Synthetic Biology Resources

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Summer 2008, the Department of Genetics at the University of Cambridge hosts a team of engineering, natural science, physical science and mathematicians undergraduates taking part in the International Genetically Engineered Machines competition (iGEM) in Synthetic Biology. This competition has a worldwide reputation with eighty-four University and Research Institutes taking part this year. iGEM-2008

[edit] Definition of Synthetic Biology

Synthetic biology (also known as Synbio, Synthetic Genomics, Constructive Biology, Extreme Genetic Engineering or Systems Biology) – the design and construction of new biological parts, devices and systems that do not exist in the natural world and also the redesign of existing biological systems to perform specific tasks. Advances in nanoscale technologies – manipulation of matter at the level of atoms and molecules – are contributing to advances in synthetic biology.

Drew Endy: Defining Synthetic Biology - Video

[edit] Basics of SynBio

At the core of synthetic biology is a belief that all the parts of life can be made synthetically (that is, by chemistry), engineered and assembled to produce working organisms. DNA code is regarded as the software that instructs life, while the cell membrane and all the biological machinery inside the cell are regarded as the hardware (or wetware as it is sometimes known) that need to be snapped together to make a living organism.

DNA synthesis reduces the time it takes genetic engineers to isolate and transfer DNA in order to build genetically modified organisms.

“We’re going to build you exactly what you are looking for: Whole plasmids, whole genes, gene fragments . . . and in one to two years, possibly a whole genome.” – John Mulligan CEO of Blue Heron Biotechnology, Washington (USA)

“There is no technical barrier to synthesizing plants and animals, it will happen as soon as anyone pays for it.” — Drew Endy, MIT

Drew Endy of MIT speculates that within 20 years human genomes will be synthesised from scratch.

At present Craig Venter holds the world’s gene-speed record for synthetically producing a 5,386 bp genome (of the virus phiX 174) in under 14 days (although there were errors in his copy).

Synthetic biologists want to work below the level of the gene, at the level of the codon – to identify codons and rearrange them to build new sets of biological instructions. Because there are 64 possible codons (four bases linked together in sets of three, or 4*4*4) but only 20 different amino acids they translate into, synthetic biologists can choose among different options for codons when they want to express a specific amino acid (known as codon optimization). It may be that one codon works better in bacteria and another in plants even though both produce the same amino acid.

Some synthetic biologists take the approach of combing through the genetic code of existing organisms and removing or reducing unnecessary codons to get a sleeker version of the genetic code. Others, by combining codons into stand-alone programming instructions, are developing “standard parts” analogous to the standard parts of electronic circuitry or the standard commands of a computer language. They keep an inventory of these standard parts, and are making them available for others to assemble into more complex genetic systems. Others are designing entirely new artificial amino acids that result from codon combinations not found in nature.

In the US and Europe some synthetic biologists hope to build an artificial “protocell” that will contain and express synthetic DNA as flexibly as a computer stores document files and runs computer programmes.

Unfortunately for would be life builders, genetic code is not as linear as computer code. While the popular view of genetics links units of DNA (genes) to specific traits, the reality is messier. In real life, genes and parts of genes co-operate in subtle and complex networks, each producing proteins that promote or suppress the behaviour of other genes. The result is a system of cellular regulation that controls the amount or timing by which a substance or trait is produced – a bit like electronic circuits that regulate electrical current.

Geneticists interested in manipulating genomes have begun mapping the interactions between genes to try to determine the full set of interactions necessary to produce a desired protein. They can represent these networks with circuit diagrams similar to those used in electronics. The set of interactions that involve a network of DNA molecules acting together to produce a protein can be referred to as a “genetic pathway” and synthetic biologists are now trying to rebuild or alter these genetic pathways as discreet sections of the genome. This involves designing not just one coding region of DNA, but several different areas of code, and then putting them together as a synthetic chromosome. By altering these networks and pathways, synthetic biologists can increase the production of a protein or stimulate the production of an entirely different substance, such as a plastic or a drug.

[edit] An Introduction to Five Major Areas of Research in Synthetic Biology

[edit] Making Minimal Microbes – Post-modern Genomics

In 1995 Venter announced that he was first to sequence the entire genome of a living organism (the bacterium known as Hemophilus influenzae). In 2003 Venter made headlines when his team created the first synthetic virus from scratch – and it took them only 14 days to do it. Venter is notorious for pushing the boundaries on the commercial exploitation of life. His newest commercial venture, Synthetic Genomics, Inc., founded in 2005 with $30 million in venture capital, aims to commercialise a range of synthetic biology applications, starting with energy production. He was also demostrated in Minimal Genome Project (1990) in Mycoplasma genitalium that the bacterium might be able to survive with almost half its genes removed. Others are now trying to minimise the genome of organisms such as E. coli.

Venter calls Mycoplasma laboratorium a “synthetic chromosome” and his intention is to use it as a flexible biofactory into which custom-designed synthetic “gene-cassettes” of four to seven genes can be inserted, genetically programming the organism to carry out specific functions. As a first application, Venter hopes to develop a microbe that would help in the production of either ethanol or hydrogen for fuel production (See the New Synthetic Energy Agenda ). He is also looking to harness the mechanisms of photosynthesis to more effectively sequester carbon dioxide, ostensibly as a means of slowing climate change. Venter talks big. In 2004 he predicted that “engineered cells and lifeforms [will be] relatively common within a decade.”

[edit] Assembly-Line DNA – “Lego” Life-forms to Order

Drew Endy (MIT), an engineer by training, is also a computer programmer and he and those around him use computer and electronics metaphors to describe synthetic biology: A living organism is a ‘computer’ or ‘machine’ made up of genetic ‘circuits’ in which DNA is the ‘software’ that can be ‘hacked.’ He points out that, “Biological engineers of the future will start with their laptops, not in the laboratory. Let’s build new biological systems – systems that are easier to understand because we made them that way.” Endy longs for a logical and predictable biotechnology, what he and others refer to as “intentional biology.” “We would like to be able to routinely assemble systems from pieces that are well described and well behaved,” Endy explains.

The BioBrick Foundation - To do this he and his colleague at MIT, artificial intelligence pioneer Tom Knight, have invented several hundred discrete DNA modules that behave a little like electronic components. They include sequences that turn genes off and on, transmit signals between cells or change colours between red, green, yellow and blue. Knight and Endy then encourage others to combine those modules into more complex genetic circuits. They call these modules Biobricks or “standard parts” and their non-profit BioBricks Foundation maintains over 2000 BioBricks in its registry of standard parts that can be freely used by other synthetic biology researchers. Each of these BioBricks is a strand of DNA designed to reliably perform one function and to be easily compatible with other BioBricks in making longer circuits. The completed circuits are then dropped into E. coli, yeast or another microbial host to see if they function.

Every year Endy, Knight and their fellow synthetic biologists at MIT convene an International Genetically Engineered Machine Competition (known as iGEM).iGEM, now in its fifth year, mostly produces eye-catching gimmicks – bacteria that blink different colours and biological films that can be programmed to take simple photographs and display images. In 2006 the iGEM team from MIT designed E. coli bacteria that smell of bananas and wintergreen. Biological films that take photographs could be the basis of new forms of lithography for assembling computer circuits, while sweet smelling bacteria could interest the fragrance and flavouring industries.

Endy talks about building circuits into human body cells that count how many times they divide in order to prevent run-away cell growth. “I could hook it up to a suicide mechanism,” he speculates, “and any cell that divides more than 200 times, it would say, ‘Kill it, it’s forming a tumour’…” One of Endy’s long term ambitions is to re-design the seeds of a tree such that the tree is programmed to grow into a house.

[edit] Building Artificial Cells (Proto-Cell) from the Bottom Up – Ersatz Evolution

Steen Rasmussen & his research team believes their “protocell” will require three elements to sustain life – a metabolism that harvests and generates energy, an information-storing molecule (like DNA) and a membrane to hold it all together. to build a living cell entirely from scratch. While most synbio projects are top-down – re-arranging existing life or reverse-engineering.

Rasmussen is tweaking nature’s cell design for his “Los Alamos Bug.” Rather than an oily membrane keeping water inside, his cell is basically a droplet of oil, which keeps water on the outside. Furthermore, it uses a different double helix molecule to carry instructions: Rather than DNA, the Los Alamos Bug uses human-made PNA – peptide nucleic acid. PNA has the same structure and is made from the same chemical bases as DNA – G, C, A and T – but the molecule’s backbone is made of peptides, the build- ing blocks of proteins – instead of DNA’s sugar-phosphate backbone. Howard Packer, Rasmussen’s collaborator as well as a pioneer of chaos theory, says that using PNA rather than DNA is a good idea for biosafety reasons. Because PNA doesn’t exist in nature, he says, the Bug may be easier to control so it doesn’t “escape and cause problems. he argues that the protocell approach will lead to a better understanding of living and non-living systems.

PACE – Programmable Artificial Cell Evolution – is a project involving 14 European and US universities and companies and is funded by the European Commission.

[edit] Pathway Engineering – Bug Sweatshops

“Really, we are designing the cell to be a chemical factory. We’re building the modern chemical factories of the future.” – Jay Keasling, Professor of Chemical Engineering, University of California at Berkeley.

Jay Keasling is engineering the genetic pathways of cells to produce valuable drugs and industrial chemicals. Keasling’s team has synthesised about a dozen genes that work together to make the chemical processes (or ‘pathways’) behind a class of compounds known as Isoprenoids – high-value compounds important in drugs and industrial chemicals. Isoprenoids are natural substances produced primarily by plants. Because of their structural complexity, chemical synthesis of most isoprenoids has not been commercially feasible, and isolation from natural sources yields only very small quantities. Synthetic biologists at Berkeley hope to overcome these limitations by designing new metabolic pathways in microbes, turning them into “living chemical factories” that produce novel or rare isoprenoids. Most notably, they are focusing on a powerful anti-malarial compound known as Artemisinin. Backed by a $42.5 million grant from the Bill and Melinda Gates Foundation, the Berkeley team believes that synthetic biology is the tool that will allow unlimited and cheap production of a previously scarce drug to treat malaria in the developing world. In 2003 Keasling and colleagues founded a synbio start-up called Amyris Biotechnologies to bring the project to fruition. Keasling says “We’ve essentially created a platform that will allow you to produce many drugs cheaper. Down the road, we will be able to modify enzymes to produce a number of different molecules, even some that don’t exist in nature.” Amyris plans to use synthetic biology to produce commercial drugs, plastics, colourants, fragrances and biofuels.

Keasling’s lab is also attempting to re-engineer the metabolic pathways that produce natural rubber (also an Isoprenoids).101 These pathways will then be incorporated into bacteria, or in sunflowers or desert plants, to boost rubber production.

Other researchers exploring commercial uses for pathway engineering, include:

Chris Voigt, a synthetic biologist at the University of California at San Francisco announced in May 2006 that he had re-engineered a strain of salmonella to produce the precursor to spider silk – a substance as strong as Kevlar with 10 times the elasticity.

California-based Genencor has been working with chemical giant DuPont to add synthetic genetic networks to the cellular machinery of E. coli. When mixed with corn syrup in fermentation tanks, their modified bacterium produces a key component in Sorona, a spandex like fibre. DuPont hopes that its new bio-based textile will cause as much fuss as the introduction of nylon back in the 1930s.

[edit] Expanding Earth’s Genetic System – Alien Genetics

“We’re trying to expand the genetic code.” — Dr. Floyd E. Romesburg, Scripps Research Institute.

Steven Benner, a biochemist and founder of the Westheimer Institute for Science and Technology (Benner was formerly based at the University of Florida) is a pioneer of synthetic biology. He builds models of how life might function using unnatural genetic systems. His argument is simple: There is no reason the limited set of molecules in DNA should be the only form of life that has arisen in the universe and we need models of what other kind of life could be out there. “We can’t think of any transparent reason that these four bases [A, G, C and T] are used on earth,” explains Benner.

Benner has demonstrated that a number of novel biological molecules can be chemically synthesised so that they reproduce and pass on their genetic inheritance in the same way that DNA does. He sees artificial genetics as a way to explore basic questions, such as how life got started on earth, how it evolves and even what forms it may take elsewhere in the universe.

In 2004 Benner further showed that his six-letter DNA-like molecule (including letters ‘K’ and ‘X’) could support the molecular “photocopying” operation known as polymerase chain reaction, in which the molecule copies itself and then directs the synthesis of copies of copies. Since natural polymerase enzymes rejected his artificial base pairs, Benner was forced to design a new, compatible version of the enzyme polymerase.

“Considering how hard we had to work to get Earth polymerases to accept our artificial DNA, we doubt that our artificial DNA would survive for an instant outside of the laboratory on this planet,” explains Benner. “But a six-letter DNA might support life on other planets, where life started with six letters and is familiar with them. Or even DNA that contains up to 12 letters, which we have shown is possible.”

In 2005 Floyd Romesburg, a biochemist at the Scripps Institute in La Jolla, California, added an extra letter F (made from flourobenzene) to the existing four bases that occur naturally in DNA, and successfully created an enzyme that can make the modified biomolecules self-replicate.

Stanford University chemist Eric T. Kool has re-designed the existing base pair A and T to be larger – creating an expanded double helix that glows in the dark and is unusually stable at higher temperatures. Kool dubbed his new molecule xDNA (for expanded DNA): “We’ve designed a genetic system that’s completely new and unlike any living system on Earth,” announced Kool. Like Benner, Kool emphasises that expanded DNA will not pose new biosafety risks. “This new DNA couldn’t function in the natural system on Earth,” he asserts. “It’s too big. However, we like to think that one day it could be the genetic material for a new form of life, maybe here or on another planet.”

Benner and Kool haven’t built their artificial genetic systems into full organisms yet. “I suspect that, in five years or so, the artificial genetic systems that we have developed will be supporting an artificial lifeform that can reproduce, evolve, learn and respond to environmental change,” Benner predicted in 2004.

Although Benner and others are confident that artificial genetic systems will not survive outside the lab, research in this field raises profound biosafety questions. Dr. Jonathan King, a professor of molecular biology at MIT told the New York Times: “It’s a powerful technology, and like all powerful technologies it needs appropriate oversight and regulation.” One possible scenario he suggested is that proteins with artificial amino acids could elicit allergic reactions if used in drugs or in food.

[edit] International Meetings & Conferences on Synthetic Biology

Synthetic Biology 1.0 - The First International Meeting on Synthetic Biology June 10-12, 2004 at the Massachusetts Institute of Technology Cambridge, MA.

Synthetic Biology 2.0 - The Second International Meeting on Synthetic Biology, May 20-22, 2006 at the University of California, Berkeley, CA, USA.

Synthetic Biology 3.0 - The Fourth International Meeting on Synthetic Biology, 24th-26th June 2007, Zurich, Switzerland

Synthetic Biology 4.0 - The Fourth International Meeting on Synthetic Biology, October 10-12, 2008 Hong Kong University of Science and Technology, Hong Kong.

iGEM - The International Genetically Engineered Machines (iGEM) competition is an annual, worldwide competition that involves undergraduate and graduate students in synthetic biology. It differs radically from most high-level educational experiences in that the participants often begin with limited backgrounds in science.

iGEM 2006 - The Jamboree, November 4-5, 2006, MIT, Cambridge, MA, USA.

iGEM 2007

iGEM 2008

[edit] Tools and Web-resources of SynBio

The BioBricks Foundation

A BioBrick standard biological part is a standard biological part that meets the technical and legal standards set forth by the BioBrick Foundation (BBF). Each distinct BioBrick standard biological part is a nucleic acid-encoded molecular biological function (e.g., turn on/off gene expression), along with the associated information defining and describing the part. BioBrick standard biological parts is open and free-to-use collection of standard biological parts.

BBF Technical Standards

BioBricks Web Home Page

Registry of Standard Biological Parts

[edit] Implications of Synthetic Biology

"One of the dreams of synthetic biology is that we will one day be able to produce any chemical in a microorganism by introducing the appropriate biosynthetic and tailoring enzymes and, in the process, replace environmentally unfriendly and/or arduous chemical synthesis routes." - Jay Keasling

[edit] Building a Better Bio-Weapon – What does synthetic biology mean for bioweapons?

“I expect that this technology will be misapplied, actively misapplied and it would be irresponsible to have a conversation about the technology without acknowledging that fact.” – Drew Endy, Synthetic Biologist, MIT.

Then there was the flu. The strain of avian influenza that jumped to humans early in the last century (H1N1), sometimes known as “The Spanish Flu,” killed somewhere between 20 and 50 million people worldwide in 1918-1919 – a higher death toll than all of World War I. Despite the lethal nature of the highly communicable virus, efforts to reconstruct it began in the 1950s. (By that time the H1N1 strain was eradicated from the earth – having disappeared with its last victims.) In 1997, Dr. Jeffrey Taubenberger of the US Armed Forces Institute of Pathology in Washington, DC succeeded in recovering and sequencing fragments of the viral RNA from preserved tissues of 1918 flu victims buried in the Alaskan permafrost. Eight years later, Taubenberger’s team and collaborating researchers at Mount Sinai School of Medicine in New York and the US Centers of Disease Control (CDC) in Atlanta adannounced that they had resurrected the lethal virus. They published details of the completed genome sequencing in Nature and details of the virus recreation in Science. About ten vials of the flu virus were produced with the possibility that more could be made to accommodate research needs, according to the CDC scientist who inserted the virus into a living cell, the last step in its reconstruction. Craig Venter later described the resurrection of the 1918 flu virus as “the first true Jurassic Park scenario.”

But concerns about synbio’s bioweaponry potential are not limited to the construction or reconstruction of virulent microorganisms. Work in the area of pathway engineering is allowing synthetic biologists to construct the genetic networks that code for particular proteins and these synthetic networks can then be inserted into microbial hosts such as E. coli or yeast. Microbes could function as “biofactories” to produce natural protein poisons such as snake, insect and spider venoms, plant toxins and bacterial toxins such as those that cause anthrax, botulism, cholera, diphtheria, staphylococcal food poisoning and tetanus. In addition, biowarfare experts are concerned that protein engineering could be used to create hybrids of protein toxins.

A 2003 declassified CIA document from the US, entitled “The Darker Bioweapons Future,” acknowledges that, “Growing understanding of the complex biochemical pathways that underlie life processes has the potential to enable a class of new, more virulent biological agents engineered to attack distinct biochemical pathways and elicit specific effects...The same science that may cure some of our worst diseases could be used to create the world’s most frightening weapons.”

Synbio’s rapidly changing nature will also affect the way that nations conduct war.

"The same science that may cure some of our worst diseases could be used to create the world’s most frightening weapons.” — CIA report, “The Darker Bioweapons Future”

[edit] The New Synthetic Energy Agenda – Rebooting Biofuels

“We think this area [Synthetic Genomics] has tremendous potential, possibly within a decade, to replace the petrochemical industry.” — Craig Venter speaking at Synthetic Biology 2.0

Synthetic biology’s promoters are hoping that the promise of a very “green” techno-fix – synthetic microbes that manufacture biofuels cheaply or put a chill on climate change – will prove so seductive that the technology will win public acceptance despite its risks and dangers.

Craig Venter’s new company, Synthetic Genomics, Inc. aims to use microbial diversity collected from seawater samples as the raw material to create a new synthetic microbe – one that is engineered to accelerate the conversion of agricultural waste to ethanol. Department of Energy report called From Biomass to Biofuels: “A robust fusion of the agricultural, industrial biotechnology, and energy industries can create a new strategic energy independence and climate protection.” In addition to the energy independence mantra, environmental groups such as Natural Resources Defense Council (NRDC) are championing the development of certain types of ethanol as a climate-friendly fuel that could reduce global emissions of carbon dioxide (CO2).

Fuel ethanol can be produced in two ways :-

The first is by breaking down agricultural starches into sugar, which is then fermented into ethanol. In Brazil ethanol is processed from sugar cane; in the US the primary feedstock is corn. The US Department of Energy calculates that if all corn now grown in the US were converted to ethanol, it would satisfy only about 15 percent of the country’s current transportation needs. Others put that figure as low as 6 percent. In fact, every bushel of corn grown in the US consumes between a third and a half-gallon of gasoline – making it a costly and inefficient feedstock for alternative energy.

A second approach is to produce ethanol from cellulose, the fibrous material found in all plants. Cellulosic ethanol can be made from any leftover plant materials, including woodchips, rice hulls, grasses (such as switchgrass and miscanthus) and straw. There are abundant sources available for cellulosic ethanol, as leaves and stalks – normally considered waste – could become feedstocks. Processing ethanol from cellulose has the potential to squeeze at least twice as much fuel from the same area of land as corn ethanol, because much more biomass is available per acre. Miscanthus for example, a perennial grass native to China yields approximately 3,000 gallons of cellulosic ethanol per acre.

The synthetic biology approach is to custom design a microorganism that can perform multiple tasks, incorporating built-in cellulose-degrading machinery, enzymes (e.g. Cellulase) that break down glucose, and metabolic pathways that optimise the efficient conversion of cellulosic biomass into biofuel. Aristides Patrinos of Synthetic Genomics describes the all-in-one approach: “The ideal situation would essentially just be one big vat, where in one place you just stick the raw material – it could be switch grass – and out the other end comes fuel….” A team from the University of Stellenbosch (South Africa), collaborating with engineering professor Lee Lynd at Dartmouth University (USA), has engineered a yeast that can survive on cellulose alone, breaking down the plant’s cell walls and fermenting the derived sugars into ethanol. Meanwhile, Lynd’s group at Dartmouth is working with a modified bacterium that thrives in high-temperature environments and pro-duces only ethanol in the process of fermentation.

At Purdue University’s Energy Center, Senior Research Scientist, Dr. Nancy Ho, has developed a modified yeast that can produce 40 percent more ethanol from biomass than naturally occurring yeast, and she is now working with petroleum companies to convert straw into fuel.

The Nobel Prize-winning head of the prestigious Lawrence Berkeley Lab, Dr. Steven Chu, grabbed headlines last year when he suggested that synthetic biology could be used to rewire the genetic networks in a cellulose-crunching bug found in the gut of termites. As a first step, the Berkeley Lab is sequencing microorganisms living in the termite’s gut, to identify genes responsible for degrading cellulose.

The US DOE considers cellulosic ethanol a “carbon neutral” fuel source (meaning that the amount of CO2 absorbed in growing the plants that produce the biomass roughly equals the amount of CO2 produced in burning the fuel. But these “carbon offset” calculations are controversial because they are difficult, if not impossible, to substantiate). Deeming cellulosic ethanol carbon neutral, however, will likely mean that it will qualify as a Clean Development Mechanism (CDM) activity under the Kyoto Protocol – a scheme established to reward polluting companies with emissions credits if they invest in “clean energy” projects in the global South. Civil society critics regard CDM as industry “greenwashing,” a publicly subsidised scheme that will not combat climate change or diminish its causes. Under the CDM, Northern industries that grow large plantations of energy crops in the South can be allowed to offset these projects against their emissions. Of the 408 registered CDM activities as of mid-November 2006, 55 are described as biomass energy projects. India serves as “host country” for 32 of the 55 projects.

But converting plant biomass to fuel isn’t the only way that synbio could upend the energy sector. Craig Venter’s 2-year microbe-collecting expedition netted previously unknown species of bacteria that capture sunlight with photoreceptors and convert it into chemical energy. Since photosynthesis is capable of producing minute levels of hydrogen, Venter’s team is exploring the idea of altering photosynthesis in cells to produce hydrogen.

“Basically, we are taking the modern principles of synthetic biology and trying to replace crude oil.” — Jack Newman, Amyris Biotechnologies

The US military also wants to use synthetic biology for energy production. The US government’s Defense Advanced Research Projects Agency (DARPA) is funding a collaboration between Richard Gross of Polytechnic University (New York) and gene synthesis company DNA 2.0 (Silicon Valley, California) to develop a new kind of energy-rich plastic that can be used first for packaging and then reused as fuel. DNA 2.0 aims to synthetically design the enzymes to produce the polymer. The company claims that soldiers in the field will be able to burn the plastic that wraps their supplies, recovering 90% of the energy as electricity.

[edit] Synthesizing New Monopolies from Scratch – Synthetic Biology and Intellectual Monopoly

Diamond vs. Chakrabarty, the 1980 US Supreme Court case that opened the door to the patenting of all biological products and processes, easily extends to synthetic biology. In language that perfectly describes today’s synthetic organisms, the 1980 Court determined that, “…the patentee has produced a new bacterium with markedly different characteristics from any found in nature and one having the potential for significant utility. His discovery is not nature’s handiwork, but his own: accordingly it is patentable subject matter.”

Unaltered genetic material in its natural environment is not patentable, but once isolated, modified, purified, altered or recombined, genetic material – including synthetic DNA – becomes fair game for monopoly patent claims.

Patents have already been granted on many of the products and processes involved in synthetic biology (see Table below). Examples include: • Patents on methods of building synthetic DNA strands • Patents on synthetic cell machinery such as modified ribosomes • Patents on genes or parts of genes represented by their sequencing information • Patents for the engineering of biosynthetic pathways • Patents on new and existing proteins and amino acids • Patents on novel nucleotides that augment and replace the letters of DNA

Some of these patents cast an extremely wide net. For example, US Patent 6,521,427, issued to Glen Evans of Egea Biosciences (a California - based subsidiary of pharma giant Johnson & Johnson) includes broad claims on a method for synthesizing entire genes and networks of genes comprising a genome, as the ‘operating system’ of living organisms – potentially a description of the entire synthetic biology en-deavour. Other patents awarded to Jay Keasling and his colleagues at Berkeley’s synthetic biology lab cover methods for inserting artificial metabolic pathways into bacteria and testing them for expression of new compounds.

MIT’s non-profit Registry of Standard Biological Parts was created as a communal repository for sharing, using, and improving on the interchangeable modules – the BioBricks – that can be assembled to create biological systems in living cells. However, MIT’s Drew Endy estimates that about one-fifth of the biological functions encoded by parts of BioBricks are already covered by patent claims (held by individuals and organizations not associated with MIT’s BioBrick project).

An article in Nature describes multiple patents held by Sangamo Biosciences as a “stranglehold” on zinc finger technologies, their uses in drug discovery and the regulation of gene expression.199 MIT and Scripps Research Institute also hold patents on zinc fingers.

Such systems are used to design genetic circuits in silico before synthesizing DNA in vivo. US Patent 5,914,891 owned by Stanford University describes genes as ‘circuits’ and claims: “A system and method for simulating the operation of biochemical networks [that] includes a computer having a computer memory used to store a set of objects, each object representing a biochemical mechanism in the biochemical network to be simulated.” If enforced, such broad claims could create a gatekeeper- like monopoly on the field of synthetic biology, which requires massive computation and computer memory to carry out the synthesis and design of DNA networks.

US Patent 6,774,222, entitled “Molecular Computing Elements, Gates and Flipflops,” issued to the US Department of Health and Human Services in 2004. The patent involves DNA logic devices that operate in a manner analogous to their electronic counterparts – for both computation and control of gene expression.

“The patent covers the combination of nucleic-acid binding proteins and nucleic acids to set up data storage, as well as logic gates that perform basic Boolean algebra. The patent notes that the invention could be used not only for computation but also for complex (‘digital’) control of gene expression.

Some advocate for an “open source” strategy, mimicking the free software movement in computing. Drew Endy and his former colleague Rob Carlson first coined the term “open source biology” while at Berkeley’s Molecular Sciences Institute in the late 1990s and both continue to promote the idea as an integral part of their vision for synthetic biology. Their model is Linux – the non-proprietary computer operating system that hundreds of thousands of programmers developed voluntarily, building on each other’s work and releasing their improved source code back to common ownership. Endy ensures that all his lab work is made public on a wiki (publicly editable web pages) and makes the sharing of genetic sequences a cornerstone of MIT’s Registry of Standard Biological Parts. designing genetic code into abstracted BioBrick that easily snap together, Endy believes it will someday be possible for anyone to participate in the design of synthetic organisms. He imagines a new class of professionals similar to today’s graphic designers that will design new biological devices on laptops and then send those designs by email to gene foundries.

[edit] Synthetic Conservation - What are the implications of gene synthesis and digital DNA for conserving genetic resources and the politics of biodiversity?

“In the old days, all biology was ‘in vivo’ – in life. Then scientists learned how to grow organisms ‘in vitro’ – in glass. Now biology is ‘in silico.’” – Nathanael Johnson, "Steal This Genome", East Bay Express.

Storing Diversity Digitally (or Goodbye CGIAR… Hello Google): When a team of synthetic biologists announced in 2005 that they had successfully resurrected and rebuilt a fully working version of the 1918 flu virus, it foreshadowed the era of electronic biodiversity – digital storage of DNA. Scientists predict that within a few years it will be easier to synthesise a virus than to request it from a culture collection or find it in nature. Within a decade it may be possible to synthesise bacterial genomes. Existing ex situ collections of microbial strains (as well as seeds and animals) rely on the maintenance of biological samples. If DNA can be rapidly sequenced and the code stored digitally in silico the potential exists for an organism’s genome to be resurrected in vivo via synthetic biology.the price of gene sequencing continues to fall.

Today, members of the World Federation of Culture Collections (WFCC) in 66 countries store over 1.3 million different samples of bacteria, viruses, fungi and other microbes. Given sufficient time and money, virtually any of these samples can be sequenced. If those same samples were stored digitally, DNA molecules of any desired sequence could be downloaded at the click of a mouse anywhere in the world.

DNA databases like GenBank could become as user-friendly as Google. In fact, the titanic search engine has signaled interest in storing all of the world’s genomic data in their google-farms (large complexes of servers and hard drives).

In November 2006 researchers from Germany’s Max Planck Institute for Evolutionary Anthropology in Leipzig announced that they have sequenced one million base pairs of DNA taken from the bone of a Neanderthal. An archaic human species, the Neanderthal has been extinct for some 30,000 years, but researchers estimate they will have a complete genome, 3.2 billion base pairs in length, in about two years.

“The ability to synthesize functional genes and groups of genes should increase access to genetic materials for all scientists because exchange of actual genetic material will not be necessary. Scientists will be able to synthesize genes from published DNA sequences alone. A positive consequence of this is that a greater number of scientists can have access to genes once their sequences are published. This will impact the use of material transfer agreements and contracts.” – DOE report on Synthetic Genomics.

Biopiracy: New Pathways for Bio-Burglars?

The combination of rapid ‘lab on a chip’ gene sequencing devices with ever faster DNA synthesisers means that it will someday be possible to turn DNA samples into information at one location, beam them digitally to another location and then reconstruct them as physical samples anywhere else on the planet. This opens new pathways for biopiracy.

If the genetic pathways for producing valuable natural substances that are traditionally derived from plants, animals and microorganisms can be identified by computers and fabricated by synthetic microbes in the laboratory, it could, among other things, usher in a new and more complex era of biopiracy.

[edit] Synthetic Commodities – Implications For Trade

“We’re making it easier for people to make anything. They can make good things, they can make bad things, and if we’re going there, we’re going there very fast, at alarming exponential rates.” – Professor George Church, Harvard University geneticist and cofounder of Codon Devices.

Synthetic biologists are quick to identify the potential benefits of synthetic biology for the global South – particularly in the form of life-saving medicines and cheap biofuels. However, the most far-reaching impacts on poor economies, livelihoods and cultures are likely to come if synthetic organisms start to displace existing commodities.

Pathway engineers in Jay Keasling’s lab to engineer metabolic pathways in sunflowers and guayule that produce small quantities of natural rubber. They are also attempting to engineer a rubber-producing tobacco. Alongside their engineering work on rubber crops, Keasling’s colleagues intend to create a strain of bacteria that will produce high quality natural rubber straight from the microbe.Initially they are transferring genetic networks for rubber production into three microbes (Escherichia coli, Saccharomyces cerevisiae and Aspergillus nidulans), and will ultimately focus on whichever organism works best as a productive host for their rubber biofactory. If rubber-producing synthetic organisms and enhanced rubber crops are commercially successful, the USDA hopes to meet all domestic rubber requirements this way.

If the ability to cheaply produce other compounds from microbial factories – including drugs, tropical oils, nutrients and flavourings – is ultimately achieved through synthetic biology, there will be a dramatic impact on the global trade in traditional commodities.

[edit] SynBioSafety

“An engineer’s approach to looking at a biological system is refreshing but it doesn’t make it more predictable. The engineers can come and rewire this and that. But biological systems are not simple…And the engineers will find out that the bacteria are just laughing at them.” – Eckard Wimmer, molecular geneticist at the State University of New York at Stony Brook, who synthesised poliovirus.

The whole point of synthetic biology, after all, is to create novel organisms that are substantially different from those that exist in nature: synthetic DNA is often made-to-order and extensively manipulated, it’s not simply transferred from elsewhere in nature. As synbio products move from laptop to lab and out into the real world, the question on everyone’s mind will be, “Is it safe?”

Synthetic biologists claim that because they are building whole systems rather than simply transferring genes, they can engineer safety into their technology (e.g., by programming cells to self-destruct if they begin reproducing too quickly). That assumes, of course, that the life builders have complete mastery over their art – an impossible standard since synthetic biologists, for all their talk of circuits, software and engineering, are dealing with the living wetware of evolution and all its unpredictability. Like GMOs before them, organisms created through synthetic biology are far from being well understood.

Scientists are still learning that when they introduce a foreign gene into an organism it can produce uncertainty about the gene’s function as well as the function of the DNA into which it is inserted. They have also discovered that the vast “non-coding” sequences of DNA (so-called “junk” DNA), long considered irrelevant because they yield no proteins, may actually play indispensable roles in affecting an organism’s function, health and heredity. Recent scholarship on gene regulation and expression emphasises the non-coding regions of DNA that transmit information in the form of RNA and on the importance of factors outside the DNA sequence. For all the talk about synthetic bio’s genetic circuits and off-the-shelf parts, a living organism is not a logical and predictable machine.

According to Jonathan Tucker and Raymond Zilinskas, “the risks attending the accidental release of such as organism from the laboratory would be extremely difficult to assess in advance, including its possible spread into new ecological niches and the evolution of novel and potentially harmful characteristics.”

Microbes, the main target of synthetic biologists, are promiscuous and can exchange genetic material with soil and gut bacteria. The fashioning of short discrete synthetic pieces of code whether as BioBrick or other active genetic elements raises concerns that synthetic sections of DNA, under some circumstances, could be transferred to naturally occurring bacteria via the process of ‘horizontal gene transfer.’ Once incorporated into natural bacteria they could alter the functioning and behavior of natural microbial ecosystems – affecting the environment in unforeseen and unpredictable ways.

[edit] Synthetic Biology's Poster Child - Microbial Production of Artemisinin to Treat Malaria

WHO regards artemisinin-based drugs as the best hope for treating over one million people – most of them African children – who would otherwise die of malaria each year. However, a global shortfall in the supply of natural artemisinin, which is extracted from sweet wormwood plants (Artemisia annua), has kept the price of this much-prized compound out of reach for poor people. Using synthetic biology to combat malaria is compelling: a technological fix comes to the rescue when investments in malaria prevention and control in Africa are declining, and failing.

In April 2006, Professor Jay Keasling of the University of California - Berkeley and 14 collaborators announced in Nature they had succeeded in engineering a yeast strain to produce artemisinic acid, which is a necessary step in the production of artemisinin itself. Using sophisticated bioinformatics and screening techniques, the team claims to have discovered the genes involved in Artemisia annua’s natural production of artemisinic acid, and managed to insert and express them in a modified yeast strain. The microbe thus behaves like a miniature factory to produce artemisinic acid. According to Keasling, what’s left to do is to increase the yields of artemisinic acid, and then use “high-yielding chemistry” to convert artemisinic acid to Artemisinin.

WHO requires that artemisinin be mixed with other malaria drugs (a drug combination known as Artemisinin Combination Therapies or ACTs) to prevent the malaria parasite from developing resistance. Novartis’s proprietary ACT drug (known as Coartem) is the only one that has received pre-clearance from WHO (meaning that it is approved for procurement by UN agencies), giving Novartis a virtual monopoly on ACT drugs. According to a 2006 study on artemisia conducted by the Royal Tropical Institute of the Netherlands: “This monopoly-like situation has created an imperfect market defined by scarcity of raw materials, speculation and extremely high retail prices.

[edit] List of Recent Synthetic Biology Patents

[edit] List of Companies with Synthetic Biology Activities

[edit] See Also

BioBrick

iGEM

Synthetic biology

New Synthetic Energy Agenda

Isoprenoids

Artemisinin

Metabolic Network

[edit] External Links

Drew Endy: “The Implications of Synthetic Biology” Video on the Internet

Drew Endy: Defining Synthetic Biology - Video

Jay Keasling: Renewable Energy from Synthetic Biology Video

[edit] References