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Accelerate your work in 2018: Fellowship, Prizes, Workshop

We’re thrilled to open up applications for the 2018 Foresight Fellowship, Feynman Prizes and Student Award, and Spring workshop starting now!



The 2018 Foresight Fellowship

After the excellent strides by our inaugural class of 2017 Foresight Fellows, we are glad to continue the Foresight Fellowship in 2018 to help committed change-makers create the future humanity needs.

Specific benefits to Fellows during the program:

  • Sponsorship to attend at least one invite-only Foresight workshop or event
  • Connection to Fellows and mentors
  • Representation on our website, in our newsletter, and in a short video on their work
  • Other opportunities to increase their skills to succeed in their endeavors

We’ll consider all applications, but especially welcome applications in the fields of Nanotechnology (molecular machines, atomically-precise construction), Artificial Intelligence & Artificial General Intelligence, Cybersecurity, Blockchains, and Longevity.

Apply via this form – the first round of applications close on February 28, 2018.



Integrated Molecular Machines Workshop,

May 5-6, Washington University

We are very pleased to have 2016 Nobel Laureate Sir Fraser Stoddart, Northwestern University, as Honorary Chair and Prof. Jonathan Barnes, Washington University, as Workshop Chair for our spring research meeting.

We invite you to apply to participate in this highly interactive workshop, “Integrated Molecular Machines: From Materials to Nanosystems,” to be held May 5-6, 2018, at Washington University, St. Louis, Missouri.

To get an idea of what to expect at these workshops,

We’ll consider all applications, but especially welcome applications in the following fields: atomically-precise 3D structures and molecular machines, including construction pathways using chemistry, applied physics, biochemistry, molecular biology, and engineering; design and construction of complex structures and molecular machines built via organic and inorganic synthesis; objects and devices constructed from DNA, RNA, proteins, or biomimetic polymers; construction via scanning probe; and other approaches to building with increasing precision from the bottom up, including applying artificial intelligence to design and construction challenges.

Apply via this form – the first round of applications ends February 28, 2018.



Feynman Prizes & Foresight Student Award

Feynman Prizes

Two prizes in the amount of $5,000 each will be awarded to the researchers whose recent work has most advanced the achievement of Feynman’s goal for nanotechnology: molecular manufacturing, defined as the construction of atomically-precise products through the use of molecular machine systems. Synonyms include “atomically precise manufacturing” (APM) and “productive nanosystems”. Separate prizes will be awarded for theoretical work and for experimental work.

The winners of this year’s prizes will be announced by May 2018 and invited to accept the prize at the highly interactive workshop, “Integrated Molecular Machines: From Materials to Nanosystems,” to be held May 5-6, 2018, at Washington University, St. Louis, Missouri (see above). Honorary Co-Chair of the workshop will be Sir Fraser Stoddart, Northwestern University and one of the three molecular machine pioneers to share the 2016 Nobel Prize in Chemistry.

For each Prize, a travel stipend of up to US$1500 will be provided for the winner (or one member of a winning team) to attend the Workshop and accept the Prize.

This prize is given in honor of Richard P. Feynman who, in 1959, gave a visionary talk at Caltech in which he said “The problems of chemistry and biology can be greatly helped if our ability to see what we are doing, and to do things on an atomic level, is ultimately developed — a development which I think cannot be avoided.”

Additional Information here – submissions/nominations are due March 20, 2018.


Foresight Distinguished Student Award

The Foresight Distinguished Student Award was established in 1997, and is given to a college student or graduate student whose work is notable in the field of atomically-precise nanotechnology.

The award includes a $1,000 prize and an expense-paid trip to the spring Foresight Workshop “Integrated Molecular Machines: From Materials to Nanosystems,” to be held May 5-6, 2018, at Washington University, St. Louis, Missouri. The prizewinner must accept in person at the award ceremony. The prizewinner will receive complimentary full registration including reception, coach airfare and up to 2 nights hotel (arranged by Foresight Institute, Sat. night stay may be required), and the physical award.

Additional Information here – submissions/nominations are due March 20, 2018.

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Our next Seminar: Artificial General Intelligences & Corporations @Internet Archive

Seminar on Artificial General Intelligences & Corporations

hosted by Foresight Institute@ Internet Archive

Click here to access the ticket sale.

Even if we don’t know yet how to align Artificial General Intelligences with our goals, we do have experience in aligning organizations with our goals. Some argue corporations are in fact Artificial Intelligences – legally at least we treat them as persons already.

Let’s spend an afternoon examining AI alignment, especially whether our interactions with different types of organizations, e.g. our treatment of corporations as persons, allow insights into how to align AI goals with human goals.

While this meeting focuses on AI safety, it merges AI safety, philosophy, computer security, and law and should be highly relevant for anyone working in or interested in those areas.

Discussions on the day include:

Overview of AI Safety & definitions

  • Allison Duettmann, AI Safety Researcher at Foresight Institute, Advisor to EthicsNet

Corporations as Artificial General Intelligences (based on this literature review for a grant given by Paul Christiano on the legal aspects of AGI as corporations)

  • Peter Scheyer, Foresight Institute Fellow in Cybersecurity & Corporate AGI, Cybersecurity Veteran

Overview of the traditional field of AI alignment, with focus on CHAI’s approach to AI alignment

  • Mark Nitzberg, Executive Director of the UC Berkeley Center for Human Compatible AI

Aligning long-term projects with incentives in governmental institutions

  • Tom Kalil, former Deputy Director for Policy for the White House Office of Science & Technology Policy, Senior Advisor at the Eric & Wendy Schmidt Group

Building a 501c3 organization and similarities to AI alignment

  • Brewster Kahle, Founder of the Internet Archive, Digital Librarian, and Philanthropist

Civilizations as relevant superintelligence (based on this paper co-authored with Christine Peterson, and Allison Duettmann for the First UCLA Risk Colloquium)

  • Mark Miller, Senior Fellow of the Foresight Institute, pioneer of agoric computing, designer of several object-capability programming languages

This seminar will be highly interactive – we welcome your engagement throughout the session.

Do you have something valuable to add to the discussion? Especially regarding the legal aspects?


We thank The Internet Archive for hosting, and look forward to tackling this complex but important problem with you, 

Foresight Institute 

Buy a ticket

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Ultrafast DNA robotic arm: A step toward a nanofactory?

DNA origami illustration: robot  arm on base plate

Electric fields drive the rotating nano-crane – 100,000 times faster than previous methods. (Image: Enzo Kopperger / TUM)

Glowing molecules at the ends of the DNA robot arm as it rotates

Rotation of the arm between two docking points (red and blue). (Image: Enzo Kopperger / TUM)

Ultrafast molecular machines made using DNA nanotechnology have now been demonstrated. Over the past several years molecular machines made using DNA nanotechnology, especially the scaffolded DNA origami technology, have grown more complex and more functional (see, for example, here, here, here, and here). Long-time Foresight member Dr. Robert P. Meagley writes to point out that the speed of such machines increased five orders of magnitude with a new approach published last week, and to point out that it “would be fun to put a fragment of this stuff” (an antenna-reactor complex published 18 months ago) “on the end of” such a DNA machine. Could such a combination evolve into a path toward general purpose, high-throughput atomically precise manufacturing? From the Technical University of Munich “Piecework at the nano assembly line“:

Fast computer control for molecular machines

Scientists at the Technical University of Munich (TUM) have developed a novel electric propulsion technology for nanorobots. It allows molecular machines to move a hundred thousand times faster than with the biochemical processes used to date. This makes nanobots fast enough to do assembly line work in molecular factories. The new research results will appear as the cover story on 19th January in the renowned scientific journal Science [Abstract].

Up and down, up and down. The points of light alternate back and forth in lockstep. They are produced by glowing molecules affixed to the ends of tiny robot arms. Prof. Friedrich Simmel observes the movement of the nanomachines on the monitor of a fluorescence microscope. A simple mouse click is all it takes for the points of light to move in another direction.

“By applying electric fields, we can arbitrarily rotate the arms in a plane,” explains the head of the Chair of Physics of Synthetic Biological Systems at TU Munich. His team has for the first time managed to control nanobots electrically and has at the same time set a record: The new technique is 100 000 times faster than all previous methods.

DNA-Origami Robots for the Manufacturing Plants of Tomorrow

Scientists around the world are working on new technologies for the nanofactories of the future. They hope these will one day be used to analyse biochemical samples or produce active medical agents. The required miniature machines can already be produced cost-effectively using the DNA-origami technique.

The only reason these molecular machines have not been deployed on a large scale to date is that they are too slow. The building blocks are activated with enzymes, strands of DNA or light to then perform specific tasks, for example to gather and transport molecules.

However, traditional nanobots take minutes to carry out these actions, sometimes even hours. Therefore, efficient molecular assembly lines cannot, for all practical intents and purposes, be implemented using these methodologies.

Electronic Speed Boost

“Building up a nanotechnological assembly line calls for a different kind of propulsion technology. We came up with the idea of dropping biochemical nanomachine switching completely in favour of the interactions between DNA structures and electric fields,” explains TUM researcher Simmel, who is also the co-coordinator of the Excellence Cluster Nanosystems Initiative Munich (NIM).

The principle behind the propulsion technology is simple: DNA molecules have negative charges. The biomolecules can thus be moved by applying electric fields. Theoretically, this should allow nanobots made of DNA to be steered using electrical impulses.

Robotic Movement Under the Microscope

To determine whether and how fast the robot arms would line up with an electric field, the researchers affixed several million nanobot arms to a glass substrate and placed this into a sample holder with electrical contacts designed specifically for the purpose.

Each of the miniature machines produced by the lead author Enzo Kopperger comprises a 400 nanometer arm attached to a rigid 55 by 55 nanometer base plate with a flexible joint made of unpaired bases. This construction ensures that the arms can rotate arbitrarily in the horizontal plane.

In collaboration with fluorescence specialists headed by Prof. Don C. Lamb of the Ludwig Maximillians University Munich, the researchers marked the tips of the robot arms using pigment molecules. They observed their motion using a fluorescence microscope. They then changed the direction of the electric field. This allowed the researchers to arbitrarily alter the orientation of the arms and control the locomotion process.

“The experiment demonstrated that molecular machines can be moved, and thus also driven electrically,” says Simmel. “Thanks to the electronic control process, we can now initiate movements on a millisecond time scale and are thus 100 000 times faster than with previously used biochemical approaches.”

On the Road to a Nanofactory

The new control technology is suited not only for moving around pigments and nanoparticles. The arms of the miniature robots can also apply force to molecules. These interactions can be utilized for diagnostics and in pharmaceutical development, emphasizes Simmel. “Nanobots are small and economical. Millions of them could work in parallel to look for specific substances in samples or to synthesize complex molecules – not unlike an assembly line.

So what kind of tools could a speedy nanoarm deploy to build complex structures? Mechanical force, as suggested above, is certainly one possibility. Another possibility, however, is the suggestion above by Dr. Meagley to place one or more antenna-reactor complexes at the tips of nanomachine arms to implement a series of spatially directed plasmon-enhanced photocatalysis steps to build complex nanostructures. As described by this Rice University press release from July of 2016 written by Jade Boyd “Rice’s ‘antenna-reactor’ catalysts offer best of both worlds“:

Technology marries light-harvesting nanoantennas to high-reaction-rate catalysts

In a find that could transform some of the world’s most energy-intensive manufacturing processes, researchers at Rice University’s Laboratory for Nanophotonics have unveiled a new method for uniting light-capturing photonic nanomaterials and high-efficiency metal catalysts.

Rice University’s antenna-reactor plasmonic catalysts combine a light-harvesting nanomaterials with highly efficient metal catalysts. In this image, “islands” of reactive palladium dot the aluminum oxide surface of an underlying aluminum crystal, which serves as a photonic antenna to capture light and activate the catalytic islands. (Image courtesy of D. Swearer/Rice University)

Each year, chemical producers spend billions of dollars on metal catalysts, materials that spur or speed up chemical reactions. Catalysts are used to produce trillions of dollars worth of chemical products. Unfortunately, most catalysts only work at high temperatures or high pressure or both. For example, the U.S. Energy Information Agency estimated that in 2010, just one segment of the U.S. chemical industry, plastic resin production, used almost 1 quadrillion British thermal units of energy, about the same amount of energy contained in 8 billion gallons of gasoline.

Nanotechnology researchers have long been interested in capturing some of the worldwide catalysis market with energy-efficient photonic materials, metallic materials that are tailor-made with atomic precision to harvest energy from sunlight. Unfortunately, the best nanomaterials for harvesting light — gold, silver and aluminum — aren’t very good catalysts, and the best catalysts — palladium, platinum and rhodium — are poor at capturing solar energy.

The new catalyst, which is described in a study this week in the Proceedings of the National Academy of Sciences, is the latest innovation from LANP, a multidisciplinary, multi-investigator research group headed by photonics pioneer Naomi Halas. Halas, who also directs Rice’s Smalley-Curl Institute, said a number of studies in recent years have shown that light-activated “plasmonic” nanoparticles can be used to increase the amount of light absorbed by adjacent dark nanoparticles. Plasmons are waves of electrons that slosh like a fluid across the surface of tiny metallic nanoparticles. Depending upon the frequency of their sloshing, these plasmonic waves can interact with and harvest the energy from passing light.

In summer 2015, Halas and study co-author Peter Nordlander designed an experiment to test whether a plasmonic antenna could be attached to a catalytic reactor particle. Graduate student Dayne Swearer worked with them, Rice materials scientist Emilie Ringe and others at Rice and Princeton University to produce, test and analyze the performance of the “antenna-reactor” design.

Swearer began by synthesizing 100-nanometer-diameter aluminum crystals that, once exposed to air, develop a thin 2- to 4-nanometer-thick coating of aluminum oxide. The oxidized particles were then treated with a palladium salt to initiate a reaction that resulted in small islands of palladium metal forming on the surface of the oxidized particles. The unoxidized aluminum core serves as the plasmonic antenna and the palladium islands as the catalytic reactors.

Swearer said the chemical industry already uses aluminum oxide materials that are dotted with palladium islands to catalyze reactions, but the palladium in those materials must be heated to high temperatures to become an efficient catalyst.

“You need to add energy to improve the catalytic efficiency,” he said. “Our catalysts also need energy, but they draw it directly from light and require no additional heating.”

One example of a process where the new antenna-reactor catalysts could be used is for reacting acetylene with hydrogen to produce ethylene, Swearer said.

Ethylene is the chemical feedstock for making polyethylene, the world’s most common plastic, which is used in thousands of everyday products. Acetylene, a hydrocarbon that’s often found in the gas feedstocks that are used at polyethylene plants, damages the catalysts that producers use to convert ethylene to polyethylene. For this reason, acetylene is considered a “catalyst poison” and must be removed from the ethylene feedstock — often with another catalyst — before it can cause damage.

One way producers remove acetylene is to add hydrogen gas in the presence of a palladium catalyst to convert the poisonous acetylene into ethylene — the primary component needed to make polyethylene resin. But this catalytic process also produces another gas, ethane, in addition to ethylene. Chemical producers try to tailor the process to produce as much ethylene and as little ethane possible, but selectivity remains a challenge, Swearer said.

As a proof-of-concept for the new antenna-reactor catalysts, Swearer, Halas and colleagues conducted acetylene conversion tests at LANP and found that the light-driven antenna-reactor catalysts produced a 40-to-1 ratio of ethylene to ethane, a significant improvement in selectivity over thermal catalysis.

Swearer said the potential energy savings and improved efficiency of the new catalysts are likely to capture the attention of chemical producers, even though their plants are not currently designed to use solar-powered catalysts.

“The polyethylene industry produces more than $90 billion of products each year, and our catalysts turn one of the industry’s poisons into a valuable commodity,” he said.

Halas said she is most excited about the broad potential of the antenna-reactor catalytic technology.

“The antenna-reactor design is modular, which means we can mix and match the materials for both the antenna and the reactor to create a tailored catalyst for a specific reaction,” she said. “Because of this flexibility, there are many, many applications where we believe this technology could outperform existing catalysts.”

Whatever the potential for combining ultrafast molecular machines with plasmonic antennas and catalytic reactors, the metallic nanoparticles used by Halas and her collaborators could be supplemented with a variety of other, often atomically precise, plasmonic antennas and catalysts. How diverse a collection of components have we accumulated for use in possible proto-nanofactories?
—James Lewis, PhD

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2015 Feynman Prize winner named 2018 Australian of the Year

UNSW Sydney scientist Professor Michelle Simmons, the 2018 Australian of the Year, is presented with her award by the Australian Prime Minister Malcolm Turnbull. CREDIT: Salty Dingo

It is always a pleasure when those whose work toward Feynman’s goal for nanotechnology—molecular manufacturing, defined as the construction of atomically-precise products through the use of molecular machine systems—whom we have recognized with a Foresight Institute Feynman Prize are subsequently also recognized by the wider community for the importance of their contributions. For example, Sir J. Fraser Stoddart, the winner of the Experimental portion of the 2007 Foresight Institute Feynman Prize, was one of the three scientists to share the 2016 Nobel Prize in Chemistry. A couple days ago, Michelle Simmons, the winner of the Experimental portion of the 2015 Foresight Institute Feynman Prize was named 2018 Australian of the Year in recognition of her pioneering research and inspiring leadership in quantum computing. A public release from the University of New South Wales “UNSW Sydney scientist Michelle Simmons is Australian of the Year“:

UNSW Sydney congratulates Scientia Professor Michelle Simmons, who has been named 2018 Australian of the Year in recognition of her pioneering research and inspiring leadership in quantum computing.

Simmons, who is a UNSW Professor of Physics and Director of the Australian Research Council Centre of Excellence for Quantum Computation and Communication Technology, CQC2T, based at UNSW, received her award from the Australian Prime Minister, Malcolm Turnbull, at a ceremony at Parliament House in Canberra.

As Centre Director, she leads a team of more than 200 researchers at eight Australian universities who are developing a suite of technologies for quantum computing, information storage and communications.

Professor Simmons’ research group is the only one in the world that can manipulate individual atoms to make atomically precise electronic devices. Her team at CQC2T is leading the world in the race to develop a quantum computer in silicon.

Last year, she also established Australia’s first quantum computing company, bringing together representatives of governments, industry and universities in a unique $83 million consortium based at UNSW to develop and commercialise the Centre’s world-leading research.

UNSW President and Vice-Chancellor Professor Ian Jacobs said: “Michelle is highly deserving recipient of this great honour and will be a wonderful role model for all Australians.

“With her scientific vision, she has established UNSW and Australia as an international leader in a key industry of the future – quantum computing – that will revolutionise most other industries.

“And she has worked tirelessly to ensure this nation will benefit economically and socially from the commercialisation of her team’s great Australian research,” Professor Jacobs said.

UNSW Dean of Science Professor Emma Johnston said: “Michelle is a pioneering scientist with a passion for pushing the boundaries which has allowed her to overcome immense technical barriers in her quest to understand how the world operates at the atomic level and then exploit this knowledge to create the quantum computers of the future.

“Her achievements and those of her team are hugely exciting for UNSW and for Australia and she is an inspiration to all young people — and women in particular — who aspire to make a difference in the world.

“Although Michelle’s work is conducted at the very smallest scale, its consequences will be enormous,” Professor Johnston said.

Professor Simmons said: “I am deeply honoured to receive this award and hope the recognition will inspire other Australians to tackle the hard challenges in life.

“Trying to control nature at its very smallest scale is phenomenally exciting and rewarding, and has been my passion for many years.

“Building a fully functioning prototype quantum computer in silicon is a massive task. But I have an excellent team with the dedication and determination to make it happen, and this award is also a wonderful recognition of their immense efforts.”

She said the Australian give-it a go attitude, the academic freedom to pursue ambitious projects and new ideas, and the collaborative culture had contributed to her success.

“I firmly believe there is no better place to undertake research than in Australia,” Professor Simmons said.

Simmons’ advice to young men and women reflects the many insights she has gained on her journey to the top: “Keep your sights high, defy others’ expectations, and be the creators, rather than just the users, of new technology,” she said.

Among their recent achievements, Simmons’ research group created the world’s first single-atom transistor, as well as the narrowest conducting wires ever made in silicon, just four atoms wide and one atom high.

Quantum computers are expected to transform most industries, including health, finance and transportation. Instead of performing calculations one after another, like a conventional computer, a quantum computer would work in parallel and be able to look at all the possible outcomes at the same time.

“A quantum computer would be able to solve problems in minutes that would otherwise take thousands of years,” says Simmons.

The UNSW approach has been to focus on making qubits out of single atoms of phosphorus or quantum dots in silicon — the material that forms the basis of today’s computer chips.

Silicon has several advantages including that it is amongst the most stable and manufacturable environments in which to host qubits, due to trillions of dollars of investment in R&D by the computer and electronics industry.

Launched last year and operating out of new laboratories at UNSW, the new company called Silicon Quantum Computing Pty Ltd has set itself the target of producing a 10-qubit integrated circuit prototype in silicon by 2022, as the forerunner to a silicon-based quantum computer.

Simmons is one of the few Australian academics to have been awarded two Australian Research Council Federation Fellowships and currently holds a Laureate Fellowship.

She has won both the Australian Academy of Science’s Pawsey Medal (2005) and Thomas Ranken Lyle Medal (2015) for outstanding research in physics, and was elected one of the youngest Fellows of the Academy in 2006. She was named NSW Scientist of the Year in 2012, and in 2015 she was awarded a Eureka Prize for Leadership in Science.

She received a Foresight Institute Feynman Prize in Nanotechnology in 2016, for “the new field of atomic electronics, which she created”. Last month she was honoured as a pioneer in quantum computing by the American Computer Museum, alongside Mark Ritter from IBM. And last year she received a €100,000 international L’Oréal-UNESCO For Women in Science Award.

She had the rare distinction for an Australian researcher of becoming an elected member of the prestigious American Academy of Arts and Sciences in 2014. She is also Editor in Chief of the first Nature Partner Journal based in Australia, npj Quantum Information.

As someone who has been cheering the progress of nanotechnology toward general purpose, high-throughput atomically precise manufacturing (APM) since reading Engines of Creation in 1986, two questions have seemed to me to be of paramount importance: (1) which of today’s methods of building atomically precise nanomachines will have a place on paths toward nanofactories; (2) what will be the earliest industries to become extremely lucrative making use of first generation molecular machine systems, and thus ignite an industrial revolution based upon APM? Could the development of quantum computing and communication be such an industry?
—James Lewis, PhD

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Unrelated de novo enzyme replaces essential enzyme in cell

Iron-rich medium supports the growth of E. coli engineered to no longer have a natural Fes enzyme. They form small, unhealthy, red colonies because they accumulate iron bound to enterobactin, and barely have enough free iron to grow. In contrast, cells containing the artificial enzyme Syn-F4 form large, healthy, white colonies because the novel protein catalyzes the cleavage of enterobactin and subsequent release of the iron needed for healthy growth. (Note: If these cells were placed on petri dishes with minimal iron, the red colonies would not appear at all because they would not have enough free iron to sustain cell growth.) Photo courtesy of Ann Donnelly/Hecht Lab/Princeton University

The first proposal of a path from then current technology to the ability to fabricate complex materials and devices by placing the atoms where you want them was made by Richard Feynman in 1959: “There’s Plenty of Room at the Bottom“, but see also this series “Feynman Path to Nanotechnology“. The second proposal to achieve this goal was made by Eric Drexler 22 years later “Protein design as a pathway to molecular manufacturing“. The past dozen years there has been a large volume of progress along this path, as documented by this review we cited a year ago (“From de novo protein design to molecular machine systems“). Recent results demonstrate a third approach to provide a function needed by a living cell to grow. In addtion to billions of years of evolution or protein design by computer, a de novo enzyme selected from a random library can replace a missing enzyme, even though it is unrelated to the natural enzyme. A hat tip to Technology Networks “Artificial Enzyme Can Catalyze Reactions” for pointing to this Princeton University press release written by Liz Fuller-Wright “Artificial enzyme: Protein designed entirely from scratch functions in cells as a life-sustaining catalyst“:

A dawning field of research, artificial biology, is working toward creating a genuinely new organism. At Princeton, chemistry professor Michael Hecht and the researchers in his lab are designing and building proteins that can fold and mimic the chemical processes that sustain life. Their artificial proteins, encoded by synthetic genes, are approximately 100 amino acids long, using an endlessly varying arrangement of 20 amino acids.

Now, Hecht and his colleagues have confirmed that at least one of their new proteins can catalyze biological reactions, meaning that a protein designed entirely from scratch functions in cells as a genuine enzyme.

Enzymes are key to all of biology, Hecht said. “Biology is the system of biochemical reactions and catalysts. Each step has an enzyme that catalyzes it, because otherwise those reactions wouldn’t go fast enough for life to exist. … An enzyme is a protein that is a catalyst. They’re the best catalysts in the universe because evolution has spent billions of years selecting them. Enzymes can increase the speed of a reaction by many orders of magnitude.’

Once Hecht and his research team had successfully created artificial proteins for E. coli, they began looking for critical functions that they could disrupt in these simple bacteria. They found four genes that, when removed, would not only render the E. coli inert — effectively dead — but which their artificial proteins could then “rescue,” or resuscitate.

They first identified these artificial proteins in 2011, and they have spent the past six years working to figure out the precise mechanisms by which their new proteins functioned, now detailed in a Jan. 15 paper in Nature Chemical Biology [abstract].

It’s important not to assume that an artificial protein will work the same way as the natural one whose deletion it is rescuing, Hecht cautioned.

Determining the mechanisms their artificial proteins used took countless experiments. “We had four different gene deletions — four different enzymatic functions,” said Ann Donnelly, lead author on the paper.

After years of experiments, the team had concluded that two of these “rescues” operate by replacing enzymes — proteins that serve to catalyze other reactions, helping them operate quickly enough to sustain life — with proteins that were not enzymes themselves, but which boost the production of other processes in the cell, she said. The third was showing progress, but the fourth had frustrated multiple researchers who came through Hecht’s lab.

But then Donnelly, who was a graduate student when she did the research and is now a research specialist in bioinformatics at the University of Pittsburgh, cracked the code.

“This artificial protein, Syn-F4, was actually an enzyme,” Donnelly said. “That was an incredible and unbelievable moment for me — unbelievable to the point that I didn’t want to say anything until I had repeated it several times.”

She only told Katie Digianantonio, a fellow graduate student, and Grant Murphy, a postdoctoral researcher, who are co-authors of the new paper. “I said, ‘I think this is an enzyme.’ I showed them the initial data and said, ’Don’t say anything to Michael. Let me do this again.” Donnelly re-purified the protein, and created a new, perfectly pure substrate for the E. coli. “I ran everything again from different preps — and when the result held up, I told Michael,” she said.

Out of the original set of proteins that could rescue gene deletions, this is the only one that has turned out to be an enzyme — at least so far, she said.

“We have a completely novel protein that’s capable of sustaining life by actually being an enzyme — and that’s just crazy,” Hecht said.

This has significant implications for industry, said Justin Siegel, faculty director of the Innovation Institute for Food and Health and an assistant professor of chemistry, biochemistry and molecular medicine at the UC Davis Genome Center, who was not involved in the research.

“Biotechnology commonly uses enzymes to carry out industrial processes for the production of materials, food, fuel and medicine,” Siegel said. “The use of these enzymes in an industrial setting often starts with an enzyme that nature evolved for billions of years for an unrelated purpose, and then the protein is tweaked to refine its function for the modern application. The report here demonstrates that we are no longer limited to the proteins produced by nature, and that we can develop proteins — that would normally have taken billions of years to evolve — in a matter of months.”

Hecht’s team had created a strain of E. coli that was missing the enzyme Fes, without which it cannot access the iron needed to sustain life. “We all need iron,” Hecht said. “Even though iron is abundant on earth, biologically accessible iron is not.” Cells have developed molecules like enterobactin, he explained, which can scavenge iron from any available source, but they then need a tool — like Fes — to wrest the iron from the tight grip of the enterobactin.

This modified E. coli strain had no way to extract, or hydrolyze, the iron from its enterobactin, until it was “rescued” by Syn-F4. The researchers had provided iron to the E. coli, but it only stained the cells red, since although they could accumulate the bound metal, they could not liberate it from enterobactin or access it for cellular use.

“And then Ann noticed … they aren’t red anymore, they’re white, which suggests the cells can break this down and get the iron, which suggests we actually have an enzyme!” said Hecht.

“Millions of years of evolution resulted in Fes, a perfectly good enzyme for hydrolyzing enterobactin,” said Wayne Patrick, a senior lecturer in biochemistry at the University of Otago in New Zealand, who was not involved in the research. “It is easy enough to study the structure, function and mechanism of Fes, and to infer something about its evolution by comparing it to related sequences. But it is much harder (and more interesting) to ask whether Fes is the solution to the biochemical problem of hydrolyzing enterobactin — or whether it is one of many solutions. Donnelly et al. have shown that an enzyme which was never born (except artificially, in their lab) nevertheless could have been an equally good solution (had it been given the opportunity).

“That line of reasoning has several implications,” explained Patrick. “One is for the life that remains to be discovered on Earth. Perhaps one day, we’ll find a natural enzyme that looks like Syn-F4 but takes the place of Fes in some microorganism or other. At least now, we’ll know to look. Another implication is for astrobiology. If there are many equally likely solutions to a biochemical problem, it becomes more likely that a solution has been found elsewhere in the universe.”

Researchers are on the cusp of a true synthetic biology, Hecht said.

E. coli has 4,000 different genes,” he said. “We didn’t test all 4,000, because the only way this experiment works is if nothing grows on minimal medium, and of the 4,000, that’s only true for some.

“We’re starting to code for an artificial genome. We’ve rescued 0.1 percent of the E. coli genome. … For now, it’s a weird E. coli with some artificial genes that allow it to grow. Suppose you replace 10 percent or 20 percent. Then it’s not just a weird E. coli with some artificial genes, then you have to say it’s a novel organism.”

This work provides yet more evidence that the solutions biology has evolved for various chemical needs comprise only a small part of the solution space that proteins provide. As the researchers conclude their published work:

Together, these four proteins show that biological challenges can be solved by molecules and mechanisms that differ substantially from those evolved by nature. Moreover, these sequences can be seen as an initial step toward artificial proteomes that provide functions necessary to sustain life.

What we do not know yet is how much more varied is the landscape of chemical reactions that can be catalyzed by nonbiological catalysts. It is not yet clear how large a role synthetic biology might play along the road from biotechnology to molecular manufacturing or productive nanosystems leading to general purpose, high-throughput atomically precise manufacturing. Will it provide variations on biology with similar materials and similar molecular machinery, or will it provide a path through more rigid and robust materials to molecular machinery build from diamondoid or similar materials?
—James Lewis, PhD

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Building atom-by-atom on insulator at room temperature

Swiss cross of 20 atoms

It’s not red and white, but the atoms are arranged in the shape of a Swiss cross (Credit: Physics department, University of Basel)

If the above picture reminds you of something like it some 27 years ago when physicists announced a nanostructure built atom-by-atom, then it is important to recognize there are multiple crucial differences between the above 2014 image of a Swiss cross formed from 20 precisely placed bromine atoms and the 1990 image of the IBM logo formed from 35 precisely placed xenon atoms (Foresight Update 9 “Spelling IBM with 35 Atoms” June 30, 1990). The Swiss cross fabrication was reported in a University of Basel press release three summers ago “Smallest Swiss cross in the world made in Basel“:

Researchers at the University of Basel have made the smallest Swiss cross in the world, out of just 20 atoms. It’s the first time a structure of single atoms has been made at room temperature—it normally has to be much colder for the structure to be stable.

The international team in the university’s physics department used the tip of an atomic force microscope, which is extremely tiny and used in nanotechnology, to place the bromine atoms on an insulating surface.

The Swiss cross they constructed measures only 5.6 nanometres square.

Physicists have been able to move around and reposition single atoms since the 1990s, when done at very low temperatures. Attempts to create these types of structures at room temperature however, had produced disappointing results up until now as they were too difficult to control and properly manipulate.

The study, which was published in the journal, Nature Communications [“Atom manipulation on an insulating surface at room temperature“, OPEN ACCESS], states that the researchers have showed that the systematic manipulation of atoms at room temperature is now possible, demonstrating a key step towards a number of new developments, including new atomic-scale data storage devices.

The 1990 paper presenting the IBM logo was done using a scanning tunneling microscope (STM) in ultra high vacuum and very low temperature (4 K) to position individual xenon atoms on a single-crystal nickel surface with atomic precision. The Xenon atoms were adsorbates, not covalently bound to the surface, and so they could be manipulated by the force exerted by the STM tip. That force contains both van der Waals and electrostatic contributions, and adjusting the position and voltage of the tip determines both the magnitude of the force, and whether it is attractive or repulsive.

It generally takes less force to move an atom along the surface than to pull it away from the surface. Therefore, it is usually possible to adjust parameters so that an STM tip can pull an atom across the surface while the atom remains bound to the surface. The decision to study xenon on a Ni (110) surface was dictated by the requirement that corrugations of the surface potential be sufficiently large for the xenon atoms to be imaged without inadvertently moving them, but small enough that enough lateral force could be exerted to move xenon atoms across the surface. Note that although the STM tip is made from tungsten wire, the chemical identity of the tip apex is not known.

The statement in the above University of Basel press release that this demonstration is “the first time a structure of single atoms has been made at room temperature” is not true, although it is true that this was the first instance in which a structure was made on an insulating surface at room temperature. An earlier demonstration was on a semiconductor surface.

The 2009 Foresight Institute Feynman Prize for Experimental work was awarded to the team of Yoshiaki Sugimoto, Masayuki Abe, and Oscar Custance for the use of atomic resolution dynamic force microscopy — also known as non-contact atomic force microscopy (NC-AFM) — for vertical and lateral manipulation of single atoms on semiconductor surfaces at room temperature. This accomplishment was reported in a 2008 paper in Science “Complex Patterning by Vertical Interchange Atom Manipulation Using Atomic Force Microscopy” [abstract] and described in an article in ScienceDaily “Scientists ‘Write’ With Atoms Using An Atomic Force Microscope“.

In this 2008 work NC-AFM using commercial silicon cantilevers with very sharp tips were used to image a Sn/Si (111) reconstructed surface by detecting the short-range chemical interaction force between the closest tip and surface atoms. A vertical interchange of tip and surface atoms was observed controlled by the mechanical properties of a hybrid tip-surface structure formed in the repulsive regime of the tip-surface interaction force.

The surface appears initially as a single atomic layer of tin (Sn) atoms grown over a Si(111) single crystal substrate. The imaged surface exhibited atomic defects consisting of single Si atoms interspersed in the Sn monolayer. After imaging the surface and placing the AFM tip directly over a single Si atom, and moving the surface toward the oscillating AFM tip, at a certain tip-surface distance am instability in the oscillation frequency occurs. Imaging the surface after the tip was retracted showed the Si atom had been replaced by a Sn atom at the same lattice position. Repeating this process multiple times resulted in the atomic symbol for silicon—Si— constructed from 12 Si atoms on a surface of Sn atoms. These manipulations could be accomplished either at room temperature or at the low temperature of 80 K.

The process described above differs from the two other methods of controlled manipulation of isolated atoms by scanning probe microscopes that had been described previous to this publication: (1) using a bias voltage from an STM to drag a weakly bound atom across a metallic surface; (2) using the attractive part of the tip-surface interaction of an AFM to laterally manipulate atoms without any active participation of the AFM tip beyond tuning the interaction of the manipulated atom with the surface.

The bonding interaction between the closest tip and surface atoms in the repulsive regime is complex, involving several atoms and leading to a complex energy landscape that could result in three outcomes: (1) interchange of tip and surface atoms; (2) atom transfer to the tip; (3) deposition of tip atoms on the surface. Simulations based on density functional theory first-principles calculations rationalize the observed result that experiments with many individual tips fall into three classes: (1) some tips alternately deposit Sn and Si atoms; (2) others only deposit Sn atoms; (3) some only deposit Si atoms. The fact that specific classes of tip had to be identified for specific manipulations accounts for the fact that it took 1.5 h to build the ‘Si’ image shown.

The 2014 paper presenting the fabrication of the Swiss cross from 20 bromide ions on an insulator surface notes that since the 1990 atomic manipulation of xenon atoms on a nickel surface, the ultimate goal has been fabrication of next-generation atomic-scale electro-mechanical devices operating at room temperature (RT) on a dielectric surface (an electrical insulator that can be polarized by an electric field). The paper further notes that on fully insulating surfaces, the smaller diffusion barrier of adsorbed species compared to covalently bounded semiconductor surfaces makes room temperature mechanical manipulation by AFM more difficult than on semiconductor surfaces. This paper presents “the first systematic atomic manipulation on an insulating NaCl(001) surface under ultra-high vacuum (UHV) conditions at RT.”

These experiments use “the recently developed bimodal dynamic mode AFM (bimodal d-AFM, a 2009 paper with the same first and last authors as this 2014 paper), in which the vertical and lateral tip-sample interactions are simultaneously detected via frequency shifts of the flexural and torsional resonance modes, respectively.” These changes result in improved resolution at the atomic scale. The tip apex of a silicon cantilever was terminated with NaCl by prior indentation to the sample surface. Imaging a 28 nm x 28 nm area with the bimodal technique revealed the typical contrast pattern of a NaCl (100) surface, with a number of defects appearing as brighter atomic sites. These were attributed to contaminating bromide ions, whose presence in the crystal was confirmed by X-ray fluorescence analysis. The concentration of bromide ions estimated by AFM was one order of magnitude higher than the crystal concentration. This difference was attributed to the effect of annealing the NaCl crystal at 80 °C. FroM their AFM images, the authors conclude that the foremost atom on the tip apex must be a sodium ion (Na+) and that the corrugation amplitude of bromide ion is about three times higher than the corrugation amplitude of chloride ion, and that the position of the bromide ion is predicted to be 20 pm (picometers) above the surface. They further conclude that the bromide ions are not adsorbed on the surface, but instead incorporated into the NaCl(001) surface layer as substitutional species in the Cl sub-lattice. Further, the bromide ions were stable to repeated imaging over the time course of the experiment.

Upon scanning at smaller tip-sample separations, a class of novel lateral manipulations appears in which a bromide ion exchanges with a chloride ion while scanning in a specific direction. The diversity of this class of lateral manipulations indicated to the authors that the mechanism is more complicated than is the case with a standard lateral manipulation in which an adatom moves on top of the surface.

To achieve more control in manipulating bromide ions, an equivalent of dynamic force spectroscopy was attempted by sequentially approaching the surface to pick up the ion, and then approaching the surface again to implant the ion at the desired surface lattice location. 95 % of the implantations were successful. The experimental data reveal that implantation only occurs if the tip is approached 100 pm closer than the pickup approach.

Theoretical calculations of the manipulation mechanisms based on density functional theory (DFT) were performed In order to understand the detailed process of the atomic manipulation. The model system included a NaCl nanocluster tip and the NaCl surface with one substitutional bromide ion. Conventional lateral manipulation has too high a transition barrier to account for the extensive lateral manipulation observed experimentally. The authors suggest a more plausible model involving the tip temporarily picking up a bromide ion, allowing the vacancy underneath to diffuse before the bromide ion is dropped into a new site. They note that the barrier for vacancy diffusion is always low, and proximity to the tip reduces the barrier to lifting the bromide ion above the surface, especially if a polar model of the tip is used. Thus this process is only viable at large tip-sample separations and is not directionally controlled.

In contrast to the more random lateral manipulationprocess, the statistical preference for implanting ions over picking up ions at closer approach made i possible to perfectly align 20 broide ion in the NaCl surface, forming a 5.64 nm by 5.64 nm ‘Swiss cross’. The authors note that this was the largest number of atomic manipulations achieved at room temperature. They further note that bromide ions are positioned at every other chloride ion site on the surface, and that the fabricated cross is “relatively stable” in that no diffusion was observed during the six hours it took to build the structure. Thus, combining theory with the bimodal dynamic force microscopy they had published five years earlier, they were able to demonstrate “how systematic atomic manipulation at RT, on any class of surface, is now possible. This is an important step towards the fabrication of advanced electromechanical systems at the nanoscale, in a bottom-up manner.” This 2014 advance has capped a 24-year journey to build a larger variety of structures on a surface, atom-by-atom, but I expect that this will not be the end of the story, and that scanning probe microscopes will continue to figure prominently in the roadmap to productive nanosystems and atomically precise manufacturing.
—James Lewis, PhD

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Funding announcements for Atomically Precise Manufacturing

Science & Innovation logo US Dept. of Energy

Credit –

Longtime Foresight member, and since October 2012 Technology Manager, Advanced Manufacturing Office, U.S. Department of Energy, David Forrest passes along these funding announcements about new opportunities at DOE:

Those of you in the Atomically Precise Manufacturing community should be aware of new funding opportunities:


The U.S. Department of Energy (DOE) today [Dec. 13, 2017] announced up to $100 million in funding for new projects as part of the Advanced Research Projects Agency-Energy’s (ARPA‑E) latest OPEN funding opportunity. OPEN will support America’s top innovators through dozens of early-stage research and development projects as they build technologies to transform the nation’s energy system. …
The deadline to submit a concept paper is February 12, 2018 at 5:00 p.m. E.T.

Energy Frontier Research Center

Today, U.S. Secretary of Energy Rick Perry announced a proposed $99 million in Fiscal Year 2018 funding for Energy Frontier Research Centers (EFRCs) to accelerate transformative scientific advances for the most challenging topics in materials sciences, chemical sciences, geosciences, and biosciences. Research supported by this initiative will provide fundamental understanding to enable future advances in energy production and use. …

Between the work in atomically precise catalysts and atomically precise membranes, I think the transformative nature of APM and the energy impact could hit all the marks for these solicitations. Scanning probe molecular assembly and integrated nanosystems may be a harder sell but could perhaps be convincingly rationalized for these solicitations.

Good luck to all who decide to apply! And please spread the word about these opportunities.

David R. Forrest, Sc.D., PE, FASM
Technology Manager
Department of Energy
Energy Efficiency and Renewable Energy
Advanced Manufacturing Office

Almost exactly a year ago, David forwarded us a New Funding Opportunity from U.S. DOE announcement. We can hope these yearly funding announcements continue and grow, and that progress toward atomically precise manufacturing secures an abundant and sustainable energy future.
—James Lewis, PhD

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Mechanical communication in a rotaxane molecular machine

Molecular structures of the protonated and deprotonated forms of the rotaxane, showing the macrocycle at each of the two alternate binding sites on the axle of the rotaxane.

The structural formula of the rotaxane 1H3+. Above: The dibenzo[24]crown-8 macrocycle circles the dibenzylammonium site on the left end of the axle, which had been protonated by the addition of acid. Below: With the addition of a suitable base, the rotaxane is deprotonated to 1H2+, and the macrocycle translates over to the 4,4′-bipyridinium unit at the right end of the axle. The bulky 1,3-Di-tert-butylbenzene groups at either end of the axle constrain the macrocycle to remain on the axle. (The “R” attached to one side of the macrocycle is a nitrile-terminated substituent irrelevant for this work.) Credit: Alberto Credi.

Mechanically interlocked molecules (MIMs), such as rotaxanes and catenanes, provide a fertile opportunity to study some of the complexities of large biological systems of molecular machines, composed of large protein molecules, with small molecular machines composed of small organic molecules containing components that can move relative to each other in response to external control. The Foresight Institute recognized the usefulness of MIMs for development of advanced nanotechnology with the award of the 2007 Feynman Prizes for Theoretical work to David Leigh FRS and for Experimental work to Sir J. Fraser Stoddart. The great potential of these small molecular machines was further recognized by the award of the 2016 Nobel Prize in Chemistry to Jean-Pierre Sauvage, Sir J. Fraser Stoddart, and Bernard L. Feringa. News of another way in which the dynamic properties of MIMs may lead, through mechanical communication of molecular information, to deeper insights into allosteric communication mechanisms of enzymes, and perhaps to the improvement of technology involving fuel cells, sensors, catalysts, and electrochemical devices comes in a press release from the University of Bologna, forwarded to Foresight by Giulio Ragazzon, the first author of the cited research “Hermes, The First Communication System For Molecules”:

It is the first artificial system in which remote parts of a molecule communicate by a dynamic mechanism. Nature uses an analogue strategy in the cellular respiration.

The unprecedented case of two different remote parts of a synthetic molecule that can dynamically exchange chemical information is described. This strategy is employed to change in a controlled manner the acidity of a molecule that becomes 10 million times less acidic: the biggest change ever obtained with an artificial molecule. In our body the process that converts nutrients in energy exploits a similar mechanism, which is still partly unknown and was never mimicked before.

As reported today in the prestigious journal PNAS [abstract, full text], the system — nicknamed Hermes — was designed, synthesized and operated by a research team based at the University of Bologna and National Research Council of Italy (CNR), led by professors Alberto Credi and Marco Lucarini.


The key component of this communication system is a rotaxane, constituted by a ring-like molecule surrounding a thread-like molecule. The ring is free to shuttle along the thread, but it cannot escape because two “stoppers” prevent its dethreading. It is thanks to this shuttling ability that the ring enables the communication between the two extremities. One of these extremities is capable of receiving electric signals, whereas the other one is responsible for the acid/base properties. When an electron is caught by the first site, the ring transfers the information to the other extremity, causing a change of the acidity of the molecule. Therefore the ring acts as a messenger, from which the nickname Hermes (the messenger of the Greek Gods) derived. The absolute novelty of Hermes is that it can provide communication between two distant regions of a molecule that would otherwise be isolated in a rapid, efficient and selective manner. It represents an incredibly challenging task that Nature performs with highly sophisticated chemical structures. Hermes achieves the same result in a system of just a few atoms, easy to synthesize with common synthetic techniques. The rotaxane is one nanometer (a billionth of a meter) long.

An inexplicable experiment

Very similar systems were synthesized and investigated at the end of the 1990s in the area of molecular machines (a field awarded with the Nobel Prize in Chemistry last year), but nobody ever realized such a unique behavior. The discovery happened thanks to a surprising and initially inexplicable experiment: the only possibility to justify the experimental observations was that the molecule was able to put the two distal extremities in communication. “During the experiments I realized that the behavior of the rotaxane radically changed in the presence of different bases” — tells Giulio Ragazzon, the young researcher who participated in the work — “Thanks to the collaboration with the group of Prof. Lucarini, which studies the behavior of unpaired electrons with magnetic resonance techniques, it was possible to confirm our hypothesis, directly observing the ring position along the thread when the molecule receives an electron”.

Relevance and future developments

Hermes deals with two fundamental subjects for molecular systems: long range communication and the coupling of electrical and chemical signals. The operation of most enzymes, natural molecules at the basis of life, relies on the former subject. The latter one lies at the foundation of key biological processes like photosynthesis and respiration, as well as of technological areas like fuel cells, sensors and catalysis. For this reason the discovery may have an impact well beyond the chemistry domain; indeed, the study is published in PNAS (Proceedings of the National Academy of Sciences), an important journal which covers all areas of Science, and not in a specialized chemistry journal as it usually happens.

With Hermes the researchers convert an electric signal into an acidity change; the same strategy, however, may be applied to process light signals or to release at will other molecules. Therefore this work could be relevant for the fields of energy conversion and drug delivery.

The project

Hermes is the result of a project started about three years ago, in the framework of the activities of the Center for Light Activated Nanostructures (CLAN) leaded by Prof. Alberto Credi. CLAN is a joint research laboratory set up by the University of Bologna and the CNR, whose the mission is the development of nanoscale molecular systems and materials able to perform actions activated by light or related stimuli. This study is the result of collaboration between CLAN and the group of Chemistry of Free Radicals at the Chemistry Department “Ciamician” of the University of Bologna. …

The fundamental concept at the basis of this research is the mimicking in artificial systems of what Nature does to form structures, obtain mechanical movements and communicate using proteins and enzymes. In this specific case the focus is on the ability to communicate and convert a signal. In performing these studies, chemists operate like engineers and architects, however manipulating systems a billion times smaller, since their building blocks are molecules. The realization of artificial machines and motors of nanometer size is of great interest for the growth of nanotechnology, that is, a technology that allows the construction of highly miniaturized structures and devices. It is generally considered that nanotechnology will not only lead to lighter, tougher and smarter materials and to smaller and more powerful computer, but also revolutionize medicine and other areas of science and technology.

The results show that the protonation of an ammonium site at one end of the axle can be reversibly modulated through an electron transfer at the bipyridinium site at the opposite end of the axle, which can exist as either a radical cation (one unpaired electron spin and one positive charge) or a dication (two positive charges). The electron transfer (redox reaction) at the bipyridinium changes the affinity of the crown ether macrocycle for the bipyridinium site. The protonation state of the dibenzylammonium site will depend on whether the macrocycle resides there or on the bipyridinium site. Thus the movement of the ring between two sites on the axle carries information between the two distant sites because the chemical or electrochemical state of one site determines the affinity of the ring to that site, and thus whether it stays or moves to the other site.

Biological molecular machine systems, small organic molecular machines with mechanically interlocked molecules, DNA origami machine systems, and combinations of various types of chemical scaffolds and catalysts, or scanning probes have been demonstrated or can be envisioned to build complex structures with atomic precision. The variety of nanostructures and functions that exist or seem possible is impressive. How can they be combined and/or improved to fill specific technological roles? What will be the limit to what we can build with them? Is there a path (or paths) to general purpose, high throughput atomically precise manufacturing?
—James Lewis, PhD

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Changing the world with a nanofabricator that could make anything

flower dissolving into constituent tiny cubes, conveying the idea of a nanofabricator building objects from molecular components, represented by tiny cubes

Image Credit: 3DSculptor /

The Foresight Institute was founded in 1986 on a vision presented by Eric Drexler in which the ultimate manufacturing technology uses a machine termed a nanofactory or nanofabricator to provide atom-by-atom control of the manufacturing process for complex objects, both large and small. Although initially controversial, this vision has been increasingly accepted over the past 32 years as progress in the underlying technologies leading in that direction has accelerated. Two essays published two weeks ago both point to Drexler’s vision and link it to a vision of the future put forward in September of 2013 by renowned British science historian James Burke, which predicts that nanofabricators will be common by 2042, and imagines the effects they will have had on the world by 2103, 90 years after Burke wrote. Burke’s September 2013 essay is available at RadioTimes “James Burke: I’ve seen the future“.

Burke bases his prediction that the world of 2103 will be unrecognizably different on the assumption that the year 2040 sees the beginning of worldwide distribution of kits to make a “nano-fabricator” able to take “dirt, air and water and a bit of cheap, carbon-rich acetylene gas”, manipulate atoms and molecules, and “produce anything you want, virtually free”. Since each of these can make a copy of itself, everyone has one by 2042.

… Sixty years later, we’ll have adapted to the new abundance and are living in small, no-pollution, autonomous communities, anywhere. Energy from spray-on photovoltaics makes any object (like a house) its own power source. So, here you are in your fabber-fabricated dwelling, filled with Mona Lisas if that’s your wish, with holographic reality transforming any room into anywhere (like: beach, sun, wind ruffling hair). So nobody travels any more. Want to see a pal, have dinner with your mother, join a discussion group? No problem: they’ll be there with you as 3D holograms, and you won’t know Stork from butter, unless you try to make physical contact (I’m avoiding sex and reproduction because that might have to be wild speculation).

The entire global environment will also be covered with quintillions of dust-sized nano-computers called motes. So your life will be constantly curated by an intelligent network of ubiquitous cyber-servants. The “motes” will know you need more food, or that it’s a bit chilly today, or that you’re supposed to call Charlie. And they’ll take the relevant action. Your shirt (motes in the fabric) will call Charlie. Either his avatar will appear, or you’ll hear his voice. Not sound waves, but brainwaves. Brain-to-brain communication (it happened for the first time in summer 2013). …

Burke continues, pointing out that nano-fabricators will thus eliminate the need for infrastructure and for government, and that the resulting abundance will eliminate the need for crime, and with it the need for privacy (“outside the boudoir”). Diseases would be eliminated. Without jobs to qualify for, education would be replaced by “learning-for-fun”. Entertainment will be “all in-brain, with accompanying holograms … Tailored to your most idiosyncratic wishes.”

In “How a Machine That Can Make Anything Would Change Everything” on SingularityHub, Thomas Hornigold comments on Burke’s prognostication (“It sounds like science fiction—although, with the advent of 3D printers in recent years, less so than it used to.”) and links the concept to Drexler’s work on “molecular assemblers” and Richard Feynman’s 1959 talk “Plenty of Room at the Bottom”.

Noting progress toward nanofabricators (citing the paper from David Leigh’s group that we recently cited), Hornigold speculates “It may well be that we make faster progress by mimicking the processes of biology, where individual cells, optimized by billions of years of evolution, routinely manipulate chemicals and molecules to keep us alive.”

After agreeing with Burke that the widespread availability of nanofabricators “will destroy the current social, economic, and political system, because it will become pointless,” Hornigold compares such a world with warnings about a world with superintelligent AI “We are limited to considering things in our own terms … there is no sense in comparing it to anything we know, because it is different in kind.”

Nanofabricators: The Creation Machine That Will Turn The World Upside Down Forever In 25 Years” by Gwyn D’Mello draws conclusions similar to those of Hornigold’s piece, and then concludes:

The thing is, the question itself is so vast, and rife with so many variables, we just can’t comprehend how it would play out. Perhaps, however, it’ll be the beginning of a new world, one where caring for everyday needs isn’t an odious task anymore. Perhaps the commotion this sort of invention will cause a new type of conflict on a global scale. Or perhaps the technology will prove impossible to accomplish after all. Either way, people like Burke believe the answer is almost at hand, and those of you reading this now might still be around to see it.

With James Burke’s five-year-old prediction of widespread use of general purpose nanofabricators able to easily copy themselves and almost anything else by 2042 simultaneously endorsed by two writers apparently on opposite sides of the world just two weeks ago, it’s difficult to avoid thinking about how long it might be until general purpose, high-throughput atomically precise manufacturing (APM) transforms the world and the entire human experience.

After Drexler’s ideas were published in 1986 and the Foresight Institute was founded, there was a general reluctance to avoid making predictions about when the ultimate manufacturing technology would arrive. About the clearest statement made during the first decade was made by Drexler in 1994. He gave two varieties of “conservative” estimates for the arrival of nanotechnology. If you are considering the benefits of nanotechnology, it is conservative to plan on 20 years. If you are concerned about competitors getting it first, it is conservative to plan on 10 years. Clearly, more than 23 years later there is no sign that anyone is close to perfecting such a device, although several paths have shown promising progress toward early, very limited, prototypes.

Closer to Burke’s timeline, in 2005 inventor, writer, and renowned futurist Ray Kurzweil predicted 2025 as the most likely year for the debut of advanced nanotechnology, and that one of the earliest applications will be advanced medical nanorobots. “By the late 2020s, nanotech-based manufacturing will be in widespread use, radically altering the economy as all sorts of products can suddenly be produced for a fraction of their traditional-manufacture costs. The true cost of any product is now the amount it takes to download the design schematics”. Kurzweil’s 2005 prediction could still conceivable[y be realized, but could it be that the advent of APM always appears to be about 20 years in the future? The Foresight Institute, in collaboration with Battelle and The Waitt Family Foundation studied the road from then current nanotechnology to APM and published a report in 2007 “Technology Roadmap for Productive Nanosystems“. Perhaps it is time for another look at paths, progress, and possible timelines?
—James Lewis, PhD

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Design of hyperstable constrained peptides

sixteen peptide topologies formed by different combinations of alpha-helices and beta strands

Sixteen topologies of de novo designed hyperstable constrained peptides. Credit: Baker lab, University of Washington

Protein design has been one of the major paths from current fabrication technology toward the goal of general purpose, high-throughput atomically precise manufacturing since Foresight co-founder Eric Drexler proposed it in 1981. It also produced some of the earliest promising results. Although de novo protein design was at first slow, progress has accelerated since David Baker (University of Washington) and Brian Kuhlman (University of North Carolina) won the 2004 Foresight Feynman Prize for Theoretical work for the creation of the RosettaDesign software for modeling and analysis of protein structures. Among recent successes: “From de novo protein design to molecular machine systems“, “Designing novel protein backbones through digital evolution“, and “Rational design of protein architectures not found in nature“. Another milestone accomplished the design of new backbone structures to fit into target binding, and opened up previously inaccessible regions of shape space to design and fabricate new parts for complex molecular machine systems. A September, 2016 news release from the Baker Lab “Accurate de novo design of hyperstable constrained peptides“:

Small constrained peptides combine the stability of small molecule drugs with the selectivity and potency of antibody-based therapeutics. However, peptide-based therapeutics have largely remained underexplored due to the limited diversity of naturally occurring peptide scaffolds, and a lack of methods to design them rationally.

In an article published in Nature this week [abstract, PDF courtesy of Baker lab], Baker lab scientists and collaborators describe the development of computational methods for de novo design of constrained peptides with exceptional stabilities. They used these computational methods to design 18-47 residue constrained peptides with diverse shapes and sizes. The designed peptides presented in the paper cover three broad categories: 1) genetically encodable disulfide cross-linked peptides, 2) synthetic disulfide cross-linked peptides with non-canonical sequences, and 3) cyclic peptides with non-canonical backbones and sequences. Experimentally determined structures for these peptides are nearly identical to their design models.

By including D-amino acids (mirror images of the L-amino acids), and thus expanding the palette of building blocks, Baker lab scientists designed peptides in a sequence and structure space sampled rarely by Nature. Indeed, the article describes successful design of a cyclic 2-helix peptide of mix chirality that represents a shape beyond natural secondary- and tertiary structure.

These designed peptides also exhibit exceptional stability to thermal and chemical denaturation, and thus could serve as attractive scaffolds for design of novel peptide-based therapeutics. More broadly, development of this new computational toolkit to precisely design constrained peptides opens the door for “on-demand” development of a new generation of peptide-based therapeutics.

This research begins with the observation that constrained peptides are an unexplored frontier for drug discovery that is made interesting by the fact that among the small number of examples known are some of the most potent pharmacologically active compounds known. these peptides are constrained by disulfide bonds or backbone cyclization to favor conformations that precisely complement their targets. The inability to achieve global shape complementarity with targets reveals the need for a method to create constrained peptides that provide precise control over the size and shape of the designed molecules. The desire of the researchers to access “broad regions of peptide structure and function space not explored by evolution” provides a motivation to incorporate non-canonical backbones and unnatural amino acids.

Of course, the computational design of covalently constrained peptides with new strutures and non-canonical backbones presents new challenges, including mixed chirality. The Rosetta software suite was used for all of the design calculations in this article. A diverse array of 18-47 residue peptides was designed. These included two classes of peptides: (1) genetically encodable (i.e., using only the 20 amino acids specified by the universal genetic code, often called the canonical amino acids) disulfide-rich peptides, (2) heterochiral peptides with non-canonical sequences. The authors note that genetic encodability has the advantage of compatibility with high-throughput selection methods like phage, ribosome, and yeast display, while incorporation of non-canonical components opens access to new types of structures. For the former class, they selected nine combinations of α-helices and β-strands. The latter class included α-helices and β-strands connected by loop segments containing D-amino acid residues, non-canonical amino acids, and cyclic structures.

Genetically encodable disulfide-constrained peptides

For the nine chosen topologies of genetically encodable disulfide-constrained peptides, Monte Carlo-based assembly of short protein fragments was used to construct backbone conformations, which were then scanned for sites capable of hosting disulfide bonds with nearly ideal geometry. One ot three disulfides bonds were incorporated and low energy sequences were designed and optimized using the Rosetta all-atom force field. Rosetta ab initio structure prediction calculations were carried out for each designed sequence, resulting in a diverse set of 130 designs for which the target structure was in a deep global free-energy minimum (i.e., the structure would be very stable). Genes were constructed for each design and expressed in the bacterium Escherichia coli or in cultured mammalian cells. Since disulfide bonds would be unlikely to form in the reducing environment of the cytoplasm, gene expression was engineered to secrete the designed proteins, which were analyzed for signs that the disulfide bond had formed consistent with the designed topology. 29 designs passed this test, and one representative design was chosen from each of the nine topologies for further biochemical characterization.

One of the nine designs produced a protein that could be crystallized. The structure was determined to a resolution of 0.209 nm. The details of the structure were in excellent agreement with the design model. The protein was thermostable and completely resistant to chemical denaturation.

The eight designs that could not be crystallized were expressed as isotopically labelled peptides and the structures determined by nuclear magnetic resonance (NMR) spectroscopy. The formation of the designed disulfide bonds was confirmed. “Taken together, the X-ray crystallographic and NMR structures demonstrate that our computational approach enables accurate design of protein main-chain conformation, disulfide bonds and core residue rotamers.”

Synthetic heterochiral disulfide-constrained peptides

To design shorter disulfide-constrained peptides incorporating
both l- and d-amino acids, the rosetta energy function was generalized to support D-amino acids and mixed chirality designs. Since chemical synthesis required to synthesize peptides that cannot be genetically encoded is laborious, automated computational screening techniques were developed to supplement Rosetta ab initio screening with molecular dynamics (MD) evaluation. Sequences were designed favoring D-amino acids at positions with positive main chain φ dihedral angle values. A single low energy design was selected for each of three topologies evaluated, chemically synthesized, and structurally characterized by NMR. All three gave NMR spectra consistent with the secondary structure of the design. High resolution NMR solution structures showed close agreement for two of the designs. The third differed from the design model by having an unwound carboxyl terminus, but a second design chosen for that topology had a structure very close to the design model. All three designs were very thermostable.

Synthetic backbone-cyclized peptides

A generalized kinematic loop closure method (named GenKIC) was implemented to samo arbitrary covalently linked atom chains capable of connecting the termini. Each GenKIC chain-closure attempt involved perturbing multiple chain degrees of freedom, then enforcing loop closure with ideal peptide bond geometry. “Sequence design, backbone relaxation, and in silico structure validation using MD simulation and Rosetta ab initio structure prediction were carried out with terminal bond geometry constraints”. Cyclic peptides were synthesized for three topologies, and their structures determined with NMR spectroscopy. All three peptides had structures very close to their design models, and all three were extremely stable to thermal denaturation and resistant to chemical denaturation. They were exceptionally stable given their small sizes.

Beyond natural secondary and tertiary structure

A “heterochiral, backbone-cyclized, two-helix topology with
one non-canonical left-handed α-helix and one canonical right-handed
α-helix” provided a final test of the design methodology. For validation by ab initio structure prediction, it was necessary to develop a new, GenKIC-based protocol since the standard Rosetta method uses uses fragments of native proteins, which typically do not contain left-handed helices. The selected design for this topology is a 26-residu protein with one D-cysteine,L-cysteine disulfide bond connecting the right-handed and left-handed α-helices. There was an excellent match between the NMR structure ensemble and the design model. This success demonstrated that the authors’ computational methods are general enough to design in a conformational space not explored by nature.

The authors point out that of the sixteen constrained peptide topologies designed, the twelve for which the strutures were experimentally determined were in close agreement with the design models. Unlike the natural constrained peptide families, these designed peptides are not limited to particular sizes, shapes, or disulfide connectivities.

Here we have focused on extending sampling and scoring methods to permit design with d-amino acids and cyclic backbones, but the new tools are fully generalizable to peptides containing more exotic building-blocks, such as amino acids with non-canonical sidechains or non-canonical backbones.

This research was clearly focused on extending de novo peptide design methods to provide a greater variety of protein components for drug discovery and therapeutic applications. Drugs and biotech therapies, whether small molecules or protein or other biomolecules, are all molecules sought to enhance or alter the functions of the complex natural molecular machine systems that comprise cells and organisms. Other complex molecular machine systems, as yet not designed, will play crucial roles along the paths to productive nanosystems and general purpose, high throughput atomically precise manufacturing.
—James Lewis, PhD

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