User:NKuldell/Q/A working page 2

Disclaimer: This page is a work in progress and reflects ongoing editing and revision by Reshma, Barry and me as well as contributions/feedback from PoETs.
Revisions as of 05.16.06 most in need of work are in italics .

Part 1: Defining the field and its capabilities

Question: How is synthetic biology different from existing, related fields like genetic engineering and metabolic engineering?

In some ways, it's no different. People have been purposefully modifying genetic material for much of recorded history via breeding and genetic crosses. With the advent of recombinant DNA technology, more methodical combination of DNA became possible. Today, genomic data is available for many of the planet's organisms AND technologies exist to make the genetic material from scratch. These two technologies of sequencing and synthesis are key enabling technologies of synthetic biology.

Traditionally, genetic engineering has been focused on making relatively small changes to biological systems, introducing a new gene into an organism for instance. An illustrative example is that of improved insulin production through genetically engineering bacterial cells to express the human gene for that protein. By contrast, synthetic biology seeks to start from a "blank slate" and ask, what can we make? Thus, instead of perturbing existing systems and organisms, synthetic biologists attempt to construct new ones. Metabolic engineering can be thought of as a specialization of synthetic biology for the purpose of retooling cellular metabolism for human purposes. Synthetic biology also has applications in other areas like materials fabrication, energy production, information processing and more.

Notably, there are different synthetic biology groups pursuing distinct agendas. Some go after applications. For example, Jay Keasling and colleagues at UC Berkeley have worked to engineer yeast to produce the antimalarial artemisinin cheaply. It is difficult to distinguish synthetic biology groups with application goals from groups working in a field such as genetic engineering. One distinguishing characteristic is that the current synthetic biology application projects have access to more information and technology, allowing them to tackle bigger problems in a more informed way.

Others in synthetic biology pursue enabling technologies (like Drew Endy's or Tom Knight's research groups at MIT). The goal of these "enabling" groups is to standardize the engineering of biology to make it more predictable. These groups borrow concepts from traditional engineering disciplines to enable the construction of multi-component biological systems using reusable and standard biological parts. The belief of these "enabling" groups is that in the long run, this standardized, less ad hoc approach to engineering biology will become the accepted approach to tackling any given application.

Despite the diverse agendas within the synthetic biology community, points of agreement can be found. These include the belief that there is enormous potential of biology as a substrate for engineering, that biological engineering is hard and that it must be pursued in a thoughtful and responsible fashion.

Question: Is there an expert review of the nature and potential benefits and risks of synthetic biology?

Here are some ideas:

• Tucker & Zilinskas, The New Atlantis, Spring 2006 link
• "Synthetic Biologists face up to security risks" Nature 436, 894-895 (18 Aug 2005) News File:Presentation material-synthbiolrisks Nat05.pdf
• "Custom-Made Microbes, at Your Service" by A Pollack NYT Science section January 17, 2006 link

Question: What questions or applications are being addressed by Synthetic Biology that aren't being explored or built using other technologies?

Some synthetic biologists are combining genomic information and synthesis technologies to re-write the genetic code from living creatures. Just as computer programmers might want to re-write the code for your PC, these synthetic biologists annotate their changes to the genetic program of the system they are studying with the hope that each element of code may be more manipulable and human-readable. Successes on this frontier include refactoring T7 [1], two genomes in one cell [2] and characterization of a minimal E coli genome [3]. Other successful efforts in synthetic biology involve metabolic engineering of simple organisms like bacteria or yeast, enabling future production of therapeutics or compounds whose natural reservoirs are in short supply. A recent noteable success in this effort is production of artemisinic acid in yeast [4], an acheivement that may allow cheap and clean production of this precursor for an antimalarial drug. Finally, synthetic biology can provide a framework for discovery-driven biologists who might like to test their existing models by building them from the ground up. These efforts are reminiscent of those in chemical engineering, where the step-wise synthesis of a novel chemical compound is used to convincingly demonstrate a complete understanding of its chemistry. Along these lines, synthetic biologists have recently published a framework for characterizing interactions of novel synthetic transcription factors [5] and have applied this framework to determine if other synthetic proteins interact in a parallel manner.

Do we want to add example of novel chemistry efforts?-NK

Question: Why is biology so hard to engineer now?

this is most similar to runner up question "impediments to progress". this may or may not be relevant for Q/A series devoted to social implications of the field. worth considering further...

Biology has several features that are difficult or lacking in other engineering mediums including

1. Biological systems can manufacture materials and chemicals fast, on very small or very large scales, with minimal toxic byproducts and under gentle reaction conditions
2. Biological systems can evolve.
3. Most importantly, biological organisms can self-replicate.

The DNA sequence has been described as the program that runs biological machines, analogous to the computer programs that run PCs. Reading and interpreting DNA sequence (strings of A's,T's,G's and C's) is just as challenging as reading and interpreting binary code (strings of 0's and 1's). Imagine that someone has given you a printout of the binary code for the Microsoft Windows operating system (without telling you what it is) and asks you what the program does. It would be an incredibly difficult question to answer. Similarly, understanding DNA sequence information is also challenging. In fact, it is an even more difficult problem because at least Microsoft Windows was written by humans in a reasonably rational way. DNA sequences were written by evolution and so our ability to understand them is limited for now. Synthetic Biology seeks to take the next step and actually "write new code" so to speak. Thus, given our lack of understanding of naturally occuring DNA code, it is not surprising that synthetic biology poses a challenge currently.

Additionally, existing descriptions of basic cellular activities do not allow the activities to be predictably combined in novel and re-useable ways. Certainly the behavior of cells is guided by laws of the natural world (physics, inheritance etc) but biology continues to surprise those who study it. And while surprises may be exciting for scientists, they constrain the activities of engineers who might like to reliably build with biological parts. Thus an important effort in synthetic biology aims to develop improved foundational technologies for reusing genetic elements. If successful, biological engineers might work with the confidence enjoyed by other engineering disciplines who don't, for example need to build a bridge to see if it will fall down. Furthermore, once tamed, the features that make the engineering of biological systems difficult may yield novel systems capable of operations and behaviors not achievable by other engineering methods.

Question: Some people may foresee a day when Synthetic Biology can build complex organisms from basic biological materials. Can simple viruses and primitive life forms already now be synthesized?

delete this Q/A?...it seems outside of implications and directions stream--NK

Viruses have been synthesized. Life forms, not yet. For example, in 2002 Cello, Paul and Wimmer reported the successful de novo synthesis of poliovirus (Science 297:1016), assembling from raw chemicals an agent that could infect mice, although it required a whopping dose relative to the natural virus that leads to infection. The authors described their efforts as “fueled by a strong curiosity about the minute particles that we can view both as chemicals and as “living” entities.” Other examples of de novo synthesis of viruses are the phiX174 bacteriophage reported in 2003 (PNAS 100:15440) and human influenza (Science 310:77) in 2005. Noteworthy are the speed with which these viruses could be made, a mere two weeks from raw chemicals to infectious bacteriophage in 2003, as well as the technology’s potential for synthesizing agents to harm rather than study nature. (e.g. Nature 2006 439:266).

Since viruses replicate only in living hosts, they are not themselves alive. A minimal life form would require self-replicating nucleic acids and a synthetic chassis in which to house them. A front-runner for the former is RNA with catalytic activity, including self-replication as described in 2001 (Science 292:1319). For the latter, lab built- membrane vesicles to encapsulate RNA were described in 2005(J Am Chem Soc 127:13213), but these assemble only through directed manipulations of experimental conditions. Thus, it seems efforts to enclose self-replicating nucleic acids in some spontaneously assembling bubble are underway but, to date, only components of a lab-generated living cell have been reported (http://www.pbs.org/wgbh/nova/sciencenow/3214/01.html)

Part 2: Defining the community

Question: Who is doing the work today?

alternatively phrased question: What is the nature of the SB community? Approaches for answering:

• estimates of numerical strength (both commercial and academic)
• international distribution?
• how are they funded?

As an approach to answering this question we may want to search for meeting attendance numbers, SB departments, jobs that use SB in description, number of papers published with SB in title or abstract and where investigators are housed. As important as who is doing the work today is who will be doing the work tomorrow, so we may want to cite iGEM growth--NK

Other ideas?

Question: Who speaks for the field?

There is no single spokesperson. This question presumes a defined and mature community and opens the opportunity for those of us answering to list ongoing activities to build community.

==Part 3: Possible future benefits of synthetic biology==

Question: What are the perceived benefits of synthetic biology?

Given Synthetic Biology's wide scope for engineering biological systems, the potential application space of synthetic biology is similarly wider. Novel medical applications, environmental remediation, energy production, biomaterials, and information processing may all be approachable through synthetic biology. In the future, cells may be quickly and predictably programmed to meet these and other discrete engineering goals. Synthetic biology may also benefit traditional biologists in their efforts to understand the natural world since these investigators may more easily test existing models of natural systems by building them from the ground up. Additionally, synthetic biology presents opportunities for synthetic chemists since cells may be considered self-replicating bags of intersting chemicals. Thus synthetic biology may enable the synthesis of novel chemical species under environmentally-gentle conditions.

Question: Who is investing in this and what do they see as the pay-off?

Currently much of the investment in the field is from the venture capital community into startup companies (e.g. Codon Devices). Codon Devices' goals are "in the short term, product opportunities include comprehensive sets of biological parts for large-scale research projects, engineered cells that produce novel pharmaceuticals, engineered protein biotherapeutics, and novel biosensor devices. In the longer term, the company's core technology is expected to enable improved vaccines, agricultural products, and biorefineries for the production of industrial chemicals and energy." [cite] Synthetic Genomics, Inc., another startup by J. Craig Venter, believes "there are potentially limitless applications for synthetic biology/genomics, everything from energy to chemicals to pharmaceuticals. In the near-term, we think that synthetic genomics has applications in the areas of cleaner and more efficient energy production, specifically in the production of ethanol and hydrogen." [cite]

The European Union has also made research in the field of synthetic biology a priority with specific funding initiatives. pdf The purpose of this funding is to stimulate science and technology research in the EU. The nonprofit Bill and Melinda Gates Foundation has made significant investment in efforts by Jay Keasling and colleagues in synthesizing large quantities of the antimalarial artemisin . Their motivation is to solve critical world health problems. [cite].

Thus the groups interested in synthetic biology span industry, government and nonprofit organizations. Each see a wealth of potential in the field but are interested in different application areas.

Question: Why would someone invest in this area as opposed to more traditional genetic engineering efforts?

delete this Q/A?...it seems redundant with "benefits" question above, although there is a place for repetition in this kind of format--NK

Genetic engineering has been focused on making relatively small changes to biological systems. For instance, introducing a new gene into an organism (like insulin). Synthetic biology seeks to start from a "blank slate" and ask, what can we make? Thus, instead of perturbing existing systems and organisms, we attempt to construct new ones. In having a wider scope for engineering biological systems, the potential application space of synthetic biology is similarly wider. One could imagine systems that range from chemical manufacturing to systems that monitor and respond to the environment in real time.

Part 4:Possible future risks of synthetic biology

NOTE: still under heavy construction I've brought all the questions of safeguards under this tent, since it might help balance the sky-is-falling feeling of this cluster. But perhaps the safeguard questions may be better placed under public perception or even community. Input? --NK

Question: While their methods are different, the end results of synthetic biology and genetic engineering seem similar: new organisms that are not seen in nature. If that is true, does it follow that synthetic biology is not bringing substantially new risks onto the scene?

(Could we more simply state this question as: does synthetic biology bring with it risks not associated with existing, related fields)-NK

The risks and rewards of synthetic biology are likely different. If synthetic biology is wildly successful then one can imagine a time when "garage inventors" could build something with biological materials. Genetic engineering, as it’s currently performed, requires substantial technical understanding of the project and access to specialized resources such as a laboratory and reagents. In the future, novel biological systems may be built with limited know-how, on a minimal budget and with no requirement for a specialized facility. It will be easy and cheap to make something not seen in nature, which means it could be done by folks who haven’t had the technology of genetic engineering at their disposal. Such democratization of biological engineering necessarily brings with it both the possibilities of a great number of useful applications as well as risks from accidental or intentional misuses. Understanding that Synthetic Biology brings with it new risks and rewards, one of the key missions of the nascent synthetic biological community is to forge a culture in which biological engineering happens responsibly.

Question: What are the existing barriers to the risk of potentially harmful synthetic biology products?

• answer should included mention of barriers in place to regulate research labs and commercial fabricators. Could also bring in surveillance ideas to monitor SB biohackers and any means of restricting products from overtly malicious agents (if there is evidence for this). As a correlary (or maybe as the lead line) can describe how community of openess and dialog (i.e. the “ethos” of current researchers) acts to anticipate and root out potential risk.

Question: Are the safeguards established to regulate/oversee genetic engineering seen as working well?

• this question can be rephrased to sound less opinion driven but seems important to include somehow as it allows us to include the fact that leadership in the research community helped setup safeguards that have successfully lowered risks from release of genetically altered organisms and accidental release of harmful ones. Can also include future SB plan for release of documentation if accidental release occurs.

===Question: Is there evidence of interest in synthetic biology capabilities in the part of terrorists?

• this question is posed from the view that those who are charged to limit the threat of terrorism may set their priorities based on hurdles that potential terrorists face in deploying destructive technologies. For example they may weigh the amount of scientific and technical know how required, the availability of expensive or controlled materials, danger to the miscreants themselves etc. Given that synthetic biology works to lower such barriers, it seems ripe for abuse but is there evidence that for such misappropriation of the technology. As part of the answer may want to explicitly describe what hurdles exist for the abuse of synthetic technologies by terrorists? as a start "DNA on demand significantly lowers barriers to potentially dangerous substances in the hands of miscreants. DNA synthesis companies have a record of synthesis orders but it’s not clear how or if that information would be shared. Most companies check sequence requests to look for ones that might encode dangerous substances and the companies can refuse to synthesize such DNA."

Part 5: still under heavy construction Social implications and public attitudes/ or Risk perception and community posture

fwiw: I prefer the first title since the second suggests risks may not be real and we have already established that community is still developing--NK

Question: Is the synthetic biology community seen as part of the genetic engineering community?

• this is a question that tries to calibrate public confidence (Q15) by asking if misgivings or trust can be infered from those surrounding genetic engineering. As indicated in the lack of public controversy over the implementation of genetically engineering safeguards and the open release of GMO products, the public has some level of confidence in those who are doing that work. Is the SB community effectively part of the same community?

===Question: What groups are closely following synthetic biology and its implications?

• Question is looking for an SB "watchdog," and there is none (at least none dedicated to SB). Public perceptions are sometimes affected by the knowledge that entities exist that focus on palpable risks, playing a “watchdog” role. If there are no public or private groups that appear to be applying vigilance against or address events involving man-made organisms, are there other assurances to offer?

Question: Is the synthetic biology community devoloping and operating awareness efforts and training aids?

• this question was originally posed to probe public awareness efforts. Premise is: for some potentially risky technologies, professional organizations themselves develop and operate awareness efforts and training aids to reduce public and worker risk and asks if the SB community already doing this. This answer might offer nice place to talk about curriculum/education efforts underway.

===Question: Are there relevant lessons to be learned from existing, related technologies?

• answer could detail perceived risks with other S/T disciplines that have confronted and managed public risks: nuclear safety, hazardous chemical, GE, cryptography. Can ask if these provide suggestions as to the future role of the SB community. Can also mention lessons that have already been translated into action.

Question:The Safety Record for GE? Some number of genetically engineered organisms have by now been unintentionally introduced into commerce and the environment. Have there been unanticipated adverse health or ecological impacts from these introductions? Who is monitoring this area?

Genetically modified crops have upset and worried many folks, in no small part because there seems to be no one who is monitoring or controlling the release of such agents. Reaction to genetically modified pets (like GFP-fish) has been small by comparison.

Question: Intramural Risk Identification? What do those working closely on SB see as the plausible way that SB might be misused? Have they taken steps to see that policy or other counter measures are taken to minimize such possibilities?

Policies are still being discussed

Question: Is Hacking Possible? SB is sometimes presented as a special form of information processing technology…a program written for assembly of organisms or parts of organisms. Is it significantly more difficult for “hackers” to cause mischief that those who wish for whatever reason to set loose the biological counterpart of a computer virus into the human environment?

Right now SB is incredibly hard. Very little works as predicted and there are only a few interchangeable parts to play with. But with time and success both these statements will be false and then hackers will have plenty to use for mischief. It might be best understood by thinking about computer operating systems and computer viruses. No computer viruses were written until lots of folks had their own computers and there were programs to attack and damage to be done.

Question: Public Confidence? As indicated in the lack of public controversy over the implementation of genetically engineering safeguards and the open release of GMO products, the public has some level of confidence in those who are doing that work. Is the SB community effectively part of the same community?

For better or worse.

Question: Current Safeguards 1 Partly through leadership in the research community, safeguards were setup to prevent risks from release of genetically altered organisms. Are these safeguards working well?

Tough to know for sure how many problems have been averted by these safeguards. For sure a lot of good research has been done without major incident.

Question: Current Safeguards 2 What are the current safeguards against the release of potentially harmful SB products….from research labs? From commercial fabricators? From biohackers? From overtly malicious agents?

There are no safeguards specific to SB. The presumption (correct or not) is to apply current safeguards that regulate recombinant DNA and GE.

Question: Worst-Case Planning? In the event that we learn of an adverse event involving a potentially hazardous manmade organism, who is ready and able to undertake effective remedial action? Has the remedial program been tested and validated by simulated game-playing or other proven techniques?

Don’t know if any “worse case scenarios” and “best case responses” have been detailed. If the response to recent natural disasters and public health threats is any guide, then we’d be foolish to expect government agencies to protect our well being through such crises.

Question: Extramural Vigilance? Public fears are sometimes eased by the knowledge that entities exist that focus on palpable risks, playing a “watchdog” role. What public and private groups appear to be applying vigilance against address events involving man-made organisms?

Nothing like the FDA or USDA oversee this effort.

Question: Public Awareness Efforts? For some potentially risky technologies, professional organizations themselves develop and operate awareness efforts and training aids to reduce public and worker risk? Is the SB community already doing this?

There is a good appreciation that some educational effort is needed.

Question: Lessons From Past Experience? In the past several S/T disciplines have confronted and managed public risks: nuclear safety, hazardous chemical, BE, cryptography. Do these provide suggestions as to the role of the SB community? Have such lessons already been translated into action?

Previous emerging S/T offer some clues and lessons for SB but history has not translated into action yet.

Runner-up questions

Part 1: defining the field and its capabilities

• Origins? How and when did SB emerge as a distinct field? From what precursors?
• Self-Selection Rules? Why did SB researchers decide to enter this new field? What background characteristics do they share?

Part 2: defining the community

Part 3: future benefits

Part 4: future risks

• Gene Transference Risk? How does SB affect the risk of horizontal gene transference?
• Extinction Risk? Is it possible that SB will lead to the eventual replacement of natural species by artificial ones?
• Process Risks? In addition to the risk of effects of new synthesized organisms – and components of organisms – is there a risk of changed scientific publishing practices, of our concept of what “life” is, of reifying the analogy between computer codes and biological code? Other?

Part 5: social implications, public attitudes

• Applications Gatekeepers? Who are the likely gatekeepers for the SB applications that emerge? Will profit potential prove to be the primary factor in deciding what applications are pursued? What intellectual-property considerations will influence what applications are pursued?
• Open Software and Risk? What is the relationship between the possibility of SB-hacking and the movement toward free and open software in the SB community?
• Worst-Case Planning? In the event that we learn of an adverse event involving a potentially hazardous manmade organism, are there those who are ready and able to undertake effective remedial action? Has the remedial program been tested and validated by simulated game-playing or other proven techniques? [If Ans= “none,” weave this Q into others?]

Cutting Room Floor?