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)

Status of Stem Cell Research

The World Stem Cell Summit in Baltimore MD held September 21-23, 2009 attracted several hundred professionals to discuss contemporary science, industry and societal perspectives on stem cells. Attendance was high, but down from last year and, similar to cancer meetings, a key theme several keynote speakers acknowledged was

the overall lack of truly meaningful progress in stem cell research in the last twenty years.

Science Focus: Safe Stem Cell Generation
The science tracks featured current research in different stem cell areas including the production of safe hESC (human embryonic stem cells) and iPS (induced pluripotent stem cells) for use in regenerative medicine, the research and therapeutic use of mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) and reports from specific sub-fields: cancer stem cells, cardiovascular stem cells and neural stem cells. Overall, the work presented was incremental and in many cases, confirming what has been known already, such as a growing confirmation that cancer stem cells are probably responsible for triggering the resurgence of cancer but cannot at present be distinguished from other cells at the time of tumor removal.

Contract Research Demand: Cell Therapies and Recombinant Proteins
One stem cell area experiencing growth is contract research organizations, the outsourcing tool of choice for research labs and pharmaceutical companies in the production of biological materials. For large contract research manufacturing such as Basel, Switzerland-based Lonza, the biggest demand area is in cell therapies. Cell therapies denote the introduction of any type of new cell into other tissue for therapeutic purposes, but in the current case generally means any variety of stem cell-based therapies. Other large contract research manufacturing organizations such as Morrisville, NC-based Diosynth (owned by Schering Plough) lead in biologics (antibodies, protein production) production, an important area for nextgen biotech where synthetic biology could have a big impact.

For smaller contract research manufacturing organizations producing test compounds (e.g.; 1 liter for $10,000) and scaling to Phase I and II clinical trial quantities such as Baltimore MD-based Paragon Bioservices, the biggest demand is for recombinant proteins. Recombinant proteins are created by inserting recombinant DNA into a plasmid of rapidly reproducing bacteria and can take many useful forms such as antibodies, antigens, hormones and enzymes.

Venture capital hot topics: zinc fingers, RT PCR, tech transfer
Zinc fingers (small protein domains that bind DNA, RNA, proteins and small molecules) have been surfacing in a variety of cutting-edge biotech innovations. In July 2009, St. Louis, MO-based biotechnology chemical producer Sigma-Aldrich (SIAL) announced the creation of the first genetically modified mammals using zinc finger nuclease (ZFN) technology to execute modifications such as taking away the tail of the zebrafish. A second example of recent landmark research involving zinc fingers is that of Carlos Barbas at Scripps who uses zinc finger proteins to reprogram serine recombinases as a more specific alternative to the homologous recombination method of genome modification. In addition, the Barbas lab has a useful web-based zinc finger protein design tool available for public use, Zinc Finger Tools.

Real-time PCR offerings continue to expand and flourish with declining prices as startup newcomer Helixis announced a $10,000 real-time PCR solution at the conference.

Bethesda, MD-based Toucan Capital, a leading investor in stem cells and regenerative medicine discussed their sixteen interesting portfolio companies such as San Diego CA-based VetStem who is conducting joint and tendon stem cell therapies for race horses.

Johns Hopkins has one of the country’s leading technology transfer programs, licensing a growing number of technologies each year (nearly 100 in the last fiscal year), and has a searchable, though not extremely user-friendly, website.

Personalized genomics inflection point

One of the world’s fastest accelerating technologies is that of genomic sequencing. The first whole human genome (6 billion base pairs) was sequenced at a cost of $3b and was completed in 2003. The current cost is $20,000 for researchers (Complete Genomics) and $48,000 for consumers (with Illumina’s EveryGenome program). Leading third-generation sequencing company Pacific Biosciences affirmed at the Cold Spring Harbor Laboratory Personal Genomes meeting September 14-17, 2009 that the company has 12 prototype instruments in operation and continues to be on track for ~$100 (“the cost of a nice dinner”) whole human genome sequencing to be commercially available in the second half of 2010. NimbleGen indicated that they may have a $2,000 exome sequencer available in 2010.

In a challenging venture capital climate, Pacific Biosciences was able to close an additional $68m round in financing on August 12, 2009. Leading commercial sequencer Complete Genomics was also notable in closing a $45m D round on August 24, 2009. The company has sequenced 14 whole human genomes to date, and hopes to sequence exponentially more, 10,000, in 2010 at a minimum cost of $5,000 per genome.

Viability of DTC genomics sector
Where the genomics technology sector has rosy prognostications, the direct-to-consumer personalized genomics market has volatility. Events in the last several months have led to questions of the sector’s viability with upheavals at the three leading companies, 23andme (“Avey Leaves 23andMe to Start Alzheimer's Research Foundation Using DTC Genomics Firm's Platform"), deCODEme (“deCODE close to broke” – Augusty 11, 2009) and Navigenics (“Navigenics Names Jonathan Lord, MD to Serve as President and Chief Executive Officer” April 7, 2009). Absent innovation, DTC genomics companies are a “window business” in the sense that the window for their current offerings may only be open for a short time with the advent of whole human genome sequencing and standardized public multi-SNP condition interpretation tools.

Figure 1. Direct-to-Consumer Genomics Offerings: ongoing price declines (Chart PDF)

As depicted in Figure 1, there are three types of Direct-to-Consumer (DTC) genomics offerings currently available directly to individuals: one-off SNP (single nucleotide polymorphism) tests for specific conditions and paternity tests, multi-SNP risk assessment tests mapping several SNPs to dozens of disease conditions and whole human genome sequencing assessing hundreds of disease risks. The five companies offering multi-SNP risk assessments are: 23andme ($399 for 111 conditions), deCODEme (42 conditions for $985), Navigenics (28 conditions for $999), Gene Essence (84 conditions for $1,195) and Pathway Genomics (77 conditions for $249). 23andme, deCODEme and Navigenics are the most transparent, disclosing the specific SNPs, research references and risk assessment methodologies for their tests, Gene Essence discloses SNPs and Pathway Genomics does not disclose anything. A detailed condition and SNP analysis is here.

Slow DTC genomics adoption
DTC genomics has had slow adoption so far for several reasons, first, there has been very little marketing, few consumers know of the availability and value proposition of DTC genomics services. Second, since automated tools are not yet available, many people are not interested in preventively managing their health, and may still perceive it to be in the responsibility and domain of health care professionals. Third, the conventional but incorrect view is that genetic information is already known (from family history), negative and deterministic. Fourth, as initially pointed out by ExperimentalMan David Ewing Duncan, there are conflicting interpretations from DTC services for the same conditions such as heart attack. This is because the scientific community has little knowledge and agreement yet regarding multi-SNP conditions. DTC companies are looking at different SNPs, assigning different quantitative risk values and employing differing estimates of overall population averages which all contribute to heterogeneous interpretations of risk for the same condition.

VC guide to anti-aging biotechnology investing

Several promising startup companies focused on the nascent but obviously significant and growing anti-aging biotechnology space were present or discussed with interest at the recent SENS4 (Strategies for Engineered Negligible Senescence) conference in Cambridge, U.K., September 3rd – 7th, 2009 (program) (full conference report).

1. Epeius Biotechnologies, San Marino, CA, USA: Rexin-G, a tumor-targeted injectable gene delivery system
2. FoldRx, Cambridge, MA, USA: small molecule therapeutics to treat protein misfolding diseases, and bind and clear undesired molecules
3. Gencia Corporation, Charlottesville, VA, USA: mitochondrial DNA rejuvenation using the rhTFAM (recombinant-human mitochondrial transcription factor A) protein
4. Genscient, Fountain Valley, CA, USA: novel chronic disease therapeutics by combining genomics and selective screening (a large Alzheimer’s Disease genetic study is in progress with Kronos and TGen)
5. Knome, Cambridge, MA, USA: whole human genome sequencing (consumer offering)
6. Neotropix, Malvern, PA, USA: oncolytic viruses for the treatment of solid tumors
7. Pentraxin Therapeutics Ltd, London, UK: small molecule drug CPHPC specifically targeting SAP (serum form of amyloid P) and removing it from the blood and brains of patients with Alzheimer’s Disease
8. Repeat Diagnostics, Vancouver, BC, Canada: telomere length measurement for total lymphocyte and granulocyte populations (consumer offering)
9. Retrotope, Los Altos Hills, CA, USA: using isotope effect to slow down damage pathways and control metabolic processes associated with oxidative stress
10. StemCor Systems, Inc., Menlo Park, CA, USA: bone marrow harvesting system
11. T.A. Sciences, New York, NY, USA: telomerase activation via the single molecule TA-65, licensed from Geron Corporation (consumer offering)
12. TriStem Corporation, London, UK: retrodifferentiation technology to create stem cells from mature adult cells

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.

Synthetic biology – what is next?

Synthetic biology is the engineering of biology, re-designing existing biological systems and designing new ones, for a myriad of purposes. The most obvious killer apps are the improved synthesis of drugs and other medicines and the synthetic generation of biofuels.

Right now the most exciting aspect of synthetic biology –suggesting that the field is getting some traction – is that three key community constituents are getting more heavily involved: traditional academic researchers (SB 4.0 conference videos and agenda), undergraduates and high school students through the annual iGEM (international genetically engineered machines) competition (1200 students from 112 teams are expected at this fall’s iGEM Jamboree at MIT, and a growing group of non-institutionally affiliated enthusiasts, diybio’ers, the 2000s version of the Homebrew Computer Club, for both wetlab (an interesting recent example) and computer modeling, simulation and data management projects.

Venture capitalists are slowly starting to realize that synthetic biology could be a huge growth industry and could be the next generation of biotechnology. Amyris is probably the best-known synthetic biology company, estimating to launch its biofuel (ethanol) business publicly in Brazil and the US in 2011.

The long road to automation
Other waves in the history of biotechnology have shown that life sciences problems tend to be much more complex, take much longer than expected to solve and ultimately underdeliver results. There is no reason to think that synthetic biology would be any different, but it is obviously not futile to work on the challenges. When the synbio community analogizes their status to the heterogeneous screws and bolts of the construction industry circa 1864, they are not kidding.

The DNA synthesis process is astonishingly unautomated, unstandardized and expensive ($0.50-$1.00 per base pair) at present (it would be $15-30 billion to synthesize the full genome of a human (ignoring ethical, legal, etc. issues)).

Synthetic biology is a new field and the demand for synthesized DNA is still small; the 2,000 or so iGEM community members are the biggest market. Ginkgo Bioworks is working to deliver robotic synthesized DNA assembly and other startups would be likely to spring up in this area. Ginkgo has also helped to expand and improve one of the main synbio tools, the Registry of Standard Biological Parts.

Roadmap for Synthetic Biology

The most pressing issue in Synthetic Biology is building the groundwork to eventually advance to large-scale commercialization. How can the field’s growth from fringe to core be accelerated? A strategic plan for the Synthetic Biology ecosystem addressing academic, commercial, geopolitical and policy issues would help.

Academically, how many new bioengineering departments per year could be added? Open source course materials are available. Undergraduate and graduate bioengineering program templates including financing guidance, an industry association, faculty databases and implementation mechanisms are needed. Current academic conferences and journals could be expanded to reflect industry growth. There could be regional hands-on workshops for different levels of trained professionals and interested high-school students, similar to Math Jamborees.

Regarding enabling tools, there is a need for research and development, access ease, standardization and scale-up. Existing tools such as the PartsRegistry, OpenWetWare and Gingko Bioworks need to be taken to the next level. Academic and corporate research programs and incubators could develop a strategic roadmap for tools. An IEEE committee could be devoted to Synthetic Biology.

Commercially, there could be specific programs to involve the financing community. Venture Capital-backed SynBio Incubators could be initiated with conferences, programs, technology transfer and onsite startup incubation. Non-academic conferences, marketing and outreach programs, contests, prizes and X Prize grand challenge competitions could reside at incubators.

Safety protocols for practitioners and public discourse is a critical area for the success of Synthetic Biology. Asilomar and the Geneva Conventions could be helpful analogs for policy development.

VC life extension opportunity redux

The VC life extension investment opportunity could happen in at least three areas: first and most importantly, translational medicine, second, health social networks and third, distantly, standardized longevity treatments and delivery systems.

Translational medicine
The biggest and most obvious longevity play for VCs is in translational medicine, shepherding and commercializing science findings from basic research to patient therapies. The vast majority, perhaps even 90% or more, of basic research findings never go beyond the lab or journal publication. A particularly high profile example of an early stage longevity company that rocketed from test tube to IPO to big pharma acquisition is Sirtris, bought by GlaxoSmithKline for $720M in June 2008. Some other early stage translational medicine longevity startups are Elixir Pharmaceuticals, Juvenon and Sierra Sciences. In the plethora of remedies claiming science support, it is critical to tightly link the research evidence to the intervention. For example, in this year’s exploding brain fitness market, there is much claim of scientific support but little published clinical trial evidence.

Health social networks
Another VC play is health social networks (for example, PatientsLikeMe, CureTogether, DailyStrength, HealthChapter, Experience Project and peoplejam). Not only can patients connect and generate group-synthesized, curated and moderated knowledge, but health social networks can also facilitate the development of personalized medicine by being a repository for the quantitative data of genomics, ongoing biomarker measurements and electronic healthcare records. Big pharma can approach patient communities for field studies and clinical trials.

Longevity treatment delivery
Standardized longevity treatments and delivery programs via private clinics are not a traditional VC play, but some interesting 10x business models may be possible. In the several years before longevity treatments are more proven and automatically administered via traditional healthcare channels, these services can be provided by private clinics as they are now.

What would improve the longevity treatment market is standardization; standardization of doctor qualifications, certifications, validations, services and treatments, and treatments supported by scientific research clearly evidenced to consumers. Currently, longevity doctors offer heterogeneous suites of services which is challenging for consumers to parse. Positioned appropriately, there is more than adequate demand despite the current lack of insurance reimbursement. Since longevity treatments are currently outside the purview of traditional medicine, third party certification (for example led by the Methuselah Foundation) could help validate doctors and treatment programs, and contribute to industry standards.

Angel investors drive innovation

The Center for Venture Research at the University of New Hampshire reported that in 2007, angels invested almost as much as venture capitalists in startup companies, $26.0 billion vs. $29.4 billion. Focused on seed and startup stage financings, angels invested in far more firms, 57,120 vs. 3,813 for venture capitalists. Angel investment growth was flat in 2007 vs. 2006 while venture capital investment grew 11%. San Francisco Bay Area angel investors comprised 10% of total angel investment activity. As with venture capital, the top four categories of angel investment in order were software, healthcare, biotech and energy.

Angel investing was once a solitary activity driven by personal networks, the practice has been formalizing in the last several years and there are now over 150 angel investor groups in the U.S. and Canada. The groups typically meet monthly where 3-6 pre-screened companies present to members. Angel investors are not disengaged retirees, 80% continue to be actively involved in the business world. Cleantech and even social venture capital are starting to be interest areas for angel investors.

Angel investors are a critical component of the entrepreneurial ecosystem and should be encouraged and sponsored by communities trying to establish a more innovative environment. For startups, angels can be an important resource for funding, feedback, contacts and exposure. The contribution and impact of angel investors can be expected to grow.