The thousand-dollar genome: the goal is almost achieved
Technology: $1,000 per genome
Inna Burkova, "Biomolecule" based on Hayden E.C. (2014). Technology: The $1,000 genome. Nature 507, 294-295.
One gets the impression that in Silicon Valley Moore's law stands on an equal footing with the laws of nature, for example, discovered by Isaac Newton. An empirical observation by Gordon Moore, co–founder of Intel, states that the basic computing characteristics of computers are improving twice every two years, and at the same time technologies are becoming cheaper. Gradually, this pattern began to penetrate into related fields of science and technology, reaching genome research.
Over the past few years, scientists in hundreds of reports have compared the slope of a straight line from Moore's law with a rapid reduction in the cost of DNA sequencing (there was this picture on the "biomolecule" [1]). For some time the statistics coincided, but in 2007 there was a qualitative leap. The price for sequencing the human genome has plummeted from 10 million US dollars to just a few thousand in just six years. This not only outstripped Moore's law, but also called into question the authority of this "immortal" postulate. And just as easy access to personal computers has changed the world, the rapid pace of development of genomic technologies has revolutionized biological research. Which, in turn, can lead to cardinal breakthroughs in medicine.
Figure 1. For the first couple of years after the completion of the Human Genome project [2]
the cost of genome sequencing decreased in accordance with Moore's law.
However, after 2007, the price began to fall more rapidly. Picture from [9].
Most of the participants in the "deep sequencing movement" believe that a fair share of success in this industry lies in the funding scheme organized by the American National Human Genome Research Institute (NHGRI). Officially called the Award for Advanced Sequencing Technologies, this program is more commonly known as $1,000 and $100,000 per genome. Since 2004, grants have been awarded under this program to 97 academic and commercial research groups, including laboratories in the largest sequencing companies.
The program catalyzed mobility and collaboration between developers and helped launch work in dozens of competing companies, preventing stagnation that could have shackled everything after the completion of the Human Genome project in 2003 [2]. "Leading companies in the market have really transformed the approach to sequencing, and it all started with NHGRI funding," says Gina Costa, who has worked for five influential companies and is currently vice president of Cypher Genomics (San Diego, USA), a company engaged in the interpretation of genomic data.
Figure 2. Christopher Short's illustration shows the stages of DNA decoding:
from the cellular level to the molecular level. Source: National Human Genome Research Institute, Associated Press.
Standing on the shoulders of giantsTo date, the $1000 per Genome program is close to achieving its goal, and this year the awarding and provision of final grants will be held.
The question arises as to how the $230 million state program has achieved such results, and could such a formula of success be applied in other industries? But Jeffery Schloss, director of genomic sciences at NHGRI in Bethesda, Maryland, who has been leading the program since the beginning, says that achieving similar success is possible only with the right and regulated partnership of public and private companies: "...One of our tasks is to choose the right tactics for cooperation with the government, so as not to interfere, but to support the development of technology in the private sector."
Sequencing of the first human genome was a large-scale event and a real technological challenge. Between 1990 and the publication of the black version of the genome in 2001, more than 200 scientists joined forces to read about 3 billion. DNA bases that contain our genetic material [3]. Francis S. Collins, head of the Human Genome project, said: "We are releasing the first edition of the Book of Life, but in fact our genome is quite difficult to interpret as specific instructions that regulate all metabolic and biological functions. Understanding how DNA actually affects human health requires studying and generalizing examples of the connection between genes and biological processes in thousands, and possibly millions of people.
For some time, the dominant DNA sequencing technology was the Sanger method – a rather slow and time-consuming process. Its essence lies in the creation of copies of DNA, the synthesis of which involves the inclusion of nucleotides with chemically modified fluorescent labels. During the dominance of this technology in the sequencer market, Applied Biosystems (Foster City, California) reigned supreme, which supplied equipment to a narrow circle of customers (mainly government laboratories), and nothing foreshadowed drastic changes.
Given the urgency of fast and error-free DNA sequencing, scientists have introduced parallel technologies and robotized the process. At a meeting convened by NHGRI in 2002, it was suggested that such a development could reduce costs by a factor of 100 over the next five years. But that wasn't enough.
At the meeting, it was suggested that reducing the price would make genome sequencing routine, and doctors would be able to perform this procedure on a par with scanning magnetic resonance imaging. It seemed too ambitious, given the state of the technology at the time. "There is doubt about the willingness of investors to spend money on such technology," says Eric Eisenstadt, a retired official who in the past led defense research projects of the US government.
However, J. Schloss and NHGRI began funding the development of completely new sequencing methods, as well as the commercial introduction of such technologies. The combination of fundamental and applied research within the framework of one program was rare for the National Institutes of Health (NIH), a parent organization above NHGRI. The project was more promising than a typical research supported by an NIH grant, as it allowed the agency to allocate small awards for promising but risky work. Schloss notes that "such flexibility is unusual for the NIH."
In addition, the program provided support to companies that could compete with Applied Biosystems. One of these companies was 454 Life Sciences. The activities of the 454 company were aimed at developing a sequencing method that would be fundamentally much faster and cheaper than the Sanger method. The technology consisted in a simpler procedure for preparing samples and conducting most reactions on a solid surface [4]. However, when the company tried to attract financing, investors shied away from cooperation, explaining that the appearance of such a technology was premature: "People say: why do you want to sequence DNA so quickly? After all, we have already completed the Human Genome project."
The pyrosequencing technology developed by 454 Life Sciences thanks to a $7 million investment from NHGRI has become quite profitable. Thus, this company was the first to begin the gradual abolition of the Applied Biosystems monopoly.
The received financing eventually helped convince private investors to enter the market too. Stephen Turner, founder and chief technology officer of Pacific Biosciences, says that the grant of 6.6 million $from NHGRI, received by his company in 2005, helped to further attract venture capital. The window "cut through" by NHGRI convinced investors to invest more substantial money in the company in order to bring the technology based on the observation of DNA synthesis in real time to mind. According to Turner, "it is possible to have highly qualified specialists in sequencing technology, but the size of the account of the company that conducts research will have a greater impact."
NHGRI's investments, which usually amount to several million dollars, could not by themselves nurture the technology and bring it from the laboratory to the market. But they could finance individual parts of it, for example, work on improving dyes, developing circuits, lasers and testing combinations of individual components.
Within the framework of the program, $88 million was invested in technologies based on nanopores – here the sequence of DNA nucleotides is "read" as it is stretched, like a thread, through a pore [5]. This technology would free from the need to carry out expensive and slow reactions that are currently used to amplify DNA molecules. But solving fundamental questions – including how to make DNA move through the pore slowly enough and at a constant speed –has become quite problematic. NHGRI has funded work to overcome these obstacles, including $9.3 million allocated to Oxford Nanopore Technologies. Turner says such investments help reduce sequencing costs before the technology gets into mass use.
Experts in the field of sequencing say that the "$1000 per genome" project has nurtured many companies and laboratories, in fact creating a new expert field. One of the most striking such examples is the company Illumina in San Diego, which has now become the leader in the sale of sequencers. Illumina, whose technology consists in reading many short pieces of DNA, has acquired several other companies and lured many scientists who were funded by NHGRI in the past. "Due to new acquisitions, Illumina is developing rapidly," says Mostafa Ronaghi, technical director of the company.
Figure 3. Advances in optics, flow cell design, and chemical clustering
allow researchers to simultaneously process multiple samples of the whole human genome.
Left: HiSeq X can sequence up to 16 genomes in less than 3 days.
Each device generates up to 1.7 TB of "raw" data.
On the right: Reagent kits for HiSeq X HD, used in the form factor of flow cells [7].
Competing sequencing technology companies are taking part in an annual meeting dedicated to industry progress. According to Turner, "this meeting is one of the most important places to discuss what is happening in the field of genomic sequencing, and allows you to share the necessary knowledge."
Shaking and shrinkageSome scientists question the achievements of the NHGRI program.
For example, Costa expresses dissatisfaction that "a lot of money was allocated for the development of nanopores, but there is not enough sense." Kevin McKernan collaborated with Costa to develop SOLiD sequencing technology (based on enzymes that "stitch" DNA fragments together). He points out that many of the companies that were funded under the "$1,000 per genome" program ultimately failed to meet the expectations that were placed on them: "the success rate of these companies is probably not much higher than in venture investment."
However, others give Schloss and his program credit for creating a favorable investment climate in the field of scientific and commercial applications. Many firms that were funded by NHGRI no longer exist – for example, 454 and Helicos BioSciences – but other grant recipients continue to work, constantly improving the technology.
"NHGRI funds small companies and academic groups to create an optimal source of information and technology development," says Ronakhi. However, they have not decided on the technologies that they need to bet on.
Sequencing still needs a lot of improvements, especially in terms of the quality of reading the DNA sequence. Despite the high cost and complexity, Sanger sequencing continues to be the standard of accuracy. And sequencing costs are no longer declining as fast as they were a few years ago. But the researchers are optimistic, and believe that another technology should replace Illumina.
Now that sequencing is becoming really cheap, we can start talking about scanning the complete genomes of individual patients, or at least those areas of it that encode proteins. But, however, it is still completely unclear how this information will help increase the quality of medical services and bring the era of the notorious personalized medicine closer [8]. Searching and finding answers to such complex questions will help to make another big leap in genomics, compared to which Moore's law will seem just a trifle.
LiteratureBiomolecule: "Cucumbers are killers, or how Jim Watson and Gordon Moore met";
- biomolecule: "Human genome: how it was and how it will be";
- International Human Genome Sequencing Consortium et al. (2001). Initial sequencing and analysis of the human genome. Nature 409, 860-921;
- Biomolecule: "454-sequencing (high-performance DNA pyrosequencing)
- Sanderson K. (2008). Personal genomes: Standard and pores. Nature 456, 23-25.
- Biosurface. Flow cells;
- Illumina: HiSeq X HD Reagent Kit;
- biomolecule: "Reproaches in narcissomics";
- Hayden E.C. (2014). Technology: The $1,000 genome. Nature 507, 294–295.
Portal "Eternal youth" http://vechnayamolodost.ru03.06.2014