Regenerative medicine: conduits, augments, and blood-vessel printing

A medical advance that could have as large an impact on disease eradication and life extension as penicillin is regenerative medicine and tissue engineering. The field was perceived as revolutionary even a few years ago, but rapid advances have made it seem almost commonplace today.

Replacement organs grown from one’s own cells are desirable since this would avoid immune system rejection and a lifetime of immunosuppressive drugs and their side effects.

Hollow organs like the bladder are easier to create than the more solid liver and kidney, and the heart is the most challenging. The current status is that several dozens of lab-generated bladders have been implanted in humans.

In the case of other organs, the present focus of tissue engineering is on conduits (e.g.; providing a link to the outside of the body for waste removal (Tengion neo-urinary conduit clinical trials)) and augments (e.g.; providing a supplemental path for normal operations (Tengion neo-kidney augment and other augments)).

Vascularization, or blood-vessel printing, is an intense area of research focus, and there is some promising progress from at least two sources, well-known regenerative medicine research leader Anthony Atala, and tissue engineering startup darling Organovo. This could be a key step in allowing more sophisticated organs to be regenerated.

Cognitive and social enhancement tools

Computer software and the internet have long been cognitive enhancement tools. Spellchecker obviated the need for spelling skills. Wikipedia and the internet obviated the need for fact memorization. There is less reason to earn a PhD if the module might be available as a cognitive plug-in within a few years.

The need to speak foreign languages is reduced with Google Translate for Android.

Social networks like Facebook are acting as a social prosthetic. It is now possible to have a massively larger context-driven social apparatus with deep-interest specificity.

Accessing, assimilating, applying, and interacting around knowledge and information has become the critical 21c skill set.

Android mobile app for 23andMe data

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

Figure 1: DIYgenomics Android mobile app view categories.

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

Figure 2: DIYgenomics health condition Alzheimer's disease.

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

Citizen science genomics

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

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

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

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

Top 10 technology trends for 2011

1. Mobile is the platform; mobile payment ubiquity could be next
2. Device proliferation continues; tablets, e-book readers, etc.
3. Connected media and on-demand streaming video, IPTV, live event interaction
4. Social shopping: grouppurchasing, commenting, recommendation, LBS
5. Sentiment engines (ex: Pulse of the Nation, We Feel Fine) are ripe for being applied much more broadly to other keyword domains; sentiment prediction
6. Big data era explosion: machine learning, cloud computing, clusters, supercomputing
7. Labor-as-a-service: microlabor, on-demand labor, global task fulfillment
8. Quantified self tracking gadgets and apps (ex: WiThings scale, myZeo, BodyMetRx, medication reminder, nutrition intake, workout coordination, DIYgenomics, etc.)
9. Personal manufacturing, digital fabrication, 3D printing ("atoms are the new bits"); slow but important niche growth
10. Real-time economics: blippy, crowdsourced forecasting, stock market prediction

(Review predictions for 2010)

Human morphology-changing technologies

To date, most technology has been human-created. It can be grouped into two categories, technologies that are not likely to have an immediate direct impact on human morphology, and those that might.

Technologies that would likely not change human morphology
There could be the rapid advent of significantly more dramatic technologies than have been experienced to date. While these new technologies could change some aspects of life, human biological drives could remain unchanged, and therefore the structure and dynamics of human societal organization, interaction, and goal pursuit could also remain unchanged. Some examples of these advances could include the realization of molecular nanotechnology, quantum computing, cold fusion, and immortality. Even with several of these revolutionary technologies implemented, the seemingly different world would not actually be structurally different if humanity is still ordered around the same familiar biologically-driven goals.

Technologies that might change human morphology
The other group of technologies is those which could possibly have a near-term impact on the structure and form of what it means to be human, for example, cognitive augmentation, genomic therapies, and synthetic biology. The area with the greatest possible change is improving human mental capability. There have been several significant advances in a variety of neurology-related fields in the last few years that if ultimately realized, could potentially alter human morphology. Even the resolution of all mental pathologies such as Parkinson’s disease, depression, stroke rehabilitation, and addiction would constitute morphological change at a basic level. Augmenting cognition and deliberately managing biophysical states would constitute morphological change at other levels.

Morphological reach of technology

Is technology simply the tools that humanity has created to further its will or a force that can change humanity? Whether arrowheads or supercomputers, humans have made technology to enable and reinforce human nature and evolutionary tendencies. However, it is possible that advanced technology could actually change humans, human nature, and biological drives, both unintentionally and by design.

Supercomputers surpass 2.5 petaflops

The biannual list of the world's fastest supercomputers was released on November 13, 2010. For the first time, supercomputing capability surpassed 2.5 petaflops with the world's fastest supercomputer, the Tianhe-1A - NUDT TH MPP, X5670 2.93Ghz 6C, NVIDIA GPU, FT-1000 8C NUDT, at the National Supercomputing Center in Tianjin China, clocking in at over 2.5 petaflops.

Figure 1 illustrates how supercomputing power has been growing in the last five years, starting at (a paltry) 136.8 gigaflops in June 2005, and experiencing four solid doublings in growth. This rate of progress is estimated to continue, and usher in the exaflop era of supercomputing by mid-decade. The IBM Roadrunner at Los Alamos was the first to achieve speeds over one petaflop in June 2008 and held onto the fastest computer seat for three measurement periods, then was surpassed by the Cray Jaguar at Oakridge for two measurement periods. China has now captured the fastest supercomputer ranking with its NUDT MPP.

Figure 1. Growth in Supercomputing Capability: Jun 2005 - Nov 2010

Source: Top 500 Supercomputing Sites List Releases

The world's supercomputers are working on many challenging problems in areas such as physics, energy, and climate modeling. A natural question arises as to how soon human neural simulation may be conducted with supercomputers. It is a challenging problem since neural activity has a different architecture than supercomputing activity. Signal transmission is different in biological systems, with a variety of parameters such as context and continuum determining the quality and quantity of signals. Distributed computing systems might be better geared to processing problems in a fashion similar to that of the brain. The largest current project in distributed computing, Stanford protein Folding@home, reached 5 petaflops in computing capacity in early 2009, just as supercomputers were reaching 1 petaflop. The network continues to focus on modeling protein folding but could eventually be extended to other problem spaces.

Bay area aging meeting summary

In the second Bay Area Aging Meeting, held at Stanford on December 4, 2010, research was presented regarding attempts to further elucidate and characterize the processes of aging, primarily in model organisms such as yeast, C. elegans (worms), and mice. A detailed summary of the sessions is available here. The work spanned some repeating themes in aging research:

Theme: processes work in younger organisms but not in older organisms
A common theme in aging is that processes function well in the first half of an organism’s life, then break-down in the second half, particularly the last 20% of the lifespan. In one example, visualizations and animations were created from the 3D tissue-sectioning of the intestine of young (4 days old) and old (20 days old) C. elegans. In the younger worms, nuclei and cells were homogenous and regularly spaced over the course of the intestine running down the length of the worm. In older worms, nuclei disappeared (an initial 30 sometimes ultimately dropped to 10), and the intestine became twisted and alternately shrunken and convoluted due to DNA accumulation and bacterial build-up.

Theme: metabolism and oxidation critically influence aging processes
Two interesting talks concerned UCP2 (mitochondrial uncoupling protein 2), an enzyme which reduces the rate of ATP synthesis and regulates bioenergy balance. UCP2 and UCP3 have an important but not yet fully understood role in regulating ROS (reactive oxygen species) and overall metabolic function, possibly by allowing protons to enter the mitochondria without oxidative phosphorylation. The mechanism was explored in results that worm lifespan was extended by inserting zebrafish UCP2 genes (not natively present in the worm).

Theme: immune system becomes compromised in older organisms
Two talks addressed the issue of immune system compromise. One team created a predictive analysis that could be used to assess an individual’s immune profile and potential response to vaccines by evaluating demographics, chronic infection status, gene expression data, cytokine levels, and cell subset function. Other work looked into the specific mechanisms that may degrade immune systems in older organisms. SIRT1 (an enzyme related to cell regulation) levels decline with age. This leads to the instable acetylation of transcription factor FoxP3 (a gene involved in immune system response), which suppresses the immune system by reducing regulatory T cell (Treg) differentiation to respond to pathogens.

Theme: systems-level understanding of aging processes
Many aging processes are systemic in nature with complex branching pathways and unclear causality. Research was presented regarding two areas: p53 pathway initiation and amyloid beta plaque generation. P53 is a critical tumor suppressor protein controlling many processes related to aging and cell maintenance: cell division, apoptosis, and senescence, and is estimated to be mutated in 50% of cancers. Research suggested that more clues for understanding the multifactorial p53 pathway could come from SnoN, which may be an alternative mechanism for activating p53 as part of cellular stress response. Neurodegenerative pathologies such as Alzheimer’s disease remain unsolved problems in aging. For example, it is not known if the amyloid beta plaques that arise are causal, or a protection mechanism in response to other causal agents. Some research looked at where amyloid beta is produced in cells, finding that after the amyloid precursor protein (APP) leaves the endosome, both the Golgi and a related recycling complex may be related in the generation of amyloid beta.

Theme: lack of conservation progressing up the model organism chain
Aging and other biological processes become more complicated with progression up the chain of model organisms. What works in yeast and worms may not work in mice, and what works in mice and rats may not work in humans. Some interesting research looked at ribosomal proteins, whose deletion is known to extend lifespan in model organisms. The key points were first that there was fairly little (perhaps less than 20%) overlap in lifespan-extending ribosomal protein deletions conserved between yeast and worms. Second, an examination of some of the shared deletions in mice (especially RPL19, 22, and 29) found some conservation (e.g.; RPL29), and also underlined the systemic-nature of biology, finding that other homologous genes (e.g.; RPL22L (“-like”)) may compensate for the deletion, and thereby not extend lifespan.

Theme: trade-offs is a key dynamic of aging processes
The idea of trade-offs is another common theme in aging; the trade-offs between processes, resource consumption, and selection. Exemplar of this was research showing that the deletion of a single gene involved in lipid synthesis, DGAT1, is beneficial and promotes longevity in mice when calories are abundant, but is also crucial for survival in calorie restricted situations. This supports the use of directed methylation to turn genes on and off in different situations. More details were presented in a second area of trade-offs: reproduction-lifespan. It is known that reproduction is costly and organisms without reproductive mechanisms may have extended lifespans. Research examined the specific pathways, finding that Wnt and steroid hormone signaling in germline and somatic reproductive tissues influenced worm longevity, particularly through non-canonical (e.g.; not the usual) pathways by involving signaling components MOM-2/Wnt and WRM-1/beta-catenin.

Conclusion
Academic aging research is continually making progress in the painstaking characterization of specific biological phenomena in model organisms, however the question naturally arises as to when and how the findings may be applied in humans for improving lifespan and healthspan. In fact there is a fair degree of activity in applied human aging research. Just as more individuals are starting to include genomic medicine, preventive medicine, and baseline wellness marker measurement in health self-management, so too are they consulting with longevity doctors. One challenge is that at present it is incumbent on individuals to independently research doctors and treatments. Hopefully in the future there could be a standard list of the anti-aging therapies that longevity doctors would typically offer. Meanwhile, one significant way for an individual to start taking action is by self-tracking: measuring a variety of biomarkers, for example annual blood tests, and exercise, weight, nutritional intake, supplements, and sleep on a more frequent basis.

Multiworld ethics and infinitarian paralysis

In an interesting 2008 essay (The Infinitarian Challenge to Aggregative Ethics), Oxford futurist scholar Nick Bostrom considers some of the issues that may arise in multiworld ethics. The central focus is on the theme of infinitarian paralysis, that individuals may not act since they think their impact is too small to matter. This is not a new theme; a classic example is not voting thinking that one voice does not matter. However, when considered in an infinite multiworld sense where every permutation of every individual and their actions exists elsewhere, perhaps individual voices really do not matter…and individual agents in any world could experience infinitarian paralysis.

As the essay suggests, humans may be able to qualify and circumscribe the issue of infinitarian paralysis and live and act unconcernedly in the current world. While this may be possible now, as humans become more rational through augmentation, and with the potential advent of artificial intelligence and hybrid beings, the specter of infinitarian paralysis may be harder to ignore. The inherent irrationality of humans together with the skill of ubiquitous rationalization is part of the cohesion of modern society. However, in a post-scarcity economy for material goods where the more immediate exigencies of living in the current world have evaporated, and biologically-derived utility functions have been re-designed, philosophical inconsistencies could well occupy a higher level of concern for thought-driven beings.