (two trans configurations) and thus have low catalytic activity, or close to each other and therefore have high catalytic activity (the two cis configurations). In one cis configuration the active catalyst is in one chiral orientation; in the other cis configuration, the catalyst is in the opposite chiral orientation. As expected, when used to catalyze an appropriate chemical reaction that can produce either one of two chiral products, the two trans forms of the motor have low activity and they produce a mixture of the two chiral products. The two cis forms of the motor have high activity. One chiral cis form produces predominantly one chiral product; the other produces predominantly the other chiral product.

The authors conclude:

Coupling of unidirectional switching to catalytic function, as demonstrated here, may prove to be a key design tool in the construction of future catalysts that can perform multiple tasks in a sequential manner.

The molecular specificity of this initial proof-of-principle demonstration is only partial. The differences in catalytic activity and the differences in chiral ratios of the reaction products are only of the order of three- or four-fold. We can hope that continued work in this direction will lead to cleaner reaction specificities resulting from programmable control of artificial molecular machines. Eventually we hope to see arrays of programmable molecular catalysts executing complex reaction sequences, leading to productive nanosysems and atomically precise manufacturing.

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First Master’s of Science in Nanomedicine degree program in US announced

We received this announcement of the new M.S. in Nanomedicine program from Radiological Technologies University – VT:

Radiological Technologies University VT, located in South Bend, Indiana is pleased to announce the approval of the first Master’s of Science in Nanomedicine degree program in the country. The formal approval was granted today through the Indiana Commission for Postsecondary Proprietary Education. Nanomedicine is the medical application of Nanotechnology which focuses its work at the cellular level to do everything from repairing tissue, to cleaning arteries, to attacking cancer cells and viruses like AIDS. The RTU Nanomedicine program is the first of its kind in the country by combining Nanotechnology with an emphasis on Medical Physics. Radiological Technologies University offers degree programs ranging from a Bachelor’s degree in Medical Dosimetry to Master’s of Science degrees in Medical Dosimetry, Medical Physics, Medical Health Physics, and Nanomedicine.

Although Foresight has no information about the details of this nanomedicine program, just one item from the NCI Alliance for Nanotechnology in Cancer news archive highlights the potential of nanomedicine, specifically the application of nanoparticles to cancer therapy. From “Nanoparticles seek and destroy drug-resistant glioblastoma“:

Glioblastoma is one of the most aggressive forms of brain cancer. Rather than presenting as a well-defined tumor, glioblastoma will often infiltrate the surrounding brain tissue, making it extremely difficult to treat surgically or with chemotherapy or radiation. Likewise, several mouse models of glioblastoma have proven completely resistant to all treatment attempts.

In a new study, a team led by scientists at Sanford-Burnham Medical Research Institute (SBMRI) and the Salk Institute for Biological Studies developed a method to combine a tumor-homing peptide, a cell-killing peptide, and a nanoparticle that both enhances tumor cell death and allows the researchers to image the tumors. When used to treat mice with glioblastoma, this new nanosystem eradicated most tumors in one model and significantly delayed tumor development in another. These findings were published in the Proceedings of the National Academy of Sciences of the USA [abstract].

“This is a unique nanosystem for two reasons,” said project leader Erkki Ruoslahti of the SBMRI. “First, linking the cell-killing peptide to nanoparticles made it possible for us to deliver it specifically to tumors, virtually eliminating the killer peptide’s toxicity to normal tissues. Second, ordinarily researchers and clinicians are happy if they are able to deliver more drugs to a tumor than to normal tissues. We not only accomplished that, but were able to design our nanoparticles to deliver the killer peptide right where it acts, at the mitochondria, the cell’s energy-generating center.”

The nanosystem developed in this study is made up of three elements. First, a nanoparticle acts as the carrier framework for an imaging agent and for two peptides. One of these peptides guides the nanoparticle and its payload specifically to cancer cells and the blood vessels that feed them by binding cell surface markers that distinguish them from normal cells. This same peptide also drives the whole system inside these target cells, where the second peptide wreaks havoc on the mitochondria, triggering cellular suicide through a process known as apoptosis.

Together, these peptides and nanoparticles proved extremely effective at treating two different mouse models of glioblastoma. In the first model, treated mice survived significantly longer than untreated mice. In the second model, untreated mice survived for only eight to nine weeks. In sharp contrast, treatment with this nanosystem cured all but one of ten mice. What’s more, in addition to providing therapy, the nanoparticles could aid in diagnosing glioblastoma; they are made of iron oxide, which makes them and the tumors they target visible by magnetic resonance imaging.

In a final twist, the researchers made the whole nanosystem even more effective by administering it to the mice in conjunction with a third peptide. Ruoslahti and his team previously showed that this peptide, known as iRGD, helps co-administered drugs penetrate deeply into tumor tissue. iRGD has been shown to substantially increase treatment efficacy of various drugs against human breast, prostate, and pancreatic cancers in mice, achieving the same therapeutic effect as a normal dose with one-third as much of the drug. Here, iRGD enhanced nanoparticle penetration and therapeutic efficacy.

In this study, the researchers tested their nanoparticles on mice that developed glioblastomas with the same characteristics as observed in humans with the disease. Once the nanoparticles reached the tumors’ blood vessels, they delivered their payload directly to the cell’s power producer, the mitochondria. By destroying the blood vessels and also some surrounding tumor cells, the investigators found they were able to cure some mice and extend the lifespan of the rest.”

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Advanced nanofactories in twenty years?

The potential of advanced nanotechnology is getting some attention from mainstream media. Late last year The Guardian web site posted a brief article on the prospects for nanofactories and atomically precise manufacturing, featuring quotes from Christine Peterson and Robert Freitas. From “Nanofactories – a future vision” by Penny Sarchet:

Mimicking nature is a recurring theme in nanotechnology and molecular nanotechnology, inspired by the natural nanostructures found in our own bodies, offers many exciting potential outcomes.

“Molecular nanotechnology is the expected ability to build our products with molecular-level precision, as nature can do,” says Christine Peterson, president of the Foresight Nanotech Institute in California. “It will bring unprecedented quality, energy efficiency and environmental sustainability”.

The recent development of an electron-powered molecular “nanocar”, by a team led by chemist Ben Feringa at the University of Groningen in the Netherlands, hints at the potential. Further indications that molecular nanotechnology is achievable are being found in the quest for ever-smaller computing.

Many of these efforts attempt to use nature’s own method of storing and transferring information – DNA. “DNA computing is the goal of building devices out of DNA that are able to act like computers, initially doing simple calculations but eventually doing everything that a macroscale computer can do,” says Peterson. …

One future prospect for molecular-scale nanotechnology is to build nanofactories. “The nanofactory is a proposed compact molecular manufacturing system that could build a diverse selection of large-scale, atomically precise products,” explains Robert Freitas Jr, senior research fellow at the Institute for Molecular Manufacturing, also in California. “The products of a nanofactory would be atomically precise, with every atom in exactly the right place, offering the ultimate in quality control. It could make products out of the strongest materials known to man – especially diamond, sapphire, and related ultra-strong ceramics. In manufacturing, it’s hard to do better than that.”

The first two-dimensional structure to be built atom-by-atom was made from silicon in 2003. However, Freitas says nanofactories are still a long way off. “We expect this will require a 20-year research and development effort and on the order of $1bn (£622m) in funding to achieve.” …

If anyone knows someone with a billion dollars they will not need for twenty years, ask them to contact Christine or Robert.

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Magnetic storage systems shrink from a million atoms per bit to twelve

Researchers at I.B.M.’s Almaden Research Center have used a scanning tunneling microscope to assemble an array of 96 iron atoms into an antiferromagnetic structure that encodes one byte (eight bits) of information. As reported in the NY Times by John Markoff “New storage device is very small, at 12 atoms“:

SAN JOSE, Calif. — Researchers at I.B.M. have stored and retrieved digital 1s and 0s from an array of just 12 atoms, pushing the boundaries of the magnetic storage of information to the edge of what is possible.

The findings, being reported Thursday in the journal Science, could help lead to a new class of nanomaterials for a generation of memory chips and disk drives that will not only have greater capabilities than the current silicon-based computers but will consume significantly less power. And they may offer a new direction for research in quantum computing. …

The group at I.B.M.’s Almaden Research Center here, led by Andreas Heinrich, has now created the smallest possible unit of magnetic storage by painstakingly arranging two rows of six iron atoms on a surface of copper nitride. …

Although the research took place at a temperature near absolute zero, the scientists wrote that the same experiment could be done at room temperature with as few as 150 atoms. …

The remainder of the article quotes Dr. Heinrich as saying that these tiny devices built with scanning tunneling microscopes are primarily of interest as a way to explore the quantum mechanical properties of the antiferromagnetic effect in the hope of developing novel nanomaterials that might lead to quantum computers. He also noted that many research groups are exploring self-assembly methods that could lead to practical manufacturing technologies to replace current microelectronic technologies.

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Foresight co-founder among panelists discussing role of technology in human existence

Foresight Institute Co-Founder and Past President Christine Peterson was among four panelists addressing the role of technology in human existence for a Stanford University Continuing Studies series. From a report in The Stanford Daily by Marshall Watkins “Bay Area thinkers ponder ‘life’“:

Christine Peterson, co-founder and president of The Foresight Institute, a public interest group seeking to educate the community on forthcoming technological advances, emphasized the increasingly prominent role that nanotechnology has come to play.

Peterson noted that nanotechnology has the potential to create new materials and make vast advances without the side effects, such as pollution, that would currently ensue. She allowed, however, that the near-invisible and highly sensitive technology might enable intrusions on privacy.

“We need to know what data is collected,” Peterson said, “how it is used and how long it is retained. We have those rights.”

Peterson highlighted the medical benefits of nanotechnology, noting, “The ability to control atoms and molecules would mean that there really isn’t a physical illness [that] we wouldn’t be able to address.”

The report quotes the moderator of the panel, author Piero Scaruffi, as stating that the four panelists were picked because “They discussed life as in the future, rather than life as in the past.” We can certainly expect that life after advanced nanotechnology has been developed will be fundamentally different from life up until that point.

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Crowd-sourced protein design a promising path to advanced nanotechnology

Less than four years ago we asked here whether online gamers playing Foldit could help perfect the de novo design of proteins that do not exist in nature. Four months ago we reported that Foldit players had succeeded where scientists had failed in solving the structure of an important viral enzyme. Now Scientific American reports that Foldit players have topped scientists in redesigning a protein—the challenge we suggested less than four years ago. From “Online gamers achieve first crowd-sourced redesign of protein“:

Obsessive gamers’ hours at the computer have now topped scientists’ efforts to improve a model enzyme, in what researchers say is the first crowdsourced redesign of a protein.

The online game Foldit, developed by teams led by Zoran Popovic, director of the Center for Game Science, and biochemist David Baker, both at the University of Washington in Seattle, allows players to fiddle at folding proteins on their home computers in search of the best-scoring (lowest-energy) configurations.

The researchers have previously reported successes by Foldit players in folding proteins, but the latest work moves into the realm of protein design, a more open-ended problem. By posing a series of puzzles to Foldit players and then testing variations on the players’ best designs in the lab, researchers have created an enzyme with more than 18-fold higher activity than the original. The work was published January 22 in Nature Biotechnology [abstract].

“I worked for two years to make these enzymes better and I couldn’t do it,” says Justin Siegel, a post-doctoral researcher working in biophysics in Baker’s group. “Foldit players were able to make a large jump in structural space and I still don’t fully understand how they did it.” …

The latest effort involved an enzyme that catalyses one of a family of workhorse reactions in synthetic chemistry called Diels-Alder reactions. Members of this huge family of reactions are used throughout industry to synthesize everything from drugs to pesticides, but enzymes that catalyze Diels-Alder reactions have been elusive. In 2010, Baker and his team reported that they had designed a functional Diels–Alderase computationally from scratch [abstract], but, says Baker, “it wasn’t such a good enzyme”. The binding pocket for the pair of reactants was too open and activity was low. After their attempts to improve the enzyme plateaued, the team turned to Foldit.

In one puzzle, the researchers asked users to remodel one of four amino-acid loops on the enzyme to increase contact with the reactants. In another puzzle, players were asked for a design that would stabilize the new loop. The researchers got back nearly 70,000 designs for the first puzzle and 110,000 for the second, then synthesized a number of test enzymes based on the best designs, ultimately resulting in the final, 18-fold-more-active enzyme.…

The article was written by Jessica Marshall and reprinted in Scientific American with permission from Nature, where it was originally published as “Victory for crowdsourced biomolecule design: Players of the online game Foldit guide researchers to a better enzyme.” The article does an excellent job of describing how researchers and game players collaborated to achieve the final result. The gamers explored much more radical changes to the protein than can be done by conventional molecular biology techniques such as directed evolution, which typic[a]lly explores only single amino acid substitutions. The researchers then physically constructed and characterized the enzyme designed by the gamers.

The choice as design target of an enzyme to catalyze Diels-Alder reactions is particularly interesting from the standpoint of developing advanced nanotechnology, also referred to as molecular manufacturing. As noted in the 2010 Science paper, this reaction is a “cornerstone” in organic synthesis, and no naturally occurring enzymes are known to catalyze this reaction. As early as 1994 Markus Krummenacker proposed the use of Diels-Alder cycloaddition in a strategy to develop molecular building blocks for molecular manufacturing (“Steps towards molecular manufacturing“).

What roles crowd-sourcing, citizen science, and de novo protein design will play in the development of molecular manufacturing, or productive nanosystems, remains to be seen, but this latest result looks like an important step alog the way.
—James Lewis

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