A Video Worth Watching from Time's Man of the Year 2010

Note: Since I posted the NASA Ames video, someone has pulled permission for both embedding and public viewing. But here is the "60 Minutes" interview filmed just after the achievement of creating a strain of mycoplasma mycoides. I'll leave the locked video here for now -- just in case the owners come to their senses.

J. Craig Venter on Synthetic Biology at NASA Ames from Ben Howard on Vimeo.

Craig Venter is Time's Man of the Year for 2010 for his team's "plug and play" creation of the first synthetic cell, Mycoplasma mycoides. This "minimal cell", a parasitic organism which can only live inside other living cells, is meant as a starting point for the creation of microscopic factory-cells.

The aim of the Venter team was.....to build a prototype for a microscopic production line. Back in May, here is what the team had to say in Science:

If the methods described here can be generalised, design, synthesis, assembly and transplantation of synthetic chromosomes will no longer be a barrier to the progress of synthetic biology … the approach we have developed should be applicable to the synthesis and transplantation of more novel genomes as genome design progresses.

So, if a microorganism could be engineered to include genes that direct the cell to do a number of functions, it would be possible to use this cell for a range of industrial tasks, such as making proteins or carbohydrates or any compounds to order, depending on demand. Theoretically, it might be possible to make biofuels, vaccines, drugs, foodstuffs and anything else genetic engineers can program the new genomes to produce.

What Venter's team really set out to do, and achieved, was show it's possible to build the world's smallest production line, inside the world's smallest factory.

Venter was not so much playing God, but following in the tradition of the great industrial pioneers of last century. He's closer to a latter day Henry Ford - the man who in the 1910s developed the production line that eventually put a car in almost every home in the Western world and became the de novo engineering tool for the mass production of everything from ice cream to tweezers.

What happens next depends on how Venter and others working in this new field can tool up this tiny production line. _Cosmos

"Synthetic Biology" is a far more clever and descriptive term than "metabolic engineering." The word "synthetic" does double duty, since not only are new biological factories to be synthetically generated, but these biological factories are to be used to synthesise valuable chemicals, materials, fuels, and drugs.

We are seeing the preface to the first chapter of a multi-volume work. Much more to come.

What Is Metabolic Engineering and Why Should We Care?

LBLNewsMetabolic Engineering is one of those bastard terms which is often spawned by science-savvy folks in academia who are functionally illiterate. For example, MIT has a lab department of Bioinformatics and Metabolic Engineering. Rice has studies in Biological Chemistry and Metabolic Engineering. Harvard teaches Systems Metabolic Engineering. Cornell has a lab for Biomolecular and Metabolic Engineering. At Berkeley, the subject falls under the Department of Chemical and Biomolecular Engineering... and so on. When will we be given entire departments of Respiratory Engineering, Mitochondrial Engineering, Liposome Engineering, or Cholesterol Membrane Engineering? There truly is no end to the number of departmental classifications that could be spawned by the postmodern twits of academia who have acquired a little bit of specialised scientific training.

Forgive me, I got a bit sidetracked. Chemical engineer Jay Keasling has published an article in Science discussing the "Future of Metabolic Engineering," in which he looks at the possibilities of creating designer molecules, cells, and micro-organisms.

In a paper published in the journal Science titled “Manufacturing molecules through metabolic engineering,” Keasling discusses the potential of metabolic engineering – one of the principal techniques of modern biotechnology – for the microbial production of many of the chemicals that are currently derived from non-renewable resources or limited natural resources. Examples include, among a great many other possibilities, the replacement of gasoline and other transportation fuels with clean, green and renewable biofuels.

“Continued development of the tools of metabolic engineering will be necessary to expand the range of products that can be produced using biological systems, Keasling says. “However, when more of these tools are available, metabolic engineering should be just as powerful as synthetic organic chemistry, and together the two disciplines can greatly expand the number of chemical products available from renewable resources.”

...Metabolic engineering is the practice of altering genes and metabolic pathways within a cell or microorganism to increase its production of a specific substance. Keasling led one of the most successful efforts to date in the application of metabolic engineering, when he combined it with synthetic organic chemistry techniques to develop a microbial-based means of producing artemisinin, the most potent of all anti-malaria drugs. He and his research group at JBEI are now applying that same combination to the synthesis of liquid transportation fuels from lignocellulosic biomass. In all cases, the goal is to engineer microbes to perform as much of the chemistry required to produce a desired final product as possible.

“To date, microbial production of natural chemical products has been achieved by transferring product-specific enzymes or entire metabolic pathways from rare or genetically intractable organisms to those that can be readily engineered,” Keasling says. “Production of non-natural specialty chemicals, bulk chemicals, and fuels has been enabled by combining enzymes or pathways from different hosts into a single microorganism, and by engineering enzymes to have new function.”

These efforts have utilized well-known, industrial microorganisms, but future efforts, he says, may include designer molecules and cells that are tailor-made for the desired chemical and production process. _LBLNews_via_BrianWang

Sound familiar, this metabolic engineering? Like a contrived illegitimate offspring of genetic engineering, synthetic biology, and metabolomics? It's bad enough to have a proliferation of -omics, such as genomics, proteinomics, metabolomics, glycomics, lipomics . . . It is almost enough to turn a person homicidalomic.

Psychiatry with its DSM is almost as insane. But these irrational and cumbersome systems of classification tend to evolve by the method of poorly punctuated disequilibrium, leaving those downstream to deal with the offalness of it all.

Does Keasling simply want to excel in a field that another researcher -- Craig Venter -- has already staked out -- synthetic biology? Venter has long since founded a company called Synthetic Genomics. Is it possible that Keasling is unwilling to share the same field with a person such as Venter, who is already hot on the trail of the very things that Keasling claims to be pursuing in the name of Metabolic Engineering? Fine. Do the same thing, but call it something different. No one will ever know.

Controlling Microbial Genes: Beyond Synthetic Biology

While other gene-expression techniques need to be engineered for a particular gene, Collins says, the RNA-based switch "can be used to control any gene of interest." Other switches rely on proteins to regulate gene expression. But the use of proteins requires several steps, which means they're not as fast to make as the RNA switches. _TR

Kill switch: From top left to bottom right, these images show bacteria dying over the course of a few minutes. Researchers flip a genetic switch that causes the bacteria to make proteins that cause them to burst.
Credit: PNAS
Scientists at Boston University have developed the ability to control the activity of any microbial gene -- reducing or even stopping any gene's protein synthesis activity.

...researchers at Boston University, led by biomedical engineering professor James Collins, have developed a highly tunable genetic "switch" that offers a greater degree of control over microbes. It makes it possible to stop the production of a protein and restart it again. The switch, which could be used to control any gene, can also act as a "dimmer switch" to finely tune how much protein a microbe would produce over time.

The researchers made a highly effective microbe "kill switch" to demonstrate the precision of the approach. For years, researchers have been trying to develop these self-destruction mechanisms to allay concerns that genetically engineered microbes might prove impossible to eradicate once they've outlived their usefulness. But previous kill switches haven't offered tight enough control to pass governmental regulatory muster because it was difficult to make it turn on in all the cells in a population at the same time.

...Collins's switch, described online in the Proceedings of the National Academy of Sciences, turns a modified gene on and off. The switch is created by sequences of DNA that can be added to any gene that a bioengineer wants to regulate. When the cell takes the first step toward expressing that gene--making an intermediate molecule of RNA that can be "read" to make the relevant protein--it also creates the RNA switch. When the first, "off" RNA switch is made, it latches onto the ribosome, preventing it from making a particular protein. When the second, "on" switch is made, it pulls the first RNA switch off of the ribosome and binds to it the switch, freeing the ribosome to resume production.\

Depending on how they're designed, production of the RNA switches can be regulated by exposing the bacteria to a particular chemical. By controlling how much of the "on" and "off" RNAs are made, it's also possible to regulate protein production over a continuum, not just turn it totally on or off.

...Such a kill switch could be useful in microbes designed to, for example, break down environmental toxins. Once the microbes have cleaned up a toxin, "you could spray the area with an innocent compound that triggers cells to expire on command," says Collins. The kill switch could also be coupled to other synthetic biology tools such as genetic clocks in order to design bacteria that live for a given number of days.

These switches make it possible "to do the kinds of things people like me struggle to do," says Robertson. One of the main challenges for a company like Joule, he says, is complying with regulations about environmental containment of genetically modified organisms, and Collins's switch could help.

Collins is currently working to combine the switches to make what he calls tunable "switchboards." "We want to tune genes like a rheostat," he says. Such a switchboard might be used to control a population of cells so that they first put their energies toward growing their population. Then, when engineers deem it timely, they can administer chemical signals that cause the cells to gradually ramp up production of a fuel, for example. _TechnologyReview

By starting with a gene-packed bacterium, the scientists could conceivably "tune" the cell to behave just like a wide range of other bacterial species -- depending upon which genes were "switched on or off" at the time. The only thing missing would be a means to generate new controllable genes on the fly.

This type of development will actually be blended into the field of synthetic biology -- but it will extend the field significantly. Now, instead of simply designing new life forms which will behave as designed, synthetic biologists can design "programmable life forms" which can serve as flexible test beds for a wide range of genetic experiments.

The possibility for the transfer of such techniques to mammalian cells should be setting off warning klaxons among the dieoff.orgy lefty-Luddites from Berkeley to Manhattan to Brussels. And to think they're worried about genetically modified foods!