Cutting Edge

This illustration shows a strand of DNA traveling through a nanopore. With IBM's approach, some layers periodically stop the DNA strand while another measures its properties to determine its genetic information.

(Credit: IBM)

It took 13 years for researchers to catalog all the information in a human genome the first time. Now IBM believes it can do better--somewhat perversely by equipping a newer genetic sequencing method with brakes.

Big Blue is among those who believe electronics technology can be applied to the task of sequencing a person's genes, thereby bringing genetic testing into the computing era and lowering its cost to something like $100 to $1,000.

IBM is working on prototype DNA-processing electronics that slurps strands of DNA through an extremely small hole called a nanopore, measuring the electrical properties of the chemicals as they go by to determine the genetic information. That technique is used beyond IBM, but what Big Blue researchers have been working on is a way to slow down, an essential step toward improving its precision, said Gustavo Stolovitzky, manager of the IBM Functional Genomics and Systems Biology Group.

IBM Chief Executive Sam Palmisano is scheduled to unveil the project and what the company calls its "DNA transistor" Tuesday in a talk, "IT Innovation in Healthcare," at the Cleveland Clinic, IBM said.

The ultimate goal for such research is affordable genetic sequencing. "It would allow DNA sequences to be more or less routine," Stolovitzky said, forecasting that the technology will arrive in five or ten years.

OK, but why should you care?

"It would enable the possibility of going to the doctor with some infection, and the doctor gets the sequence pretty much on spot of the bacteria affecting the patient or the virus is in the blood," Stolovitzky said.

Or another possibility: knowing patients' specific genotypes could mean doctors would know if they had a negative reaction to some drug. That could mean some drugs useful that today are banned could become useful to a subset of the population.

IBM isn't the only one working on this technology. In addition to various academic efforts, start-up 23andMe offers some genetic analysis today.

The genes of animals and plants are encoded in DNA with just four molecular-scale substances--adenine, thymine, guanine, and cytosine. Their particular order governs not only their the formation of humans and other organisms but also the day-to-day biochemistry that keeps us alive.

IBM's sequencing technique to transcribe this biochemical data has been under way for three years, and it's easier said than done. The company is in the process of creating a new prototype device updated to reflect what IBM learned from an earlier one that didn't work as hoped.

"Translocation control we should have in a year's time more or less," Stolovitzky said, referring to the ability to ease the DNA through the nanopore one pair at a time.

The distance scales alone make the work difficult. Each DNA base is about 5 or 6 angstroms away from its neighbor--about half a billionth of a meter. By comparison, a human hair is colossal, about a ten-thousandth of a meter in diameter. And the DNA strands slip through a nanopore that's 2 to 3 billionths of a meter wide.

One problem with the nanopore approach is that it's hard to distinguish the four substances, called bases, as they slip through the hole. The four bases have overlapping electrical properties, so the more time spent measuring each, the better the accuracy.

IBM's approach uses a flat device about 250 nanometers on a side. It has very thin alternating layers of metal and a material called a dielectric. The nanopore is bored through these layers using an electron beam from a tunneling electron microscope, Stolovitzky said.

On one side of the layer is the DNA, unzipped from its familiar double-helix configuration with two strands of matched bases into a single strand with single bases. The single-strand is important in part because the distance between each pair increases to between 5 and 6 angstroms, making them more manageable than the double strand with bases 3.4 angstroms apart, he said.

The strand is pulled through the nanopore by an electrical field that attracts the negatively charged strand. But in the nanopore, some layers are electrically switched on to fix the strand in place for a tick of an electronic clock while another layer makes its measurement, Stolovitzky said.

Even slowed down, the process is fast compared with humans toiling away with pipettes and polymerase chain reaction equipment in a lab. "We think 1 millisecond should be a reasonable time to measure (a base)," Stolovitzky said. In other words, it would take about a second to perform 1,000 measurements.

The human genome has about 3 billion base pairs, so that's still a lot of time to do a full analysis. But it's sill more complicated because the chromosomes that house the genetic data must be broken up into smaller strands for practical reasons.

But IBM Research is happy to pursue a number of projects that may not pay off immediately, including work touching on nanotechnology, computing, and biotechnology. Whether it'll all come to fruition remains to be seen, but one way or the other, it's likely you'll know your own genetic data within a matter of years.

Don Eigler moved the first individual atom 20 years ago, and shortly afterward, he wrote IBM's name with 35 Xenon atoms.

(Credit: IBM)

When IBM researcher Don Eigler picked up and moved the first individual atom 20 years ago today, he paved the way for what arguably was the smallest publicity stunt ever: Big Blue's logo made from a precise arrangement of 35 Xenon atoms.

But moving tiny atoms had big consequences by making the idea of assembling devices atom by atom very real. And the company has built on that nanotechnology foundation, storing information on specific gold atoms, collecting carbon monoxide molecules into computer logic circuits, and pursuing a vision for vastly more compact computing technology.

Despite the progress, Eigler is cautious about when or even if his ideas for computing will bear fruit.

"We did the introduction, and we're in chapter 1," Eigler said. "This is way off in the future, if it ever comes about. I cannot conceive, under the best circumstances, this is going to happen in 10 or 15 years."

Boggled
Eigler, now an IBM fellow, said he was "boggled" that day he moved his first atom with an IBM device called a scanning tunneling microscope. He programmed the system to make the move, then held his breath while his screen went blank during the actual operation.

"You can't see it while you actually move it. Then you see the picture come in and say, 'Yes, it's there,'" Eigler said. He moved the atom back and forth three times to make sure that it really worked: "For us, that's (a) sort of sacred thing. The key thing and most important thing about science is reproducibility. If you can't reproduce your own result, you might as well forget it. It's as if you'd never done it."

Shortly after that, in November 1989, Eigler arranged the 35 atoms to spell IBM. There was, of course, publicity in it for the company, but Eigler had no complaints. For one thing, it demonstrated that IBM really could control atoms with atomic-scale precision and that its work wasn't just a fluke. For another, Eigler was grateful that IBM let him pursue his work.

"It was more than a publicity stunt. Emotionally, for me, it was much more important. This is going to sound hokey, but it's the truth. IBM picked me up off the scrap heap of science and gave me every opportunity a scientist could hope for to be successful," Eigler said. "As far as I was concerned, it was payback time."

No mass manufacturing
Eigler and colleagues have been working on the technology since, but so far, the benefits have been indirect. That's because moving and studying atoms with a scanning tunneling microscope and its offshoot, the atomic-force microscope, is a far cry from assembling computing devices that operate at much larger scales.

"Being able to put atoms together with atomic-scale precision at a level that allows you to deliver a marketable product is something that is largely hope and vision for our future," Eigler said. "We are not there yet."

There are other directions of nanotechnology research; Eigler called out graphene and topological insulators as possibilities. Eigler, though, remains excited to pursue his own long-term vision for computers that process information without today's reliance on the movement of electrons.

IBM Fellow Don Eigler in his lab.

(Credit: IBM)

Specifically, he's interested in using the quantum mechanical property called spin for computing. The conventional conception for this general idea, called spintronics, uses spin to control the flow of electric current, but Eigler wants to use spin alone.

"My goal is to do everything we need to do for computation--logic, storage, information transport--but without moving electrons around at all," Eigler said.

One advantage of the approach is that it avoids electrical current that produces the waste heat that's a major limiting factor in today's computers. Another is that it can enable three-dimensional computing designs much more densely packed with processing power than today's two-dimensional circuitry etched onto silicon wafers.

Spin engineering
The spin of one atom can affect that of its neighbor. The hard part is arranging atoms in order to harness that effect and perform useful computing operations.

"We have to learn how to engineer things so they work the way we want them to work. If you have two atoms, each has spin, and those spins are coupled together in usually two, three, or even four different ways," he said. "You have to place them in the appropriate relationship with one another."

One milestone toward this goal was work by Gerhard Meyer of IBM's Zurich Research Laboratory and others to store data in the form of electrical charges on individual atoms of gold, Eigler said.

In another, IBM's Christopher Lutz found that he could trigger a "molecule cascade," in which a series of carbon monoxide molecules could transmit information. The metastable molecules could store energy, then release it from one neighbor to another similar to a chain of balanced dominoes falling.

Lutz then found a way to arrange those molecules into basic logical processing units of computers, "and gates" and "or gates" that are foundations of today's computers. It didn't use spin, but it's a step in that direction, Eigler said.

Building blocks
One possible intermediate step between moving single atoms and mass manufacturing is what Eigler calls nano plug-ins. If physicists and engineers could figure out how to construct individual logic gates out of a complicated molecule, IBM chemists might be able to figure out a way to synthesize such units in quantity. Next would come the assembly process of snapping these units together appropriately.

"That strategy for building things that work on a very small scale may well be what we see in the future," Eigler said.

And it may arrive, even if his spin-based computation doesn't. "It may be (used with) regular conventional electronics, (or) with carbon nanotubes or graphene," he said. This brings him to the point about why IBM Research invests in such distantly useful technologies.

"The knowledge we're generating in the process of getting there," Eigler said, "is likely to feed into the industry much sooner than the actual outcome--if we ever get to that outcome."

IBM already had technology that could measure extremely subtle forces among atoms, but a nanotechnology development a the company's Zurich Research Laboratory shows a new level of sensitivity: the ability to distinguish positively charged atoms from those that are neutral or negatively charged.

The atomic force microscope maps what's below by detecting subtle changes in forces of attraction.

(Credit: IBM)

Researchers at the Zurich lab, along with colleagues at the University of Regensburg and Utrecht University, used an atomic force microscope (AFM) with a tuning-fork detector arrangement on the tip of its probe to distinguish among gold atoms that were positively charged, neutral, or negatively charged. The researchers describe their approach in the June 12 issue of Science.

"The AFM with single-electron-charge sensitivity is a powerful tool to explore the charge transfer in molecule complexes, providing us with crucial insights and new physics to what might one day lead to revolutionary computing devices and concepts," said Gerhard Meyer, who IBM's work with the AFM and its precursor, the scanning tunneling microscope (STM), in a statement.

Just how sensitive, exactly? IBM says the arrangement can detect a force less than 1 piconewton, which for comparison is the force of gravitational attraction of two adults a half kilometer apart. And according to Wolfram Alpha, it takes a force of 65 piconewtons to pull a strand of DNA apart by pulling on each end.

IBM has been steadily advancing its atomic-level research for years, using its technology to detect, move, and now study individual atoms. This nanotechnology research is far from practical today for the holy grail of nanotechnology, mass-producing devices by assembling them atom by atom, but it's a step in that direction.

Differences in the frequency that a tuning-fork arrangement on IBM's atomic force microscope can distinguish between charged and uncharged gold atoms.

(Credit: IBM)

The new technology could help with a variety of research areas, IBM argues: molecular electronics for nanocomputing devices, catalysis of chemical reactions, and the inner workings of solar cells' conversion of light energy into electrical energy.

"Mapping the charge distribution on the atomic scale might deliver insight into fundamental processes in these fields," said IBM researcher Leo Gross.

It's hard to precisely study individual atoms--the warmer the temperature, the more they jiggle. To reach the new sensitivity level, the researchers had to chill their experimental apparatus to 5 kelvin, or minus 451 Fahrenheit.

An atomic force microscope works by measuring the attractive force between its tip and atoms below. To achieve greater sensitivity, the researchers attached a two-prong tuning fork that vibrates at a certain natural frequency. Moving it closer to atoms subtly speeds or slows this natural resonant frequency.

One reason the research is significant: molecular electronics use substrates that don't conduct electricity. Scanning tunneling microscopes, though, require a conducting substrate beneath the molecule in question, IBM said.