Medical nanorobots win poll on engineering's Next Big Thing

Thanks to Robert A. Freitas Jr. for passing along this news item. NewScientist recently conducted a poll of its readers on What will be engineering’s Next Big Thing?. The answer to the question “Which technology do you think will have the biggest impact on human life in the next 30 years?“:

The clear winner with 3,097 votes — 35 per cent of the total — is Catherine McTeigue’s prediction of nanorobots that will repair cancerous cells:

Nanorobots fight the medical battles of the future

“Say the word “cancer” and people are fear-ridden. Projects being undertaken to harness nanotechnology and develop nanorobots to enter into the human body and repair cancerous cells, without the need for life-changing, disfiguring and painful chemotherapy, will have the greatest impact in the next 30 years. Watching loved ones suffer will be a thing of the past as the robots aid speedy recoveries, mortality rates drop, and as the technology is used more frequently, so will the cost, that oft deciding factor. An enormous step forwards for all mankind, in the form of a microscopic creature.”

The winning suggestion is a bit vague as to just what kind of medical nanorobots are envisioned. Recent posts (here, here, and here) suggest that near-term, incremental nanotechnology could be successful in curing cancer by selectively killing cancer cells while sparing normal cells. However, the phrase “repair cancerous cells” suggests advanced medical nanotechnology, of the type Freitas has proposed, that could be capable of molecular level repair of cells rather than necessarily killing cancerous cells. On the other hand, using near-term nanotechnology to deliver into cancer cells siRNA or miRNA to alter cellular gene expression might also make it possible to “repair cancerous cells”. The next poll we would like to see is something to the effect of “How do you think medical nanorobots will be developed over the next 30 years?”

'Good Cholesterol' nanoparticles silence cancer-promoting genes and destroy cancer cells

The lipid-coated silica nanoparticles described here last week are only one of several very promising approaches to using nanotechnology to treat cancer. ScienceDaily points to an MD Anderson news release reporting a very different type of nanoparticle used to destroy cancer cells “‘Good Cholesterol’ Nanoparticles Seek and Destroy Cancer Cells“:

High-density lipoprotein’s hauls excess cholesterol to the liver for disposal, but new research suggests “good cholesterol” can also act as a special delivery vehicle of destruction for cancer.

Synthetic HDL nanoparticles loaded with small interfering RNA to silence cancer-promoting genes selectively shrunk or destroyed ovarian cancer tumors in mice, a research team led by scientists from The University of Texas MD Anderson Cancer Center and the University of North Texas Health Science Center reports in the April edition of Neoplasia [abstract, full text PDF].

“RNA interference has great therapeutic potential but delivering it to cancer cells has been problematic,” said Anil Sood, M.D., the study’s senior author and MD Anderson’s director of Ovarian Cancer Research and co-director of the Center for RNA Interference and Non-Coding RNA at MD Anderson. “Combining siRNA with HDL provides an efficient way to get these molecules to their targets. This study has several important implications in the ability to fight certain cancers.”

Sood and Andras Lacko, Ph.D., professor of Molecular Biology and Immunology at UNT Health Science Center, jointly developed the nanoparticles, which build on Lacko’s original insight about HDL’s potential for cancer drug delivery.

The next step is to prepare for human clinical trials, the two scientists said. “If we can knock out 70, 80 or 90 percent of tumors without drug accumulation in normal tissues in mice, it is likely that many cancer patients could benefit from this new type of treatment in the long run,” Lacko said.

Only cancer and liver cells express HDL receptor

Previous studies have shown that cancer cells attract and scavenge HDL by producing high levels of its receptor, SR-B1. As cancer cells take in HDL, they grow and proliferate. The only other site in the body that makes SR-B1 receptor is the liver. This selectivity for cancer cells protects normal, healthy cells from side effects.

Previous attempts to deliver siRNA by lipsomes and other nanoparticles have been hampered by toxicity and other concerns. The tiny bits of RNA, which regulate genes in a highly targeted fashion, can’t simply be injected, for example.

“If siRNA is not in a nanoparticle, it gets broken down and excreted before it can be effective,” Sood said. “HDL is completely biocompatible and is a safety improvement over other types of nanoparticles.”

The team developed a synthetic version of HDL, called rHDL, because it’s more stable than the natural version.

Fewer and smaller tumors, less toxicity

Using rHDL as a delivery method has other advantages as well. rHDL has not shown to cause immunologic responses, helping to minimize potential side effects, Lacko said, and it exhibits longer time in circulation than other drug formulations or lipoproteins. Also, because SR-B1 is found only in the liver, an rHDL vehicle will help block and treat metastasis to that organ.

Researchers first confirmed the distribution of SR-B1 and the uptake of rHDL nanoparticles in mice injected with cancer cells. They found that siRNA was distributed evenly in about 80 percent of a treated tumor. As expected, the nanoparticles accumulated in the liver with minimal or no delivery to the brain, heart, lung, kidney or spleen. Safety studies showed uptake in the liver did not cause adverse effects.

Using siRNA tailored to the individual gene, the researchers separately shut down the genes STAT3 and FAK in various types of treatment-resistant ovarian cancer tumors. STAT3 and FAK are important to cancer growth, progression and metastasis; however, they also play important roles in normal tissue so targeting precision is vital.

The siRNA/rHDL formulation alone reduced the size and number of tumors by 60 to 80 percent. Combinations with chemotherapy caused reductions above 90 percent.

Conventional approaches to target STAT3 have met limited success, Sood said. FAK, which is over expressed in colorectal, breast, ovarian, thyroid and prostate cancers, is particularly aggressive in ovarian cancer and one reason for its poor survival rate. While previous attempts have targeted FAK with liposomal nanoparticles or small molecule inhibitors, these methods are not tumor-specific and are more likely to harm normal cells, the scientists noted.

Next Step: Clinical Studies

“In order to help expedite the study’s progress to a clinical setting, we have identified 12 genes as biomarkers for response to STAT3-targeted therapy,” Sood said. “Next, we’ll work with the National Cancer Institute Nanoparticle Characterization Lab to develop a formulation of the HDL/siRNA nanoparticle for human use.” …

Candidate nanoparticle cancer therapies must deal with numerous issues. What agents are being delivered? How does each agent affect each type of cancer? What resistance can the cancer cell evolve? How does the nanoparticle protect the therapeutic agent(s) from destruction, and target cancer cells while avoiding healthy cells? Is the nanoparticle toxic or immunogenic? The diversity of nanoparticles showing promise, each type with its own unique set of advantages, inspires hope that nanotechnology will soon contribute to successful treatment of patients.

Promise and challenge on the road to practical graphene electronics

Three recent news items illuminate the promise and challenge on the road to practical graphene electronics. In the first, IBM announced a new speed record for an experimental graphene transistor that looks exceptionally promising for processing analog signals. It was produced on a “diamond-like carbon” substrate using standard semiconductor manufacturing processes. From “IBM shows smallest, fastest graphene processor“, by Agam Shah:

… The transistor has a cut-off frequency of 155GHz, making it faster and more capable than the 100GHz graphene transistor shown by IBM in February last year, said Yu-Ming Lin, an IBM researcher.

The research also shows that high-performance, graphene-based transistors can be produced at low cost using standard semiconductor manufacturing processes, Lin said. That could pave the way for commercial production of graphene chips, though Lin could not say when manufacturing of such chips would begin.

Commercialized graphene transistors will provide a performance boost in applications related to wireless communications, networking, radar and imaging, said Phaedon Avouris [winner for experimental work, 1999 Feynman Prize in Nanotechnology], an IBM fellow. Graphene is a single-atom-thick layer of carbon atoms structured in a hexagonal honeycomb form.

The transistor was developed as part of research IBM is conducting for the U.S. Department of Defense’s DARPA (Defense Advanced Research Projects Agency) program to develop high-performance RF (radio frequency) transistors. Avouris said the military has considerable interest in graphene transistors.

The flow of electrons is faster on graphene transistors than conventional transistors, which enables faster data transfers between chips, Lin said. That makes it promising technology for applications such as networking that require communications at fast speeds and high frequencies.

Graphene transistors may be able compute faster than conventional transistors, but are not ideal for PCs yet, Lin said. Because of the lack of energy gap in natural graphene, graphene transistors do not possess the on-off ratio required for digital switching operations, which makes conventional processors better at processing discrete digital signals.

By contrast, the continuous energy flow makes graphene better at processing analog signals, Lin said. Graphene’s high electron speed allows for faster processing of applications in analog electronics where such a high on-off ratio is not needed. …

In a second development, researchers have found that atomic vacancies in graphene can give rise to magnetic properties that were entirely unexpected because carbon has no d or f electrons. PhysOrg.com points to this University of Maryland news release “UMD Scientists Make Magnetic New Graphene Discovery“:

University of Maryland researchers have discovered a way to control magnetic properties of graphene that could lead to powerful new applications in magnetic storage and magnetic random access memory.

The finding by a team of Maryland researchers, led by Physics Professor Michael S. Fuhrer of the UMD Center for Nanophysics and Advanced Materials is the latest of many amazing properties discovered for graphene. …

In their new graphene discovery, Fuhrer and his University of Maryland colleagues have found that missing atoms in graphene, called vacancies, act as tiny magnets — they have a “magnetic moment.” Moreover, these magnetic moments interact strongly with the electrons in graphene which carry electrical currents, giving rise to a significant extra electrical resistance at low temperature, known as the Kondo effect. The results appear in the paper “Tunable Kondo effect in graphene with defects” published this month in Nature Physics [abstract]. …

Fuhrer thinks that if vacancies in graphene could be arranged in just the right way, ferromagnetism could result. “Individual magnetic moments can be coupled together through the Kondo effect, forcing them all to line up in the same direction,” he said.

“The result would be a ferromagnet, like iron, but instead made only of carbon. Magnetism in graphene could lead to new types of nanoscale sensors of magnetic fields. And, when coupled with graphene’s tremendous electrical properties, magnetism in graphene could also have interesting applications in the area of spintronics, which uses the magnetic moment of the electron, instead of its electric charge, to represent the information in a computer.

“This opens the possibility of ‘defect engineering’ in graphene – plucking out atoms in the right places to design the magnetic properties you want,” said Fuhrer.

The third item reports that graphene transistors may solve one of the major problems associated with silicon electronics—graphene transistors could cool themselves rather than have to spend energy dissipating heat with fans or water cooling. From “Graphene transistors could cool themselves“, by Isaac Leung:

Researchers with the University of Illinois have found graphene transistors have a nanoscale cooling effect which reduces their temperature.

Mechanical science and engineering professor William King and electrical and computer engineering professor Eric Pop led the team, which published the findings in the 3 April advance online edition of the journal Nature Nanotechnology [abstract]. …

The research team used an atomic force microscope tip as a temperature probe to make the first nanometer-scale temperature measurements of a working graphene transistor.

The measurements revealed that thermoelectric cooling effects can be stronger at the areas where the graphene touches the metal contacts, and this effect overpowers resistive heating, actually lowering the temperature of the transistor.

This self-cooling effect means that graphene-based electronics could require little or no cooling, allowing even greater energy efficiency and increasing graphene’s attractiveness as a silicon replacement.

The University of Illinois News Bureau adds a few additional details. From “Self-cooling observed in graphene electronics“, by Liz Ahlberg:

… The measurements revealed surprising temperature phenomena at the points where the graphene transistor touches the metal connections. They found that thermoelectric cooling effects can be stronger at graphene contacts than resistive heating, actually lowering the temperature of the transistor.

“In silicon and most materials, the electronic heating is much larger than the self-cooling,” King said. “However, we found that in these graphene transistors, there are regions where the thermoelectric cooling can be larger than the resistive heating, which allows these devices to cool themselves. This self-cooling has not previously been seen for graphene devices.” …

“Graphene electronics are still in their infancy; however, our measurements and simulations project that thermoelectric effects will become enhanced as graphene transistor technology and contacts improve ” said Pop, who is also affiliated with the Beckman Institute for Advanced Science, and the Micro and Nanotechnology Laboratory at the U. of I. …

Protein, RNA, DNA: Nanotechnology finds a multitude of paths to attack cancer cells

Nanoparticles designed to deliver drugs for cancer therapy made from nanoporous silica or from HDL cholesterol have been highlighted in recent posts. As evidence for the variety of approaches under development, these three items concern three different types of nanoparticles based respectively on protein, RNA, and DNA. In the first of these, cytoplasmic vaults, large structures of protein with some small RNA molecules, found in the cytoplasm of most eukaryotes, have been engineered to encapsulate large cargoes of toxic and water-insoluble drugs and deliver them into cancer cells. PhysOrg.com points to this UCLA news release: “Scientists engineer nanoscale vaults to encapsulate ‘nanodisks’ for drug delivery“

… In recent years, researchers have grappled with the challenge of administering therapeutics in a way that boosts their effectiveness by targeting specific cells in the body while minimizing their potential damage to healthy tissue.

The development of new methods that use engineered nanomaterials to transport drugs and release them directly into cells holds great potential in this area. And while several such drug-delivery systems — including some that use dendrimers, liposomes or polyethylene glycol — have won approval for clinical use, they have been hampered by size limitations and ineffectiveness in accurately targeting tissues.

Now, researchers at UCLA have developed a new and potentially far more effective means of targeted drug delivery using nanotechnology.

In a study to be published in the May 23 print issue of the journal Small (and currently available online [abstract]), they demonstrate the ability to package drug-loaded “nanodisks” into vault nanoparticles, naturally occurring nanoscale capsules that have been engineered for therapeutic drug delivery. The study represents the first example of using vaults toward this goal. …

Vault nanoparticles are found in the cytoplasm of all mammalian cells and are one of the largest known ribonucleoprotein complexes in the sub-100-nanometer range. A vault is essentially barrel-shaped nanocapsule with a large, hollow interior — properties that make them ripe for engineering into a drug-delivery vehicles. The ability to encapsulate small-molecule therapeutic compounds into vaults is critical to their development for drug delivery.

Recombinant vaults are nonimmunogenic and have undergone significant engineering, including cell-surface receptor targeting and the encapsulation of a wide variety of proteins.

“A vault is a naturally occurring protein particle and so it causes no harm to the body,” said Rome, CNSI associate director and a professor of biological chemistry. “These vaults release therapeutics slowly, like a strainer, through tiny, tiny holes, which provides great flexibility for drug delivery.”

The internal cavity of the recombinant vault nanoparticle is large enough to hold hundreds of drugs, and because vaults are the size of small microbes, a vault particle containing drugs can easily be taken up into targeted cells.

With the goal of creating a vault capable of encapsulating therapeutic compounds for drug delivery, UCLA doctoral student Daniel Buhler designed a strategy to package another nanoparticle, known as a nanodisk (ND), into the vault’s inner cavity, or lumen.

“By packaging drug-loaded NDs into the vault lumen, the ND and its contents would be shielded from the external medium,” Buehler said. “Moreover, given the large vault interior, it is conceivable that multiple NDs could be packaged, which would considerably increase the localized drug concentration.” …

In a major advance for the nascent field of RNA nanotechnology, nanoparticles composed solely of chemically modified RNA were assembled, found to survive circulation in the bloodstream, be non-toxic and non-immunogenic, internalize into cancer cells specifically, and silence expression of cancer-promoting genes. PhysOrg.com points to this Univerity of Cincinnati news release “Researchers Construct RNA Nanoparticles to Safely Deliver Long-Lasting Therapy to Cells“:

Nanotechnology researchers have known for years that RNA, the cousin of DNA, is a promising tool for nanotherapy, in which therapeutic agents can be delivered inside the body via nanoparticles. But the difficulties of producing long-lasting, therapeutic RNA that remains stable and non-toxic while entering targeted cells have posed challenges for their progress.

In two new publications in the journal Molecular Therapy, University of Cincinnati (UC) biomedical engineering professor Peixuan Guo, PhD, details successful methods of producing large RNA nanoparticles and testing their safety in the delivery of therapeutics to targeted cells.

The articles, in advance online publication, represent “two very important milestones in RNA nanotherapy,” says Guo.

“One problem in RNA therapy is the requirement for the generation of relatively large quantities of RNA,” he says. “In this research [abstract], we focused on solving the most challenging problem of industry-scale production of large RNA molecules by a bipartite approach, finding that pRNA can be assembled from two pieces of smaller RNA modules.” …

In his most recent research, Guo and colleagues detail multiple approaches for the construction of a functional 117-base pRNA molecule containing small interfering RNA (siRNA). siRNA has already been shown to be an efficient tool for silencing genes in cells, but previous attempts have produced chemically modified siRNA lasting only 15-45 minutes in the body and often inducing undesired immune responses.

“The pRNA particles we constructed to harbor siRNA have a half life of between five and 10 hours in animal models, are non-toxic and produce no immune response,” says Guo [abstract]. “The tenfold increase of circulation time in the body is important in drug development and paves the way towards clinical trials of RNA nanoparticles as therapeutic drugs.”

Guo says the size of the constructed pRNA molecule is crucial for the effective delivery of therapeutics to diseased tissues.

RNA nanoparticles must be within the range of 15 to 50 nanometers,” he says, “large enough to be retained by the body and not enter cells randomly, causing toxicity, but small enough to enter the targeted cells with the aid of cell surface receptions.…

Previous studies have encased therapeutic siRNA in a polymer coating or liposome for delivery to cells.

“To our knowledge, this is the first naked RNA nanoparticles to have been comprehensively examined pharmacologically in vivo and demonstrated to be safe, as well as deliver itself to tumor tissues by a specific targeting mechanism,” he says. “It suggests that the pRNA nanoparticles without coating have all the preferred pharmacological features to serve as an efficient nanodelivery platform for broad medical applications.”

Finally Y-shaped DNA molecules can assemble into core-shell structures that incorporate defined functions into engineered molecules. PhysOrg.com points to this Cornell University article by Bill Steele “‘DNAsomes’ can deliver multiple drugs or genetic therapy“

DNA isn’t just for genetics anymore. Cornell researchers are using synthetic DNA to make nanoparticles, dubbed DNAsomes, that can deliver drugs and genetic therapy to the insides of cells.

Dan Luo, professor of biological and environmental engineering, and colleagues report their work in the Jan. 3 issue of the journal Small [abstract, free PDF].

DNAsomes, Luo said, can carry multiple drugs as well as RNA molecules designed to block the expression of genes, an improvement over other drug-delivery systems such as liposomes (tiny wrappers of the phospholipid molecules that make up cell membranes) or polymer nanoparticles. Also, some other delivery systems can be toxic to cells, the researchers said.

In its natural habitat in the nucleus of a cell, DNA consists of long chain molecules that are complementary, attaching to one another like a string of Lego blocks over their entire length to form the famous double helix. The Luo research group creates short chains of synthetic DNA designed to attach over only part of their length so they will join into shapes like crosses, Ts or Ys.

DNAsomes are assembled from Y-shaped units, each made up of three strands of DNA. A lipid molecule is attached to the tail of the Y, and drugs to be delivered are chemically bonded to the arms. When the goal is to block the expression of genes with molecules of siRNA (small interfering RNA), the synthetic DNA can be designed with a section complementary to the RNA so that the RNA will loosely attach to it. Delivering siRNA has been a particular challenge for other drug-delivery systems, the researchers noted.

In water solution, the combination of DNA, which is attracted to water molecules, and lipids, which are repelled by water, causes the Y units to self-assemble into hollow spheres from 100 to 5,000 nanometers in diameter, consisting of multiple layers of DNA, lipid and cargo.

“The beauty of this is that the body of the thing is also a body of drugs,” Luo said. About the size of a virus, the DNAsome will be engulfed by the cell membrane and taken into a cell in a similar way as a virus, he explained. The DNAsome can be tagged with molecules that target a particular kind of cell, such as a cancer cell. …

The variety of very different molecular architectures that these researchers have engineered to meet similar purposes illustrates the richness of the toolkit that nanotechnology is providing to satisfy major unmet medical needs.

Combined computational and experimental study illuminates motions of molecules across a surface

How do molecules with one, two, or three “legs”, each with a “foot” that binds to a receptor on a surface, move across the surface in the presence of competing receptors that are free in solution? Will understanding how such molecules move lead to the ability to control movement molecule by molecule? A team of researchers from Ireland and the Netherlands illuminated the first question and appears confident that the answer to the second question is “yes”. ScienceDaily points to this news release from Ireland’s Tyndall National Institute “Are we only a hop, skip and jump away from controlled molecular motion?“

We may very well be, according to a study in this month’s Nature Chemistry [abstract]. Controlling how molecules move on surfaces could be the key to more potent drugs that block the attachment of viruses to cells, and will also speed development of new materials for electronics and energy applications. The study is the culmination of a EU-funded collaboration between Tyndall National Institute, UCC researcher Dr. Damien Thompson and colleagues at University of Twente in the Netherlands. Dr. Thompson performed computer simulations that enabled a greater understanding of how two-legged molecules move along patterned surfaces, in a kind of molecular hopscotch.

Widespread industrial uptake of nanotechnology requires cheap, easy and robust solutions that allow manipulation of matter at the smallest scales and so a key enabling feature will be the ability to move material around molecule by molecule. One of the major difficulties is the very different physics that operates at the scale of atoms and molecules; water, for example, feels more like treacle [molasses] to a molecule, and molecules tend to huddle and stick together due to microscopic forces between their atoms. Dr. Thompson explains: “The experiments performed by the group at Twente were very elegant. They involved making two-legged molecules and using a fluorescence microscope to watch how they move along a wet surface. The molecules are hydrophobic, meaning they don’t like water, and the surface was pockmarked with hydrophobic cavities so a weak glueing interaction, based on a mutual dislike of water, drives the interaction between the molecules and the surface.

While the energetics of this type of interaction was worked out over a decade ago by George Whitesides’s group at Harvard, it’s usefulness for materials development was limited because little was known until now on the paths that the molecules take”.

Because the molecules have multiple legs, they display a surprisingly rich behaviour at the surface, beyond simply attaching/detaching, with Dr. Thompson’s computer simulations complementing the experiments and showing the different mechanisms by which the molecules move. The motion switches from walking to hopping to flying, as the environment changes.

Dr. Thompson continues: “Access to high performance computing facilities enabled us to model the different pathways and aid interpretation of the microscopy results. We ran most of the simulations on our own Science Foundation Ireland-supported computing clusters at Tyndall, and also did a few larger-scale calculations at the Irish Center for High End Computing. It’s an exciting time for research as experiments and simulations are finally on the same page; the experiments can finally drill down far enough to see molecule-scale features while advances in computing mean we can routinely model systems composed of hundreds of thousands, and even millions, of atoms”.

If researchers succeed in controlling molecular motion on surfaces, the next challenge will be to build arbitrary assemblages from a set of molecular building blocks.

This entry was posted on Sunday, April 24th, 2011 at 1:00 PM and is filed under Computational nanotechnology, Molecular Nanotechnology, Nano, Nanotech, Nanotechnology, Research. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.

New software aids design of 3-D DNA structures

Recent demonstrations of the ability to build complex 3-D shapes from DNA (this post and previous work by William Shih and collaborators published in Science August 2009 abstract) create demand for an easier way to design complex shapes from folded DNA strands. Now new software facilitates designing three dimensional shapes using scaffolded DNA origami. Physorg.com points to this written by Anne Trafton, MIT News Office “Origami: Not just for paper anymore“:

… A major hurdle to [designing complex curved and bent structures from a folded DNA strand] has been automation of the design process. Now a team at MIT, led by biological engineer Mark Bathe, has developed software that makes it easier to predict the three-dimensional shape that will result from a given DNA template. While the software doesn’t fully automate the design process, it makes it considerably easier for designers to create complex 3-D structures, controlling their flexibility and potentially their folding stability.

“We ultimately seek a design tool where you can start with a picture of the complex three-dimensional shape of interest, and the algorithm searches for optimal sequence combinations,” says Bathe, the Samuel A. Goldblith Assistant Professor of Applied Biology. “In order to make this technology for nanoassembly available to the broader community — including biologists, chemists, and materials scientists without expertise in the DNA origami technique — the computational tool needs to be fully automated, with a minimum of human input or intervention.”

Bathe and his colleagues described their new software in the Feb. 25 issue of Nature Methods. In that paper [abstract], they also provide a primer on creating DNA origami with collaborator Hendrik Dietz at the Technische Universitaet Muenchen. “One bottleneck for making the technology more broadly useful is that only a small group of specialized researchers are trained in scaffolded DNA origami design,” Bathe says.

… “DNA is in many ways better suited to self-assembly than proteins, whose physical properties are both difficult to control and sensitive to their environment,” Bathe says.

Bathe’s new software program interfaces with a software program from Shih’s lab called caDNAno, which allows users to manually create scaffolded DNA origami from a two-dimensional layout. The new program, dubbed CanDo, takes caDNAno’s 2-D blueprint and predicts the ultimate 3-D shape of the design. This resulting shape is often unintuitive, Bathe says, because DNA is a flexible object that twists, bends and stretches as it folds to form a complex 3-D shape.

A PDF of the paper has been made available by the Dietz Lab at TU Munich here. An accompanying editorial “Into the fold” [abstract, full text requires free registration] gives a one-page overview of DNA origami and its potential applications. It points to the above paper and a paper [abstract] from Shih and his colleagues on purifying DNA nanostructures with improved yield of intact structures, and it discusses what is yet needed for DNA origami to reach its full potential: other and longer DNA single strands to use as scaffolds, improved methods to chemically conjugate functional groups to specific DNA sites, and a “top-down design solution” to fully automate design. Now we know what developments to watch for!

DNA nanotechnology builds 3D forms with complex curves (includes video)

Miniature architectural forms – some no larger than viruses – have been constructed through a revolutionary technique known as DNA origami. Now, Hao Yan, Yan Liu and their colleagues at ASU’s Biodesign Institute have expanded the capability of this method to construct arbitrary, two- and three-dimensional shapes, mimicking those commonly found in nature.

Such diminutive forms may ultimately find their way into a wide array of devices, from ultra-tiny computing components to nanomedical sentries used to target and destroy aberrant cells or deliver therapeutics at the cellular or even molecular level.

In today’s issue of Science [abstract], the Yan group describes an approach that capitalizes on (and extends) the architectural potential of DNA. The new method is an important step in the direction of building nanoscale structures with complex curvature – a feat that has eluded conventional DNA origami methods. …

“Our goal is to develop design principles that will allow researchers to model arbitrary 3-D shapes with control over the degree of surface curvature. In an escape from a rigid lattice model, our versatile strategy begins by defining the desired surface features of a target object with the scaffold, followed by manipulation of DNA conformation and shaping of crossover networks to achieve the design,” Liu said.

To achive this idea, Yan’s graduate student Dongran Han began by making simple 2-D concentric ring structures, each ring formed from a DNA double helix. The concentric rings are bound together by means of strategically placed crossover points. These are regions where one of the strands in a given double helix switches to an adjacent ring, bridging the gap between concentric helices. Such crossovers help maintain the structure of concentric rings, preventing the DNA from extending. …

Varying the number of nucleotides between crossover points and the placement of crossovers allows the designer to combine sharp and rounded elements in a single 2-D form …

The network of crossover points also can be designed in such a way as to produce combinations of in-plane and out-of-plane curvature, allowing for the design of curved 3D nanostructures. While this method shows considerable versatility, the range of curvature is still limited for standard B form DNA, which will not tolerate large deviations from its preferred configuration – 10.5 base pairs/turn. However, as Jeanette Nangreave, one of the paper’s co-authors, explains, “Hao recognized that if you could slightly over twist or under twist these helices, you could produce different bending angles.”

Combining the method of concentric helices with such non-B-form DNA (with 9-12 base pairs/turn), enabled the group to produce sophisticated forms, including spheres, hemispheres, ellipsoid shells and finally—as a tour de force of nanodesign – a round-bottomed nanoflask, which appears unmistakably in a series of startling transmission electron microscopy images …

Yan hopes to further expand the range of nanoforms possible through the new technique. Eventually, this will require longer lengths of single-stranded DNA able to provide necessary scaffolding for larger, more elaborate structures. He credits his brilliant student (and the paper’s first author) Dongran Han with a remarkable ability to conceptualize 2-D and 3-D nanoforms and to navigate the often-perplexing details of their design. Ultimately however, more sophisticated nanoarchitectures will require computer-aided design programs – an area the team is actively pursuing.

The successful construction of closed, 3-D nanoforms, such as the sphere, has opened the door to many exciting possibilities for the technology, particularly in the biomedical realm. Nanospheres could be introduced into living cells for example, releasing their contents under the influence of endonucleases or other digestive components. Another strategy might use such spheres as nanoreactors – sites where chemicals or functional groups could be brought together to accelerate reactions or carry out other chemical manipulations.

These 3D structures are large and complex compared with the 2.0 nm diameter of the DNA double helix. PowerPoint slides of several figures from the Science paper can be downloaded without a subscription. One of these shows the sphere to be 42 nm in diameter, the prolate ellipsoid to be 35 nm by 66 nm, and the round-bottomed nanoflask to be 40 nm wide and 70 nm tall.

Real-time monitoring of atomic force microscope probes

The use of atomic force microscopes to manipulate atoms on surfaces (particularly on silicon surfaces—see for example this post and this post) is one promising alternative path for advancing nanotechnology toward productive nanosystems and molecular manufacturing. As was apparent in a recent interview of Professor Philip Moriarty of the University of Nottingham, many of the major technical obstacles encountered with atomic force microscopes involve the quality and reproducibility of the tips. Physorg.com points to a National Institute of Standards and Technology (NIST) news release of a way to improve AFM tips. “Getting the Point: Real-Time Monitoring of Atomic-Microscope Probes Adjusts for Wear“

Scientists at the National Institute of Standards and Technology (NIST) have developed a way to measure the wear and degradation of the microscopic probes used to study nanoscale structures in situ and as it’s happening. Their technique can both dramatically speed up and improve the accuracy of the most precise and delicate nanoscale measurements done with atomic force microscopy (AFM).

If you’re trying to measure the contours of a surface with a ruler that’s crumbling away as you work, then you at least need to know how fast and to what extent it is being worn away during the measurement.

This has been the challenge for researchers and manufacturers trying to create images of the surfaces of nanomaterials and nanostructures. Taking a photo is impossible at such small scales, so researchers use atomic force microscopes. Think of a device like a phonograph needle being used, on a nanoscale, to measure the peaks and valleys as it’s dragged back and forth across a surface. These devices are used extensively in nanoscale imaging to measure the contours of nanostructures, but the AFM tips are so small that they tend to wear down as they traverse the surface being measured.

Today, most researchers stop the measurement to “take a picture” of the tip with an electron microscope, a time-consuming method prone to inaccuracies.

NIST materials engineer Jason Killgore has developed a method for measuring in real time the extent to which AFM tips wear down. Killgore measures the resonant frequency of the AFM sensor tip, a natural vibration rate like that of a tuning fork, while the instrument is in use. Because changes to the size and shape of the tip affect its resonant frequency, he is able to measure the size of the AFM’s tip as it works—in increments of a tenth of a nanometer, essentially atomic scale resolution. …

The potential impact of this development is considerable. Thousands of AFMs are in use at universities, manufacturing plants and research and development facilities around the world. Improving their ability to measure and image nanosized devices will improve the quality and effectiveness of those devices. Another benefit is that developing new measurement tips—and studying the properties of new materials used in those tips—will be much easier and faster, given the immediate feedback about wear rates.

We can also hope that this method will facilitate the manipulation of atoms for mechanosynthesis being done by pioneers like Zyvex Labs, Prof. Moriarty, and the team that won the 2009 Feynman Prize for Experimental work.

Nanotechnology boosts anticancer drug cocktail many times over

Using nanoparticles for drug delivery, particularly to treat cancer, has been under development for several years. Liposomes were one of the earliest and simplest types of nanoparticles used for cancer drug delivery, and were often not much more complex than vesicles of lipid bilayer, typically less than 200 nm in diameter, encapsulating an anticancer drug. Now more complex and sophisticated nanoparticles promise to be much more effective in treating cancer. We thank KurzweilAI for pointing to this news release from Sandia National Laboratories and the University of New Mexico “Sandia and UNM lead effort to destroy cancers: Boosting medicine with nanotechnology strengthens drug cocktail many times over“

Melding nanotechnology and medical research, Sandia National Laboratories, the University of New Mexico, and the UNM Cancer Research and Treatment Center have produced an effective strategy that uses nanoparticles to blast cancerous cells with a mélange of killer drugs.

In the cover article [abstract] of the May issue of Nature Materials, available online April 17 , the researchers describe silica nanoparticles about 150 nanometers in diameter as honeycombed with cavities that can store large amounts and varieties of drugs.

“The enormous capacity of the nanoporous core, with its high surface area, combined with the improved targeting of an encapsulating lipid bilayer [called a liposome], permit a single ‘protocell’ loaded with a drug cocktail to kill a drug-resistant cancer cell,” says Sandia researcher and UNM professor Jeff Brinker, the principal investigator. “That’s a millionfold increase in efficiency over comparable methods employing liposomes alone — without nanoparticles — as drug carriers.”

The nanoparticles and the surrounding cell-like membranes formed from liposomes together become the combination referred to as a protocell: the membrane seals in the deadly cargo and is modified with molecules (peptides) that bind specifically to receptors overexpressed on the cancer cell’s surface. (Too many receptors is one signal the cell is cancererous.) The nanoparticles provide stability to the supported membrane and contain and release the therapeutic cargo within the cell.

A current Food and Drug Administration-approved nanoparticle delivery strategy is to use liposomes themselves to contain and deliver the cargo. In a head-to-head comparison of targeted liposomes and protocells with identical membrane and peptide compositions, Brinker and colleagues report that the greater cargo capacity, stability and targeting efficacy of protocells leads to many times greater cytotoxicity [destruction] directed specifically toward human liver cancer cells.

Another advantage to protocells over lipsomes alone, says lead author Carlee Ashley, a Harry S. Truman post-doctoral fellow at Sandia’s California site in Livermore, is that liposomes used as carriers need specialized loading strategies that make the process more difficult. “We’ve demonstrated we can just soak nanoparticles to load them with unique drug combinations needed for personalized medicine. They effectively encapsulate toxins as well as siRNA [ribonucleic acid] that silence expressions of proteins.”

RNA, the biological messenger that tells cells which proteins to manufacture, in this case is used to silence the cellular factory, a way of causing apoptosis or cell death. “Si” is short for “silence.”

The lipids also serve as a shield that restricts toxic chemotherapy drugs from leaking from the nanoparticle until the protocell binds to and takes hold within the cancer cell. This means that few poisons leak into the system of the human host, if the protocells find no cancer cells. This cloaking mitigates toxic side effects expected from conventional chemotherapy.

Instead, the particles — crafted small enough to float under the radar of the liver and other cleansing organs — can circulate harmlessly for days or weeks, depending on their engineered size, seeking their prey. …

“Proteins modified with a targeting peptide that binds to a particular carcinoma exhibit a 10,000-fold greater affinity for that cancer than for other unrelated cells,” Ashley said. …

The method may be commercially available in five years, researchers estimate.

During the past few weeks several very different types of nanoparticles have been reported as showing great promise, and these will be the subject of additional posts soon. Nanomedicine, and especially targeted drug delivery, is looking like an area where accelerating progress is demonstrating the value of investing in building increasingly complex nanostructures. Will this trend continue until we reach the point of atomically precise manufacture of medical nanorobots?

Much faster directed evolution of proteins could speed development of molecular machine systems

One of the principal recommendations of the Technology Roadmap for Productive Nanosystems was to “Support the development of modular molecular composite nanosystems (MMCNs)” (see Productive Nanosystems: A Technology Roadmap, page 12 of 198-page PDF) in which large DNA frameworks (of the sort that we cited last week) are to be used to support relatively rigid functional objects of engineered proteins. Such proteins could be engineered through either rational design or directed evolution (for an excellent update on the latter see this post by Eric Drexler on Metamodern from October 2010). Laboratory-directed evolution can, however, be laborious, so anything to make it faster and easier might substantially advance this approach. Now ScienceDaily points to this Harvard Gazette article by Steve Bradt that announces a major improvement “Speeding up biomolecular evolution: New approach proves 100 times faster than before“:

Scientists at Harvard University have harnessed the prowess of fast-replicating bacterial viruses, also known as phages, to accelerate the evolution of biomolecules in the laboratory. The work, reported in the journal Nature [abstract], could ultimately allow the tailoring of custom pharmaceuticals and research tools from lab-grown proteins, nucleic acids, and other such compounds.

The researchers, led by Professor David R. Liu, say that their approach — dubbed “phage-assisted continuous evolution,” or PACE — is roughly 100 times faster than conventional laboratory evolution, and far less labor-intensive for scientists.

“Most modern drugs are based on small organic molecules, but biological macromolecules may be better suited as pharmaceuticals in some cases,” said Liu, a professor of chemistry and chemical biology at Harvard and an investigator with the Howard Hughes Medical Institute. “Our work provides a new solution to one of the key challenges in the use of macromolecules as research tools or human therapeutics: how to rapidly generate proteins or nucleic acids with desired properties.”

Liu and Harvard co-authors Kevin M. Esvelt and Jacob C. Carlson achieved up to 60 rounds of protein evolution every 24 hours by linking laboratory evolution to the life cycle of a virus that infects bacteria. This phage’s life cycle of just 10 minutes is among the fastest known. Because this generation time is so brief, the phage makes a perfect vehicle for accelerated protein evolution. The PACE system uses E. coli host cells to produce the resulting proteins, to serve as factories for phage production, and to perform the key selection step that allows phage-carrying genes encoding desired molecules to flourish.

In three protein evolution experiments, PACE was able to generate an enzyme with a new target activity within a week, achieving up to 200 rounds of protein evolution during that time. Conventional laboratory evolution methods, Liu said, would require years to complete this many rounds of evolution. …

It remains to be seen just how general this method will be since it depends on linking the activity to be evolved to protein production in bacteria. Nevertheless, it looks like the individual components of MMCN development are progressing nicely. Perhaps the next challenge is to see if the pieces can be put together to make effective molecular machine systems, leading eventually to atomically precise productive nanosystems.

Nanotechnology in Civil Infrastructure

Nanotechnology in Civil Infrastructure is a state-of-the art reference source describing the latest developments in nano-engineering and nano-modification of construction materials to improve the bulk properties, development of sustainable, intelligent, and smart concrete materials through the integration of nanotechnology based self-sensing and self-powered materials and cyber infrastructure technologies, review of nanotechnology applications in pavement engineering, development of novel, cost-effective, high-performance and long-lasting concrete products and processes through nanotechnology-based innovative processing of cement and cement paste, and advanced nanoscience modeling, visualization, and measurement systems for characterizing and testing civil infrastructure materials at the nano-scale.

Nanotechnology application In Energy Sector

Nanotechnology applications could provide decisive technological breakthroughs in the energy sector and have a considerable impact on creating the sustainable energy supply that is required to make the transition from fossil fuels. Possibilities range from gradual short- and medium-term improvements for a more efficient use of conventional and renewable energy sources all the way to completely new long-term approaches for energy recovery and utilization. With enough political will – and funding – nanotechnology could make essential contributions to sustainable energy supply and global climate protection policies. The technological foundation is there, all it takes is political leadership to create the right research and investment conditions to make it happen.