Genomics for the new biomedicine

One of the most profound advances in biology and medicine has been the sequencing of entire genomes, including the human genome. The end product was the availability of the complete genetic blue print of organisms of importance to medicine and biotechnology. This changed how we conducted science. Cloning individual genes was no longer a limiting factor. Instead, entire scientific communities set upon understanding how genes interact with each other in pathways and across pathways so as to explain complex biological and physiological processes. For the biotechnology and pharmaceutical industries, the identification, cloning, and engineering of a single gene to produce a key biological product such as erythropoietin, was no longer an attractive investment prospect. Instead, companies that produced either a clinically tested end-product, or provided entire platforms for high throughput screening, were the only ones being funded. The new benchmark for success is now speed and comprehensiveness, which are orders of magnitude greater than just ten years ago.

This advance did not come with one discovery but a number of disruptive technologies including PCR, capillary sequencing and parallel and fast computing. These were combined and collectively improved incrementally with the introduction of innovative computational algorithms and robotics. But the business model of genomics suffered, in part because of its success. Companies that provided computational services to pharmaceutics floundered, genomic discovery companies failed or were completely converted to drug development organisations, companies providing databases for profit collapsed and venture capital ceased to invest in technology platforms. As the data became progressively public, the competitive differential between industry and academia disappeared. Pharmaceutical companies assisted government projects, such as the HapMap Project and put genomic data into the public domain so that no single entity would have pre-competitive advantage. As we entered the 21st century, the prospects for a ‘for-profit’ genomics company other than a tools provider, appeared grim.

However, the situation has abruptly changed. In the last two years, an explosion of technological advances in nucleic acid sequencing was dramatically changing the landscape in genomics yet again. The fundamental difference is that the new technologies sequence single fragments using highly multiplex platforms of up to a billion sites simultaneously, thus increasing the speed and capacity of sequencing by 100 to 100,000 fold from current methods, while dropping the costs by almost the same degree. The companies providing these third generation sequencing technologies are 454/Roche with its GL-FLX, and Solexa/Illumina with its 1G Genome Analyzer. Soon ABI (ABI SOLiD) and Helicos (HeliScope) will launch their own versions of single molecule sequencing as well. Devices such as the ABI 3730 began the commoditisation of DNA sequencing, however, the sequencing by single molecule synthesis of Helicos and Solexa will prove to break the “sound barrier” of genome sequencing: for example, the sequencing an individual’s entire genome for US$1000 at a speed that enables clinical decision making.

When compared to standards of 1990, when the human genome sequencing effort began, the total cost of sequencing has fallen 6 orders of magnitude with a proportionate increase in speed. This log-linear rate of advance (a 10 fold reduction every three to four years), resembles the pace of increase in hard disk capacity, described by Kryder’s Law and the rate of change of computer chip capacity, described by Moore’s Law. These linkages are a reflection of the importance of computational capacity to sequencing firepower. This continuous increase in capacity, speed, and economy in DNA sequencing, enables dramatically new applications in much the way the increase in RAM and hard disk storage moved computers from being simply fast calculators to real-time simulators of 3-dimensional fantasy worlds.

With the current rate of advance, we can expect to sequence with 1 X coverage the human genome for $1000 USD before 2013. Chances are this goal can be achieved before 2013 at much greater genome coverage because of advances in sequencing technologies on the horizon. At a $1,000, this is thought to be the price point where clients in the clinical sector would be willing to pay for whole genome sequence information of individual patients (See Figure 1).

All this has brought about a resurgence of interest by the investment community for sequencing technologies. Helicos has previously attracted over $67 million funds from top-tier investment consortia such as; Atlas Venture, Flagship Ventures, Highland Capital Partners, MPM Capital and Versant Ventures. Big players in the market are also seeing the potential of third generation sequencing technologies and are acquiring biotech companies that develop and own them. For example, Roche Diagnostics, which was the exclusive worldwide distributor of 454 Life Sciences’ Genome Sequencer systems and reagents since May ’05, acquired 100% of 454 Life Sciences Corp in May 2007. Likewise for Illumina which completed the acquisition of Solexa in January 2007.

The end-products of this resequencing surge will change the conduct of biotechnology and pharmaceutical R&D as much as molecular biology did in the 1980’s. The dramatic speed in genotype-phenotype associations will expand the possibilities of linked molecular diagnostics with therapeutics (theranostics) for precise patient stratification. Resequencing of entire genomes will enable the better engineering of antibiotic producing microbes, and of protein production of recombinant molecules. We predict another bump in discovery productivity which will make the slowness of clinical validation even more acute. However, the greatest advance will be to enhance our ability to confront and control biological complexity.

Thus, the new genomics will speed the incorporation of systems biology approaches into pharmaceutical and biotechnology industry. The current “systems” approaches use high throughput technologies and computational modeling to arrive at a roadmap for therapeutic intervention. This roadmap is then used to guide drug and biomarker development. A systems biology strategy involves the sensing and measurement of a comprehensive set of cellular responses, precise measurement at multiple time points or doses, and digitalising the data so that they can be computed to create a mathematical model. The final act is making predictions based on that model. Virtually every big pharmaceutical company is exploring this systems pharmacological approach as a strategy to improve the efficiency of the discovery pipeline. The new genomic technologies will be the foundation of this genome-to-systems movement.

Where will this all go? If the trends in genomic biology are any indication, the centre will be the link between computational power and innovation and biological experimentation. Similar to how computational chemistry is becoming progressively critical in the drug development process, so will computational biology. At some point, the idea of a merger or joint venture between IBM Life Sciences and Pfizer will become a distinct possibility. As disruptive technologies turn the scientific world topsy-turvy, the ones who survive are those with strong vestibular systems that can ride the waves.

Suggested Reading:

• Kitano H. A robustness-based approach to systems-oriented drug design.
• Nat Rev Drug Discov. 2007 Mar;6(3):202-10.
• Bennett ST, Barnes C, Cox A, Davies L, Brown C. Toward the 1,000 dollars human genome. Pharmacogenomics. 2005 Jun;6(4):373-82.
• Petretto E, Liu ET, Aitman TJ. A gene harvest revealing the archeology and complexity of human disease. Nat Genet. 2007 Nov;39(11):1299-301.

Edison T. Lium

Genome Institute of Singapore

Professor Edison Liu graduated from Stanford University and its medical school. From 1987-96, he was professor of medicine, biochemistry and epidemiology at the University of North Carolina, and Director of its Specialised Program of Research Excellence in Breast Cancer. From 1996-2001, Professor Liu was the Division Director of Clinical Sciences (Intramural program) at the US National Cancer Institute. In 2001, he was appointed the executive director for the Genome Institute of Singapore. He has received the Rosenthal Award from the American Association of Cancer Research and the Brinker International Award from Susan Komen Foundation for his breast cancer research. He is currently the President of the Human Genome Organisation (HUGO).