Little things that count
Optimising natural talent
The use of chemical makeup found in single cell organisms to transform raw materials into environmentally friendly products is a novel approach to manufacturing but it is not as far-fetched as it appears, as E&T discovers.
Imagine bacteria acting as a mini-manufacturing facility, creating products such as medicine, plastics and fuels. It may all sound like something from a Michael Crichton novel, but far from it. This science fiction is well on its way to becoming a reality, driven by work around the globe at research establishments.
One of the leading hot-beds of this technology - dubbed synthetic biomanufacturing - is a group of Utah State University researchers in the colleges of science and engineering who have joined together to create the Synthetic Biomanufacturing Centre.
Building on advances in synthetic biology, single-cell organisms have the possibility of producing high-value compounds to help solve some of the world's most pressing health, agricultural and energy problems.
There is the opportunity to use nature's highly efficient factories - biological cells - as the manufacturing centres of the future. The new Synthetic Biomanufacturing Centre will focus on using the inherent chemical machinery present in single-cell organisms, both prokaryotic and eukaryotic, to transform raw materials into usable low cost bioproducts.
Their goal is to adapt single-cell organisms through synthetic biology to become small solar- or chemically-powered factories, which may use CO2 as their primary carbon source, and that will secrete or emit useful and natural biomaterials and energy.
The centre will also develop the downstream bioprocessing techniques necessary to collect, separate, purify, concentrate, and prepare the new biomaterials for commercial products.
"Bioscientific advances have reached a point where it is now possible to design living cells to produce things that previously could only be made in chemical factories," Dr Leland Foster, executive director of USTAR (Utah Science Technology and Research initiative) Synthetic Biomanufacturing Centre, says. "We want to take advantage of these new capabilities."
As with many modern disciplines, there is a great variance between what one company would call biomanufacturing and another would call synthetic biomanufacturing, but Dr Foster is clear on the distinction. "When you talk about synthetic biology that is an enormously broad term and everyone you speak with has a different definition of what it is," he says.
"On the one extreme, it is creating life off-the-shelf. You have all of the parts and pieces like in an automobile factory and you can get a promoter for a gene; you can get the gene and all of the control agents and bolt them together. And, all of a sudden, voilà!, you have life. That's on the far extreme.
"But, to me, synthetic biology is one level of what we would previously have called genetic engineering. Some of the difference being that you actually manufacture outside of the organism the base structure or sort of BioBricks [see sidebar, p65]. Then you insert these bricks into your organism. A BioBrick is a self-contained unit that manipulates a certain part of the gene; it is an operand, synthetically produced and inserted into the gene arm.
"It's not just a matter of transferring one gene from nature into an organism, which would be what genetic engineering was a few years ago; but it is actually doing laboratory manipulations further than has been done and then re-inserting into a micro-organism."
The centre will first focus on identifying and creating the cell platforms best suited for biomanufacturing environments. The team will then create methods to allow the organisms to use both solar and chemical energy to power the biomanufacturing process which will secrete or excrete the desired naturally synthesised product.
The synthesised product will then be used to create things, such as a renewable fuel or pharmaceuticals that can then be moved into the marketplace.
According to Dr Foster, these technologies are similar to the silicon infrastructure that made silicon-based electronics the transforming technology of the 20th century.
Bioprocessing new products
The second phase at the centre will be aimed at the identification and creation of new products that can be created in these single-cell organisms and the downstream bioprocessing required to convert the biomaterials into useful commercial products.
"What we are doing is inducing living micro-organisms to produce useful chemicals," Dr Foster explains. "For example, let's take an antibiotic, which may be difficult to chemically synthesise, perhaps even impossible. It may be possible to work with the genetics of bacteria to induce them to actually make chemical alterations to some core-based chemical by attaching various groups here or there, but otherwise is impossible or very difficult to do in the test tube."
Another approach that the centre is looking at is to manufacture bioplastics. "There are some organisms - naturally occurring in the environment - that may produce precursors to bioplastics at extremely low levels," adds Dr Foster. "If we were to take these organisms out of nature, isolate their capability for doing that and introduce them into a flexible bacterial-based manufacturing system, then we could increase the production of those bioplastic precursors to much higher levels and produce them more economically."
A lot of the work is based on the use of BioBricks developed by MIT which are, in essence, off-the-shelf building blocks for the biofactory. "That is the essence of having parts and pieces of the genetic code and its operating system on the shelf that we pull off the shelf and assemble together like Lego toys," explains Dr Foster. "We insert those inside our bacteria and those insertions then turn that bacterium into a mini manufacturing facility.
"Our centre is developing a flexible common manufacturing process to which individuals who are interested in producing various helpful chemicals in any form bring their product and say, 'I want to produce this in a biosystem, can you adapt your manufacturing system to allow it to be produced?'. And the answer is now, hopefully, yes."
Understanding complex proteins
Work on understanding proteins has been going on for some time but, as Dr Foster explains, it is the movement from studying single proteins to more complex arrangements that has led to this burgeoning industry. "Historically, biologists have always tried to study nature one protein at a time - they study it for years and years and put all the proteins together like Lego.
"What we are doing is attacking the problem from the other end. We say 'let's throw all that out and assemble the minimum organism and its characteristics possible to maintain independent life'. So, in other words, we wipe the slate clean and say we need a few of these and a few of these and let's put them together and see if we can get this thing to work as opposed to trying to tease apart centuries of evolution.
"Part of the reason why this is not a common practice approach by scientists, is that all of the glamour, all of the Oscars, the Nobel prizes, are given out for the manipulation of the gene and getting the bacterium to produce a very useful bioplastic which would replace petroleum-based feed stocks, be biodegradable and also be as utilitarian as the current plastics are. But the problem is that those are usually produced at very minute amounts on the laboratory bench, in sufficient amounts to get a paper in a journal.
"We take it to the next step, and that is once the organism is producing a product. How do you process it on an industrial scale so that, from the bacteria that are producing small amounts each, you can produce trainloads or carloads of plastic.
"I would say that it is the blue collar end of the white collar line."
As for what you would see if you visited one of these biomanuafcturing facilities of the future, Dr Foster likens it to a microbrewery. "You would have the fermenting vessel, where all of the bacteria that have been synthetically manipulated are produced," he says. "Then you have to grow them in the millions, so you have a large fermenter and then, from there, you then move through the downstream process, the extraction of the bioplastic precursors from the soup that the bacteria are growing in."
Rather than developing any particular product, the centre is focusing on developing a standard but flexible processing system.
"What we are focusing on is how to produce or create an adaptable manufacturing system through which we can place whatever useful chemical anyone would come to the door with."
Combatting malaria with wormwood
There have already been some small successes. Dr Foster tells the story of an anti-malarial drug made from Wormwood in Vietnam and China. "The material can be isolated from the natural source, but it cannot be synthesised cheaply in a test tube," he says.
"The Gate Foundation is funding work that is trying to get useful micro-organisms - like we are talking about - to produce the same kind of chemical that the Wormwood plants were producing and produce a very inexpensive source of an anti-malarial which could then be used in developing countries.
"I think there would be a great deal of support, even among those who are not very anxious to consume genetically-modified corn in their breakfast cereal."
BioBricks as building blocks
BioBrick standard biological parts are DNA sequences of defined structure and function. They share a common interface and are designed to be composed and incorporated into living cells to construct new biological systems.
They represent an effort to introduce the engineering principles of abstraction and standardisation into synthetic biology. BioBrick parts were introduced by Tom Knight at MIT, while Drew Endy, now at Stanford, and Christopher Voigt, at UCSF, are also heavily involved in the project.
One of the goals of the BioBricks project is to provide a workable approach to nanotechnology employing biological organisms. Another, more long-term goal is to produce a synthetic living-organism from standard parts that are completely understood.
Each BioBrick part is a DNA sequence held in a circular plasmid; the 'payload' of the BioBrick part is flanked by universal and precisely defined upstream and downstream sequences which are technically not considered part of the BioBrick. These sequences contain six restriction sites for specific restriction enzymes (at least two of which are isocaudomers), which allows for the simple creation of larger BioBrick parts by chaining together smaller ones in any desired order.
In the process of chaining parts together, the restriction sites between the two parts are removed, allowing the use of those restriction enzymes without breaking the new, larger BioBrick apart.
There are three levels of BioBrick parts: parts, devices and systems. Parts are the building blocks and encode basic biological functions (such as encoding a certain protein, or providing a promoter to let RNA polymerase bind and initiate transcription of downstream sequences); devices are collections of parts that implement some human-defined function (such as producing a fluorescent protein whenever the environment contains a certain chemical); systems perform high-level tasks (such as oscillating between two colours at a predefined frequency).
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