Biodesign: a Prevalent Cultural Trope

A new science or technology field really starts to capture the imagination and become mainstream when it seeps into art and culture. This is increasingly evident with bioart, bioprinting, and synthetic biology.

In bioart (using biological materials to make art), there have already been several phases starting with bacteria drawings in petri dishes and more recently culminating in DNA manipulation, live cells growing into cultured shapes in galleries, and the Algae Opera (an opera singer’s CO2 producing algae in real-time for audience consumption).

Bioprinting is an emerging field which marries the 3D printing revolution with biohacking and DIYlabs in the 3D printing of designed human materials for aesthetic and functional purposes.  

Synthetic biology (the design and construction of biological devices and systems) is being featured in art shows alongside industry conferences and in film festivals, including in its own Bio-Fiction, an international synthetic biology science, art, and film festival series.

Not only are we making art with biology as an artistic material, culture is being made in new ways through biology. 

The theme of biodesign is becoming prevalent as a cultural trope through the rapid expansion of designed biology into the arts, culture, collective human consciousness, and science and technology. These ideas are becoming quite normal, which can only mean that their demise through kitschification and cliché could be coming soon in a subsequent era of anti-bioart, post-bioprinting, post-synbio!

Future of Life Sciences: Top 10 List

The next wave of the biotechnology revolution is underway and promises to reshape the world in ways even more transformative than the agricultural, industrial, and information revolutions that preceded it.

It is not unimaginable that at some point, all biological processes, human and otherwise, could be understood and managed directly.

Here is a top ten list of key areas of contemporary advance in life sciences:

1. Synthetic Biology and Biotechnology 
2. Regenerative Medicine and 3D Printing 
3. Genomics, “Omics,” and Preventive Medicine 
4. Neuroscience 
5. Nanotechnology 
6. Big Health Data and Information Visualization 
7. Quantified Self (QS), Wearable Computing, and the Internet-of-Things (IOT) 
8. DIYscience, Citizen Science, Participatory Health, and Collective Intelligence 
9. Aging, Rejuvenation, Health Extension, and Robotics 
10. Space 

More information: Slideshare talk from the Max Planck Institute

Venter's Deep Linkage: Microbiome, Synbio, Genomics, and Computing

As usual, Craig Venter’s remarks on April 16, 2013 at UC Berkeley did not disappoint - they were inspirational, informative, and demonstrative of progress. Of note is the multidisciplinarity amongst different branches of his labs’ work, for example using synthetic DNA to perform genomic error correction in stem cell operations, genome transplantation between yeast and bacterial species, and linking microbiome activities to pathology and synthetic biology/biofuel synthesis. Some key points were:

• Microbiome – YASP (yet another sequencing problem) – While the human genome is currently thought to contain about 42,000 genes, the microbiome has 10 million genes across diverse phyla, taxa, and species 
• Biofuel – to obtain engineered algae with the desired phenotype that would be a viable alternative to oil, 300 parameters must be engineered 
• Gene function – even in the minimal genome for Mycoplasma genitalium, there are 50 genes whose function is unknown 
• New gene discovery – so far in general scientific discovery, 80 million genes have been found, 95% from ocean water sampling; again in these ‘design components for the future,’ function is unknown 
• ‘Digital phenotype’ is needed for health advance and big health data stream integration – an extended EMR with standardized transmittable digital data for all manner of phenotypic data, both phenotype 1.0 (e.g.; health history, prescriptions, lab results, etc.) and phenotype 2.0 (e.g.; digital omics profiles like proteomics and metabolomics).

Longevity genomics paper retracted

On July 22, 2011, a high-profile longevity genomics paper published in Science in July 2010 was retracted. The paper, ‘Genetic Signatures of Exceptional Longevity in Humans,’ was the work of Thomas Perls and Paola Sebastiani (Boston University). The initial study had been revised per editorial concerns that arose last year, but has now been retracted possibly due to issues related to the replicatability the findings.

The revised study results were presented by the team at the American Aging Association meeting in June 2011. These data featured nine single SNP associations (versus two previously), and linked 281 SNPs to signatures for exceptional longevity (versus 180 SNPs previously). The overall conclusion remained unchanged - that

centenarians, while having the same disease mutational profiles as non-centenarians, have other specific aspects to their genetic profiles which indicate a signature for exceptional longevity

Conference report: interventional anti-aging

The focus of the 40th annual meeting of the American Aging Association held June 3-6, 2011 in Raleigh NC USA was emerging concepts in the mechanisms of aging.

Many usual topics in aging were covered such as dietary restriction (DR), inflammation, stress resistance, homeostasis and proteasome activity, sarcopenia, and neural degeneration.

Newer methods like microRNAs and genome sequencing were employed to investigate gene expression variance with aging and genetic signatures of longevity.

Aging as a field continues to mature including by using a systems approach to tracing conserved pathways across organisms, sharpening definitions of sarcopenia, frailty, and healthspan, and distinguishing interventions by age-tier (early-onset versus late-onset).

A pre-conference session on late-onset intervention concluded that there are numerous benefits to deriving such interventions.

Conference talks applied the biology of aging in a translational manner to intervention development.

• Using an individual’s own stem cells to regenerate organs for transplantation and as a cell source for cellular therapies could be a powerful near-term solution to disease.
  
• Several proposed interventions were pharmaceutical, myostatin inhibition, losartan, JAK pathway inhibitors, and enalapril for frailty and sarcopenia, and metformin to promote Nrf2 anti-inflammation response.
  
• In dietary restriction, protein restriction was found to be better than general calorie restriction. Short-term fasting may be helpful in chemotherapy, surgery, and acute stress, simultaneously increasing the killing of cancer cells by chemotherapy, while improving the survival of normal cells.
  
• Immune system interventions remain elusive, although statins may help to improve cellular-senescence promoted bacterial infection.
  
• Engineered enzymes may be useful in lysosomal catabolism.
  
• Dietary restriction mimetics, most promisingly involving TOR (TORC1 inhibition and rapamycin), may be more feasible than dietary restriction.

More details: Meeting Summary preprint.

Genomic polymorphisms trigger phantom limb pain and synesthesia

Well-known cognitive neuroscientist V.S. Ramachandran (“Phantoms in the Brain”) has been extending his original phantom limb pain research into new realms over the last several years, facilitated by the advent of new tools such as fMRI and genomic analysis.

It turns out that phantom limb pain is related to other anomalies such as synesthesia, a ‘mis-wiring’ of the senses such that stimulation to one sense results in an experience in another (for example, someone may see Monday as red). In all of these cases, there is an overabundance of neural connections in the brain. Genomic polymorphisms prevent these connections from being pruned normally.

Synesthesia is 7-8 times more common in artists, which begs the question of creativity measurement. A synesthete’s depiction of the world he or she sees may look like creativity to non-synesthetes, but is it reporting or creativity from the synesthete’s viewpoint? Synesthetes of the same type would need to assess creativity.

Android mobile app for 23andMe data

DIYgenomics released a personal genome Android app update on January 9, 2011 adding three new elements of functionality: the ability to upload and store 23andMe data in the app, multiple views for health risk, drug response, and athletic performance (Figure 1), and a quality ranking system for each SNP.

Figure 1: DIYgenomics Android mobile app view categories.

What is this information?
Selecting any item displays a list of variants or SNPs (places of potential genetic typos), such as for Alzheimer's disease (Figure 2). The locus, gene and variant (SNP) details are shown, along with the normal type (e.g.; no mutation) for 23andMe data (if it exists) in black, an individual's 23andMe data (if loaded) with normal alleles in green and mutations (polymorphisms) in red. Stars (from 1-5) indicate the research quality of the SNP (per the journal ranking of the study, the number of cases and controls, etc.). The colored blocks show which service providers cite the SNP (per color legend), and how many studies they cite.

Figure 2: DIYgenomics health condition Alzheimer's disease.

What does this information mean?
In Health Conditions, a mutation (polymorphism) presented in red generally indicated being at higher potential risk for developing a condition. In Drug Response, a mutation could mean that the normal dose of the drug may not work as well, that there could be side effects, or that there could be a higher change of addiction (for substances). In Athletic Performance, the favorable mutation (green), suggests greater than average athletic capability.

Citizen science genomics

A group of interested citizen scientists came together to explore how they could make their 23andMe personal genomic data actionable. A small (n=7) non-statistically significant pilot study was conducted looking at polymorphisms (e.g.; typos) in SNPs in the MTHFR gene and their connection to Vitamin B deficiency and high (undesirable) homocysteine levels. Four out of seven participants, though healthy, had high baseline homocysteine levels. For five of the study participants, a regular drugstore multivitamin worked best for reducing homocysteine levels. Overall, homocysteine levels were reduced 19%, commensurate with 23% reductions achieved in traditional clinical trials.

This is an important example for two reasons: the preventive medicine model and the crowdsourced research model.

1. This study illustrates one approach to the challenge of preventive medicine. Prospective tracking of genomic data + phenotypic data + interventions could help to establish baseline measures of wellness in large populations, shift health management responsibility to individuals, and potentially prevent or delay the clinical onset of conditions.
   
2. This study shows the value of crowdsourcing citizen scientists for research studies as they increasingly have access to their health information, may be willing to contribute their data to various studies, and have the interest and motivation to investigate conditions of personal relevance.

Paper: Citizen Science Genomics as a Model for Crowdsourced Preventive Medicine Research, December 23, 2010

Synbio in space

Many interesting applications of synthetic biology in space missions were discussed at the Synthetic Biology workshop held October 30-31, 2010 at NASA Ames in conjunction with the National Academies Keck Futures Initiative. Scientists from a variety of backgrounds came together to brainstorm solutions in an integrative approach. The most impressive aspect was how different areas of synthetic biology have been progressing enough to discuss ideas and techniques that could be applied to space missions in a robust way.

Environment enhancement
One of the most important areas that synthetic biology may be able to help with is in making space environments more manageable and habitable by humans. The regolith, the powdery blanket covering the moon and Mars, may likely need to be ameliorated into harder less dusty surfaces.

Biomining
Synthetic biology could be helpful in creating microbes to faster weather regolith/rock for an order of magnitude quicker release of bioessential elements such as Magnesium, Calcium, Potassium, and Iron. (related publications)

Biomaterials and self-building habitats
Synthetic biology could help to create microbes for use in building structures, both as scaffolds and by growing on scaffolds. Bacterially-generated alternatives to Portland cement (bricks made from bacteria, sand, calcium chloride, and urea) are currently being investigated, along with other plant-development inspired architectures.

New gene function
While the discovery of new mammalian genes has become saturated, the majority of newly sequenced ocean-based microbes continue to have novel gene functions. Some of these may be quite useful in space environments, for example, D. radiodurans, which can withstand significant radiation and rebuild its DNA when damaged.

Space economics – the Basalt Economy
The economics of space suggest that synthetic biological solutions might be developed more readily for space challenges, and later deployed on Earth as the technologies mature. The main constraint for space is developing in-situ solutions that are cheaper than lifting materials from Earth, as opposed to creating competitive products for Earth-based supply chains (e.g.; synthetic biofuel).

Tools
Whole human genome and metabiome sequencing, genome synthesis and assembly, and genetic design and proofing software (bioCAD) as shown in Figure 1 are all improving. A vast industry similar to that of semiconductor design and manufacture could likely develop for synthetic biology.

Figure 1: Example of SLIC/Gibson/CPEC gene sequence assembly (Source)

Rational growth in consumer genomics

The overall tone of the Consumer Genetics Show, held June 2-4, 2010 in Boston MA, was a pragmatic focus on the issues at hand as compared with the enthusiasm and optimism that had marked the conference’s inaugural event last year. One of the biggest shifts was the new programs that some top-tier health service providers have been developing to include genetic testing and interpretation in their organizations. It also became clear that the few widely-agreed upon success stories for genomics in disease diagnosis and drug response (i.e.; warfarin dosing) have been costly to achieve and will not scale to all diseases and all drugs. Cancer continues to be a key killer app for genomics in diagnosis, treatment, prognosis, cancer tumor sequencing, and risk prediction. Appropriate approaches to multigenic risk assessment for health risk and drug response remain untackled. Greater state and federal regulation seems inevitable. Faster-than-Moore’s-law improvements in sequencing costs continue as Illumina dropped the price of whole human genome sequencing for the retail market from $48,000 to $19,500.

There was generally wide agreement that from a public health perspective, personalized genomics is scientifically valid, clinically useful, and reimbursable in specific situations, but not universally – at this time, better information should be obtained for some people, not more information for all people. The focus should be on medical genetics strongly linked to disease, and on pharmacogenomics in treatment. For example, genomic analysis is required for some drugs by the FDA (maraviroc, cetuximab, trastuzumab, and dasatinib), and recommended for several others (warfarin, rasburicase, carbamazepine, abacavir, azathiprine, and irinotecan). A key point is to integrate the drug test with the guidance for drug dosage.

Even when genomic tests are inexpensive enough to be routine, interpretation may be a bottleneck as each individual’s situation is different when taking into account family history, personal medical history, and environmental and other factors. One idea was that the 20,000 pathologists in the US could be a resource for genomic test interpretation; pathologists are already involved as they must certify genetic test data in CLIA labs. Genomic tests and their interpretation would likely need to be standardized and certified in order to be reimbursed in routine medical care. A challenge is that health service payers are not interested or able to drive genomic test product design.

Key science findings

1. The Regulome and Structural Variation

Michael Snyder presented important research that the regulome, the parts of the genome located around the exome (the 1-2% of the genome that codes for protein), may be critical in understanding disease genesis and biological processes. The complexities of RNA are just beginning to be understood. It is known that there is more than just the simple transcription of DNA to RNA involved in controlling gene expression. For example, there is also tight regulation in splicing newly synthesized RNA molecules into the final RNA molecule and in translating messenger RNA to ribosomes to create proteins. Research findings indicate a global/local model of gene regulation, that there are master regulators with universal reach and local regulators operating on a local range of 200 or so genes.

Snyder also presented updates on his lab’s ongoing research into the structural variation of the human genome. A high-resolution sequencing study has been conducted regarding the amount of structural variation in humans, finding that there are ~1,500 structural variations per person that are over 3 kilobases long and that the majority of the structural variations are 3-10 kilobases long with a few extending to 50-100 kilobases (application of this research: Kasowski M, Science, 2010 Apr 9).

2. Reaching beyond the genome to the diseasome, proteome, and microbiome

Several scientists addressed the ways in which science is quickly reaching beyond the single point mutations and structural variation of the genome to other layers of information. There is a need for the digital quantification of the epigenome, the methylome, the transcriptome, the proteome, the metabolome, and the dieaseome/VDJome. For example, the immune system is one of the best monitors of disease state and progression. The strength of individual immune systems can be evaluated through the VDJome (the repertoire of recombined V-D-J regions in immune cells; cumulative immunoglobulin and T-cell receptor antigen exposure)

There are many areas of interest in proteomics including protein profiling, protein-protein interactions, and post-translational modification. A large-scale digital approach to proteomics was presented by Michael Weiner of Affomix. A key focal area is post-translational modification. At least one hundred post-translational modifications have been found, and two are being investigated in particular: phosphorylation (the signal transduction can possibly indicate tumor formation) and glycosylation (possibly indicating tumor progression).

The microbiome (human microbial bacteria) and host-bacteria interactions are an important area for understanding human disease and drug response, and for Procter & Gamble in creating consumer products. The company has basic research and publications underlying products such as the ProX anti-wrinkle skin cream (Hillebrand, Brit Jrl Derm, 2010), rhinovirus, and gingivitis. The company has a substantial vested interest in understanding the microbiome with its variety of nasal, oral, scalp, respiratory, skin, and GI tract-related products.

Genomics: progress in exomes and structural variance

The fast rate of progress in many areas of genomics was the most salient dynamic of the Future of Genomic Medicine III conference at Scripps in San Diego CA, March 5-6, 2010. Cancer genomics and pharmacogenomics continue to blossom as wide-ranging fields of applied genomics. Aging and genomics, and the role of genetics in studying disease and the microbiome are nascent and growing. Importantly coming to the forefront for the first time is structural analysis and exome analysis.

Structural analysis of genomes concerns copy number variation (multiple copies of genes), inserted genes, deleted genes, inverted genes and other structural changes, and is found in all classes of traits and disease. There is thought to be 12% structural variation between humans as opposed to 0.1% SNP variation between humans. SNP variation is the 'typos' at specific genetic locations where the normal nucleotide combination is 'AA' and some people have the risk alleles 'AT' or 'TT.”

Using exomes (the 1-2% of the genome that contains protein coding regions) as a cheaper alternative to whole human genome sequencing, and conducting basic SNP analysis together with more complex structural variation analysis, and possibly methylation analysis (which genes are blocked from expression), and RNA transcriptome analysis (levels of DNA expression), could bring more sophistication to DNA analysis for myriad purposes including pharmacogenomics and disease analysis.

Some interesting startup companies are starting to realize these new aspects of genomic medicine:

• Cellular Dynamics, Madison WI (human cells derived from induced pluripotent stem (iPS) cells)
• Integrated Diagnostics, Seattle WA (predictive blood assays of organ-proteins; UCLA melanoma clinical trial)
• Population Diagnostics, Melville NY (copy number variation analysis for pharmacogenomics)

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.

Personal genome citizen science

Enough people are in possession of SNP genotype data from direct-to-consumer genomic services (e.g., 23andme, deCODEme, Navigenics) that collaborative citizen science genomics is starting to make sense. Participants could contribute genotype data for individual SNPs or their genotype data file (600,000 – 1 million SNPs) to secure peer collaboration platforms, with different levels of permissioning to different groups of ‘gene friends.’

Personal genome citizen science could be carried out in a number of domains ranging from ancestry to health to athletic performance. Research could both replicate and extend existing academic studies and look for new associations between genomic profiles and disease. Citizen scientists could explore and identify different kinds of phenotypic data to collect and apply in attempts to make genomic data meaningful and useful. The proven benefits of opening up datasets to the wisdom of the crowds could be expected with open personal genome research too.

Personal genome citizen science examples taken from the DIYgenomics Citizen Genomes Project list:

• One fun citizen science genomics project could be applying the information in the WIRED article “Don’t tell Geico, you may be a natural born bad driver.” DIY scientists could look up their genotype value for the relevant SNP (rs6265) on the BDNF gene and match this with actual driving records.
• Another project a Silicon Valley-based DIYbio team is starting to look into is Vitamin B12 deficiency. The two relevant SNPs on the MTHFR gene, rs1801133 and rs1801131, are genotyped by 23andme and maybe also by deCODEme and Navigenics. The first step is looking up genotype values for these SNPs, (AG and GT for one participant, for example). For more information on being a peer participant in this study, please contact m AT melanieswan.com
• A third opportunity concerns the application of existing genetic association studies to peer cohorts. For example, the long-awaited results from a Boston University centenarian study were presented in November 2009. Part of this study found 18 SNPs on the ADARB1 and ADARB2 genes for RNA editing associated with centenarians. Citizen scientists could identify individuals with the favorable genotypes for these SNPs and investigate whether these people have corresponding lack of phenotypic biomarkers of aging.
• Even better than having low-cost DNA sequencing tests for consumers would be being able to self-genotype in DIYbio labs. An early example of this was Katherine Aull genotyping herself for hemochromatosis.

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.

Aging research: systems biology, genomics and new tools

Three important themes emerged from the Buck Institute’s Systems Biology Symposium of Aging held November 10-13, 2009. The themes were progress in the overall understanding of aging as a systems biology problem, the role of genomics in aging, and new tools development for aging research. Happily, some immediately applicable tidbits were discussed: the findings of the protective response of endurance exercise, and the use of resistance exercise as a countermeasure to sarcopenia. (Mark Tarnopolsky)

Theme 1: Aging is a systems biology problem
Inflammation
Increasingly, aging is being understood as a systems biology problem involving cascades of signals across multiple pathways, many of which break down with aging. In younger organisms, problems are managed automatically as they arise, but in older organisms, the resolution processes do not work as well. When cells become damaged as a consequence of aging, they can either self-destruct through apoptosis (regulated cell death) or become senescent (living on without dividing). Senescent cells persist in tissues, where they may secrete inflammatory proteins. Many major age-related diseases, including atherosclerosis, heart attack, stroke and metabolic syndrome, share an inflammatory pathogenesis. The build-up of senescent cells can lead to both degenerative disease (aging) and hyper-proliferative disease (cancer). There are some efforts underway to facilitate the removal of senescent cells, for example, using an MMP inhibitor to kill senescent cells.

Dynamic regulatory continua
It is being suggested that more and more aspects of living systems such as humans are dynamic regulatory continua, and that there may be optimum points on the continuum which become harder to maintain with aging. One example of a dynamic regulatory continuum is the interrelation of cholesterol, fats, and Alzheimer’s disease. Having lower levels of the 142 alpha-beta plaques is neuroprotective, for example, but higher levels become harmful. One technique for understanding dynamic regulatory continua is to look at explaining the events at one biological level in terms of the events at the levels above and below them. (John Tower)

Signaling pathways
There is more of an effort to examine whole processes such as pathway networks and the chain of events in DNA transcription and translation. Current knowledge of signaling pathways is fairly primitive. The role of mRNA translation is being investigated as it is known to be related to growth promoting activities like cancer. There is the general translation of RNA, but this can be further modulated by the cell. In addition, signaling pathways are not working alone, there are probably many pathways converging. For example, there is likely cross-talk between several important signaling pathways such as the insulin pathway, the TGF-beta pathway, the IGF-1 pathway, and the TOR pathway. (Heidi Tissenbaum) In another example of the systemic interactions of aging, amyloid-binding compounds were found to suppress protein aggregation models in concert with homeostatic function (i.e., autophagy, chaperones, etc.). (Gordon Lithgow)

Theme 2: The role of genomics in aging
As with many areas of biology and medicine, the role of genomics is becoming increasingly important in aging. While it is known that there is little variation (0.1%) among SNPs in human genomes, 12% of the genome may vary structurally (copy-number variations, deletions, inversions and insertions of genes). On the threshold of whole human genome sequencing, it is being realized that SNP data alone is insufficient for a genomic understanding of health; more levels of data and annotated data, potentially including RNA sequencing to see protein expression will be needed. (Mike Snyder)

Variation in genomes
Three areas of research were presented regarding genome variation and aging. First were the long-expected results of Boston University's genome-wide association study (GWAS) on centenarians. The study found 150 SNPs in the genetic signature of longevity, 33 of which meet genome wide significance and are replicated. The most important longevity genes, most already associated with aging pathways, were: IL7 (immune system), CDKN2B (tumor suppressor), and APOE, CTNNA3, TOMM40, SORCS1, and SORCS2 (Alzheimer’s disease). (Tom Perls)

Related results were confirmed by personal genomics company 23andme. A study of senior athletes found that this cohort exhibited lower risk than the database in general. Ten chronic disease conditions were reviewed including coronary artery disease, breast cancer, prostate cancer, heart attack, type 2 diabetes, high blood pressure, high cholesterol, and macular degeneration. (Joanna Mountain) However, other research found that there is not a full overlap between genes conferring longevity and genes conferring increased healthspan. (Monica Driscoll)

Variation in genomic expression
Four interesting research findings found variation in genomic expression between older and younger organisms. First, another centenarian study found significant diversity of microbial communities in different age groups. For example, there was a high level of expression of certain miRNAs in older livers (miRNA-200c, miRNA-141, and miRNA-31). (Claudio Franceschi) A second study found that a full third of genome expression changed with age in worms. (Simon Melov)

A third study found a general relaxation in translational control and protein production during aging. It was proposed that increased or sloppy protein expression might contribute to proteotoxicity. (Monica Driscoll) Applying a systems biology and network analysis approach, a fourth study looked at how the structure of biological networks declines with age. The AGEMAP (a gene expression database for aging in mice) was reviewed, finding 26% fewer edges (edge nodes on the network) in 24 month old mice vs. 16 month old mice. It is possible that gene expression networks could lose integrity with age. An unexplored but possible explanation is that if there if less transcription, then network edges disappear. (Daniel Promislow)

Theme 3: New tools development for aging research
New approaches and tools are critical to advancing the study and potential remedy of aging, and three interesting talks were presented. First, progress in microfluidics and microscopy was discussed, particularly an exceptional development in electron microscopy that may allow the noninvasive molecular-resolution imaging of live samples (Figure 1). Usually electron microscopy is a destructive technique as the electron beam destroys the sample in the process of inspecting it. (paper: Noninvasive Electron Microscopy with Interaction-free Quantum Measurements). (Fatih Yanik)

Figure 1: In vivo noninvasive molecular imaging.

Image credit: http://www.rle.mit.edu/bbng

A second area of improvement has been in the targeted analysis of specific proteins. Now that there are robust measures for mRNA, proteins and post-translational modifications are the next areas of interest. Traditional shotgun analysis techniques are being improved upon by targeted analyses of specific proteins using mass spectrometry. The process is to take a protein mixture, produce peptides through proteolysis, collect a snapshot of multiple peptides at once, and use mass spectrometry to separate them by their mass. This method greatly expands protein identification and analysis capabilities, including the ability to do time course experiments. (Mike MacCoss)

Third, a genomic database tool, PharmGKB, was presented. The database facilitates a systems approach to pharmacology. Researchers can search for pharmacogenes, for example, given a drug and putative indication, ranking all genes in the genome for the likelihood of interactions. The database contains information regarding over 500 drugs, 500 diseases, and 700 genes with genotyped variants as of November 2009. (Russ Altman)

Top 10 technology trends for 2010

Some of the freshest ideas in 2009 were botnet futures (Daemon, Daniel Suarez), a variety of neuro scanning applications (The Neuro Revolution, Zack Lynch), a systems approach to Earth (Whole Earth Discipline, Stewart Brand), accelerating economic development through charter cities (Charter Cities, Paul Romer), automatic markets for fungible resource allocation (Broader Perspective, Melanie Swan), and the notion that the next-generation of technology needed to solve intractable problems could be non-human understandable and come from sampling the computational universe of all possible technologies (Conversation on the Singularity, Stephen Wolfram).

Heading into a brand new decade, there are several exciting technology areas to watch. Many are on exponential improvement curves, although from any viewpoint on an exponential curve, things may look flat. Most of this blog’s big predictions for 2009 came true. Here’s what could happen in the next year or so:

1. Closer to $100 whole human genome
Third-generation DNA sequencer Pacific Biosciences estimates that they are still on track for a late 2010 release of single-molecule real-time sequencing technology that could eventually lead to less than $100 whole human genome sequencing.

2. Mobile continues to be the platform
There will likely be a greater launch and adoption of addictive location-based services (LBS) like FourSquare, Gowalla and Loopt, together with social networking, gaming, and video applications for the mobile platform. Continued trajectory of smartphone purchases (one in four in the U.S.). iPhone and Android app downloads double again. Gaming expands on mobiles and on the console platform with Avatar and maybe other 3-D console games. Internet-delivered content continues across all platforms.

3. 22nm computing node confirmed for 2011
Intel possibly confirming and providing more details about the 22nm Ivy Bridge chip planned for commercial release the second half of 2011. The September 2010 Intel Developer’s Forum may feature other interesting tidbits regarding the plans for 3-D architectures and programmable matter that could keep computing on Moore’s Law curves.

4. Supercomputers reach 15% human capacity
Supercomputing capacity doublings have been occurring each few years and could likely continue. As of November 2009, the world’s fastest supercomputer was the Cray Jaguar, running at 1.8 petaflops (1.8 x 10¹⁵ flops), approximately 10% of the estimated compute capacity of a human.

5. Confirmation of synthetic biology fuel launch for 2011
Pilot plants are running and the commercial launch of the first killer app of synthetic biology, synthetic fuel, could be confirmed for 2011. Sapphire Energy and Synthetic Genomics are generating petroleum from algal fuel; LS9, petroleum from microbes; Amyris Biotechnologies, ethanol, and Gevo, biobutenol.

6. Smart grid and smart meter deployment
In energy, more utilities moving to deploy internal smartgrid network management infrastructure and starting to replace consumer premises equipment (CPE) with advanced metering infrastructure (AMI) for automated utility reading and customer data access. Dozens of efforts are underway in the U.S. (Figure 1).

Figure 1: U.S. Smart Metering Projects Map as of Jan. 2010

7. Increased choice in personal transportation
More electric vehicle offerings, greater launch of alternative fuels, a potential Tesla IPO announcement, and more widespread car share programs (i.e., City CarShare, Gettaround).

8. Real-time internet search dominates
More applications allow real-time search functionality through content aggregation, standards, and more granular web searches. Search could be 40% real-time, 40% location-based, 20% other.

9. Advent of health advisors and wellness coaches
Hints of personalized medicine start to arrive with the unification of health data streams (i.e., genomics, biomarker, family and health history, behavior, and environment) into personalized health management plans. Early use of health monitoring devices (i.e., FitBit, DirectLife) as a prelude to biomonitors.

10. WiMax roll-out continues
Clear adds more markets to its current 26. Increasing importance of integrated data stream management (video, voice, etc.) on fixed and mobile platforms.

Probably not happening in 2010 but would be nice…

• Kinko’s buys high-end 3-D printer (i.e., ZPrinter 650 or Dimension Elite or uPrint) and DIY product design communities go professional (i.e., Shapeways, Ponoko)
  
• Nanotechnology demonstrations of mechanical synthesis and positional assembly

Still waiting for significant progress regarding…

• 4G/LTE roll-out
• Driverless cars, on-demand personal rapid transport systems
• Ubiquitous sensor networks
• OLEDs

Genomics – The Global Opportunity

Genomics is particularly interesting as a candidate area for possibly making the most difference the most quickly to the most people worldwide by contributing to developments in energy, food and public health.

A full understanding of genomics, the instruction set for life, could mean a more comprehensive ability to manipulate both the world around us and the world within us. Biology evolved to be just good enough to survive and genomics provides the critical next-generation toolkit for its greater exploitation. With the possibility of a complete understanding of biology and the ability to engineer life to be optimum, traditional limits can be overcome, moving from the gene therapies of today (replacing or silencing one gene) to working with whole genomes and possibly creating new ones.

The global challenge and opportunity is for humanity to move safely and expediently into the genomic era of biological manipulation.

The agricultural applications of genomics have been underway for some time in the form of genetically-modified crops. Energy applications of genomics are in development using synthetic biology to generate fossil fuel replacements and are estimated to be ready for commercial launch in 2011. The public health application of genomics is especially promising, using genomics to further understand and eradicate disease. Genetic information is already starting to be medically actionable and is likely to become increasingly useful over time. Its two main current uses are in pharmacogenomics, personalized therapeutics, categorizing drug responders and non-responders for tailored treatment, and in routing higher-risk individuals to earlier screenings for chronic diseases such as prostate cancer and breast cancer. It is estimated that each individual is in the upper 5% risk tier for at least one chronic disease and that $100,000 per person per condition could be saved as a result of earlier detection. By 2010, according to a World Health Organization (WHO) report, cancer will surpass heart disease as the world’s greatest killer, and in fact, developing countries could be at the highest risk due to smoking and high-fat diets.

As our molecular understanding of disease progresses and genomic technologies continue to decrease in cost and become increasingly medically relevant, the use of genomics could become quite widespread. Physicians could start to see the precise, additive information conferred by genomics as a means of improving the care now delivered, finding themselves initially encouraged and eventually regulated into incorporating genomics in care regimens. Pharmaceutical companies are already using genomics as a means of improving efficacy in drug discovery and delivery, providing much-needed assistance to their ailing cost structures. Individuals worldwide could have unprecedented access to their health information which could prompt a much greater level of responsibility-taking and health self-management.

Preventive Medicine and Docs vs. Genomics

Despite NIH Director Francis Collins’ strong support of personalized genomics (he claims he lost 15 pounds after finding out through direct-to-consumer genetic testing that he is at higher risk for Type 2 Diabetes) and noting that the only way to successfully transition to the genomic era is with a skilled professional work force, doctors are taciturn about embracing genomics, and rarely try it even when it is made available to them and their patients for free (less than 5% uptake in a recent example with El Camino Hospital and DNA Direct making genomic testing available to 1000 physicians).

Top 10 reasons doctors will probably not be the ones implementing genomic data in patient care, in rank order. Physicians...

1. think they have to be the domain experts of any health area they direct for patients and are too constrained, unwilling or unable to be a genomics domain expert
2. do not see the clinical utility of genomics
3. have the attitude that genomics is optional, not required
4. have a precedent for non-adoption of preventive medicine tools as evidenced by slow uptake of molecular diagnostics
5. driven by liability, malpractice fears
6. self-direct per insurance non-reimbursability
7. believe genomics overconsumes scarce medical resources
8. are already cost, time, new knowledge acquisition constrained
9. are resistant to change and enjoy autonomy in directing their own practices
10. do not have specific tools for implementing genomics in their practices

Number one reason physicians would adopt genomics:

1. if their peers did

Physicians are intelligent and could easily adopt genomics
In reality the way that genomics adoption unfolds in the traditional health care system could be straightforward. Once regulated, physicians would have no choice but to adopt. Whole human genomes would be on file in patient Electronic Medical Records (EMR) and genomics tests could be a few more items on the standard blood test menu where primary care physicians interpret results within quantified ranges. Even though physicians are spending on average only 12 minutes with each patient per year in the US, they are required to spend 100-200 hours per year on Continuing Medical Education, and being quite intelligent, could easily master the basics of delivering genomic medicine.

Best quotes from the September 2009 National Coalition for Professional Education in Genetics (NCHPEG) meeting:

• “Not only is genomic data useless, educating physicians about genomic data is useless”
• “Learning about genomics might be useful to my practice, so would speaking Spanish, but I’m not going to do it”

Solution: new care provider tier for Preventive Medicine

The disincentives to physician adoption of genomic medicine are really part of the bigger issue of how societies are going to shift to preventive medicine in general.

The traditional health care model of physicians and insurance companies is probably not going to deliver preventive health, a new tier of care providers, entrepreneurs, is.

Figure 1. Future Health

Image: MS Futures Group, Oct. 2009

A model for the future of health care is presented in Figure 1. The patient is at the center, increasingly taking responsibility for managing their own health. Easy-to-use tools, both devices and web-based software, could provide the first shell of actionable health information to individuals. Over time (decades), there is no reason that the primary care provider could not be superseded by automated health monitoring tools.

New Era Preventive Care Specialists: the Health Advisor
The next preventive medicine shell is the new tier of health care providers. When consumers say “I have my genomic data, now what?” traditional doctors say, “I have no idea what to do with that” or “That is not clinically useful,” but the New Era Preventive Care Specialists do not. They show what to do with personalized data by using genome-in-the-cloud browser tools to make genomic data intelligible and actionable. They incorporate genomic data, together with family history and current phenotype and biomarker data into an overall care plan (when is Keas finally going to launch? what about Omicia?), with a systemic approach (when will Entelos license their virtual patient technology to consumer-pointing applications?).

The Health Advisor (analagous to the Financial Advisor) could be one of the fastest growing new job areas. The business model may be traditionally trained experts in general medicine, genomics, nutrition and sports medicine coming together in private clinics to work in the new paradigm of exploding volumes of digitized health data (both health metrics collected daily and genomic, transcriptomic, etc. data) together with EMRs. One first service could be EMR assembly where patients own and control the data. Other services could include all manner of personalized health plan creation and monitoring. Anti-aging treatments would be another logical area for inclusion.

Health Savings Account (HSA) Dollars
Accustomed to the third-party pay model, consumers may object to paying for medical services (although they do shell out several billions of dollars per year for weight-loss products) but instead of paying directly out-of-pocket, it is quite possible that preventive care services could be purchased with pre-tax HSA dollars, as more than half of U.S. large-company plans may be offering as an insurance option. This marketing point that should not be lost on the new era of preventive health providers.

Health Literacy Toolkit

With one key life sciences focus shifting to health as opposed to healthcare (as HealthCamp founder Mark Scrimshire exhorts) and to preventive, predictive health management as opposed to therapy and treatment, there should be the concept of a health literacy toolkit that would be a component of standardized knowledge, such as how to write, drive or get a job.

Definition of health literacy
Surprising but emblematic of the traditional health mentality (e.g.; treat illness) is the prevailing definition of health literacy…”a patient’s ability to acquire and understand information about a condition and options once diagnosed…” Moving into the preventive era, the definition of health literacy needs to shift from being backward-looking to forward-looking. Having health knowledge ahead of time could inform behaviors to prevent, slow or lessen the development of disease. Health literacy should be a general set of knowledge for everyone to know, not related to a condition once a patient has it.

Gap between health literacy and demand for health information
A U.S. Department of Health and Human Services (HHS) study finds that only 12% of adults have proficient health literacy (p. 26); that nearly 9 out of 10 adults may lack the skills needed to manage their health and prevent disease.

The biggest reason for low health literacy could be a lack of appropriately accessible and presented health information.

A Pew Internet Study “The Social Life of Health Information” in June 2009 finds that 61% of U.S. adults are looking for health information online. The gap between health literacy and the demand for health information suggests that there is a substantial opportunity for a range of health information services and management tools, many of which could be fee-based such as the LIVESTRONG nutrition and exercise management program.

Health literacy toolkit
What should be the components of a standard health literacy toolkit? Many professionals (e.g.; physicians, academicians, etc.) believe that even HDL/LDL cholesterol information is too complicated for the lay public, but this just cannot be correct. When simple numeric information is presented clearly, people of any background and capability are often quite able to understand it and take action. For example, when utility bills started to provide straightforward quantitative data regarding power consumption, including day/night usage and costs, many people shifted their behavior in a positive informed way.

Figure 1: Ongoing Total Cholesterol readings for one individual

Figure 1 illustrates an example individual’s ongoing total cholesterol readings presented in a clear and informative way. Anyone inspecting the chart can easily identify the overall trend, down, which is good, wonder about the range of numeric measurements (157-185) vs. the average and how this translates into good or bad health tiers (e.g.; under 200 is generally good, but a rising trend that is still under 200 could be an indication of arising health issues for that individual), and inquisitively wonder about the peaks. The next level of information would be HDL and LDL readings, small lipids as is now de rigueur and triglycerides, but even this simple plot of total cholesterol measures is understandable, useful and potentially actionable. It is also the perfect level of information for individuals who are interested in being responsible for self-managing their health but from an efficient, easily-actionable level that does not require deep engagement of time or knowledge acquistion.

Some of the most obvious aspects to include in a health literacy toolkit would be nutritional information and its interpretation, caloric consumption and expenditure and ongoing quantitative measures of health from blood analysis and other tests (e.g.; blood pressure, glucose, cholesterol, BMI, weight, VO2 max, etc.). The data can be summarized (with detail available) and directly linked to actionable explanatory information (e.g.; measures may go up or down if they were not measured at the same time or situation, for example if a meal had been eaten before some but not all of the measurements). Other components of a standard health literacy toolkit could include where and how to obtain information and tools for self-tracking, how to integrate multiple data sources into a unified view, and how and what to expect when interacting with the medical community. Genomics is already part of the health literacy toolkit for early adopters and could become a standard toolkit component for everyone within five years, already helpful Genetics 101 sites are emerging.

Automated health monitoring tools
Health-self management in large quadrants of the population could accelerate with the advent of automated health monitoring tools that would capture frequent datapoints and aggregate the information into easily viewable web-based charts. Many devices such as blood pressure monitors, heart monitors and scales are now battery-intensive Bluetooth-enabled which is a nice intermediate step but what is really needed is for all of these monitoring devices to be directly on home WiFi networks. Where possible, having the monitoring applications directly on the smartphone is another obvious step rather than having separate devices. There are some WiFi-enabled devices, for example the FitBit calorimeter, which has been delayed in launching, and glucose monitors such as the GlucoMON, however its $75/month subscription fee appears exorbitant.

Genomics: highest-impact near-term advance

Genomics is making faster progress than any other technology in recent history. Usually the vista from any point on an exponential curve looks flat to the experiencer but not so with consumer genomics, the field is exponentiating from any vantage point. Genomics scientific research and commercialization issues were discussed with excitement at the first-ever consumer genomics conference in Boston, June 9-11, 2009. (A PDF of this blogpost is available here.)

Summary

1. Advent of the whole human genome: Automatic whole human genome sequencing of all individuals could likely be a reality in the next few years
   
2. Medically actionable now: Genetic data is medically actionable now and becoming increasing more so, particularly in routing higher-risk individuals into earlier screening. It is estimated that each individual is in the upper 5% risk tier for at least one chronic disease.
   
3. New ICT era (information and communications technology): Genomic data requires a significant new level of information processing, storage and transfer. One whole human genome can range from 6GB-8TB in terms of the data currently transferred between researchers.
   
4. Social inevitability: Widespread genomic sequencing appears to be inevitable which has great benefits together with social challenges such as revealing non-paternity (10-15% in the U.S.), terminal disease conditions and reproductive issues (e.g.; recessive carrier status).
   
5. Heightened role of the consumer: Consumers will have unprecedented access to health information about themselves and could take a much more active and self-directed role in their health management, more likely responding favorably than being consumed with their ‘incidentalome.’
   

Genetic tests – what is now available

Physician-ordered tests (generally insurance-reimbursed)

• For some time, physicians have been ordering any number of one-off genetic tests for specific conditions such as Cystic Fibrosis, Huntington’s Disease, breast cancer (mutations in the BRCA1 and BRCA2 genes) and other conditions. Physicians can also order any of the below tests for patients.
  

Consumer-ordered tests (no doctor-order required, unreimbursed)

• Single condition tests (DNA Direct, $200-1,000)
  
• SNP Chip risk assessment tests (23andme ($399, down from $1,000), DeCODEme ($985), Navigenics ($2,499))
  
• Whole genome scan (Knome ($99,500)) or whole exome scan (Knome ($24,500)) [The price just dropped from $350,000 to $99,000, but it would still seem silly to purchase now when a few more zeros might drop off within months]
  
• Personal Genome Project (PGP), Harvard Medical School, genome sequencing for free in exchange for open data publishing, now expanding from ten subjects to 100,000
  
• Family planning genetic screening: Counsyl
  
• Mate compatibility analysis based on immune system variation: ScientificMatch, GenePartner (The next obvious component would be including recessive disease carrier status in the back-end matching algorithms of dating services)

Out of work due to technological advance:

elevator operator, stock broker, physician(?)

Current genomic testing issues: validity and utility
Validity
There are differing levels of data validity depending on which chip array and methodology is used to sequence the genomic data. Illumina reports being at two 9s now (e.g.; 99.99% error free; experiencing one error per 1,000 reads) and is hoping to move to four and then six 9s of quality. Sequencing is done at different levels of coverage ranging from 1x to 30x coverage, meaning how many times a sequence is read; 30x coverage is the most accurate and highest industry standard at present.

A few people who have tried multiple DTC (direct-to-consumer) SNP chip offerings have found consistent genotyping data (e.g.; having a ‘CT’ at a certain SNP), but different interpretations in lifetime risk probabilities as different markers are evaluated and rolled up into risk assessments across the companies. The risk of false negatives and false positives abounds.

Direct-to-consumer genomic testing companies:

Heterogeneous breast cancer markers assessed

Sources: Navigenics, DeCODEme, 23andme

Not only do different services map different markers to meta conditions like cardiovascular disease, but the most relevant medical SNPs are often not included in DTC SNP chips, probably due to patent and cost issues. A notable example is Myriad, which owns patents on the breast cancer-related BRCA1 and BRCA2 genes. This has become the focus of a timely lawsuit brought by the ACLU regarding the patentability of natural materials such as genes and industry norms of how genes are licensed for diagnosis and therapy.

Whole human genome sequencing renders the patented-gene issue moot as anyone having access to their raw data could look up their genotypes for particular SNP/rsid numbers such as those corresponding to the BRCA1 and BRCA2 genes. (Knome customers can do this now). There will be a need for interpretation tools appropriately aggregating multiple risk alleles. Fee-based or open source genomic data interpretation tools like the SNPedia’s Promethease report could proliferate.

Utility

People would like to know definitively if they are going to have a disease but aside from monogenic conditions (for example, Muscular Dystrophy, Huntington’s Disease, sickle cell disease and Cystic Fibrosis), most chronic diseases are polygenic and influenced by many factors. The current genetic testing for these conditions does not deliver a simple Yes/No, but rather assesses the lifetime risk probability for an individual and whether the individual is at higher or lower risk than the average.

There is ample room for risk interpretation mechanisms for polygenic conditions to become more sophisticated, right now the practice is a multiplicative technique, taking the risk value for each genotyped allele associated with the condition and multiplying them together; weighting and cluster-evaluation would be obvious refinements that research may support over time.

Genetic variation and disease causality
NHGRI and other GWAS (genome-wide association studies) researchers find that genes, as they have been studied so far, only account for a small percent of explaining disease. However, studies have been preliminary, the 1,000 genomes studied may not be enough for complete understanding, for example, about 35 common diseases have been found to have widely replicated common variants. One next step targeted by the NHGRI is to look at rare variants, low-frequency (e.g.; 1-2%) GWAS variants with intermediate penetrance, to possibly explain a larger percentage of disease causality. Simultaneously, our systemic understanding of biology is slowly improving, it seems that in many disease cases it may not be the gene or genotype, but rather the number of copies of the same gene (CNVs), translocations, inversions, and other problems with gene expression and DNA repair that are responsible for disease.

Knowledge gap
Genomic technology has been moving so fast that at present, most physicians do not have genetic training. The genetics community is the primary party helping to generate, interpret, present and monitor genomic data. Over time, other communities like physicians and genetic counselors (one of the world’s fastest-growing job categories) will hopefully become helpful in interpreting data together with patients. Genetic training is a key target area of CME (continuing medical education), for example the National Coalition for Professional Education in Genetics' "Genetics Education for Health Professionals: What are the Key Messages? How do we deliver them?” (Sep 2009) and Harvard Medical School’s “What the Primary Care Provider needs to know about the Genetic Basic of Adult Medicine” (Oct 2009).

Medical relevancy
That disease has a molecular basis is now undisputed and medicine is slowly shifting to reorganize around this. Presently, 1,400 genes can be tested to inform various clinical decisions, and 225 are deemed clinically significant. 100 new tests are being added annually. In some cases, medical information exists but is not being used, for example a straightforward marker for poor drug metabolizers, CYP2D6. About 10% of Caucasians are poor metabolizers however this is not routinely tested for ahead of time (nor in the DTC SNP chip tests mentioned above) and the same drugs are given to all patients in a trial and error process, sometimes in lower doses (e.g.; warfarin) due to fear of overdosing those for whom it could be harmful.

Another example of medical relevancy in genomic testing is the NHGRI’s GWAS study finding of the first nine genetic risk variants for type 2 diabetes: TCF7L2, IGF2BP2, CDKN2A/B, FTO, CDKAL1, KCNJ11, HHEX/IDE, SLC30A8 and PPARG; particularly the first one, TCF7L2. Higher-risk individuals identified early in life could receive targeted healthcare.

Additive statistical approach
So far, general genomic testing suggests that on average, each patient is in the upper 5% risk tier for at least one chronic disease (e.g.; cancer, cardiovascular disease, myocardial infarction, etc.) and that there is value in understanding genomic risk factors earlier in life. Whole human genome sequencing automatically at birth could mean a lifetime of personally relevant healthcare.

Although genomic tests do not predict polygenic disease definitively, they are medically actionably in taking conventional risk percentages (e.g.; American female lifetime breast cancer risk = 12%; American male lifetime prostate cancer risk = 16%) and layering on the specific genetic risk of the individual to route higher-risk individuals to screening and therapeutics earlier. Several researchers estimate that the earlier identification of higher risk patients could reduce overall healthcare costs by about ~$100,000 per person per condition.

Patient behavior: a key component of medical actionability
Although there is no known cure for Alzheimer’s Disease, and even a firm diagnosis can only be made at autopsy, Boston University’s REVEAL study has shown that people do change their behavior after receiving a positive diagnosis for Alzheimer’s Disease (mainly through purchasing supplements and some increase in exercise). It is also known that mid-life cholesterol levels correlate with Alzheimer’s Disease, so the highly actionable behavior for someone with an APO E4 positive allele could be more closely managing cholesterol intake.

Family history
The role of family history is another important component of disease prevention, diagnosis and management, and there are starting to be helpful web-based tools for consumers to assemble, manage and access family history data such as My Family Health Portrait.

Technology status
Technology advance has been the key enabler of the genomics revolution. The first genome sequencing project, completed in 2003 cost $3b. Now, the cost of genetic sequencing is dropping to the point where a $100 whole human genome may be available in the next few years, in 2010 according to Pacific Biosciences. There are several next-gen sequencing platforms in process now to supercede the current array-based method.

Next-gen sequencing platforms
Next-gen genomic sequencing platforms are generally falling into two categories, those using synthesis (specifically multiplex cyclic sequencing by synthesis) and those not using synthesis. Some of the most interesting next-gen companies using synthesis are Pacific Biosciences, Ion Torrent Systems and RainDance Technologies. Some of the most exciting non-synthesis-based next-gen sequencing companies are Oxford Nanopore Technologies, and NABsys and Halcyon. NABsys and Halcyon are electromagnetically-based rather than optically-based which means they are not dependent on light or fluorescence so the cameras can go much faster, perhaps 10,000 frames per second. Harvard Medical School maintains a nice overview of current and emerging gene sequencing technologies.

Transcriptome, proteome, metabolome, microbiome…
In addition to improving the cost and speed of existing genomic scanning, sequencing advances could open up the way to the eventual characterization of the whole cell and its interactions through the sequencing of the transcriptome, the proteome, the metabolome, the microbiome and other biological features. In the farther future, histone modification sequencing, DNA methylation, acetylation and phosphorylation are other characterization processes of interest that could be included.

Petabyte data era: processing, storage and transfer challenges
The biggest challenge consuming national genomic research labs at present is data processing and network communications. Genomic data is growing at 10x per year (vs. Moore’s Law growing at 1.5x per year). Research labs have problems with data storage, mapping and access, together with intra-site data transfer and external transfer. Shipping terabyte drives via fedex is the best current data transfer method, and at least one lab finds resequencing data cheaper than storing it.

The raw data of the 6b base pair whole human genome is 6GB, not challenging to store, but challenging to work with, it is not like just opening up and manipulating a word document. New data processing algorithms will need to be developed to interact with whole genome data, link it to reference tools and make it searchable and meaningful. Whole businesses can be formed to focus on genomic data curation alone (a second wind for Google?).

Even though the most basic raw data version of the whole human genome is 6GB, the full collection of files in use by researchers for one whole human genome may reach 8TB. The full works may include an intensity file, a BAN file (binary), a SAN file (searchable) and other files with coordinates, variations and other aspects. Part of the challenge is that appropriate data abstractions from the raw sequencing output are not yet known so all the data is kept. There is not yet a good reference model. Apparently, the Archeron X-Prize for genomics (sequencing 100 human genomes within 10 days or less at a maximum cost of $10,000 per genome) remains outstanding not because it cannot be done, but because the results cannot be recapitulated.

Testing inevitability and social implications
It seems quite possible that initial and ongoing whole human genome sequencing (and eventually, on-demand proteome, metabalome, microbiome, etc. sequencing) would be a routine component of everyone’s EMR (electronic medical record) available to both patients and physicians for ongoing predictive, preventive healthcare monitoring. There are some important social implications of widespread whole human genome testing, for example:

Non-paternity
One genetic issue is non-paternity (studies suggest 10-15% is the ongoing rate of non-paternity in the U.S.). In the era of whole human genome sequencing, paternity would be quite easy to trace. One possible impact is that the divorce rate could increase and single mothers could be stratified into lower economic tiers.

Right not to know
Another genetic issue is that of a person’s right not to know about their medical situation. With improving remedies, the right not to know becomes a lot less important. Also it may be quite straightforward for practitioners to deliver healthcare without breaching the patient’s right not to know their genetic information as they do currently. With more actionable treatments, it could become the social norm to know your genetic profile, to learn about potential conditions and work collaboratively with others with similar conditions in attempts to mobilize long-tail medicine, as PatientsLikeMe health social network participants are doing to run their own clinical trials.

Discrimination
GINA, the Genetic Information Nondiscrimination Act of 2008, protects U.S. citizens from discrimination by employers and insurance companies. It is a step in the right direction, but many are not reassured. The law has some holes, such as not covering long-term care providers, and will have to be strengthened via interpretation as real-life cases arise.

DNA Forensics – Gattaca?
In an age of inexpensive genomic testing, the on-demand testing of other people (such as a prospective mate, business partner, supervisor or tenant), as portrayed in the movie Gattaca, could easily occur; one such example provided decisive evidence in a recent divorce case. DNA privacy would become impossible as a practical matter. DNA privacy would become impossible as a practical matter. However, precisely because everyone would be subject to genetic openness and since the present world is not one of scarcity and control as the dystopian Gattaca, it may be that DNA testing and knowledge would not be a substantive issue. Already, several individuals in support of hastened scientific advance and open medicine have open-sourced their genomic data on the SNPedia or via the Personal Genome Project.

Venture capital investment opportunities
There are many exciting potential opportunities for venture capitalists, entrepreneurs and researchers in helping to realize the genomics revolution. The money is already arriving before the physicians as companies, backed by varying degrees of research, seek to monetize genetic risk. The potential demand for personal genomic products and services could be enormous, for example, the marker for weight-loss products is a $40b/year. Here are some potential opportunities:

• Personalized genetic testing, counseling, supplements and other action programs and remedies, for example, Inherent Health’s Weight Management, Heart Health and other tests, and the APO E Gene Diet.
  
• More DTC (direct-to-consumer) genetic testing and interpretation offerings stratified towards differing enduser tiers (e.g.; the aggressive early adopter, the lay person, the Boomer, the Gen Y’er)
  
• A line of genomic testing services to be offered by spas and private clinics; positioned as a luxury item vs. a medical necessity to accelerate adoption
  
• Next-gen sequencing, and next-next-gen sequencing, innovating the technology and the applications to commercialize the technology
  
• Web-based tools for integrating medical records, family history and genomic data, facilitating data collection, entry and access
  
• Genetic literacy products and services for physicians and consumers
  
• Web-based tools to appropriately and dynamically aggregate multiple risk alleles into chronic disease meta conditions such as cancer and cardiovascular disease
  
• Fee-based genomic data interpretation tools like the SNPedia’s Promethease
  
• Data processing algorithms to interact with whole genome data, making it searchable and meaningful with links to external reference databases
  
• Genomic data curation
  
• Cloud computing for genomic data analysis
• Health social networks or other tools for deep longitudinal monitoring over time by consumers/patients of many complex health factors
  

Conclusion
As our molecular understanding of disease progresses and genomic testing continues to decrease in cost and become increasingly medically relevant, adoption could become extremely widespread almost overnight. Physicians could start to see the additive, precise information conferred by genomic testing as a means of improving the care they now deliver, finding themselves initially encouraged and eventually forced into the genomic revolution. Pharmaceutical companies could start to use genomic testing and pharmacogenomics as a means of improving efficacy in drug discovery and delivery, providing some much-needed assistance to their ailing cost models. Consumers could be radically empowered to become curious about and responsible for self-managing their health with automated easy-to-use tools. Genomics as an enhanced approach to healthcare could transform the quality of life worldwide for all humanity.