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Second grant to allow faster sequencing

The Whitehead Institute for Biomedical Research has received a three-year, $7 million grant from the National Human Genome Research Institute to develop chip-based genome sequencing machines that can sequence 7 million DNA lettes per day, or 2 billion letters per year.

Once these machines are up and running, it will be possible to use as few as 20 machines to sequence an entire mammalian genome in one year, according to Whitehead scientists.

Slated for introduction into NIH genome laboratories in three years, these machines will accelerate the national Human Genome Project's efforts to sequence the entire 3 billion DNA letters that make up a human being by year 2003. They also will reduce the cost of the capital equipment for future facilities by a factor of 10. Scientists anticipate that the need for cost-effective DNA sequencing machines will continue to increase in the new millennium as applications of the Human Genome Project extend into biomedicine.

The proposed sequencing machines will incorporate a microfabricated "chip" device that miniaturizes the process of electrophoresis, the method currently used to read DNA landmarks. The device can sequence DNA at 10 times the speed of existing commercial technology, and it is completely automated. In addition, the Whitehead Institute machines will be geared to read significantly longer stretches of DNA, which is crucial to reduce the time it takes to piece together overlapping fragments.

"This project is a collaborative effort between the Whitehead Institute BioMEMS Engineering Group and the Whitehead/MIT Center for Genome Research," said Whitehead member Professor Paul Matsudaira of the Division of Bioengineering and Environmental Health. "Our goal is to create, on a rapid timetable, a transferable technology that can substantially accelerate the efforts of NIH genome centers to sequence the human genome."

The Whitehead Institute's bioengineering scientists, led by Professor Matsudaira and Dr. Dan Ehrlich, a research scientist in the Center for Biomedical Engineering, will build a prototype machine the first year and then develop multiple units for the Whitehead/MIT Center for Genome Research, which will serve as a test site for the machines' reliability from a user's perspective. By the second or third year, scientists hope to have refined the machines, which can then be transferred to NIH genome centers across the country.

"A key characteristic of these machines is their ability to read stretches of DNA that are more than 600 to 800 base pairs long. The longer read-lengths are absolutely crucial to cost effective sequencing of the entire genome," said Dr. Eric Lander, professor of biology and director of the Whitehead/MIT Center for Genome Research.

"Called BioMEMS sequencers, one of these machines will replace 40 to 50 of the standard ABI machines currently used in genome laboratories around the world," said Dr. Ehrlich. "Instead of the manually loaded 48-lane plates used with ABI machines, the BioMEMS sequencers will use two chips, each capable of running 384-lanes at a time for 25 runs per day. The system contains two chips so that one is always running while the other is being refreshed and loaded."

The chip consists of thin channels etched in a type of glass currently used in flat-panel laptop and television displays. The machine is automated and fits on a standard coffee table, said Dr. Ehrlich. Because the amount of sample used and the time involved in separating DNA samples is low, the BioMEMS sequencer will reduce the cost and decrease the time it takes for genomic sequencing.

"The system will have a target hardware cost of $60,000 to $100,000 per unit, making it feasible to sequence an entire mammalian genome in a year with a capital investment of less than $2-3 million in sequencing apparatus," said Professor Matsudaira.

"The Whitehead Institute group brings a rare combination of expertise to this project, so we are very excited about the potential that they will achieve success rapidly," said Jeff Schloss at the National Human Genome Research Institute. "This technology is exciting for several reasons: it obviates the need to pour gels, is highly automatable, and should yield excellent data quality. If fully realized, microchannels have the potential to dramatically reduce the cost of high-throughput sequencing and other types of DNA analysis."

These microchips are the fruits of efforts to marry precision engineering technologies with molecular biology, and in particular, to apply microelectromechanical systems (MEMS) to biology. In addition to accelerating sequencing, these new technologies, called BioMEMS, will bring desktop-size instruments to the palm of physicians' hands, enable on-the-spot DNA diagnosis of infectious diseases (thereby reducing waiting time and costs in health care delivery), and provide a reliable method for DNA typing and paternity testing in law enforcement.

In fact, this same technology is currently being readied for use in Florida and North Carolina for DNA forensics. This particular application of the chip is 100 times faster than current technology and would allow law enforcement officials to do an elaborate DNA fingerprint in about two minutes. The technology has already been proved in this area, and Drs. Ehrlich and Matsudaira are working toward building a portable device with a grant from the National Institute of Justice.

A version of this article appeared in the March 17, 1999 issue of MIT Tech Talk (Volume 43, Number 23).

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