The biomolecular interface and the definition of living

Definitional and classification issues often arise in any field of heightened focus and progress (e.g.; what is a planet?). For the many fields integrating organic and inorganic materials, an interesting issue comes up as to what is the definition of life. Many different gradations of living things are emerging.

Some interesting new cases of living materials are the idea of organic sensors made of biomaterial placed on buildings, self-replicating crystals and biological scaffolding for stem cell grown organs and 3D tissue printing.

De novo materials synthesis
One exciting aspect of the living/non-living classification is the new synthesis of both organic and inorganic materials. Scientists are creating de novo engineered proteins and other biological materials, non-naturally occurring inorganic materials with superior properties using molecular manufacturing techniques and hybrid organic-inorganic materials, with the best of organic and inorganic properties in one object, for example rotaxanes which could be used in quantum computing.

Definition of integration
Not just the definition of what is living arises, but also the definition of the integration of organic and inorganic materials. Alan H. Goldstein proposes that a true integration of organic and inorganic material involves communicating back and forth, not just a system which has properties or components of both organic and inorganic systems.

The future of biomolecular interfaces

The future of biomolecular interfaces is probably a further blurring of the underlying substrates as the focus is more relevantly on the properties and requirements of any challenge at hand.

Ethics of the future: self-copies

Just as the future of science and technology is rife with legal opportunities and psychological study possibilities, so is it with ethical issues. One interesting example is the case of individuals having multiple copies of themselves, either embodied or digital.

1. Can I self-copy?

The first issue is how different societies will set norms and legal standards for having copies. The least offensive first level would be having a backup copy of mindfiles for emergency and archival purposes, much like computer backups at present. People take pictures and videos of their experiences, why not of their minds? The other end of the extreme would be the most liberal societies allowing all manner of digital and embodied copies. The notion of regulating copies brings up an interesting potential precedent, that currently, the creation of children is largely unregulated on a global basis.

2. When and where can I run my self-copy(ies)?

A second issue is, given copies, under what circumstances can and should they be run. A daily backup is quite different from unleashing hundreds of embodied copies of oneself. Physically embodied copies would consume resources just as any other person in the world and there would likely be some stiff initial regulations since national population doubling, trebling or more overnight would not likely be a useful shock to society. Not to mention the difficulty in quickly obtaining and assembling the required resources for a full human copy; despite the potential advances in 3D human tissue and organ home printers by then.

Digital copies is the more obvious opportunity for running self-copies and could be much more challenging to regulate. In the early days, the size and processing requirements of uncompressed mindfiles would likely be so large that a runtime environment would not be readily available on any home machine or network but would rather require a supercomputer.

3. Am I a copy?

A third interesting problem is whether it would be moral for copies to know that they are copies, and the related legal issues regarding memory redaction as explored in Wright's "Golden Age" trilogy. Depending how interaction between originals and copies is organized, it may not matter. Psychologically for the originals and the copies, it may matter a lot. The original may 'own' the copies or the copies may have self-determination rights. In the case of an embodied copy, it is hard not to argue for their full personhood but somehow a digital instance seems to have fewer rights, although it may come to be that shutting down an instance of a digital mind, even with a recent full memory backup and integration, is just as wrong as a physical homicide.

Interesting ethical issues could arise for originals and copies alike as to what to share with the others; should horrifying experiences be edited out as Brin's Kiln People do at times? There would be both benefits and costs to experiencing the death of a self-copy, for example. It would not seem ethical to make self-copies explicitly for scientific research purposes to garner information from their deaths, but it does seem fully ethical to have multiple self-copies for with different life styles, some healthier and some less healthy to investigate a) whether a healthy life style matters and b) to selfishly share exciting experiences from less risk averse copies back with the longer-lived healthier copy.

Indeed in the new medical era of a systemic understanding of health and disease where n=1, what better control examples to have than of yourself! However, epigenetic mutations and post-translational modifications may be much harder to equalize across copies than memories and experiences.

The issue of the definition of life arises as some people may want the abridged meta-message or take-away from experiences, indeed this is one of the great potential benefits of multiple copies, while others may wish to preserve the full resolution of all experiences. The standard could accommodate both, with the summary being the routine information transfer with the detail archived for on-demand access.

4. What can I do with my self-copies?

Societies might like to attempt to establish checks and balances to prevent originals from selling copies of themselves or others into slavery to reap economic benefits, as dystopially portrayed in Ballantyne's "Capacity". Especially in a potential realm of digital minds, there are many potential future challenges with rights determination and enforcement.

The 'AI abdication' defense is the argument that societies that are sufficiently advanced to have the ability to run self-copies would also have other advancements developed and in use such as some sort of consciousness sensor identifying existing and emerging sentient beings and looking after their well-being, a beneficent policing. There are numerous issues with the AI abdication defense, including its unlikely existence from a technical standpoint, whether humans would agree to use such a tool, whether a caregiving AI could be hacked and other issues. However, technology does not advance in a vacuum and society generally matures around technologies so it is likely that some detriment-balancing counter initiatives would exist.

For example, would it be moral to create sub-sentient beings as sex slaves or personal assistants? This may be an improvement over the current situation but is not devoid of moral issues. At some point, as more about consciousness has been characterized and defined, a list of intelligence stratifications and capabilities could be a standard societal tool. Animals, humans and AIs would be included at minimum. A future world with many different levels of sentience seems quite possible.

Next-gen computing for terabase transfer

The single biggest challenge presently facing humanity is the new era of ICT (information and communication technology) required to advance the progress of science and technology. This constitutes more of a grand challenge than do disease, poverty, climate change, etc. because solutions are not immediately clear, and are likely to be more technical than political in nature. The raw capacity in information processing and transfer is required and also the software to drive these processes at higher levels of abstraction to make the information useable and meaningful. The computing and communications industries have been focused on incremental Moore’s Law extensions rather than new paradigms and do not appear to be cognizant of the current needs of science, and particularly the magnitude.

Computational era of science
One trigger for a new ICT era is the shift in the way that science is conducted. The old trial and error lab experimentation has been supplemented with informatics and computational science for characterizing, modeling, simulating, predicting and designing. Life sciences is the most prominent area of science requiring ICT advances, for a variety of purposes including biological process characterization and simulation. Genomics is possibly the field with the most ICT urgency; genomic data is growing at 10x/year vs. Moore’s Law at 1.5x/year for example, however nearly every field of science has progressed to large data sets and computational models.

Mindfile deletion

How do you know that your mindfile will not be deleted, either on purpose or by accident? What would you do if your mindfile is stored in memory and not allowed to run? How would you know that you are not being run? Is not running the equivalent of being dead? How will you know that you are getting the processing power and bandwidth in your contract when reality is simulated and hardware test results could be simulated too?

There are at least two levels of challenges to address, akin to current physical world needs, first, survival needs and second, needs and rights when interacting with others.

Establishing rights for mindfiles
There will need to be ways to assure basic ‘human’ rights in a potential era of uploading brains to digital software files. There could be many misuses of massive databanks of mindfiles: they could be deleted at will (digital genocide) or by mistake by careless ISPs/data center managers, sold, kidnapped, copied, bred, hiveminded or discriminated against via less bandwidth and processing power. If the reality experienced by mindfiles is simulated, how would anyone know that the virtual reality they experience is the one they want to experience? A code or key could be created so that individual mindfiles could not be copied without the owners permission, agreement or knowing; perhaps like the telomere-shortening system used by biological cells. Pervasive externally run audit software could maintain lists of mindfile citizens (a future role for the nation-state) and periodically query each mindfile to determine its status and whether it is running. As usual, the white hats would need to stay ahead of the black hats.

Reducing naked Darwinism
With less transparency and social pressure, it is possible that the behavioral smoothing that has arisen in contemporary society would dissolve. Codes of conduct for mindfiles could be developed, probably with a much heightened awareness and refinement of the respectful treatment of consciousnesses. If virtuality is 100% sousveilled, this should not be a problem. In addition, mechanisms such as barriers, permissioning tiers and firewalled gardens could arise to prevent stronger minds from terrorizing and controlling weaker minds or different minds. The real goal would be to rearchitect social pressure in ways that are continually empowering to all individuals. Some mindfiles may prefer heavily controlled virtual environments, others may wish to venture onto the interstitial wildnets.

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.

Aging is solvable

That aging is understandable and solvable, not necessarily immediately but ultimately, was one topic not seeing a lot of opposition at the American Aging Association (AGE) conference in Phoenix AZ May 29 – June 1, 2009. Key research highlights are below.

Aging is a key contemporary concern, on the order of climate change, as all countries worldwide have populations increasingly stratified towards aging. Aging is not just a medical condition but a key challenge to be resolved for advanced societies to be successful in the long-term. Productivity, healthcare costs and happiness and comfort could all be improved with advances in the remedy of aging. Aging has advanced from a nebulous concept to concrete mechanisms that can be understood and managed. Thematically, most of the bioparts impacted in aging (cells, genes, proteins, neurons, etc.) seem to still be present in older organisms, just not functioning the way they did when the organisms were younger, suggesting that it may be possible to manage and reverse aging processes, and confirming the systemic nature of aging including, for example, the role of a healthy microenvironment and cell-cell signaling. Reductionism as an approach has proved unsuccessful.

Aging is a multidisciplinary phenomenon, involving different deterioration processes in different tissues over time. Aging involves a variety of fields (immunology, cancer, regenerative medicine, cognition, micronutrients, etc.) and a variety of levels of research species (C. elegans (worms), Drosophila (flies), mice, rats and humans). At AGE, the organizational structure was a focus on systems pathways, particularly signaling and hormones, together with a look at the role of proteins in aging.

AGE was an excellent place to obtain a broad and deep comprehension of how aging works. The systemic rigor required to characterize the process-intensive nature of aging has been making significant progress, with a much more detailed understanding of the complex nested multifactor pathways now existing as compared with that of even a few years ago. It is clear that the painstaking characterization work could be further improved with automation and quantitative tools, especially for example, digital linkage of aging pathways across organisms.

As with other life sciences areas, the potential widespread quick and cheap availability of the sequencing of genomes, proteomes, etc. is likely to dramatically change how the science of aging is conducted, though not guarantee quick solutions. As pathways continue to be confirmed, they can be digitized into software and nearly indefinite simulated iterations could be run before conducting time-consuming and expensive bench experiments in confirmation.

Many interventions work for extending the lifespans and healthspans of lower order organisms, for example knocking out any one of 200 known genes may extend the lifespan of the C. elegans worm but the specifics and replicability of the mechanisms in higher order organisms are not known. It does not make sense to directly translate point solutions up to mammals given the systemic nature of the organisms and aging processes. Even moving one biomarker for alcohol consumption from monkeys to humans is not direct.

Exciting new research findings
Reference links below and conference abstracts here

1. 3-D organ printing: Use only biologics (cells and cell products) in a scaffold-free tissue engineering process to print 3-D tissues and organs which can be vascularized prior to implantation, relying on developmental biology to trigger the cells to fuse and self-assemble into organs. (Gabor Forgacs, video, lab, organ printing)
   
2. Stem cell antibodies: Improve existing cardiac stem cell therapies (only 1% of cells reach the intended destination) by using specific antibodies for better targeting and retention of stem cells at sites of tissue injury. Replace cardiomyocytes with adult stem cells. (Jim Larrick, paper, general information)
   
3. Stem cells: Amplify and rejuvenate adult stem cells for injection into knees and hips as an alternative to surgical replacements. (Regenexx)
   
4. Bioremediation: Use natural enzymes to remediate biological build-ups; cholesterol oxidase from Brevibacteria to reduce 7KC cholesterol in atherosclerosis and A2E-degrading enzymes to improve macular degeneration. (John Schloendorn, research program, paper)
   
5. Life extension: Examine the mechanisms of dietary restriction (DR) with further elucidation of TOR (target of rapamycin) pathways, a fast growing area of research. Find that inhibiting a downstream gene in the TOR pathway, HIF-1 (a transcription factor important for growth and metabolism), extends lifespan in worms. (Pankaj Kapahi, paper)
   
6. Life extension: Generate a 10x lifespan extension in C. elegans by silencing many components of insulin/IGF-1 signaling (IIS) possibly via the disruption of PIP3 (a key signaling molecule required for the membrane tethering of many signaling molecules). (Puneet Bharill, paper)
   
7. Amyloid plaque reduction: Use a known plaque imaging agent, ThT (Thioflavin T), as a therapeutic for amyloid plaques. (Silvestre Alavez, lab affiliation, paper)
   
8. Cancer protection: Find that naked mole rats have two layers of anti-cancer protection, humans have only one. p16 is the first-line-of-defense anti-cancer protection mechanism found in naked mole rats. Humans (and other organisms) also have p16 (a suite of three genes), perhaps the mechanism for its upregulation (probably a cell:cell signaling dynamic) in naked mole rats could be understood and turned on with an enzyme in humans. (Andrei Seluanov, earlier research)
   
9. Cognitive function: Find that neurogenesis is possible in aged organisms with exercise followed by cognitive stimulation (e.g.; tackling a puzzle or challenge); organisms can benefit by building up a larger reservoir of brain cells earlier in life by being exposed to a variety of external stimulation. (Gerd Kempermann) This author’s speculation: Perhaps neurogenesis could be further harnessed for brain enhancement beyond currently realizable human capacities as this mechanism is better understood.
   
10. Aging biomarkers: Upstream the aging focus to prevention by measuring biomarkers and introducing interventions. Some suggested biomarkers of aging are p16 gene levels (which can be decreased with exercise), telomere length, the level of senescent cells, and the number of circulating lymphocytes in the immune system (measure total T cells (CD3+), B cells (CD19+) and CD28 absolute numbers on CD8+ T cells). (Kronos research projects, test menu; telomere length measuring)
    
11. Hormones-IGF: Find no conclusive evidence of insulin-like growth factor's (IGF) ability to retard natural aging, though on an individual basis some people may find it useful. (Marc Blackman)
    
12. Hormones-HRT: Find that hormone replacement therapy (HRT) can be good for improving cognitive function and bone loss in women that do not have a risk of heart disease; HRT should be started with the onset of menopause, not later. (Barbara Sherwin, Eef Hogervorst)
    
13. Cost of reproduction: Find that ovary removal in grasshoppers resulted in a 25% increased lifespan, contributing to existing evidence regarding the high cost of reproduction. (John Hatle) This author’s speculation: In the farther future, in humans, it could be quite desirable to closely manage fertility, turning it on and off at will, if fertility is even necessary.
    
14. Micronutrients: Find tremendous nutritional benefits from the consumption of fruits with skin, especially blueberries (pterostilbene that reduces oxidative stress), blackberries, raspberries, red grapes, pomegranates, cranberries, plums, strawberries, cherries, pears and apples (phytochemicals that provide cancer prevention), walnuts (preventing the inflammation and oxidative stress of brain aging:), green tea (catechins that reduce cardivascular and cancer risk) and tempeh (fermented whole soy bean with folate is healthier than tofu (processed soy bean curd)). (Blueberries: Agnes Rimando, Rolf Martin; Apples: Rui Hai Liu, Walnuts: James A. Joseph, Green tea: Vojo Deretic, Tempeh: Eef Hogervorst)
    
15. Calorie restriction (CR)/dietary restriction (DR): Find that in humans, improved biomarkers for CR/DR, vegan and raw food diets that result in the extension of the onset of aging challenges. (John Holloszy)
    
16. Aging mice testbed: A mouse type that sufficiently recapitulates early aging, the human WS phenotype (Werner syndrome), has been created which could hasten mammalian aging research. (David Kipling)
    

Conclusion
Aging is a key contemporary issue. Research is advancing both incrementally and radically in every area of aging. The highest immediate impact could come from working on aging problems upstream at important fulcrum points that impact everything below them, such as genetics, epigenetics and the immune function. The research is progressing and it is starting to be time for VCs, big pharma and DIYbio’ers to take advantage of the many interesting and actionable possibilities.

The future of computing – rotaxanes?

One of the great human endeavors at the moment is being able to work at the molecular scale (e.g.; 1-100 nm), using organic and inorganic materials for a variety of purposes ranging from basic materials to computing to electronics to life sciences therapeutics to energy. This includes the designed direction of existing molecular processes (e.g.; biology) and the synthesis of novel materials, structures and dynamic behavior.

Three of the most interesting advances in working at the molecular scale and examples of bio-infotech convergence are described below…

1) Hybrid organic-inorganic rotaxanes
First is the March 2009 work of David Leigh’s lab at the University of Edinburgh in creating hybrid organic-inorganic rotaxanes. A rotaxane (rota/wheel + axis) is a mechanically-interlocked molecular structure, essentially a dumbbell shape with a ring around its middle (Figure 1), often man-made but occasionally existing in nature. In this case, the dumbbell portion of the hybrid organic-inorganic rotaxane is an organic amine, the ring around the middle is a metal.

Figure 1: Rotaxane graphical schematic and crystal structure (source)

The benefit of metal-organic frameworks is that they have the properties of both organic and inorganic materials; structural and functional properties from organic materials and electronic, magnetic and catalytic properties from inorganic materials. This rotaxane molecule has directed shuttle-like behavior, where the metal ring around the center can be pushed to bind at either end, with its biggest potential application being in quantum computing.

2) Bio-inorganic interfaces
A second interesting example of molecular scale work and bio-infotech convergence is biocomposites/GEPIs (genetically-engineered peptides for inorganics) which regulate cell behavior and improve binding at bio-inorganic interfaces by modifying surface chemistry and immobilizing infection-causing bioactive molecules. Candan Tamerler’s lab at the University of Washington is doing some interesting work in this area. Improved bio-inorganic interfaces are needed for reduced infection and seamless interaction between human wetware and implants: heart, hip, prosthetics, eye, brain, etc.

3) DNA nanotechnology
The third interesting bio-infotech convergence example is DNA nanotechnology, the notion of using DNA as a structural building material (for example, for self-directed rapid templating) rather than as an information carrier. One key use is employing DNA as a programmable scaffolding for the self-assembly of nanoscale electronic components, meaning that scaffolds comprised of self-assembled DNA serve as templates for the targeted deposition of ordered nanoparticles and molecular arrays. DNA is formed into tubes and then metallized in solution to produce ultra-thin metal wires. John Reif’s lab at Duke University, Erik Winfree’s lab at Caltech and many other groups are working on DNA nanotechnology. Moving to the molecular scale for electronics manufacture is imperative for maintaining Moore’s Law computing performance improvements.

Future implications
It seems likely that working at the molecular scale and bio-infotech convergence will continue to grow. Organic-inorganic hybridization approaches could proliferate to exploit the full suite of properties afforded by organic and inorganic inputs, and as researchers suggest, lead to novel properties and the ability to harness molecular dynamics for human use.

Expanding notion of Computing

As we push to extend inorganic Moore’s Law computing to ever-smaller nodes, and simultaneously attempt to understand and manipulate existing high-performance nanoscale computers known as biology, it is becoming obvious that the notion of computing is expanding. The definition, models and realms of computation are all being extended.

Computing models are growing
At the most basic level, how to do computing (the computing model) is certainly changing. As illustrated in Figure 1, the traditional linear Von Neumann model is being extended with new materials, 3D architectures, molecular electronics and solar transistors. Novel computing models are being investigated such as quantum computing, parallel architectures, cloud computing, liquid computing and the cell broadband architecture like that used in the IBM Roadrunner supercomputer. Biological computing models and biology as a substrate are also under exploration with 3D DNA nanotechnology, DNA computing, biosensors, synthetic biology, cellular colonies and bacterial intelligence, and the discovery of novel computing paradigms existing in biology such as the topological equations by which ciliate DNA is encrypted.

Figure 1. Evolving computational models (source)

Computing definition and realms are growing
At another level, subtly but importantly, where to do computing is changing from specialized locations the size of a large room in the 1970s to the destktop to the laptop, netbook and mobile device and smartphone. At present computers are still made of inorganic materials but introducing a variety of organic materials computing mechisms helps to expand the definition of what computing is. Ubiquitous sensors, personalized home electricity monitors, self-adjusting biofuels, molecular motors and biological computers do not sound like the traditional concept of computing. True next-generation drugs could be in the form of molecular machines. Organic components or organic/inorganic hybrid components, as the distinction dissolves, could be added to many object such as the smartphone. A mini-NMR or mini-Imager for mobile medical diagnostics from a disposable finger-prick blood sample would be an obvious addition.

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.