The ability of molecular biologists to sequence the human genetic code promises to usher in a new era of genetic medicine, but that doesn’t mean science can accurately read personal genetic codes.
The sequencing of the DNA comprising the code is still far too slow, costly and inaccurate to allow the kind of sequencing of specific tissues that is necessary to understand many particular genetic problems of individual patients.
A radical new method of DNA sequencing being explored by Stuart Lindsay, professor of physics and the director of the Center for Single Molecule Biophysics in the Biodesign Institute at ASU, could make the long-dreamt-of era of true genetic medicine possible with extremely rapid, accurate and low-cost sequencing of single DNA molecules. However, a number of significant technical hurdles still need to be overcome before the idea can be considered a usable technology.
With the goal of overcoming these technical challenges, the National Human Genome Research Institute (NHGRI) of the National Institutes of Health has awarded a $550,000, three-year grant to Lindsay to further develop a nanotechnology project for rapid genetic profiling. The award is just one of seven given this year in NHGRI’s Revolutionary Genome Sequencing Technologies grant program, which the institute says is aimed at “the development of breakthrough technologies that will enable a human-sized genome to be sequenced for $1,000 or less.”
As a scientist, however, Lindsay is careful in not claiming a breakthrough yet.
“There is still a fair amount of harsh reality to deal with,” he says. “As we work harder on the project, we haven’t yet encountered any fundamental problems that say this is impossible – but we have encountered lots of challenges that still need to be solved. But this is what scientific research is about. We are making solid progress, and every time a new problem has come up, we have found a way around it. This grant is a wonderful opportunity to continue the work.”
Lindsay’s new sequencing technology involves using Atomic Force Microscopy (AFM), which customarily is used to analyze the surface structure of materials at molecular resolution with the ultra-small tip of a sensitive probe, in combination with naturally occurring ring-shaped sugar molecules called cyclodextrins. Lindsay believes that the ring molecules, when paired with the AFM probe tip, can effectively be used as sensors to “read” the sequence of amino acid code (DNA “bases”) in the human genome that comprises many millions of bases.
“Cyclodextrins are Mother Nature’s little molecular rings,” Lindsay says. “They are just big enough to slide a strand of DNA through. Conveniently, Mother Nature also makes them with neat little reactive groups on the side, so you can do chemistry with them.”
Through the reactive groups on the side of the rings, Lindsay’s technology proposes to attach the ring to the sensitive AFM tip, which would thread an anchored DNA molecule into the ring and pull it through, recording the subtle differences in the “bumps” resulting from the friction of the different DNA bases with the ring. The resulting data could thus be translated into the precise sequence of the DNA molecule.