Dmitri V. Vezenov, assistant professor of chemistry at Lehigh University, was recently named recipient of a $905,000, three-year grant from the National Human Genome Research Institute (NHGRI).
Part of the National Institutes of Health, the NHGRI recently announced the latest round of $13 million in grants, which were awarded to speed the development of innovative sequencing technologies that reduce the cost of DNA sequencing and expand the use of genomics in medical research and health care.
A team led by Vezenov will apply force spectroscopy – a technique used to measure intermolecular interactions and mechanical properties of polymer molecules – to DNA that is undergoing arrested polymerization to initially demonstrate one-molecule-at-a-time analysis of changes in molecular mechanics. The ultimate goal of the project is to achieve a resolution of a single base.
Using optical, near-field probes, the methods of force spectroscopy can be advanced into techniques having a massively parallel format, in which millions of single DNA base additions can be followed at the same time. The identification of the bases will be done exclusively on the basis of changes experienced by the DNA molecule as a whole.
Vezenov's team aims to demonstrate a low-cost tabletop setup suitable for use in a general biology or hospital laboratory.
"Scanning force microscopy is a powerful tool with which to visualize the molecular and nano-world, but it cannot be used to 'read' the genetic code," says Vezenov. "In the last decade, advances in force spectroscopy – a related technique – have led to some interesting discoveries of the rich mechanical properties of single DNA molecules. We now know, for example, about a stretching transition in a DNA duplex that no one could have foreseen."
Vezenov says his group will try to answer a scientific question of the ultimate resolution that one can achieve when measuring forces in biomolecules: Can we detect a difference of a single base?
"If we can," he says, "there are serious implications for genomics, because one can then imagine sequencing without the fluorescent labels and time-consuming purification steps that are the current state of the art. We hope to contribute to the transition of full genome sequencing from something that only a government or a few companies can do to something that an average physician can also do."
Robert Flowers, professor and chair of Lehigh's department of chemistry, said the NIH study panel recognized that the novel approach proposed by Vezenov had the potential to revolutionize genome sequencing.
"The department is thrilled that he is having such an important impact this early in his career," Flowers said.
Funding breakthrough technologies
NHGRI Director Francis S. Collins said significant progress has been made in recent years to develop faster and more cost-effective sequencing technologies, and that the institute is committed to supporting innovative efforts to benefit scientific labs and medical clinics.
"These technologies will eventually revolutionize the way that biomedical research and the practice of medicine are done," Collins says.
Since 1990, the NHGRI has invested approximately $380 million to develop and improve DNA sequencing technologies. As a result, costs of DNA sequencing have fallen more than 50-fold in the past decade – fueled in part by tools, technologies and process improvements developed as part of the successful project to sequence the human genome.
However, it still costs roughly $10 million to sequence 3 billion base pairs, or the amount of DNA found in the genomes of humans and other mammals.
The NHGRI's near-term goal is to lower the coast of sequencing a mammalian-sized genome to $100,000. This would allow researchers to sequence the genomes of hundreds, or even thousands of people in studies to identify genes that contribute to common, complex diseases.
Ultimately, the institute's vision is to cut the cost of whole-genome sequencing to $1,000 or less, which would enable the sequencing of an person's genome as part of routine medical care. This would enable doctors to tailor the diagnosis, treatment and prevention of disease to each person's unique genetic profile.
Jeffrey Schloss, NHGRI program director for technology development, stressed the importance of support for innovative sequencing technologies.
"Many of these new approaches have shown significant promise, yet far more exploration and development are needed if they are to be useful to the average researcher or physician," Schloss said. "We look forward to seeing which of these technologies fulfill their promise and achieve the quantum leaps that are needed to take DNA sequencing to the next level."
The National Institutes of Mental Health, which is widely known as the nation's medical research agency, includes 27 institutes and centers, and is a component of the U.S. Dept. of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical, and translational medical research, and it investigates causes, treatments and cures for both common and rare diseases.
Vezenov came to Lehigh in the spring of 2006 following post-doctoral studies with Harvard's George M. Whitesides, one of the world's most renowned chemists. His research interests include force spectroscopy of soft matter, nanostructural characterizations of materials and surfaces, optical near field techniques and optofluidics. Vezenov received his doctorate in chemistry from Harvard, his master's in chemistry from Case Western Reserve University, and his undergradute degree in chemistry from Moscow State University in Russia.