Scanning Probe Microscopy for the rest of us

Some years ago in an earlier post, I mentioned that somebody had 3d-printed some parts for a scanning probe microscope. The bulk of their work has now been lost to the sands of the Great 404 Desert, but some more recent projects are much more promising.

One is an effort from Academia Sinica in Taiwan, described in detail on Instructables.com, using movements from DVD players. When a project can borrow a mass-market part like this, the result is often surprisingly affordable.

Another project from the Lego2Nano folks in London involves Lego bricks.

Another project from the University of Rhode Island is a Lego model illustrating the mechanical principles of probe microscopy. As far as I can determine this project is not a real microscope.

A company in Luxembourg is selling a Lego SPM kit for 2950 euros. It's possible this is a commercialized version of the Lego2Nano microscope.

Some more advanced efforts include this instructional probe microscope designed at the MIT Media Lab, and this PhD thesis from McGill University in Montreal.

Dr. Drexler's blog

Dr. Eric Drexler founded the field of advanced nanotechnology with a 1981 paper in the Proceedings of the National Academy of Sciences, and his book Engines of Creation published in 1986. These two publications laid the intellectual foundation for a complete revision of human manufacturing technology. Like any major shift in technology, there are risks to be aware of, but the promise of advanced nanotechnology is vast: clean cheap manufacturing processes for just about anything you can imagine, products that seem nearly magical by today's standards, medical instruments and treatments far more advanced than today's medicine.

Dr. Drexler has continued to work in the field for over twenty years, promoting research into developmental pathways and awareness of the potential risks. His thoughts on nanotechnology (and technology in general) are unique. With the publication of his Metamodern blog, these are now publicly available. His postings cover a broad range of topics, ranging from the books he's been reading lately to common and misleading errors in molecular animations to his most recent observations and insights on developmental pathways to advanced technologies.

Graphene memory device at Rice University

James Tour and colleagues at Rice University have demonstrated a switch (described in Nature Materials) composed of a layer of graphite about ten atoms thick. An array of such switches can be built in three dimensions, offering very high densities of storage volume, far exceeding what we now see in hard disks and flash memory USB widgets. The switch has been tested over 20,000 switching cycles with no apparent degradation. The abstract of the Nature Materials article reads:

Transistors are the basis for electronic switching and memory devices as they exhibit extreme reliabilities with on/off ratios of 10⁴–10⁵, and billions of these three-terminal devices can be fabricated on single planar substrates. On the other hand, two-terminal devices coupled with a nonlinear current–voltage response can be considered as alternatives provided they have large and reliable on/off ratios and that they can be fabricated on a large scale using conventional or easily accessible methods. Here, we report that two-terminal devices consisting of discontinuous 5–10 nm thin films of graphitic sheets grown by chemical vapour deposition on either nanowires or atop planar silicon oxide exhibit enormous and sharp room-temperature bistable current–voltage behaviour possessing stable, rewritable, non-volatile and non-destructive read memories with on/off ratios of up to 10⁷ and switching times of up to 1 μs (tested limit). A nanoelectromechanical mechanism is proposed for the unusually pronounced switching behaviour in the devices.

It will be several years before memories based on these switches are available for laptops and desktops, but it's a cool thing. To my knowledge, the mechanism is not yet known, so there may be some interesting new science involved as well.

Encouraging news about mechanosynthesis

Yesterday there was a very encouraging posting (by guest blogger Tihamer Toth-Fejel) on the Responsible Nanotechnology blog, regarding recent goings-on with mechanosynthesis. What the heck is mechanosynthesis? It is the idea that we will build molecules by putting atoms specifically where we want, rather than leaving them adrift in a sea of Brownian motion and random diffusion. Maybe not atoms per se, maybe instead small molecules or bits of molecules (a CH₃ group here, an OH group there) with the result that we will build the molecules we really want, with little or no waste. The precise details about how we will do this are up for a certain amount of debate. We used to talk about assemblers, now we talk about nanofactories, but the idea of intentional design and manufacture of specific molecules remains.

The two items of real interest in the CRN blog posting are these.

First, Philip Moriarty, a scientist in the UK, has secured a healthy chunk of funding to do experimental work to validate the theoretical work done by Ralph Merkle and Rob Freitas in designing tooltips and processes for carbon-hydrogen mechanosynthesis, with the goal of being able to fabricate bits of diamondoid that have been specified at an atomic level. If all goes well, writes Toth-Fejel:

Four years from now, the Zyvex-led DARPA Tip-Based Nanofabrication project expects to be able to put down about ten million atoms per hour in atomically perfect nanostructures, though only in silicon (additional elements will undoubtedly follow; probably taking six months each).

Second is that people are now starting to use small machines to build other small machines, and to do so at interesting throughputs. An article at Small Times reports:

Dip-pen nanolithography (DPN) uses atomic force microscope (AFM) tips as pens and dips them into inks containing anything from DNA to semiconductors. The new array from Chad Mirkin’s group at Northwestern University in Evanston, Ill., has 55,000 pens - far more than the previous largest array, which had 250 pens.

So there are two take-home messages here. First, researchers are getting ready to work with the large numbers of atoms needed to build anything of reasonable size in a reasonable amount of time. Second, this stuff is actually happening rather than remaining a point of academic discussion.

Toth-Fejel writes:

What happens when we use probe-based nanofabrication to build more probes? ...What happens when productive nanosystems get built, and are used to build better productive nanosystems? The exponential increase in atomically precise manufacturing capability will make Moore’s law look like it’s standing still.

Interesting stuff.

Adventures in protein engineering

Proteins are a good material to consider for an early form of rationally designed nanotechnology. They are cheap and easy to manufacture, thoroughly studied, and they can do a lot of different things. Proteins are responsible for the construction of all the structures in your body, the trees outside your window, and most of your breakfast.

Why don't we already have a busy protein-based manufacturing base? Because the necessary technologies have arisen only in the last couple of decades, and because older technologies already have a solid hold on the various markets that might otherwise be interested in protein-based manufacturing. Finally, most researchers working with proteins aren't thinking about creating a new manufacturing base. But people in the nanotech community are thinking about it.

One of the classical scientific problems involving proteins is the "protein folding problem". Every protein is a sequence of amino acids. There are 20 different amino acids, which are strung together by a ribosome to create the protein. As the amino acids are strung together, the protein starts folding up into a compact structure. The "problem" with folding is that for any possible sequence of amino acids, it's not always possible to predict how it will fold up, or even whether it will always fold up the same way each time.

But maybe you don't need a solution for all possible sequences. Maybe you can limit yourself to just the sequences that are easy to predict. People have been studying proteins for a long time and it's easy to put together a much shorter list of proteins whose foldings are known. Discard any proteins that sometimes fold differently, to arrive at a subset of proteins whose foldings are well known and reliable.

The next issue is extensibility. Having identified a set of proteins whose foldings are easily predictable, would it be possible to use that knowledge to predict the foldings of larger novel amino acid sequences? A trivial analogy would be that if I know how to pronounce "ham" and I know how to pronounce "burger", then I should should know how to pronounce "hamburger". A better analogy would be Lego bricks or an Erector set, where a small alphabet of basic units can be used to construct a vast diversity of larger structures.

If we can build a large diversity of big proteins and predict their foldings correctly, we're on to something. Then we can design things with parts that move in predictable ways. Some proteins (like the keratin in your fingernails or a horse's hooves) have a good deal of rigidity, and we can think about designing with gears, cams, transmissions, and other such stuff.

More developments in cancer treatment

Here are some more new cancer therapies under development. Many of these involve some flavor of nanoparticle (a fancy word for a molecule), and a few involve nanomachines (a molecule that does something more interesting than just sitting there).

• http://www.technologyreview.com/Nanotech/18999/ -- The new nanoengineered system, designed by physician and researcher James Baker and his colleagues at the University of Michigan, contains gold nanoparticles with branching polymers called dendrimers that sprout off the nanoparticle's surface. The particles could be used to launch a multiprong attack against tumors. The dendrimer arms can carry a number of different molecules, including molecules that target cancer cells, fluorescent imaging agents, and drugs that slow down or kill the cells. Once enough of the nanoparticles have gathered inside cancer cells, researchers could kill the tumors by using lasers or infrared light to heat up the gold nestled inside the dendrimers.
• http://www.technologyreview.com/NanoTech/wtr_16690,319,p1.html -- A single treatment of drug-bearing nanoparticles effectively destroys prostate cancer tumors in mice ...the researchers mix together a prostate cancer drug (docetaxel) and polymers that are already FDA-approved... The polymer formed spheres with the drugs trapped within. The researchers then chemically attach pieces of RNA, called aptamers, to the surface of the spheres. The RNA folds into shapes that fit into complementary structures on the surface of prostate-cancer cells... [In placebo groups] almost all the mice died during the experiment. In contrast, all of the mice injected with the targeted nanoparticles survived, and in most cases (five out of seven) the tumors disappeared.
  
• http://www.rsc.org/publishing/journals/CC/article.asp?doi=b800528a -- We present experimental data that demonstrate the potential of synthetic crown ether modified peptide nanostructures to act as selective and efficient chemotherapeutic agents that operate by attacking and destroying cell membranes.
  
• http://www.eurekalert.org/pub_releases/2008-03/uoc--urd033108.php -- Researchers from the Nano Machine Center at the California NanoSystems Institute at UCLA have developed a novel type of nanomachine that can capture and store anticancer drugs inside tiny pores and release them into cancer cells in response to light... the device is the first light-powered nanomachine that operates inside a living cell... [reported on] March 31 in the online edition of the nanoscience journal Small.
  
• http://mednews.wustl.edu/news/page/normal/11449.html -- The nanoparticles are extremely tiny beads of an inert, oily compound that can be coated with a wide variety of active substances. In an article published online in The FASEB Journal, the researchers describe a significant reduction of tumor growth in rabbits that were treated with nanoparticles coated with a fungal toxin called fumagillin. Human clinical trials have shown that fumagillin can be an effective cancer treatment in combination with other anticancer drugs... the nanoparticles' surfaces held molecules designed to stick to proteins found primarily on the cells of growing blood vessels. So the nanoparticles latched on to sites of blood vessel proliferation and released their fumagillin load into blood vessel cells. Fumagillin blocks multiplication of blood vessel cells, so it inhibited tumors from expanding their blood supply and slowed their growth.
  
• http://nano.cancer.gov/news_center/2008/feb/nanotech_news_2008-02-15c.asp -- ...Regulators and drug developers are concerned that these delivery systems may prove difficult to manufacture on a consistent basis... A new study from James Baker, Jr., M.D., PI, Cancer Nanotechnology Platform Partnership at the University of Michigan, and colleagues provides data showing that such concerns can be overcome... the investigators present the results of studies designed to show that they could achieve consistent and specific targeting and cell-killing activity across multiple manufacturing batches of a dendrimer-based therapeutic agent.
  
• http://www.physorg.com/news82653370.html -- A team of investigators has designed a nanoscale, polymeric drug delivery vehicle that when loaded with a widely used anticancer agent cures colon cancer in mice with a single dose... To create their drug delivery vehicle, the investigators used a highly branched polymer, known as a dendrimer, that naturally forms nanoparticles with myriad sites for drug loading. In this particular case, the researchers created what they call a bow-tie polyester dendrimer, whose molecular structure somewhat resembles a bow-tie with two discrete halves... On one half of the dendrimer, the researchers attached a second polymer, poly(ethylene glycol) (PEG), in order to make the dendrimer water soluble... Next, the investigators attached the anticancer drug doxorubicin to the other half of the dendrimer using a chemical linkage designed to break when exposed to acidic conditions. Not coincidentally, the inside of tumor cells is acidic, while the bloodstream has a neutral pH. Results presented in this paper show that the resulting drug-dendrimer formulation releases virtually all of its drug within 48 hours in acidic conditions but less than 10 percent of its payload at neutral pH.
• http://www.azonano.com/news.asp?newsID=4087 -- A new type of cancer detector... the simple and inexpensive system, which can be built from off-the-shelf components, can rapidly detect the presence of cancer biomarkers – telltale proteins in body fluids that can signal the presence of malignant tumors – at very low levels... “With this technology, a future scenario might be that you go to the doctor every year for an annual checkup; he draws about 10 cc’s of your blood and runs it through our machine,” said Soman. “The machine is equipped to detect the biomarkers for all the common types of cancer. Half an hour later it produces a list of the biomarkers that it has found. And then either a software program or the physician examines this list to determine whether you have any cancers that need treating.”
  
• http://nanotechwire.com/news.asp?nid=4703 -- There is a growing recognition among cancer researchers that the most accurate methods for detecting early-stage cancer will require the development of sensitive assays that can identify simultaneously multiple biomarkers associated with malignant cells. Now, using sets of nanoparticles designed to aggregate in response to finding more cancer biomarkers, a team of researchers funded by the Alliance for Nanotechnology in Cancer has developed a multiplexed analytical system that could detect cancer using standard magnetic resonance imaging (MRI).
  
• http://www.forbes.com/claytonchristensen/2008/02/22/cancer-nanotechnology-therapies-lead-clayton-in_jw_0222claytonchristensen_inl.html -- A survey of several different developments, but not much deep discussion of any of them. More of a businessman's-eye view of things, not too surprising for Forbes.
  

TAT variant with magnetic particles

My last posting about targeted alpha therapy discussed the expense of preparing a sample of radioactive actinium, aside from which, targeted alpha therapy should be a very effective and specific and hopefully affordable cancer therapy. Quentin Pankhurst of the London Centre for Nanotechnology has been working with particles of iron oxide, which has very low toxicity and can be attached to antibodies just like the actinium atoms in cages. Iron oxide can be magnetized so each particle can be a permanent magnet. A magnetized particle can then be detected from outside the body using a weak EM field generated by a hand-held device, or it can be heated with a strong EM field, to the point of destroying the cancer cell .

By combining the iron oxide particle with an antibody for the HER2 protein found in breast cancer cells, Pankhurst should be able to achieve the same specificity and effectiveness that Sloan-Kettering has gotten with radioactive actinium, at vastly lesser cost. In order to commercialize this and related applications, Pankhurst has founded Endomagnetics, a start-up based in Houston, Texas.

Why should iron oxide be so much less expensive than radioactive actinium? "Iron oxide" is the chemical name for rusty metal, which is easy to make and store, and readily available in auto scrap yards everywhere. Actinium-225, the isotope used for TAT, has a half-life of ten days, so you can't make a big batch and store some for later use. According to this website at the Oak Ridge National Laboratory: "The actinium-225 is formed from radioactive decay of radium-225, the decay product of thorium-229, which is obtained from decay of uranium-233. The National depository of uranium-233 is at ORNL, and we have developed effective methods for obtaining thorium-229 (half-life 7340 years) as our feed material to routinely obtain actinium-225."