Towards a $1,000 Genome Sequencing Test

Bioengineering professor Xiaohua Huang is combining micro and nano-fabrication technologies with high-throughput DNA analysis to develop a $1,000 genome-sequencing technology, the goal of a new 10-year National Institutes of Health (NIH) initiative that could dramatically change the nature of biomedical research.

Miniaturization of existing technologies has reduced the cost of sequencing mammalian genomes from $3 billion a few years ago to as little as $10 million today. Now, the NIH wants to slash that cost during the next 10 years by at least another four orders of magnitude.

Huang's goal is to replace the current generation of sequencing machines with a fundamentally different analytical approach and a single miniaturized device. He said that such a novel device could be based on a process that breaks the human diploid genome into hundreds of millions of pieces and then amplifies and sequences all of them in parallel.

He has developed an amplification technology to clone individual DNA molecules from a whole human genome in highdensity arrays of millions of wells on the surface of silicone plates the size of a microscope slide. Huang plans to use the DNA clones as templates for genome-scale sequencing. One method his laboratory is developing is called DNA sequencing by denaturation. By keeping track of DNA subunits—deoxyadenosine (A), deoxyguanosine (G), deoxycytosine (C), or deoxythymidine (T)—when they are sequentially removed from each immobilized fragment, the entire genome sequence can be determined with a high degree of accuracy.

Bioengineering professor Xiaohua Huang holds a silicone disk with millions of wells on its surface. After short segments of human DNA are allowed to fall into each well, he plans to use a biochemical technique to determine the subunit sequence of each one as part of a process to determine a person's complete genome sequence.

“The reaction at the core of our technology is just the usual DNA sequencing reaction called Sanger dideoxy sequencing and a DNA denaturation process, but an unprecedented parallelization of it will give us the information we need,” says Huang.

Not only will routine genomic sequencing detect genetic diseases and genetic predispositions to disease, but Huang says it also could be used to genotype cancer cells.

"There may be hundreds of distinct mutations that lead to one type of cancer, such as breast cancer," says Huang. "But not all breast cancers are alike." He says it will become increasingly important for doctors to know which subtype of breast, pancreatic, or lung cancer is present in an individual patient's genome so treatment can be tailored to achieve the best possible results.