New market tools are emerging that could be much better (real-time and objective) indicators of performance than the traditional methods of speculation-driven stock market price, quarterly reporting, and financial statements.
These tech tools are a nice response to the perceived social economic malaise of the times, and could help to realize some of the new thinking promulgated by both theorists and activists that markets are more of a Darwinian game of the fittest rather than an invisible hand meeting favorably for all parties.
We pipette colorless liquids from one tube to another … we’re trying to cure cancer and change the world.
What was different was the degree of sophistication in the approaches, the easy multi-disciplinarity that researchers are bringing to the field, a more comprehensive understanding of the constituent materials (for example, the 5’ DNA does a lot of things: degradation, elongation, binding, etc. in a dynamic system where different processes come online to change resource use per osmolarity, temperature, etc.), and the contemplation of process portability across model organisms, for example from yeast to mammalian cells. The conference structure focused on the overall status and issues of the industry in a panel with leading scientists, and had talks regarding foundational technologies and applications.
Metrology advances are needed, in units, reference standards, etc.; for example when shipping a gene expression module to colleagues in Shenzhen, what units should be employed?
We need to do regenerative medicine without scaffolds, we know biological cells can differentiate into 3-D, how can we engineer this to happen?
Programmable materials are an important input to synthetic biology as they may allow ongoing control over the dynamic processes of living cells. RNA is exemplar as a programmable substrate since it can be used to sense the presence of small molecules in cells and control gene expression by influencing which proteins are made and many other cellular activities . In the keynote talk, Gerald Joyce (Scripps) discussed the specifics of exploiting RNA with a technique analogous to PCR (polymerase chain reaction), where an exponential number of copies of DNA are made to trigger desired cellular behaviors. In this case, an exponential number of copies of certain ligands (building-block molecules that bind with other molecules to trigger reactions in cells) are made that a certain enzyme-making RNA binds to for carrying out a desired cellular function .
Not only can RNA be used on a unitary basis to direct cellular actions, it can also be used as a component in constructing gene networks that serve as sophisticated molecular control devices like switches and circuits. Christina Smolke (Stanford) presented research using RNA to build synthetic controllers, for example a ribozyme-based device that can be used to detect metabolites non-invasively, a ribosome binding site-based device that can degrade harmful chemicals into neutral products, and a splicing-based device that can be used to target cell death . A potential application was discussed using a synthetic RNA device to regulate cell signaling and T-cell proliferation in mammalian cells . Alan Arkin (UC Berkeley and LBNL) suggested desirable ways to increase the complexity of synthetically generated devices, for example, assembling complexity from the constituent properties of the materials that is modular or context-free in deployment, and by having diverse RNA control elements on a single transcript . This could also make devices more replicable.
After the theme of RNA as a programmable material and synthetic genetic network regulatory element, another de facto theme was the capability to manipulate organelles.
David Savage (UC Berkeley) presented work regarding carboxysomes (protein-enclosed bacterial organelles). Synthetic organelles could be constructed that would be useful for a variety of cellular activities, including improving on current biological processes like RuBisCO leakage (an enzyme involved in the first major step of carbon fixation). Synthetic organelles could be developed based on previous work characterizing carboxysomes with shell and cargo fluorescent tagging , and recent work improving the stability and well-formedness of shells through shell-protein modification, particularly by adding a novel protein, CsoS1D, discovered by Cheryl Kerfeld’s lab (UC Berkeley and LBNL) [7,8].
Wallace Marshall (UCSF) discussed the importance of understanding and controlling organelle size, shape, and composition, the trade-offs between lipid and starch storage and controlled metabolism, for example. Tuning flagellar length could be important in the understanding and remedy of ciliary diseases , and experimental research suggested in one case that the quantity of LF4 (long flagella) protein being injected could be the key fulcrum of the control system. Organelle-tuning could have a broad range of useful applications, for example tuning up and down the ability of vacuoles to tolerate toxic compounds.
Michelle Chang (UC Berkeley) pointed out how the toxicity of fluorine makes it useful in drugs, and perhaps synthetic biology techniques could improve its effectiveness. A naturally-occurring fluorine-specific enzyme (FIK) was examined that demonstrated dramatic improvement in recognizing molecules . Leor Weinberger (Gladstone Institute and UCSF) discussed synthetic viral circuits called therapeutic interfering particles (TIPs) that have been shown to reduce HIV/AIDS infection rates. The TIPs replicate conditionally in the presence of the pathogen and spread between individuals .
Hana El-Samad (UCSF) discussed the benefits of using hybrid biological and computer-based systems, where software algorithms were used to control a gene expression circuit’s behavior in real-time through a light-responsive module .
John Dueber (UC Berkeley) discussed the benefits of controlling the volume of enzymes expressed in cells, optimizing flux through cells. A desirable tool for this is combinatorial libraries to manage expression in multi-gene pathways. Further, when there are flux limitations in the pathway that cannot be managed with gene expression, there has been some interesting work building synthetic scaffolds to co-locate pathway enzymes around the areas of interest .
Nathan Hillson (LBNL) presented ways to automate and speed up the engineering cycle (design-build-test) with a component repository, selected components, and assembled components. Software design automation for assembly tools were discussed such as the JBEI-ICE repository platform and the GLAMM design tool.
Liu CC, Arkin AP. The case for RNA. Science. 2010 Nov 26;330(6008):1185-6.
Lam BJ, Joyce GF. An isothermal system that couples ligand-dependent catalysis to ligand-independent exponential amplification. J Am Chem Soc. 2011 Mar 9;133(9):3191-7.
Liang JC, Bloom RJ, Smolke CD. Engineering biological systems with synthetic RNA molecules. Mol Cell. 2011 Sep 16;43(6):915-26.
Chen YY, Jensen MC, Smolke CD. Genetic control of mammalian T-cell proliferation with synthetic RNA regulatory systems. Proc Natl Acad Sci U S A. 2010 May 11;107(19):8531-6.
Lucks JB, Qi L, Mutalik VK, Wang D, Arkin AP. Versatile RNA-sensing transcriptional regulators for engineering genetic networks. Proc Natl Acad Sci U S A. 2011 May 24;108(21):8617-22.
Savage DF, Afonso B, Chen AH, Silver PA. Spatially ordered dynamics of the bacterial carbon fixation machinery. Science. 2010 Mar 5;327(5970):1258-61.
Roberts EW, Cai F, Kerfeld CA, Cannon GC, Heinhorst S. Isolation and Characterization of the Prochlorococcus Carboxysome Reveals the Presence of the Novel Shell Protein CsoS1D. J Bacteriol. 2011 Dec 9.
Klein MG, Zwart P, Bagby SC, Cai F, Chisholm SW, Heinhorst S, Cannon GC, Kerfeld CA. Identification and structural analysis of a novel carboxysome shell protein with implications for metabolite transport. J Mol Biol. 2009 Sep 18;392(2):319-33.
Wemmer KA, Marshall WF. Flagellar length control in chlamydomonas--paradigm for organelle size regulation. Int Rev Cytol. 2007;260:175-212.
Weeks AM, Coyle SM, Jinek M, Doudna JA, Chang MC. Structural and biochemical studies of a fluoroacetyl-CoA-specific thioesterase reveal a molecular basis for fluorine selectivity. Biochemistry. 2010 Nov 2;49(43):9269-79.
Metzger VT, Lloyd-Smith JO, Weinberger LS. Autonomous targeting of infectious superspreaders using engineered transmissible therapies. PLoS Comput Biol. 2011 Mar;7(3):e1002015.
Milias-Argeitis A, Summers S, Stewart-Ornstein J, Zuleta I, Pincus D, El-Samad H, Khammash M, Lygeros J. In silico feedback for in vivo regulation of a gene expression circuit. Nat Biotechnol. 2011 Nov 6;29(12):1114-6.
Whitaker WR, Dueber JE. Metabolic pathway flux enhancement by synthetic protein scaffolding. Methods Enzymol. 2011;497:447-68.
Some important social intelligence skills are empathy, compassion, and a positive mental outlook. These skills can be taught as any other skills such as leadership and goal-setting. Some of the important aspects of developing empathy are self-awareness, self-compassion, active listening, and the ability to experience or identify with the thoughts and emotions of others.
One way to deliver social intelligence-building experiences is on the mobile platform. A virtual coach ('Siri 2.0') can send you randomly-timed messages like the examples below. If you are interested, sign up now for the beta launch the DIYgenomics Social Intelligence Mobile app by messaging our personal virtual coaches led by Marbet Grant 650-209-0872 or marbetgrant AT gmail.com.
What is one of your best qualities? Think about how you know you have this quality. Who else has this quality? Where are useful places in your life that you might use this quality?
When you really stop to think about it, what is really great about your life right now?
Where are you today? How are you feeling in your body right now?
What do you feel grateful for right now?
What’s one of your biggest flaws that a lot of other people might have too?
There is an interesting link between philosophy, technology innovation, and complexity theory. A claim has arisen that people may be feeling unsettled, that they no longer belong to certain normative groups like ‘Americans’ or ‘doctors.’ One reason could be the fast pace of technology innovation and adoption which has been creating a pervasive, accelerating, and possibly irreversible culture of biotechnicity. Paradoxically, technology innovation may also be the resolution.
This feeling of being unsettled is that of experiencing an anxious uncanniness of what it means to be a doctor, a Christian, a New Yorker, or whatever. This has long been identified by philosophers (e.g.; Plato, Socrates, Kierkegaard, etc., and more recently Jonathan Lear) as (a lesser-known definition of) irony; when individuals experience a sense of dissumlation (dissimulation).
A further claim is not that anxious uncanniness is harmful or undesirable, but rather that ironic uncanny experiences should be cultivated as the only way out, a key means of growth. Growing by pushing out of one’s comfort zone is parallel to dynamics in the cycles of technology innovation and complexity theory. In technology innovation, the chaotic foment at the end of a paradigm (like the vacuum tube or perhaps oil) forces innovation into a new paradigm. In complex systems, after symmetry-breaking and the development of entropy, adding energy helps to rebalance systems to attain the next node of progress.
It is quite possible that consciousness may not be an objectively definable phenomenon, but rather a convenient illusion created by humans to provide a context for understanding reality. While machines such as CT scans and MRIs measure human cognition, it may not be possible to measure the direct qualities of consciousness. Philosophers and others have pointed out that consciousness may be a subjective quality arising from the operation of the brain.
One reason that a more detailed look at consciousness may be interesting is in the contemplation of non-human intelligence. Given the aspect of subjective qualia surrounding the label consciousness, it might be insulting to non-human intelligence to be referred to as having consciousness, the more objective attribute ‘self-aware’ being preferable. If human consciousness does not exist, non-human consciousness would be even less likely to exist.
Now that citizen science in the health domain is becoming more established, it is relevant to scale it up to tackle larger projects. Several things can be done such as the definition and introduction of liability and oversight models that would be the analogue of the traditional IRB (institutional review board), and the professionalization of participant roles in the study ecosystem such as that of the study manager.
A more subtle issue is to develop an epistemology of citizen science. This would provide a structure and context for exploring the knowledge that is derived from citizen science. One question is whether new kinds of knowledge are being formed through group collaborations such as wikipedia and health social networks. Another question is characterizing the differences (if any) in the types of knowledge generated by traditional medicine, self-experimentation, and health collaboration communities.
One nice aspect of aging conferences is that there are usually a few gems of information that can be applied immediately in humans. Several actionable solutions were highlighted at the 40th annual meeting of the American Aging Association held June 3-6, 2011 in Raleigh NC USA (conference summary), in the areas of pharmaceuticals, nutrition, lifestyle, exercise, and fasting.
In summary, hypertension drug losartan may help sarcopenia, the healthier fats and antioxidants in walnuts, blueberries, and nectarines may facilitate health, hot tubs may reduce blood pressure, endurance exercise is better for older adults, and protein restriction may be the best form of caloric restriction.
In pharmaceuticals, the prescription drug losartan (an angiotensin receptor blocker) is typically used to treat hypertension and high blood pressure. It may also have anti-aging benefits in combating sarcopenia and frailty by improving muscle remodeling and grip strength.
In nutrition, recommendations were for walnuts, blueberries, and nectarines. Walnuts are good because they are the only nut containing a significant amount of alpha-linolenic acid (ALA), and because they are mainly composed of polyunsaturated fatty acids (PUFA, both omega-3 and omega-6) rather than monounsaturated fatty acids (MUFA), as most other nuts. Blueberries continue to be an important suggestion for anti-aging. They contain anthocyanins, antioxidants which may prevent inflammation and help to improve brain signals and memory function. The 2011 Blueberry Health Study reported that individual cognitive performance improved 1% over a one year period from consuming one half cup to two cups of blueberries per day. Necatrines (and acai) also have antioxidant properties and have been found to reduce oxidative damage and improve longevity in Drosophila melanogaster (Boyd, Free Radic Biol Med, 2011).
A lifestyle anti-aging remedy was found in nonhuman primates. Heated hydrotherapy, e.g.; jacuzzis, two times a week for 30 minutes at 39-41 degrees C, induced heat shock response (which declines with age) and increased production of heat shock proteins 70 and 90 which resulted in reduced blood pressure.
Exercise is always a good anti-aging improvement especially since 60% of U.S. adults over 60 have insufficient physical activity. Type II fibers (fast-twitch) are most vulnerable to aging so instead of trying to improve these, for older adults, it is better and easier to maintain Type I fibers associated with endurance exercise. For example, 70-80 year olds running 2-3 miles a few times a week had the glucoregulation profiles of sedentary adults in their 20s.
Fasting, especially amino acid (e.g.; protein) deprivation, before chemotherapy and surgery was found to help in reducing injurious impact.
In a breath of good news for Japan this year, RIKEN's supercomputer "K Computer" vaulted to the top slot in world supercomputing in June 2011 as tracked by Top 500 Supercomputer Sites.
Remarkably, capability more than tripled to over 8 petaflops per second (8 quadrillion calculations per second, measured as the Maximal LINPACK performance achieved), after supercomputer performance had been asymptoting at close to 1 pf and 2 pfs for the last three years (Figure 1). China's Tianhe-1A at the National Supercomputing Center in Tianjin was in second place, and the US's Jaguar Cray at Oak Ridge National Lab in third.
The capacity tripling constitutes obvious potential benefits to scientific computing, the realm of applications for which supercomputers are used. It is hoped that these kinds of quantitative changes may eventually lead to qualitative changes in the way other problems are investigated, for example how the brain works.
Synthetic Biology 5.0: The Fifth International Meeting on Synthetic Biology, was held at Stanford University June 15-17, 2011. There were 700 registered attendees, 400 posters, and 100 people at peak on the live ustream video broadcast. Synthetic biology (synbio) is the design and construction of new biological entities such as enzymes, genetic circuits, and cells or the redesign of existing biological systems. Engineering principles are applied to harness the fundamental components of biology; biology is an engineering medium.
One of the biggest areas of current activity in synbio is metabolic engineering, optimizing genetic and regulatory processes within cells to increase the cells' production of certain substances, for example biofuel generation. Techniques range from directly deleting and/or overexpressing the genes that encode for metabolic enzymes to targeting the regulatory networks in a cell to efficiently engineer the metabolism.
The question then becomes ‘how long will it take’ to do certain things. Synthetic biologists have buckled in for the long-term, focusing on the biology revolution being to this century what the computer revolution was to the past century. To be more precise (and congruent with engineering), it may not be that all biology is in the end finitely discoverable and explainable, but rather that even in systems ecologies, manipulations can be conducted effectively within bands wide enough to reach goals and limit risk. An example of a classic problem illustrating the trade-offs of synbio is whether it would be better to engineer wheat that impedes rust or a virus that eats the rust on the wheat.
A recurring theme at synbio conferences is the diversity of approaches. There are three main types, first is extending engineering capacity in the building blocks of nature that are already synbio workhorses such as E. coli and yeast. Second is canvassing nature for additional functionality, including cataloging the natural world and the entire human metabalome, peptidome, virome, bloodome, etc. Third is de novo engineering from scratch to build necessary functionality in minimal cells/minimal genomes, including the possibility of supplementing nature-provided parts with newly created amino acids and nucleotide base pairs. An example that considers the trade-offs between approaches is engineering up from minimal cells versus engineering down from organisms that already have some of the needed functionality, for example up from E. coli or down from rhizobia, soil bacteria that have nitrogen fixation (biosynthesis) capability.
There was an attempt to define some of the grand challenges in synbio, which can be categorized as building block, biology characterization, and systems engineering challenges.
Health social networks have been growing steadily over the last few years – the leader PatientsLikeMe now has 100,000 patients and 500 conditions listed. Numerous other personal health collaboration communities exist.
The health social network segment is now getting mature enough to expand its focus from deep, specific interest communities, often around disease, to also thinking about going mainstream to attract hundreds of thousands, and eventually millions of people to explore a wide variety of physical and mental performance areas.
Just as people have hobbies, exercise, and entertainment activities of preference, so too may they have health collaboration focus areas in the future.
There are differences between the conceptualization of time in computing systems and the human conceptualization of time. At the most basic level in computing, time is synonymous with performance and speed. At the next level in computing, there are “more kinds of time” than in the human and physics perspective where time is primarily continuous. In computing, time may be discrete, synchronous and asynchronous, absolute and relative, and not elapsing at all.
Computing is now making time even more malleable as a side effect of the quest to develop concurrent systems (multi-cores and multi-processors, and cluster, grid, and cloud computing), in at least four ways. One technique is using functional languages such as Haskell, LISP, Scheme, Clojure, and F# where sets of items and processes may not need to be temporally ordered. A second method is enhancing existing computer languages with new commands like ‘happensbefore’ and concurrency control mechanisms like ‘lock free queues’ to manage multiple threads of code operating simultaneously. A third means is creating new models with less time dependency like MapReduce which automatically parallelizes large data problems into finding all possible answers (‘map’), and determining relevancy (‘reduce’). A fourth technique is extending alternative models such as clock free methods and asynchronous computing and restructuring problems to be distributed for more expedient resolution.
The building of intelligent systems is a special problem in computing. There are many approaches ranging from attempts to model human thinking, including the conceptualization of time, to attempts to building intelligent systems from scratch. All models might benefit from incorporating biological time models such as temporal synchrony, the notion of a high-level background synchronization of processes.
Computers are already great time-savers. Computing approaches to contemporary problems like concurrency and building intelligent systems are increasing the ability to manipulate time. Ultimately, humans may be able to greatly extend the control of time, for all intents and purposes creating more time.
Nanoparticles (particles smaller than 100 nm where materials display different properties than at the bulk state) are frequently used in nanomedicine for drug delivery and other purposes. The sophistication and specificity of nanoparticle use is growing, particularly for delivering drugs past the lipid bilayer barrier of the cell wall to the inside of cells (cytosolic drug delivery) where they can target biophysical processes more easily. Two advances focus on cytosolic drug delivery, using light and peptides to break the endosomes (carrying vehicles) to release drugs directly into the cytosol.
One advance is in the development of nanoparticles (size-tunable (30-200 nm) highly monodispersed mesoporous silica nanoparticles) that can be loaded with a variety of compounds and released into the cytosol via light-mediated endosomal breakage, as illustrated in Figure 1 (Febvay et al, Nano Lett, 2010).
Figure 1: Nanoparticle cargo discharge through light-activation.
A second advance is in cytosolic drug delivery with nanoparticles using a peptide, GALA, to encourage endosomal breakage. GALA (comprised of repeating sequences of Glu-Ala-Leu-Ala) mimics the function of viral fusion protein sequences that mediate escape of virus genes from endosomes (Nakase et al, Methods Mol Biol, 2011).
The Third Bay Area Aging meeting was held at Berkeley on May 8, 2010.
Rapamycin (more technically known as the mammalian target of rapamycin (mTOR)), has long been examined in aging since it is a protein that regulates a range of cellular behavior including growth, proliferation, motility, and survival. Initially hoped to be useful in treating cancer, rapamycin later turned out not to kill tumors due to systems biology; when mTOR is given and the TOR pathway is knocked out, the ERK pathway is upregulated instead.
However new research presented by Remi-Martin Laberge (Buck) shows that there is hope for rapamycin in the context of inflammation prevention. The normal process is that DNA damage response leads to NF-kB (a protein controlling DNA transcription) activation which leads to IL-6/8 (inflammation-related proteins) buildup, but with an mTOR introduction of rapamycin, instead IL-1a (an immune-response regulator) is obtained which prevents inflammation.
The prevention of inflammation is thought to be critical in anti-aging as many aging pathologies start with inflammation which later escalates to waste-build up and tissue break-down. This work is part of ongoing SASP (senescence-associated secretory phenotype) research by the Campisi lab (recent papers on p53 and p38MAPK).
Matt Barber (Stanford) presented work regarding a recently discovered SIRT (Silent Information Regulator) protein. SIRT7 is a chromatin-associated protein and site-specific histone H3 K18 deacetylase. There is a potential connection with SIRT7 and oncogenesis in that SIRT7 interacts with ELK4 (a pathway upregulated in cancer) to suppress a tumor suppressive gene expression network and helps stabilize aggressive cancer phenotypes.
Randy Ashton (Berkeley) showed research regarding the increased ability to dopaminergiacally pattern hESCs to facilitate regenerative therapies for Parkinson’s disease. This was accomplished by making a protein important in neural development, sonic hedgehog, more sensitive through polyvalency.
Brett Robison (Buck) presented work suggesting that normal proteasome function is required for full lifespan in yeast. The proteasome is an important location for waste degradation in cells. Aging cells showed impaired protein homeostasis and decreased proteasome function but it is unclear if this is cause or effect. Theodore Peters (Buck) also showed that maintaining protein homeostasis is important for healthy aging.
Well-known cognitive neuroscientist V.S. Ramachandran (“Phantoms in the Brain”) has been extending his original phantom limb pain research into new realms over the last several years, facilitated by the advent of new tools such as fMRI and genomic analysis.
It turns out that phantom limb pain is related to other anomalies such as synesthesia, a ‘mis-wiring’ of the senses such that stimulation to one sense results in an experience in another (for example, someone may see Monday as red). In all of these cases, there is an overabundance of neural connections in the brain. Genomic polymorphisms prevent these connections from being pruned normally.
Synesthesia is 7-8 times more common in artists, which begs the question of creativity measurement. A synesthete’s depiction of the world he or she sees may look like creativity to non-synesthetes, but is it reporting or creativity from the synesthete’s viewpoint? Synesthetes of the same type would need to assess creativity.
This year’s attendance was double last year’s at the Mobile Health conference, held at Stanford University May 4-5, 2011. The main theme last year was monetizing mobile health apps, without any real ideas of how to do so. This year the main theme was app fever – everyone either having or thinking that they need to have an app. No one seemed to be immune - large and small health service providers, physician groups, insurers, and entrepreneurs alike are scrambling to launch apps.
a plug and play platform where app creators can select different widgets for app customization. The most obvious mobile health app widgets would be for appointment scheduling, prescription management, lab test results, physician interaction, and EMRs.
Since app fever reaches far beyond the health sector, GeoCities/Dreamweaver-level platforms, much more accessible to the layperson than Google App Inventor and unified mobile code base tools, could cause even greater activity in the already booming mobile sector.
Man continues to master the manipulation of matter and timescales further up and down the chain from observable quotidian life. Regarding time, ultrafast materials is the area of science that deals with phenomena occurring in picoseconds and faster.
The familiar time scale is one second, easily measurable with a stop watch. A picsecond is 10-12 of a second or 0.000000000001 seconds, a timescale used in high speed electronics. A femtosecond is 10-15 of a second, the timescale of molecular vibrations and carrier interactions in solids. An attosecond is 10-18 of a second, the timescale of electron motion at atomic levels.
Scientists are now finding in nature that most energy transfer and charge transfer transactions are typically taking place at the vibrational range, at the femtosecond timescale. A prominent example is the rhodopsin photoreceptor for vision. Traditional models for describing these dynamics, e.g.; Bloch’s single-electron band structure model, work for condensed matter but not for regular matter.
ultrafast phase transitions, and ultrafast biological processes. Electronic structural dynamics deal with bond dynamics, valence charge flow, charge transfer, and electronic phase transitions.
One new tool being applied is the femtosecond X-ray. Since femtosecond X-rays interact with atomic cores, they are useful for obtaining direct information about atomic positions as compared with traditional optical measurements which only provide indirect information. This has immediately transferable implications in electronics manufacturing and biological applications.
Moving beyond the femtosecond scale, a next-generation light source at the attosecond time scale is being planned for the 2020 timeframe at Lawrence Berkeley Lab.