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Advancing nanotechnology with protein building blocks

This is a molecular cage created by designing specialized protein puzzle pieces. Every color represents a separate protein, where cylindrical segments indicate rigid parts and ribbon-like segments indicate flexible parts of each protein chain. The grey sphere in the protein cage was placed there to indicate the empty space in the middle of the container and is not part of the molecular structure. (Credit: Todd Yeates, Yen-Ting Lai/UCLA Chemistry and Biochemistry)

An advance in protein engineering targeted to better drug delivery methods or artificial vaccines is also an important step toward a general capability to build nanostructures by assembling designed protein domains in a designed rigid configuration. A hat tip to ScienceDaily for reprinting this UCLA news release written by Kim DeRose “Building molecular ‘cages’ to fight disease“:

UCLA biochemists have designed specialized proteins that assemble themselves to form tiny molecular cages hundreds of times smaller than a single cell. The creation of these miniature structures may be the first step toward developing new methods of drug delivery or even designing artificial vaccines.

“This is the first decisive demonstration of an approach that can be used to combine protein molecules together to create a whole array of nanoscale materials,” said Todd Yeates, a UCLA professor of chemistry and biochemistry and a member of the UCLA–DOE Institute of Genomics and Proteomics and the California NanoSystems Institute at UCLA.

Published June 1 in the journal Science [abstract], the research could be utilized to create cages from any number of different proteins, with potential applications across the fields of medicine and molecular biology.

UCLA graduate student Yen-Ting Lai, lead author of the study, used computer models to identify two proteins that could be combined to form perfectly shaped three-dimensional puzzle pieces. Twelve of these specialized pieces fit together to create a molecular cage a mere fraction of the size of a virus.

“If you just connect two random proteins together, you expect to get an irregular network,” said Yeates, senior author of the study. “In order to control the geometry, the idea was to make a rigid link holding the two proteins in place as if they were parts of a toy puzzle.”

The specifically designed proteins intermesh to form a hollow lattice that could act as a vessel for drug delivery, he said.

“In principle, it would be possible to attach a recognition sequence for cancer cells on the outside of the cage, with a toxin or some other ‘magic bullet’ contained inside,” said Yeates. “That way, the drug could be delivered directly to certain targets like tumor cells.” …

A second breakthrough

A second paper co-authored by Yeates creates similarly designed molecular cages using multiple copies of the same protein as building blocks. The scientists control the shape of the cage by computing the sequence of amino acids necessary to link the proteins together at the correct angles. The research, also published today in Science [abstract], resulted from a collaboration between the UCLA team and professor David Baker [co-winner of the 2004 Foresight Institute Feynman Prize for Theoretical Molecular Nanotechnology] at the University of Washington.

This alternative method represents a more versatile approach because it requires only one type of protein to form a structure, Yeates said. However, devising different kinds of links between the identical proteins remains a major challenge. Lead author Neil King, a postdoctoral scholar at the University of Washington and a former student of Yeates, took the numerous computer-generated possibilities and tested each version experimentally until he found one which produced the right behavior.

The first paper reported a tetrahedral supramolecular 12-subunit cage about 16 nm in diameter, with an open center 5 nm in diameter. Each subunit comprised a trimer of one protein and a dimer of a different protein, fused together in a specified geometry. The second paper used trimers of a single protein as building blocks:

… to design a 24-subunit, 13-nm diameter complex with octahedral symmetry and a 12-subunit, 11-nm diameter complex with tetrahedral symmetry. The designed proteins assembled to the desired oligomeric states in solution, and the crystal structures of the complexes revealed that the resulting materials closely match the design models. The method can be used to design a wide variety of self-assembling protein nanomaterials.

Taken together, these two papers document a major advance in designing proteins to use as atomically precise building blocks.
—James Lewis, PhD

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Foresight Institute at Space Frontier Conference

Foresight’s Director of Development and Outreach Desiree D. Dudley will speak on a panel at the Space Frontier Foundation’s NewSpace 2012 conference at NASA-Ames July 26-28. Right now the schedule has the panel titled “Approaching the Tipping Point: How Emergent Technologies Will Change the Way We Look at the Future of Spaceflight” at 2pm Saturday the 28th. From the Conference home page:

The next disruptive innovation is already underway and it is in space.
The commercial space industry is building a new market with efficient business processes, a wide spectrum of technology, and almost prescient investors. It’s been said that the first trillionaires will be made through space industrialization and we’re going to show how space pioneers are creating new products and profits. NewSpace is undergoing rapid expansion, similar to the Internet explosion of the 1990′s, and needs to be filled with revolutionary businesses like yours.

The Space Frontier Foundation’s annual conference is one of the most important commercial space conferences in the nation, and will be in July in Silicon Valley. NewSpace 2012 is where networking with leaders, supporters, investors and activists evolves into enterprises that propel the industry upward. It will host a wide-range of thought-provoking panels and visionary keynote speakers that will surpass NewSpace 2011′s already highly-praised programming. …

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DNA tiles provide faster, less expensive way to fabricate complex DNA objects

Wyss researchers have built numerals, letters, and a number of other structures using short strands of DNA as building blocks. (Credit: Wyss Institute at Harvard University)

A substantial addition has been made to the toolkit for structural DNA nanotechnology. Currently the only general way to build arbitrarily complex 100-nm-scale DNA objects is scaffolded DNA origami, in which a long (about 7000 bases), biological single stranded DNA molecule is folded into a pre-determined shape through binding to a specially designed set of short, synthetic “staple” strands. A new method now programs self-assembly of arbitrarily complex 150-nm DNA objects from hundreds of distinct single-stranded tiles, each a 42-base strand folded into a 3nm by 7nm tile and attached to four neighboring tiles. With each tile a pixel, the tiles assemble to form a 310-pixel, 150nm-square canvas. A hat tip to ScienceDaily for reprinting this Wyss Institute news release “Wyss Institute Develops New Nanodevice Manufacturing Strategy Using Self-Assembling DNA “Building Blocks”“:

Researchers at the Wyss Institute have developed a method for building complex nanostructures out of short synthetic strands of DNA. Called single-stranded tiles (SSTs), these interlocking DNA “building blocks,” akin to Legos®, can be programmed to assemble themselves into precisely designed shapes, such as letters and emoticons. Further development of the technology could enable the creation of new nanoscale devices, such as those that deliver drugs directly to disease sites.

The technology, which is described in today’s online issue of Nature [abstract], was developed by a research team led by Wyss core faculty member Peng Yin, Ph.D., who is also an Assistant Professor of Systems Biology at Harvard Medical School. Other team members included Wyss Postdoctoral Fellow Bryan Wei, Ph.D., and graduate student Mingjie Dai. …

In focusing on the use of short strands of synthetic DNA and avoiding the long scaffold strand, Yin’s team developed an alternative building method. Each SST is a single, short strand of DNA. One tile will interlock with another tile, if it has a complementary sequence of DNA. If there are no complementary matches, the blocks do not connect. In this way, a collection of tiles can assemble itself into specific, predetermined shapes through a series of interlocking local connections.

In demonstrating the method, the researchers created just over one hundred different designs, including Chinese characters, numbers, and fonts, using hundreds of tiles for a single structure of 100 nanometers (billionths of a meter) in size. The approach is simple, robust, and versatile. …

A short video shows how the single strand tiles assemble to create complex DNA objects.

According to coverage at “DNA tiles pave the way“, each shape takes about one hour to produce, compared to a week by the DNA origami technique. In addition it appears to be less expensive since one complete set of tiles costing about £4500 is estimated to be able to make 2 x 1093 possible shapes. With DNA origami a distinct set of staple strands is required for each new shape. On the other hand, yield with the new technique is only 6-40% compared to 95% with DNA origami.

Which technique will prove more convenient for constructing complex systems of molecular machines remains to be seen, but the fact that the new technique is faster and less expensive should speed design-fabricate-test iterations.
—James Lewis, PhD

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Carbon nanotube graphene composite improves downhill bike rim

Greg Minnaar riding the new nano-enhanced DH rim at the 2012 World Cup Opener in South Africa (credit: Zyvex Technologies)

The superiority of nanostructured materials continues to find real commercial applications. A hat tip to for reporting this success from Zyvex Technologies for their proprietary carbon nanotube and graphene engineered composite material. From Zyvex News “The world’s first nano-enhanced carbon fiber downhill bike rim“:

The world’s first molecular nanotechnology company, Zyvex Technologies, and ENVE Composites announced an exclusive partnership to provide a bicycle rim specifically for downhill mountain biking that uses the latest advanced materials comprised of nano-enhanced carbon fiber. This new bicycle rim gives a significant competitive advantage to the downhill cycling market as proven during the last year in development and testing. The ENVE DH rim provides performance benefits to all downhill cyclists including those that compete at the highest levels of World Cup racing.

ENVE used Zyvex Technologies’ nano-enhanced carbon fiber technology called Arovex, which is a carbon nanotube and graphene engineered composite material that uses the proprietary Kentera technology to create chemical bonds on the carbon nanotubes. It provides an advantage in toughness without compromising strength. It also protects from fracture damage. ENVE has an exclusive license for this advanced technology for cycling applications.

ENVE developed the first nano-enhanced carbon fiber downhill bike with the intention of its riders winning a World Cup. After being in development for over a year, the rim carried ENVE sponsored rider Greg Minnaar (see photo) to victory at the 2012 World Cup opener in South Africa.

It will be a long road from nanostructured composites to complex molecular machine systems, but successful early steps provide incentives to continue along the development road.
—James Lewis, PhD

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New Darpa program may accelerate synthetic biology path to advanced nanotechnology

Darpa’s Living Foundries program is looking to transform biology into an engineering practice. Photo: VA

Synthetic biology promises near-term breakthroughs in medicine, materials, and energy, and is also one promising development pathway leading to advanced nanotechnology and a general capability for programmable, atomically-precise manufacturing. Darpa (US Defense Advanced Research Projects Agency) has launched a new program that could greatly accelerate progress in synthetic biology by creating a library of standardized, modular biological units that could be used to build new devices and circuits. A hat tip to for pointing to a recent article in Wired Danger RoomDarpa, Venter launch assembly line for genetic engineering“:

… The program, called “Living Foundries,” was first announced by the agency last year. Now, Darpa’s handed out seven research awards worth $15.5 million to six different companies and institutions. Among them are several Darpa favorites, including the University of Texas at Austin and the California Institute of Technology. Two contracts were also issued to the J. Craig Venter Institute. Dr. Venter is something of a biology superstar: He was among the first scientists to sequence a human genome, and his institute was, in 2010, the first to create a cell with entirely synthetic genome.

“Living Foundries” aspires to turn the slow, messy process of genetic engineering into a streamlined and standardized one. Of course, the field is already a burgeoning one: Scientists have tweaked cells in order to develop renewable petroleum and spider silk that’s tough as steel. And a host of companies are investigating the pharmaceutical and agricultural promise lurking — with some tinkering, of course — inside living cells.

But those breakthroughs, while exciting, have also been time-consuming and expensive. As Darpa notes, even the most cutting-edge synthetic biology projects “often take 7+ years and tens to hundreds of millions of dollars” to complete. Venter’s synthetic cell project, for example, cost an estimated $40 million.

Synthetic biology, as Darpa notes, has the potential to yield “new materials, novel capabilities, fuel and medicines” — everything from fuels to solar cells to vaccines could be produced by engineering different living cells. But the agency isn’t content to wait seven years for each new innovation. In fact, they want the capability for “on-demand production” of whatever bio-product suits the military’s immediate needs.

To do it, Darpa will need to revamp the process of bio-engineering — from the initial design of a new material, to its construction, to its subsequent efficacy evaluation. The starting point, and one that agency-funded researchers will have to create, is a library of “modular genetic parts”: Standardized biological units that can be assembled in different ways — like LEGO — to create different materials.

Once that library is created, the agency wants researchers to come up with a set of “parts, regulators, devices and circuits” that can reliably yield various genetic systems. After that, they’ll also need “test platforms” to quickly evaluate new bio-materials. Think of it as a biological assembly line: Products are designed, pieced together using standardized tools and techniques, and then tested for efficacy. …

The Darpa Living Foundries solicitation will remind long-term Nanodot readers of discussions of the need for an engineering perspective in the development of advanced nanotechnology centered on molecular manufacturing:

The Microsystems Technology Office (MTO) of the Defense Advanced Research Projects Agency (DARPA) is sponsoring an Industry Day for “Living Foundries,” a new DARPA program. The goal of the Living Foundries program is to apply an engineering framework to biology to harness its use as a technology and drive its advance as a manufacturing platform. In turning biological production into an engineering space where the only limit is the creativity of the designer, Living Foundries aims to enable on-demand production of new and high-value materials, devices and capabilities for the Department of Defense and establish a new manufacturing capability for the United States.

Because of the multidisciplinary nature of Living Foundries, DARPA is looking to engage the wider research community from fields both outside and inside the biological sciences to develop new ideas, approaches and tools to overcome current limitations and to create revolutionary capabilities.

Current, primitive examples of engineering biology rely on an ad hoc, laborious, trial-and-error process, wherein one successful project does not inform subsequent, new designs. This approach combined with the complexity of biological systems restricts current, one-off efforts to modifying only a small set of genes and constructing simple, isolated genetic circuits and metabolic pathways. Consequently, we are limited to producing only a small fraction of the vast number of possible chemicals, materials, and living systems that would be enabled by the ability to truly engineer biology. Through an engineering-driven approach to biology, Living Foundries aims to create a rapid, reliable manufacturing capability where multiple cellular functions can be fabricated, mixed and matched on demand and the whole system controlled by integrated circuitry, opening up the full space of biologically produced materials and systems. Key to success will be the democratization of the biological design and manufacturing process, breaking open the field to those outside the biological sciences.

In order to achieve the vision of Living Foundries, new tools, technologies and methodologies must be developed to transform biology into an engineering practice, decoupling design from fabrication and speeding the biological design, build, test cycle. These include: design tools that span from high-level description to fabrication in cells; modular genetic parts that allow a combination of systems to be designed and reproducibly assembled; methods for developing and fine-tuning new genetic parts and systems; well-understood test platforms, “cell-like” systems and chassis that readily integrate new genetic designs in a predictable fashion; next generation DNA synthesis and assembly techniques; and tools that allow for routine system characterization and debugging, among others. Further, these technological advances and innovations must be integrated to prove-out and push the boundaries of biological design towards the ultimate vision of point-of-use, on-demand, mass-customization biological manufacturing. …

If Darpa’s Living Foundries program achieves its ambitious goals, it should create a methodology, toolbox, and a large group of practitioners ready to pursue a synthetic biology pathway to building complex molecular machine systems, and eventually, atomically precise manufacturing systems.
—James Lewis, PhD

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Foresight Presents: “GENOGEN: Regenerating Skin for Life”, with Dr. Nancy Mize

Foresight Presents: “GENOGEN: Regenerating Skin for Life
Dr. Nancy Mize
Date/Time: Thursday, May 31, 2012, 6:30pm in PDT
Drinks/Dinner: 6:30pm, Talk: 7:30pm
RSVP: $40 via to
Location: Ristorante Don Giovanni
235 Castro Street, Mountain View, CA 94041

GENOGEN is developing products that activate resident skin stem cells to stimulate local areas of regeneration of skin naturally – the way children heal. GENOGEN’s first product is a re-purposed agent, currently FDA and EU approved and marketed, and used in humans for over 5 years, with significant utility in the aesthetics sector for treatment of aging skin. Localized skin delivery of the stem cell activator with a growth matrix activates local regeneration and repair in situ – with no stem cell isolation, no stem cell prep, no surgery, extraction or re-implantation – resulting in accelerated healing and young skin.

NANCY K MIZE, PhD, Scientist, Innovator, and CEO of GENOGEN Inc., has researched stem cell activators since 2000, and is the co-inventor on 11 issued patents. Dr. Mize served as the BioMarker Expert for Personalized Medicine at Pacific BioDevelopment, the Director of Protein Bioinformatics at Hyseq/Nuvelo, and Scientist, Drug Delivery Technologies at Alza Corporation. Dr. Mize holds a PhD from UCSF in Cell Biology in the department of Human Physiology, BS from UC Berkeley and has completed Postdoctoral studies at the European Molecular Biology Laboratory (EMBL), Heidelberg, and Genentech.

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Novel silicon nanostructure extends battery life

The new double-walled silicon nanotube anode is made by a clever four-step process: Polymer nanofibers (green) are made, then heated (with, and then without, air) until they are reduced to carbon (black). Silicon (light blue) is coated over the outside of the carbon fibers. Finally, heating in air drives off the carbon and creates the tube as well as the clamping oxide layer (red). (Image courtesy Hui Wu, Stanford, and Yi Cui)

A clever new method for making hollow silicon nanostructures produces a battery anode that is not quickly destroyed by the stress of repeated charging and discharging. A hat tip to for reprinting this SLAC National Accelerator Laboratory news release written by Mike Ross “New nanostructure for batteries keeps going and going“:

For more than a decade, scientists have tried to improve lithium-based batteries by replacing the graphite in one terminal with silicon, which can store 10 times more charge. But after just a few charge/discharge cycles, the silicon structure would crack and crumble, rendering the battery useless.

Now a team led by materials scientist Yi Cui of Stanford and SLAC has found a solution: a cleverly designed double-walled nanostructure that lasts more than 6,000 cycles, far more than needed by electric vehicles or mobile electronics.

“This is a very exciting development toward our goal of creating smaller, lighter and longer-lasting batteries than are available today,” Cui said. The results were published March 25 in Nature Nanotechnology [abstract].

Lithium-ion batteries are widely used to power devices from electric vehicles to portable electronics because they can store a relatively large amount of energy in a relatively lightweight package. The battery works by controlling the flow of lithium ions through a fluid electrolyte between its two terminals, called the anode and cathode.

The promise – and peril – of using silicon as the anode in these batteries comes from the way the lithium ions bond with the anode during the charging cycle. Up to four lithium ions bind to each of the atoms in a silicon anode – compared to just one for every six carbon atoms in today’s graphite anode – which allows it to store much more charge.

However, it also swells the anode to as much as four times its initial volume. What’s more, some of the electrolyte reacts with the silicon, coating it and inhibiting further charging. When lithium flows out of the anode during discharge, the anode shrinks back to its original size and the coating cracks, exposing fresh silicon to the electrolyte.

Within just a few cycles, the strain of expansion and contraction, combined with the electrolyte attack, destroys the anode through a process called “decrepitation.”

Over the past five years, Cui’s group has progressively improved the durability of silicon anodes by making them out of nanowires and then hollow silicon nanoparticles. His latest design consists of a double-walled silicon nanotube coated with a thin layer of silicon oxide, a very tough ceramic material.

This strong outer layer keeps the outside wall of the nanotube from expanding, so it stays intact. Instead, the silicon swells harmlessly into the hollow interior, which is also too small for electrolyte molecules to enter. After the first charging cycle, it operates for more than 6,000 cycles with 85 percent capacity remaining.

Cui said future research is aimed at simplifying the process for making the double-wall silicon nanotubes. Others in his group are developing new high-performance cathodes to combine with the new anode to form a battery with five times the performance of today’s lithium-ion technology.

In 2008, Cui founded a company, Amprius, which licensed rights to Stanford’s patents for his silicon nanowire anode technology. Its near-term goal is to produce a battery with double the energy density of today’s lithium-ion batteries.

With a clever new method to produce novel nanostructures, a material like silicon, which has been very well studied for half a century as the basis for an important technology, can fill unexpected new roles. A few decades from now, when atomically precise manufacturing provides a general method for making arbitrarily complex nanostructures, we can expect many more surprising developments.
—James Lewis, PhD

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Foresight Institute on Singularity Hub (video)

foresight’s Director of Development and Outreach Desiree D. Dudley was featured recently on Singularity Hub talking about Foresight and nanotechnology. Topics addressed include Foresight’s series of dinner lectures, its upcoming technical conference, a new youth outreach program, Foresight’s relationship with the general futurist community, and the balance of emphasis on near-term nanotechnology and advanced molecular manufacturing. The interview led to a discussion of the role of synthetic biology in the development of nanotechnology, and the interfaces between the materials science and the biotechnology aspects of nanotechnology. The video is available on YouTube.
—James Lewis, PhD

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Drug-resistant cancer cells cannot resist plasmonic nanobubbles

Dmitri Lapotko. (Credit: Jeff Fitlow/Rice University)

In yet another wrinkle in the rapidly developing area of using nanotechnology to enhance cancer chemotherapy, targeted nanoparticles were used to produce “nanobubbles” inside cancer cells instead of to deliver a chemotherapy drug to the cancer cells. In laboratory tests, the nanobubbles proved to be much more efficient in specifically killing cancer cells while sparing neighboring healthy cells. A hat tip to ScienceDaily for reprinting this Rice University news release with its embedded video “‘Nanobubbles’ plus chemotherapy equals single-cell cancer targeting“:

Using light-harvesting nanoparticles to convert laser energy into “plasmonic nanobubbles,” researchers at Rice University, the University of Texas MD Anderson Cancer Center and Baylor College of Medicine (BCM) are developing new methods to inject drugs and genetic payloads directly into cancer cells. In tests on drug-resistant cancer cells, the researchers found that delivering chemotherapy drugs with nanobubbles was up to 30 times more deadly to cancer cells than traditional drug treatment and required less than one-tenth the clinical dose.

“We are delivering cancer drugs or other genetic cargo at the single-cell level,” said Rice’s Dmitri Lapotko, a biologist and physicist whose plasmonic nanobubble technique is the subject of four new peer-reviewed studies, including one due later this month in the journal Biomaterials and another published April 3 in the journal PLoS ONE [Open Access research article]. “By avoiding healthy cells and delivering the drugs directly inside cancer cells, we can simultaneously increase drug efficacy while lowering the dosage,” he said. …

Rice’s nanobubbles are not nanoparticles; rather, they are short-lived events. The nanobubbles are tiny pockets of air and water vapor that are created when laser light strikes a cluster of nanoparticles and is converted instantly into heat. The bubbles form just below the surface of cancer cells. As the bubbles expand and burst, they briefly open small holes in the surface of the cells and allow cancer drugs to rush inside. The same technique can be used to deliver gene therapies and other therapeutic payloads directly into cells.

This method, which has yet to be tested in animals, will require more research before it might be ready for human testing, said Lapotko, faculty fellow in biochemistry and cell biology and in physics and astronomy at Rice. …

To form the nanobubbles, the researchers must first get the gold nanoclusters inside the cancer cells. The scientists do this by tagging individual gold nanoparticles with an antibody that binds to the surface of the cancer cell. Cells ingest the gold nanoparticles and sequester them together in tiny pockets just below their surfaces.

While a few gold nanoparticles are taken up by healthy cells, the cancer cells take up far more, and the selectivity of the procedure owes to the fact that the minimum threshold of laser energy needed to form a nanobubble in a cancer cell is too low to form a nanobubble in a healthy cell

A given molecular targeting strategy can only achieve a certain ratio of entering cancer cells to entering healthy cells. As the cancer evolves to become more resistant to the drug, that ratio becomes inadequate to kill cancer cells while sparing healthy cells. But because the laser pulse can be precisely controlled, the ratio of gold nanoparticles in cancer cells to the amount in healthy cells is sufficient to ensure that nanobubbles only form in cancer cells, so the drug can only enter the cancer cells. If this approach works as well in an animal model as it does in laboratory cell cultures, it might develop into an effective therapy to kill drug-resistant tumor cells.
—James Lewis, PhD

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