Part 21 (1/2)

I want to focus on a third conception of synthetic biology: the idea of turning biotechnology from an artisa.n.a.l process of one- off creations, developed with customized techniques, to a true engineering discipline, using processes and parts that are as standardized and as well understood as valves, screws, capacitors, or resistors. The electrical engineer told to build a circuit does not go out and invent her own switches or capacitors. She can build a circuit using off-the-shelf components whose performance is expressed using standard measurements. This is the dream of one group of synthetic biologists: that biological engineering truly become engineering, with biological black boxes that perform all of the standard functions of electrical or mechanical engineering--measuring flow, reacting to a high signal by giving out a low signal, or vice versa, starting or terminating a sequence, connecting the energy of one process to another, and so on.

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Of course an engineer understands the principle behind a ratchet, or a valve, but he does not have to go through the process of thinking ”as part of this design, I will have to create a thing that lets stuff flow through one way and not the other.” The valve is the mechanical unit that stands for that thought, a concept reified in standardized material form which does not need to be taken apart and pa.r.s.ed each time it is used.

By contrast, the synthetic biologists claim, much of current biotechnological experimentation operates the way a seventeenth- century artisan did. Think of the gunsmith making beautiful one- off cla.s.sics for his aristocratic patrons, without standardized calibers, parts, or even standard-gauge springs or screws. The process produces the gun, but it does not use, or produce, standard parts that can also be used by the next gunsmith.

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Is this portrayal of biology correct? Does it involve some hyping of the new hot field, some denigration of the older techniques? I would be shocked, shocked, to find there was hype involved in the scientific or academic enterprise. But whatever the degree to which the novelty of this process is being subtly inflated, it is hard to avoid being impressed by the projects that this group of synthetic biologists has undertaken. The MIT Registry of Standard Biological Parts, for example, has exactly the goal I have just described.

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The development of well-specified, standard, and interchangeable biological parts is a critical step towards the design and construction of integrated biological systems. The MIT Registry of Standard Biological Parts supports this goal by recording and indexing biological parts that are currently being built and offering synthesis and a.s.sembly services to construct new parts, devices, and systems. . . . In the summer of 2004, the Registry contained about 100 basic parts such as operators, protein coding regions, and transcriptional terminators, and devices such as logic gates built from these basic parts. Today the number of parts has increased to about 700 available parts and 2000 defined parts. The Registry believes in the idea that a standard biological part should be well specified and able to be paired with other parts into suba.s.semblies and whole systems.

Once the parameters of these parts are determined and standardized, simulation and design of genetic systems will become easier and more reliable. The parts in the Registry are not simply segments of DNA, they are functional units.9 43

Using the Registry, a group of MIT scientists organizes an annual contest called iGEM, the International Genetically Engineered Machine compet.i.tion. Students can draw from the standard parts that the Registry contains, and perhaps contribute their own creations back to it. What kinds of ”genetically engineered machines” do they build?

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A team of eight undergraduates from the University of Ljubljana in Slovenia-- cheering and leaping onto MIT's Kresge Auditorium stage in green team T-s.h.i.+rts-- won the grand prize earlier this month at the International Genetically Engineered Machine (iGEM) compet.i.tion at MIT. The group--which received an engraved award in the shape of a large aluminum Lego piece--explored a way to use engineered cells to intercept the body's excessive response to infection, which can lead to a fatal condition called sepsis. The goal of the 380 students on 35 university teams from around the world was to build biological systems the way a contractor would build a house--with a toolkit of standard parts. iGEM partic.i.p.ants spent the summer immersed in the growing field of synthetic biology, creating simple systems from interchangeable parts that operate in living cells. Biology, once thought too complicated to be engineered like a clock, computer or microwave oven, has proven to be open to manipulation at the genetic level. The new creations are engineered from snippets of DNA, the molecules that run living cells.10 45

Other iGEM entries have included E. coli bacteria that had been engineered to smell like wintergreen while they were growing and dividing and like bananas when they were finished, a biologically engineered detector that would change color when exposed to unhealthy levels of a.r.s.enic in drinking water, a method of programming mouse stem cells to ”differentiate” into more specialized cells on command, and the mat of picture-taking bacteria I mentioned earlier.

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No matter how laudable the a.r.s.enic detector or the experimental technique dealing with sepsis, or how cool the idea of banana- scented, picture-taking bacteria, this kind of enterprise will cause some of you to shudder. Professor Drew Endy, one of the pioneers in this field, believes that part of that reaction stems from simple novelty. ”A lot of people who were scaring folks in 1975 now have n.o.bel prizes.”11 But even if inchoate, the concerns that synthetic biology arouses stem from more than novelty. There is a deep-seated fear that if we see the natural world of biology as merely another system that we can routinely engineer, we will have extended our technocratic methods into a realm that was only intermittently subject to them in a way that threatens both our structure of self-understanding and our ecosystem.

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To this, the synthetic biologists respond that we are already engineering nature. In their view, planned, structured, and rationalized genetic engineering poses fewer dangers than poorly understood interventions to produce some specific result in comparative ignorance of the processes we are employing to do so. If the ”code” is transparent, subject to review by a peer community, and based on known parts and structures, each identified by a standard genetic ”barcode,” then the chance of detecting problems and solving them is higher. And while the dangers are real and not to be minimized, the potential benefits--the lives saved because the scarce antimalarial drug can now be manufactured by energetic E. coli or because a cheap test can demonstrate a.r.s.enic contamination in a village well--are not to be minimized either.

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I first became aware of synthetic biology when a number of the scientists working on the Registry of Standard Biological Parts contacted me and my colleague Arti Rai. They did not use these exact words, but their question boiled down to ”how does synthetic biology fare in intellectual property's categories, and how can we keep the basics of the science open for all to use?” As you can tell from this book, I find intellectual property fascinating--lamentably so perhaps. Nevertheless, I was depressed by the idea that scientists would have to spend their valuable time trying to work out how to save their discipline from being messed up by the law. Surely it would be better to have them doing, well, science?

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They have cause for concern. As I mentioned at the beginning of this chapter, synthetic biology shares characteristics of both software and biotechnology. Remember the focus on reducing functions to black boxes. Synthetic biologists are looking for the biological equivalents of switches, valves, and inverters.

The more abstractly these are described, the more they come to resemble simple algebraic expressions, replete with ”if, then”

statements and instructions that resolve to ”if x, then y, if not x, then z.”

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If this sounds reminiscent of the discussion of the Turing machine, it should. When the broad rules for software and business methods were enunciated by the federal courts, software was already a developed industry. Even though the rules would have allowed the equivalent of patenting the alphabet, the very maturity of the field minimized the disruption such patents could cause. Of course ”prior art” was not always written down.

Even when it was recorded, it was sometimes badly handled by the examiners and the courts, partly because they set a very undemanding standard for ”ordinary expertise” in the art.

Nevertheless, there was still a lot of prior experience and it rendered some of the more basic claims incredible. That is not true in the synthetic biology field.

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Consider a recent article in Nature, ”A universal RNAi-based logic evaluator that operates in mammalian cells.”12 The scientists describe their task in terms that should be familiar.

”A molecular automaton is an engineered molecular system coupled to a (bio)molecular environment by 'flow of incoming messages and the actions of outgoing messages,' where the incoming messages are processed by an 'intermediate set of elements,'

that is, a computer.” The article goes on to describe some of the key elements of so-called ”Boolean algebra”-- ”or,” ”and,”

”not,” and so on--implemented in living mammalian cells.

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These inscriptions of Boolean algebra in cells and DNA sequences can be patented. The U.S. Department of Health and Human Services, for example, owns patent number 6,774,222: 53

This invention relates to novel molecular constructs that act as various logic elements, i.e., gates and flip-flops. . . .

The basic functional unit of the construct comprises a nucleic acid having at least two protein binding sites that cannot be simultaneously occupied by their cognate binding protein. This basic unit can be a.s.sembled in any number of formats providing molecular constructs that act like traditional digital logic elements (flips-flops, gates, inverters, etc.).