Page last updated at 05:06 GMT, Tuesday, 6 October 2009 06:06 UK

DNA sequencing in a holey new way

By Jason Palmer
Science and technology reporter, BBC News

Depiction of DNA in nanohole (IBM)
DNA molecules will be held in place by tiny voltages within the nanohole

IBM will announce on Tuesday how it intends to hold DNA molecules in tiny holes in silicon in an effort to decode their genetic secrets letter by letter.

Their microelectronic approach solves one of two long-standing problems in "nanopore" DNA sequencing: how to stop it flying through too quickly.

The aim is to speed up DNA sequencing in a push toward personalised medicine.

IBM's chief executive Sam Palmisano will announce the plans to the Medical Innovation Summit in the US on Tuesday.

While sequencing the genomes of humans and animals has become relatively routine in a laboratory setting, the ability to quickly and cheaply sequence genomes of individuals remains out of reach.

That widely available genetic information will help bring about the era of "personalised medicine" - in which preventative or therapeutic approaches can be tailored to individuals based on their specific genetic makeup.


"There have been a number of attempts to sequence DNA much faster than it was sequenced when the first human genome was announced," said Gustavo Stolovitzky, a computational biologist from IBM.

Chromosome depiction (SPL)
Individual genetic information will lead to more directed therapies

"All of them use some complicated sample preparation - chopping the DNA, amplifying, reverse transcribing - and some sophisticated and labour-intensive optics," Dr Stolovitzky told BBC News.

"All this makes sequencing faster, but still slower and more expensive than it needs to be before it could be used for personalised medicine."

Instead, Dr Stolovitzky and colleagues are pursuing a method involving silicon peppered with holes just three billionths of a metre across - 20,000 times thinner than a human hair and just wide enough for one strand of DNA to pass through.

Researchers have been looking into using such nanopores for a number of years - mimicking the proteins in cell membranes that perform the same trick - because using a semiconductor offers significant advantages over biochemical and optical techniques.

"DNA nanopore sequencing continues to be one of the great candidates to do fast and cheap DNA sequencing without sample preparation or sophisticated optics, using only electronics to fetch the signal out," Dr Stolovitzky said.

Moreover, the approach could be done in a "massively parallel" way - that is, with hundreds or thousands of DNA strands passing through an array of holes on a single chip.

Trap stack

The idea is conceptually simple but devilishly difficult to carry out. Because DNA naturally carries a net electric charge, simply applying a voltage across the two sides of the chip drives the DNA strands through the holes.

However, the DNA tends to pass through too quickly to decode the identities of the individual nucleotides - letters of the genetic code - as they pass.

More than that, until they can study DNA strands moving at a more carefully controlled pace, researchers cannot develop the techniques to query the precise nucleotide they have trapped in place.

Blue Gene supercomputer (IBM)
The Blue Gene supercomputer simulated the nanopores' every atom

The IBM team have now hit on the idea of a chip composed of a stack of layers, each of which can hold a precisely-controlled voltage in a thin layer inside the nanopore.

These smaller voltages trap the negatively charged chemical groups called phosphates that separate individual nucleotides.

By cycling this internal voltage, the DNA strand can be made to advance one nucleotide at a time.

The team has used IBM's Blue Gene supercomputer to simulate the process in order to ensure it would work, and the team has built prototypes of the trapping nanopore. Tuesday's announcement marks the beginning of the testing and refinement stages of the process.

What remains is to investigate the means to identify the individual nucleotides trapped inside the nanopores, which is likely to rest on measuring some electrical or electronic property of each as it passes.

Stas Polonsky, another IBM researcher working on the project, remains convinced that with the benefit of a trapping mechanism, this last problem is tractable.

"As a company we have a lot of expertise with electrical measurements," he said.

"We have nanopores plus the whole arsenal of microelectronics - we can integrate all these ultrasensitive circuits right on a chip, which will boost the sensitivity for measurements tremendously."

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