Human microbiome and personalized medicine

In genomics, the eleventh annual meeting of Advances in Genome Biology and Technology (AGBT) was held February 24-27, 2010, and featured an eclectic mix of new research and bioinformatics tools. Genomic research was presented in a diversity of areas including human, animal, plant, and bacteria. Many research advances are coming from partnerships between one or more academic research teams together with commercial entities. The biggest buzz was around Pacific Biosciences, the 3rd generation sequencing darling, with their single-molecule real-time (SMRT) platform which is still on track for an estimated launch later this year. The platform could deliver a 30,000-fold improvement over current methods, and ultimately achieve sub-$100 whole human genome sequencing. Attendees were also wowed by 454 Roche’s bench top GS Junior System (initially announced in late 2009), making sequencing much quicker and easier, and priced at only $98,000 (a milestone for sequencing equipment which usually runs in the several hundreds of thousand dollars).

Sequencing data storage and transfer costs continue to increase with the computing industry still not cognizant of the whole new era of data processing and communications transfer that is necessary for Very Large Datasets. The NIH 1000 Genomes project, for example, is transferring many terabyte-sized files per day.

From a research standpoint, some of the most activity is in cancer genomics. A recent NIH study generated 100TB data sequencing a melanoma sample and a normal blood sample and has been refining the Most Probable Variant (MPV) Bayesian analysis method used to identify genetic mutations. Perhaps the most innovative new research activity is in RNA sequencing. Other specific findings of note are in the areas of the microbiome and genetic variation:

Human microbiome
The complex interactions between individual humans and their microbiomes could have a substantial impact on personalized medicine. In some cases of infectious disease in humans, the pathogenesis may be unknown 40-60% of the time (e.g.; respiratory disease, skin disease). Even rudimentary issues remain unsolved, for example, it may be undetectable from a simple blood draw showing staph infection whether the bacteria was on the skin surface or in the blood. Microbiome sequencing is allowing the identification of novel pathogens, and could also be useful at the human population level to assess the spread and mutation trajectory of pathogens.

Genetic variation: human and otherwise
The populations analyzed in human genome wide association studies are being expanded, with important findings for both ancestry reconstruction and medical genomics. Research was presented on African-American, Mexican-American, Bushmen, and Bantu genome studies. A deeper understanding of genetic variation is also being used to facilitate the selection of desirable qualities in agriculture and animal livestock. For example, a chicken sequencing project found 7 million unique SNPs, 5 million of which were novel, and several of which were useful in translational application.

Individuals to drive personalized medicine era

The Personalized Medicine World Congress held January 19-20, 2010 in Mountain View, CA was one of the first business conferences devoted to personalized medicine. There is a lot of excitement about personalized medicine and genomics given some recent announcements regarding whole human genome sequencing. First, Complete Genomics reported the costs of consumables (required chemical reagents), dropping to $4,400, and even $1,500 (Supporting Online Material page 27) per genome. Illumina similarly announced dramatic price drops, an estimated all-in cost of $10,000 per whole human genome with the new HiSeq 2000 machine. Illumina currently charges individuals $48,000 for whole human genome sequencing. The HiSeq 2000 is priced at $690,000 per machine and BGI (formerly the Beijing Genome Institute) has ordered 128.

Complete Genomics’ CEO Cliff Reid made an interesting point that despite genomic sequencing having been progressing at 10x improvements per year since 2006, theoretical limits are starting to be reached and the industry will probably return to regular Moore’s Law progress curves (18 month performance doublings). While third-generation sequencers such as Complete Genomics (using a short-read sequencing-by-probe-ligation technology) and Pacific Biosciences (using a single-molecule real-time sequencing by synthesis technology) may start to reach limits, fourth-generation sequencers using other technologies such as nanopores (e.g., Oxford Nanopore Technologies), and electron microscope imaging (e.g., Halcyon Molecular, ZS Genetics), may be able to keep the sequencing industry progressing at faster-than-Moore’s-Law rates.

The most hopeful comments came from Esther Dyson and Leroy Hood. Esther Dyson, pointing out the still heavy focus on health institutions rather than consumer-empowerment for transformation to the personalized medicine era said that she felt like she was “representing the PC world at a mainframe convention.” Directly paralleling the current medical system, she also noted that when Gutenberg arrived with the printing press, the priests said ‘there’s no reason people need to read the bible themselves, we can read it for them.’ However, as shown in Figure 1, personalized medicine is about wellness, not disease, and while there are certainly overlaps with the current domain of physicians, there may be minimal encroachment due to automated tools and new health ecosystem participants such as wellness advisors.

Figure 1. Wellness becomes the domain and responsibility of the individual

Leroy Hood set forth a detailed plan for the future of medicine, P4 Medicine: medicine that is predictive, personalized, preventive, and participatory. Looking for the fingerprints of health vs. disease, he envisions a future where billions of data points are investigated per individual. There could be at least four relevant data sets. One data set is the whole human genome sequence. Another could be a biannual wellness screen for 2,500 blood-based organ-specific proteins indicating possible precursors to disease. A third data set could be an immune system screen of the 10,000 B cells and 10,000 T cells, looking at the functional regions of immune receptors, and past and preset immune responsiveness. A fourth data set, in the instance of cancer, could be taking a single cancer call and sequencing 1,000 transcriptomes simultaneously to understand how cancer is expressed in particular individuals. These data sets could help to realize medicine as an information science and address the specificity of disease and wellness in individuals.

Revolutions in biology futures

Biology is continuing its progression from art to information science to engineering problem. As with many technology areas, advances in tools are driving a new era of science, and tools, science and paradigms are all evolving in biology.

DNA Sequencing
The technology for reading DNA, sequencing, is continuing to outpace Moore’s Law. Next-gen high-throughput sequencing leader Pacific Biosciences estimates their 15-minute $1000 genome solution will be on the market in 2013, more than surpassing the Archon X Prize requirements (100 people, 10 days, $10,000 per person).

DNA Synthesizing
The technology for writing DNA, synthesizing, is also extending its capability exponentially. The traditional methods involve laborious manual molecular biology tricks, oligonucleotide synthesis plus ligation, polymerase chain reaction (PCR) and polymerase assembly. These approaches have been supplanted by printing the code directly from a computer or ordering it from any of the 70 worldwide DNA synthesis foundries like Tech Dragon doing a billion dollars of business annually.

Personalized genomics and synthetic biology
The two biggest current revolutions are in personalized genomics and synthetic biology. Therapies are only in the early stages of development but personalized genetic information has the possibility of upstreaming healthcare to tailored medication and preventative interventions. Synthetic biology is using engineering to design and construct biological parts, devices and systems. The field has been developing a foundational library of standard and reliable open-source building block components; to date hundreds have been contributed to the Registry of Standard Biological Parts.

Scientific method yields to combinatorics
In any of the vast areas where biology is now an information science, empiricism and simulation are replacing the traditional scientific method. Instead of hypothesis and trial and error, nearly limitless combinations can be tested and studied for objective understanding of biological phenomena.

A more detailed look at Biology Futures is available here.