Bench Press

My favorite character on Star Trek Voyager is “the Doctor” (pictured on the left and portrayed by the very talented Robert Picardo), who despite being “merely” a computer program was able to diagnose and treat nearly any medical ailment. The best part about him was that, because he was “merely” a hologram, he was portable and able to travel through the harshest environments and across any terrain.

While I’m pretty sure we still have years to go before we start being treated by medical holograms with Robert Picardo’s sense of style and humor, the portability of diagnosis is something which we may have just taken one large step closer towards. Christine Keating’s group at Pennsylvania State University has just developed what I’ve dubbed a “Doctor-on-a-Chip” (or DoC, after all system-on-a-chip’s are called SoCs by the semiconductor industry) which have the capability to detect any number of viral pathogens on a single computer chip.

Keating and her colleagues developed a means of coating a chip with nanowires (small wires 8 micrometers long and 300 nanometers in diameter) coated with DNA strands complementary to viral genomes (so that they will bind to viral DNA/RNA if given a chance). But, instead of haphazardly coating the chip, Keating’s group was able to develop a precise, targeted method, employing electrical fields to position the nanowires to exactly where the researchers wanted them (here’s a video showing how the method works).

The picture to the left is almost kind of eerie to me in its precision, much like one would expect on a chip fabbed by Intel or IBM (or Affymetrix) which uses photolithography rather than through electrophoresis.

Impressive to say the least, but the big question remained – does it work? To test this, Keating’s group incubated the chip with suspensions of fluorescently tagged viral DNA fragments complementary to the DNA strands on the nanowires, removed the suspension, and then subjected the chip to fluorescence. What would the result be? Would one see fluorescence organized neatly in the same rows that the nanowires were deposited? Or would there be diffuse or no fluorescence, suggesting nothing at all?

See for yourself:

So, do we have a DoC in the making? Jury’s still out – as we have yet to see if this method can be scaled up, or if its even applicable in a medical setting where time is short, accuracy needs to be very high, and the ability to run controlled samples (e.g. long DNA binding period with perfect fluorescently-labeled viral DNA fragments) is hindered. But, the Keating group is already hard at work creating electrical leads which will enable a faster (and potentially more quantitative) read process for detection.

And who knows, in a few years, this may end up looking like Robert Picardo.

(Image source – Doctor) (remainder of images come from Penn State University public image archive)

Morrow, T. Li, M. Kim, J. Mayer, T. Keating, C; Programmed Assembly of DNA-Coated Nanowire Devices; Science 16 January 2009: Vol. 323. no. 5912, p. 352 DOI: 10.1126/science.1165921

Having read and watched a fair amount of science fiction during my formative years, I’ve always been enamored with the concept of nanobots being used within the human body to help maintain our health. While the reality of microscopic machines moving to normally inaccessible areas of the human body and performing life saving tasks is still decades away, researchers led by Professor James Friend at Australia’s Monash University have demonstrated a proof of concept piezoelectric ultrasonic motor that could be a crucial step in providing locomotion for the nanosurgical robots of tomorrow.

In the abstract of their paper they describe their concept as:

A motor for in vivo microbot propulsion is presented with a stator diameter of 250 µm, demonstrating the potential to directly drive a flagellum for swimming at up to 1295 rpm with a torque of 13 nN m. The motor uses coupled axial-torsional vibration at 652–682 kHz in a helically cut structure excited by a thickness-polarized piezoelectric element.

Piezoelectric ultrasonic motors like the one designed by the team are built to harness special materials that exhibit the piezoelectric effect. Materials like lead zirconate titanate, thanks to the piezoelectric effect, are capable of producing electricity when stress is applied as well as the converse, producing stress when an electrical field is applied. This effect is already used in a variety of everyday applications, such as electric guitar pickups as well as auto-focus in reflex cameras. The motor (seen below), called the Proteus, designed by Friend’s team is made up of three main components: the piezoelectric element, the stator, and the rotor.

The team began to design the Proteus by utilizing computer models (seen below) to produce a novel robust stator design. They determined a helically cut stator would serve best in transferring stress and turning the rotor. The group hopes to improve their model in future work by incorporating further criteria and motor components.

After utilizing computer models to design the stator a prototype was fabricated for physical tests. Various tests were run to ascertain the potential of the Proteus. The group’s tests are promising as they found the “output power [is] on the order of what is necessary to navigate small human arteries.” In addition to the promising power output, the stator design is currently “70% smaller than the smallest design produced so far”.

While the design of a small motor is still just a small first step towards in vivo swimming surgical nanobot I can’t help but think about the possibilities this innovation will lead to. Maybe Professor Friend can contact Dr. Gracias at John Hopkins about working on a swimming microgripper next.

All graphics and quotes from:

B Watson, J Friend and L Yeo 2009. Piezoelectric ultrasonic resonant motor with stator diameter less than 250 µm: the Proteus motor. Journal of Micromechanics and Microengineering.

While reading through VentureBeat.com, I chanced upon an article written by Dean Takahashi which caught my interest. Apparently, a team of IBM researchers have developed a microscope with 100 million times the resolution of a conventional MRI. The secret to this amazing success? Magnetic resonance force microscopy (MRFM). Combining the ideas of magnetic resonance imaging and atomic force microscopy, MRFM is sensitive enough to detect the magnetic spin of a single electron and thus, provides a substantially greater resolving power.

From IBM’s abstract:

We have combined ultrasensitive magnetic resonance force microscopy (MRFM) with 3D image reconstruction to achieve magnetic resonance imaging (MRI) with resolution <10 nm. The image reconstruction converts measured magnetic force data into a 3D map of nuclear spin density, taking advantage of the unique characteristics of the “resonant slice” that is projected outward from a nanoscale magnetic tip. The basic principles are demonstrated by imaging the 1H spin density within individual tobacco mosaic virus particles sitting on a nanometer-thick layer of adsorbed hydrocarbons.

While we have seen other exciting developments in the MR industry as well as the imaging industry, this breakthrough is especially revolutionary because of how much it influences the scientific community. If IBM’s new microscope is as good as advertised, we will be able to produce three dimensional images of viruses, view the structure and interactions of proteins, and study the physical nature of certain chemical reactions, all while evading the disadvantages which plague electron microscopy. The benefits of understanding how things work at a molecular level can lead to better modeling, better drugs, smaller chips, and maybe even better detection mediums for cancer.

Here’s a video describing the technique:

One thing great about basic biology research is that so much cool and inventive technology is built around trying to peer into the depths of how organs, tissues, and cells work their mojo. A lot of times, the best stuff is built around microscopy and imaging, because seeing is pretty much believing. And beautiful pictures make scientists just as happy as it does everyone else.

There’s an imaging technique that’s been emerging over the last ten or so years called imaging mass spectrometry, which can tell you where a whole bunch of different molecules are in tissue all in one go! Basically, you take a slice of the tissue you want to image, apply a chemical resin to it (which is called a “matrix”), and then you shine a fairly strong laser at the tissue. This causes a physical reaction in which the resin absorbs the laser, ionizes, and causes molecules from the tissue to get ejected into the air. The mass spectrometer then sucks those ejected molecules into its cavernous depths and weighs them, breaks them apart, and then weighs their fragments to try to identify what the molecules are. For proteins, this identification process is actually quite easily done.

What you end up with is a really remarkable picture, a 2D map of where a range of different molecules are in the slice of tissue. You can look at the distribution of molecules of different specific weights across the entire slice. By stacking images of adjacent slices, you can then reconstruct an approximate 3D map of where molecules are in a tissue, like a brain or a tumor. Pretty neat!

A section of a mouse brain imaged for molecules of various weight (from Stoeckli et al. (2001) Nature Medicine 7, 493–496.)

Up until now, there have been two main ways to see macromolecules like proteins and RNA in biological tissue. First, you can look at where a specific macromolecule is by sticking a fluorescent dye to it and looking for that “tag.” It’s a great technique, but it’s also pretty laborious and limited in scope, because you can only examine at most three or four things at a time or the colors will start overlapping together a little too much to reliably distinguish what you’re looking at. In addition, you have to know what molecules you’re interested in first in order to tag them.

Second, you can look at cells as a whole using high energy techniques like transmission electron microscopy (TEM), which uses beams of electrons to “X-ray” cells. Since electrons have a very short wavelength, that means that they can be blocked and scattered even by very small structures, including groups of proteins, which means that a TEM image can look at a lot of things with an insanely high amount of detail. Unfortunately, electron microscopy won’t really tell you what you’re looking at, though there are a few techniques (like sticking gold beads to stuff you’re interested in) that try to get around that. Nonetheless, it doesn’t tell you much besides the overall “visual” picture.

Imaging mass spectrometry gets over a lot of these hurdles of traditional microscopy by directly associating molecular weights with specific coordinates in a tissue sample. And because the mass spectrum measures a wide range of weights, a computer algorithm can potentially tease out patterns that might not have occurred to a researcher or doctor looking for a few things at a time. The amount of information that can be obtained from a simple mass spectrum image is tremendous. With newer, cheaper super-accuracy mass spectrometers coming out, such as the orbitrap, this technology is growing in popularity outside of specialized physics labs, and it promises to revolutionize the way a lot of science and medicine is done. In the clinic, for example, a ton more information could come out of a biopsy all at once using this technology, from identifying cancer markers to positively identifying infectious agents and inflammation. I look forward to what’s coming in the future!

Part of why I became so interested in science as a kid (apart from watching Bill Nye) was seeing the application of science in medicine. Seeing the development of new medicinal techniques thanks to innovative research made a lasting impression on me. I guess that’s why a level of childhood excitement tends to pop up when I read about things like new imaging technology and future surgical innovations.

A schematic of Dr. King's cancer filtering concept. E-selectin attracts the cancer cells thereby exposing them to TRAIL as they "roll" along the device wall. This triggers the cancer cell's death. Image: Kuldeep Rana

Once again I felt that childhood excitement popping up as I read about a new device being developed by Dr. Michael King and his group at Cornell designed to someday remove cancerous cells from a patient’s bloodstream. King’s device takes advantage of a well studied mechanism of our immune system which is the recruitment of white blood cells to blood vessel walls with adhesion molecules known as selectins. Since selectins recruit cells based on specific carbohydrates Dr. King realized that this adhesive property could be utilized for slowing down cancer cells in order to target and destroy them.

After slowing down the cancer cells to a “roll” the cells can then be exposed to a protein called TRAIL (Tumor Necrosis Factor Related Apoptosis-Inducing Ligand) resulting in the release and then the apoptotic death of the cancer cells. This makes King’s device more than a simple sieve as he explains, “It’s a little more sophisticated than just filtering the blood, because we’re not just accumulating cancer cells on the surface”.

King’s device is impressive in it’s simplicity and tests of the device’s efficacy appear promising.

King’s research showed that the device can capture and kill about 30 percent of cancer cells flowing past it a single time, with the potential to kill more in the closed-loop system of the body. Used in combination with traditional cancer therapies, King said, the device could remove a significant proportion of metastatic cells, “and give the body a fighting chance to remove the rest of them.”

The team also showed that a system in which the cancer cells “roll” over the target molecules – presenting their entire surface to the molecules – is four times more effective than a static setup in which the cells and proteins make contact at a single point.

Of course as excited as I am to see this type of work being done, as Dr. King points out moving his concept to the clinic may take many years. I’m looking forward to reading the paper in Biotechnology and Bioengineering and seeing what others will come up with from Dr. King’s work.