Synbio revolution: biology is the engineering medium

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.

The status of the synbio field was discussed, how

• it is possible to synthesize an enzyme but not design a protein
• it is possible to synthesize a chromosome but not predictably engineer a circuit
• it is not known how to engineer on a whole genome basis
• it is not known how to interface with inorganic material (e.g.; man-made substances)

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.

Theme #1: Biology is finite
The overarching theme that emerged from the conference is that

biology is detailed, systemic, dynamic, and complicated, but in the end finite

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.

Theme #2: 3 main approaches to synbio: extend E. coli capacity, biomimicry, de novo synthesis
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.

Grand challenges
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.

Building block challenge

• Synthesize the full genome of a bacterium
• Design and manufacture a minimal cell
• Design bacteria that hunt and kill tumors
• Enhance the photosynthesis process in plants
• Expand model organism culturing capability from E. coli and yeast to the vast number of microbes

Biology characterization challenges

• Understand the key interactions of band gap material in a cell
• Understand the multigenic epistasis of thousands of genes in heterologous systems
• Understand contact from a cellular basis
• Figure out how to create programmatic control of complex development steps (for example, body plan)
• Define how many changes are necessary to create a new species

Systems engineering challenges

• Define designs and specifications (that can be predictably and reliably verified and constructed)
• Improve challenges in the synthesis, design, analysis of existing systems
• Engineer for the open systems of the real world, beyond closed-environment bioreactors
• Improve tools for computer-based circuit, genome, and chromosome design
• Develop theoretical frameworks to scale synbio to bigger questions; envision the future beyond putting a lot of small pieces of DNA together more quickly and cheaply
• Develop effective means to design, generate, and test recombinant organisms in the environment (for example, injestable bacteria in humans like an organism that cures cancer or probiotic bacteria for Crohn’s disease)

Conference report: interventional anti-aging

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

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

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

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

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

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

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

More details: Meeting Summary preprint.

Engaging personal health collaborators

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.

At the first Quantified Self conference held in Mountain View CA May 28-29, 2011, an important area of discussion was regarding the best ways to build and engage community participation, whatever the topic. Here are some ways that large numbers of individuals might be enticed to come together for self-directed health exploration:

• Crowd-sourcing each piece of the value chain: the data, the questions, the financing, and the analysis
• Technology-mediated tools to make participation easy and automated
• Fun: making participation fun by using the contemporary ubiquity of gaming principles in persuasive behavior and group activity design
• Market-tools: using market design principles such as scarcity, value exchange, and currency (e.g.; reputational, points, monetary, etc.) amassing for community stickiness
• Enhancement-focus: offering many topical and aspirational frames (e.g.; performance enhancement) since not everyone is interested in “health” or “wellness”
• Low-friction interactions funneled into tiers of increasingly committed participation: making it very easy for potential participants to like, join, interact, and commit to health communities

Just as people have hobbies, exercise, and entertainment activities of preference, so too may they have health collaboration focus areas in the future.

Time malleability

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.

Concurrency trend in contemporary computing
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.

Building intelligent systems
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.

Conclusion
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.

From “The conceptualization of time in computing”