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Synthetic Biology

Life 2.0 – “Synthetic Biology” – Next Revolution

S. N. Jogdand

What is Synthetic Biology?

Existing life on earth created by nature or God(?) if considered as Life 1.0, University of California, Berkeley, USA describes Life 2.0 “Synthetic Biology” as a field that seeks to recombine the basic building blocks of life — genes, proteins and cells — in Lego-like fashion to create novel and useful entities.

While Biotechnology and Nanotechnology are already established as promising technologies, in some circles discussions have started about pico-technology and femto-technology. But next field of discussion now is synthetic Biology.

When Nobel Prize in Physiology and Medicine was awarded to Werner Arber, Daniel Nathans and Hamilton O. Smith in 1978, for the discovery of restriction enzymes and their application to problems of molecular genetics, in an editorial comment in the journal Gene, Waclaw Szybalski wrote on how this discovery will lead into the new era of synthetic biology where not only existing genes are described and analyzed but also new gene arrangements can be constructed and evaluated.

Synthetic biology is considered as an engineering application of biological science, rather than an attempt to do more science.

Synthetic biology involves the deliberate, constructive modification of cells, organisms, populations – or their major subsystems – so as to achieve human objectives. It includes artificial synthesis of the natural functional components of living systems and their non-biological analogs, genetic redesign of existing organisms, and ultimately creation of utterly new organisms de novo. In principle it puts control of the entire biosphere in human hands.

The mode of production is not synthetic because the resulting compound is still produced biologically. The term synthetic comes from the fact that the compound is produced from an organism with a genetic code that is not ordinarily found in nature.

Synthetic biology is concerned with applying the engineering paradigm of systems design to biological systems in order to produce predictable and robust systems with novel functionalities that do not exist in nature.

Synthetic biology will bring the synergistic integration of existing disciplines like biology, engineering, computer modeling, information technology, control theory, chemistry and nanotechnology.

Generating biological structures and life forms with bottom-up approach and designing artificial DNA and allowing more complex organisms to develop is part of synthetic biology. Newly designed biological structures will be further added to non-biological structures. There will be linkage of synthetic biology with artificial life.

Synthetic biology is another transformative innovation that will make it possible to build living machines from off-the-shelf chemical ingredients, employing many of the same strategies that electrical engineers use to make computer chips. With automated synthesis of DNA molecules and their assembly into genes and microbial genomes, synthetic biology envisions the redesign of natural biological systems for greater efficiency, as well as the construction of functional “genetic circuits” and metabolic pathways for practical purposes.

Some aspects of synthetic biology can be viewed as an extension and application of synthetic chemistry to biology, and include work ranging from the creation of useful new bio-chemicals to studying the origins of life.

Synthetic Biology includes the broad redefinition and expansion of biotechnology, with the ultimate goals of being able to design and build engineered biological systems that process information, manipulate chemicals, fabricate materials and structures, produce energy, provide food, and maintain and enhance human health and our environment.

Some consider biology an extension of chemistry, and thus synthetic biology can be considered an extension of synthetic chemistry.

Synthetic biology wants to work towards – (1) Engineering of biological systems (2) Redesigning life (3) Creating alternative life.

Synthetic biology helps us to reverse engineer and re-design pre-existing biological parts and devices in order to expand the set of functions that we can access and program.

The goal of synthetic biology, which builds on advances in molecular, cellular, and systems biology, is to transform biology in the same way that synthesis transformed chemistry and integrated circuit design transformed computing.

Synthetic Biology, Systems Biology and Gene Technology

The boundaries between synthetic biology and other scientific disciplines, such as gene technology, tissue engineering and the nanotechnologies, are fluid.

The term ‘Synthetic Biology’ was coined by Barbara Hobom while describing genetically engineered bacteria. However, the heavy emphasis on foundational technologies (that make the engineering of biology easier and more reliable) is an aspect which distinguishes it from genetic engineering.

The techniques involved in recombinant DNA technology are painfully slow, requiring very specific physical materials and “know-how via the guild-like structure of biology. Scientists-engineers are looking to methods that will make it easier to design and build biological systems. In contrast to gene technology as practiced up to now, with synthetic biology it is not just one gene that is modified or introduced into an organism. The changes are more radical and often involve a number of genes.

Existing biotechnology (now call it traditional!) proceeds in an ad hoc or empirical manner, which has typically restricted the degree of modification that can be reliably controlled or the goals that can be achieved, whereas, synthetic biology permits rational design and redesign of living systems at a deeper and more complex level.

Unlike Genetic Engineering, which involves transfer of a gene from one organism to another via hit-and-trial method, Synthetic Biology involves design of a genetic circuit which can have components from many distinct species. Genetic Engineering is a misnomer because there is hardly any engineering involved in the field. Synthetic Biology, however, relies heavily on the philosophy behind engineering such as previously mentioned concepts of standardization and abstraction.

The element that distinguishes synthetic biology from traditional molecular and cellular biology is the focus on (1) the design and construction of core components (parts of enzymes, genetic circuits, metabolic pathways, etc.) that can be modeled, understood, and engineered to meet specific performance criteria, and (2) the assembly of these smaller parts and devices into larger integrated systems to solve specific problems. Just as engineers now design integrated circuits based on the known physical properties of materials and then fabricate functioning circuits and entire processors (with relatively high reliability), synthetic biologists will soon design and build engineered biological systems.

There is quite a close relationship between synthetic biology and systems biology. Systems biology aims to study natural biological systems as a whole, often with a biomedical focus, and uses simulation and modeling tools in comparisons with experimental information. Synthetic biology aims to build novel and artificial biological systems, using many of the same tools, but is the engineering application of biological science rather than an extension of bioscience research.

Systems biology is a discipline that aspires to study a biological system at various levels in its entirety, ranging from cell networks to cells and complete organisms. It involves the mapping of pathways, gene and protein interactions and logical ‘circuitry’ of natural organisms at the cellular, tissue and whole-organism level and the integration of this information into a computer model. Its primary goal is to attain a quantitative and predictive understanding of a biological system. Systems biology thus, provides the analytical framework in which synthetic biology operates.

Systems biology relies heavily on the development of new tools such as computer models of complex systems, bio-informatics, and experimental techniques for exploring gene interactions.

The basis of quantitative systems biology lies in the application of engineering systems and signal theory to the analysis of biological systems. This allows the definition of systems in terms of mathematical equations and complex models – often as individual functional blocks (i.e. transfer functions). Once a system, or part of a system, has been described in this way then synthetic biology allows the reduction of the system to parts (BioParts) whose function is expressed in terms of input/output characteristics. These characteristics are then presented on a standard specification sheet so that a system designer can understand the functional characteristics of the part. The parts are then entered into a repository. The parts defined in the repository can then be combined into devices and, finally, into systems.

Different Interests

Biologists are interested in synthetic biology because it provides them another approach to analyze the living world. Physicists and Chemists find synthetic biology interesting because it helps them to probe the behavior of molecules and their activity inside living cells. Engineers are interested in synthetic biology because the living world provides a seemingly rich yet largely unexplored medium for controlling and processing information, materials, and energy.

Background

Discovery of the structure of DNA, the deciphering of the genetic code, the development of recombinant DNA technology, and the mapping of the human genome have been the pivotal steps in development of biology.

The chemical synthesis of insulin by groups in the U.S., West Germany and China, completed in 1963, demonstrated that synthesis of a protein in the laboratory was possible.

Successful synthesis of active bovine pancreatic ribonuclease A (124 residues long) proved the concept that enzyme activity could be created through synthetic chemistry, but the yields were low.

In 1968, Indian-American chemist Har Gobind Khorana received a Nobel Prize for synthesizing nucleotides (the chemical sub-units – A, T, C, G – that make up the DNA molecule), stringing them together into synthetic DNA.

By 1970s, insertion of isolated or designed DNA sequences into vectors, followed by transfer into host organisms to express encoded protein or RNA molecules resulted in the development of recombinant DNA technology.

 By February 1976, a California research team (that later founded Genentech) developed an automated process for synthesizing DNA and constructed a fully functioning synthetic gene.

Synthetic biology also traces its roots to legal and scientific development that shaped modern biotechnology through judgment on patenting in favour of bioengineered bacteria of Dr. Anand Chakrabarty in 1980

Michael Elowitz and Stanislas Leibler, biological physicists, in the year 2000 reported creating of a genetic circuit that produced a fluorescent protein.

Synthetic genomics developed subsequently. “Synthetic genomics” refers to the set of technologies that makes it possible to construct any specified gene (or full genome) from short strands of synthetic DNA called “oligonucleotides,” which are produced chemically and are generally between 50 and 100 base-pairs in length.

In 2002, researchers at Stony Brook (the State University of New York) synthesized the 7,440 letters in the poliovirus’s genome. It took the Stony Brook researchers three years to build a live polio virus from scratch. Live, infectious poliovirus was developed from customized oligonucleotides mail-ordered from a commercial supplier, using a map of the viral genome available on the Internet.

In 2003, Hamilton Smith and his colleagues at the Venter Institute developed a faster method for genome assembly, using synthetic oligonucleotides to construct a bacteriophage called φX174 (containing 5,386 DNA base-pairs) in only two weeks.

In 2005, scientists at the U.S. Centers for Disease Control and Prevention synthesized the so-called Spanish influenza virus, which was responsible for the 1918-19 flu pandemic that killed between 50 million and 100 million people worldwide.

Bill and Melinda Gates Foundation in 2004 announced a $42.5 million grant for research and development in synthetic biology.

MIT’s Technology Review in 2005 has announced of ‘bacterial factories’ as one of the top 10 emerging technologies.

Genome Redesign and Construction was further development. In 2005, Leon Y. Chan and his co-workers at M.I.T. simplified the genome of a T7 bacteriophage (a virus that attacks bacteria but is harmless to humans) by separating overlapping genes and editing out redundant DNA sequences to facilitate future modifications.

A team led by Craig Venter (formerly of the Human Genome Project) was able to synthesize a slightly smaller virus in just three weeks, raising the prospect of rapid assembly of artificial microorganisms.

Venter, who heads the Institute of Biological Energy Alternatives (IBEA), is now building a new type of bacterium using DNA manufactured in the laboratory. His team is modifying DNA from Mycoplasma genitalium, a bacterium that has the smallest number of genes (482 protein-coding genes, 43 RNA genes) of any living cell, with the goal of reducing it to only those genes necessary for life yet possesses all of the biochemical machinery needed to metabolize, grow, and reproduce. The researchers will insert the minimal life form back into a normal bacterial cell that has been stripped of its DNA. The goal of this “minimum genome project” is to build a simplified microbial platform to which new genes can be added, creating synthetic organisms with known characteristics and functionality.

The advantage of a synthetic organism over manipulating natural organisms is that, you would have a lot more control over the properties of the cell than if you rely on natural mechanisms. You would be in a better position to design exactly what you want.

With funding from the US Department of Energy (DoE), Venter’s eventual goal is to build synthetic organisms that could produce energy and mitigate climate change.

In 2003, researchers at the University of Florida created an artificial nucleotide, a human-made counterpart to one of the four chemical components that make up DNA (A, G, C and T). Since then, other researchers at the University of Florida have been able to add a second artificial letter – so that there are six in all. The newly-expanded DNA molecule can make copies of itself. The research team was able to “evolve” its artificial DNA through five generations.

Synthetic biology wants to achieve much more ambitious redesign of cells. These projects aim primarily at developing an understanding of modules (“biobricks”) that can be assembled to perform particular functions in response to appropriate signals. Two classic examples involved (a) the “repressilator,” that combines several operator/repressor elements in a system that generates oscillatory production of a green fluorescent protein reporter, and (b) the opposed expression of gene products from two different promoters to produce a “genetic toggle switch” that can be stably flipped from one state to another by external signals. In these cases, mathematical analysis guided the construction of the artificial genetic circuit. Extensions of this approach look very promising, and efforts are now underway to provide “tunable promoters” that can be used to adjust gene expression in subtle ways for use in such small-network engineered cells. Such sophistication may prove vital in projects that attempt to “rewire” cells to carry out entire biosynthetic processes involving multiple enzymatic steps.

Technologies useful for Synthetic biology

There are several key enabling technologies that are critical to the growth of synthetic biology. These are:

(1) DNA Sequencing: Fast and cheap DNA sequencing and synthesis would allow for rapid design, fabrication, and testing of systems.

(2) Fabrication: A critical limitation in synthetic biology today is the time and effort required during fabrication of engineered biological systems. By 2007, synthesis of a 1000bp gene costs approximately $800 and 2 weeks to construct. To speed up the cycle of design, fabrication, testing and redesign, synthetic biology requires more rapid and reliable de novo DNA synthesis and assembly of fragments of DNA.

(3) Modeling: Synthetic biology will benefit from better models of how biological molecules bind substrates and catalyze reactions, how DNA encodes the information needed to specify the cell and how multi-component integrated systems behave.

(4) Measurement: Precise and accurate quantitative measurements of biological systems are crucial to improving understanding of biology. Such measurements often help to elucidate how biological systems work and provide the basis for model construction and validation. Differences between predicted and measured system behavior can identify gaps in understanding and explain why synthetic systems don’t always behave as intended.

(5) Software tools: Software tools that enable system design and simulation are also needed.

Achievements So far

(1) Organism like E. coli can be modified in a big way. To make the streamlined strain, researchers at the University of Wisconsin-Madison compared the genomes of different strains of bacteria to determine which genes were crucial for the organism’s survival and which the bug could do without. They then removed these elements from the E. coli, making a smaller and more stable version of the bacteria. The new slimmed-down strain has about 15 percent less DNA. Scientists ultimately hope to remove another 5 percent. Blattner who led the project and colleagues showed that the new strain could produce a particular protein used in vaccines more efficiently than the common laboratory strain. The bacteria could ultimately provide a better way to create DNA-based therapeutics, such as gene therapy. The idea of a reduced genome “is attractive from a safety and manufacturing point of view. Blattner has founded a company, Scarab Genomics, based in Madison, WI, to develop and market the stripped-down bugs.

(2) Synthetic biologists from BostonUniversity are describing a specially engineered bacteriophage that is capable of fighting pathogenic bacterial biofilms.

(3) Living Bacteria used to create photograph: With the help of the emerging science of synthetic biology, students at UCSF and the University of Texas at Austin have created the first-ever photographs on agar populated with bacteria, instead of regular photo paper.

(4) Synthetic biology has drawn from the open source movement in software by placing all its basic tools in the public domain. MIT in USA has developed well-specified, standard, and interchangable biological parts, which is a critical step towards the design and construction of integrated biological systems. By 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.

(5) Bacteria as ‘biofactories’ – According to the World Health Organization, each year nearly 500 million people living in the tropics and subtropics become infected with malaria. Nearly three million (mostly children) die. Artemisinin, is a natural product extracted from the dry leaves of Artemisia annua, the sweet wormwood tree. Although this tree can grow in many places, it only produces artemisinin under specific agricultural and climatological conditions. It is also costly to chemically synthesize or harvest. Chinese have been using artemisinin in the herbal medicine ginghaosu for more than 2,000 years.

Classical plant breeding and selection combined with improved agricultural practices may not be adequate to lower the cost of artemisinin production to an affordable price.

Jay Keasling of the Lawrence Berkeley National Laboratory has engineered bacteria to produce artemisinin, a compound used to treat malaria. The same methods could theoretically be used to produce cancer drugs, such as Taxol, that are currently expensive.

Keasling and his research group transplanted genes from yeast and from the sweet wormwood tree into the bacterium, then bypassed E. coli‘s metabolic pathways and engineered a new one based on a metabolic pathway in yeast. As a result of their efforts, the yield of the artemisinin precursor amorphadiene in that laboratory strain of E. coli was increased by 10,000 times. Improvements of at least another order of magnitude are easily within reach. The ability to produce amorphadiene in a simple organism like E. coli opens up a whole area of possible molecular backbones that can later be functionalized to make drugs.

(6) Harvard Medical School researchers have successfully synthesized a DNA-based memory loop in yeast cells, findings that mark a significant step forward in the emerging field of synthetic biology. After constructing genes from random bits of DNA, researchers in HarvardMedicalSchool’s Department of Systems Biology, not only reconstructed the dynamics of memory, but also created a mathematical model that predicted how such a memory “device” might work.

(7) A team in Silver’s HarvardMedicalSchool lab led by Caroline Ajo-Franklin, and postdoctoral scientist David Drubin demonstrated that not only could they construct circuits out of genetic material, but they could also develop mathematical models whose predictive abilities match those of any electrical engineering system. The components of this memory loop were simple: two genes that coded for proteins called transcription factors. Transcription factors regulate gene activity. Like a hand on a valve, the transcription factor will grab onto a specific gene and control how much, or how little, of a particular protein the gene should make. Galactose sugar was the stimulant and work was done in yeast cells. Essentially what happened is that the cell remembered that it had been exposed to galactose, and continued to pass this memory on to its descendents. So after many cell divisions, the feedback loop remained intact without galactose or any other sort of molecular trigger.

The entire construction of the device was guided by the mathematical model that the researchers developed. Mathematical model not only predicted exactly how our memory loop would work, but it informed how we synthesized the genes.

If we ever want to create biological black boxes, that is, gene-based circuits like this one that you can plug into a cell and have it perform a specified task, we need levels of mathematical precision as exact as the kind that go into creating computer chips. The researchers are now working to scale-up the memory device into a larger, more complex circuit, one that can, for example, respond to DNA damage in cells. One day we’d like to have a comprehensive library of these so-called black boxes.

(8) Among the most promising short term applications of Synthetic Biology is biological production of liquid fuels. Ethanol is by no means an advanced biofuel; from both a technical and an economic perspective ethanol is a backwards biofuel. The future is all for biofuels that are high energy content (not ethanol), are not water soluble (not ethanol), can be easily integrated into the existing gasoline and diesel distribution infrastructure (not ethanol), and require minimal, if any, initial changes in engine technology (not ethanol).  Producing hydrocarbon fuels is more efficient than producing ethanol, because the former packs about 30 percent more energy per gallon. And it takes less energy to produce, too. The ethanol produced by yeast needs to be distilled to remove the water, so ethanol production requires 65 percent more energy than hydrocarbon production does. The biofuel of the future could well be gasoline.

L59, a company based in San Carlos, CA, and founded by geneticist George Church, of HarvardMedicalSchool, and plant biologist Chris Somerville, of StanfordUniversity has genetically engineered various bacteria, including E. coli, to custom-produce hydrocarbon chains.

To do this, the company is employing tools from the field of synthetic biology to modify the genetic pathways that bacteria, plants, and animals use to make fatty acids, one of the main ways that organisms store energy. Fatty acids are chains of carbon and hydrogen atoms in a particular arrangement, with a carboxylic acid group made of carbon, hydrogen, and oxygen attached at one end. If acid is removed what is left out is a hydrocarbon that can be made into fuel.

The company’s use of synthetic biology and systems biology to engineer hydrocarbon-producing bacteria is going to be a “cutting edge.” In some cases, LS9’s researchers used standard recombinant DNA techniques to insert genes into the microbes. In other cases, they redesigned known genes with a computer and synthesized them. The resulting modified bacteria make and excrete hydrocarbon molecules that are the length and molecular structure the company desires.

LS9’s current work uses sugar derived from corn kernels as the food source for the bacteria. Later they want to use cellulosic biomass, such as switchgrass, as the feedstock. It is estimated that cellulosic biomass could produce about 2,000 gallons of renewable petroleum per acre.

Amyris Biotechnologies of Emeryville, CA, is also using genes from plants and animals to make microbes produce designer fuels. Amyris has also created bacteria capable of supplying renewable hydrocarbon-based fuels. The main difference between the companies is that while LS9 is working on a biocrude that would be processed in a refinery, Amyris is working on directly producing fuels that would need little or no further processing.

Venter’s company is also working on engineering microbes to produce fuel. The company recently received a large investment from the oil giant BP to study the microbes that live on underground oil supplies; the idea is to see if the microbes can be engineered to provide cleaner fuel. Another project aims to manipulate the genome of palm trees–the most productive source of oil for biodiesel–to make them a less environmentally damaging crop.

The U.S. Department of Energy has set a goal of replacing 30 percent of current petroleum use with fuels from renewable biological sources by 2030.

(9) A novel synthetic pathway consisting of 13 enzymes derived from five different organisms has been developed to produce hydrogen from starch and water. This pathway is being developed further with the aim of producing hydrogen from cellulose, a more abundant sugar, which could provide hydrogen for fuel cells cheaply and easily.

(10) Creation of Standardized Biological Parts and Circuits: The most ambitious subfield of synthetic biology involves efforts to develop a “tool box” of standardized genetic parts with known performance characteristics—analogous to the transistors, capacitors, and resistors used in electronic circuits—from which bioengineers can build functional devices and, someday, synthetic microorganisms.

The Synthetic Biology Working Group at M.I.T. is attempting to turn this concept into a reality by developing a comprehensive set of genetic building blocks, along with standards for characterizing their behavior and the conditions that support their use. In the summer of 2004, the group established a Registry of Standard Biological Parts. The registry is made up of components called “BioBricks,” short pieces of DNA that constitute or encode functional genetic elements. Examples of BioBricks are a “promoter” sequence that initiates the transcription of DNA into messenger RNA, a “terminator” sequence that halts RNA transcription, a “repressor” gene that encodes a protein that blocks the transcription of another gene, a ribosome-binding site that initiates protein synthesis, and a “reporter” gene that encodes a fluorescent jellyfish protein, causing cells to glow green when viewed through a fluorescence microscope. A BioBrick must have a genetic structure that enables it to send and receive standard biochemical signals and to be cut and pasted into a linear sequence of other BioBricks.

As of early April 2006, the BioBricks registry contained 167 basic parts, including sensors, actuators, input and output devices, and regulatory elements. Also included in the registry were 421 composite parts, and an additional 50 parts were being synthesized or assembled. Emulating the approach employed by open-source software developers, the M.I.T. group has placed the registry on a public website (http://parts.mit.edu/) and invited all interested researchers to comment on and contribute to it. The ultimate goal of this effort is to develop a methodology for the assembly of BioBricks into circuits with practical applications, while eliminating unintended or parasitic interactions that could compromise the characterized function of the parts.

To date, BioBricks have been assembled into a few simple genetic circuits. One such circuit renders a film of bacteria sensitive to light, so that it can capture an image like a photographic negative. In other experiments, BioBricks have been combined into devices that function as logic gates and perform simple Boolean operations, such as AND, OR, NOT, NAND, and NOR. For example, an AND operator generates an output signal when it gets a biochemical signal from both of its inputs; an OR operator generates a signal if it gets a signal from either input; and a NOT operator (or inverter) converts a weak signal into a strong one, and vice versa. The long-term goal of this work is to convert bioengineered cells into tiny programmable computers, so that it will be possible to direct their operation by means of chemical signals or light.

Future Prospects

(1) Synthetic biologists could use the molecular machinery in microorganisms like Bacillus subtilis to efficiently capture the energy stored in cellulose. These approaches could lead to microorganisms producing hydrogen, to improve the fixation of carbon dioxide or nitrogen and efficiently converting sunlight energy into other chemical forms.

(2) Synthetic biologists are trying to engineer microorganisms to remediate some of the most hazardous environmental contaminants, including heavy metals, and nerve agents like sarin. Such organisms have enormous potential for decontaminating hazardous waste spills and treating byproducts from nuclear energy and disposal sites.

(3) Arkin and Chris Voigt of University Of California, San Francisco are assembling biological parts which may help E. coli fight cancer in future.

(4) Programming cells for information processing, communication and gene regulation may be possible in future.

(5) Synthetic prokaryotes: As proposed by J. Craig Venter as long ago as 1999, there is a possibility of creating totally artificial prokaryotic organisms. This project has already spawned at least one new company (Synthetic Genomics) under Venter’s leadership.

(6) Synthetic eukaryotes (probably a form of yeast). Manipulation of nitrogen fixation, photosynthesis, hydrocarbon production and other such processes may be initial targets in the design of artificial nucleated, organelle-containing cells. Uncertainties in the step to multicellularity limit predictions about eventual artificial plants and animals for the time being.

(7) It isn’t unreasonable to suggest that the ability to manipulate stem cells and embryos could be combined with the ability to create novel genes and produce striking products (perhaps photosynthetic farm animals that require much less feed).

(8) Smart drugs: Synthetic biology might speed up our advances towards a synthetic molecular assembly that encapsulates a drug in an inactive form. A smart drug includes a diagnostic module that will sense molecular disease indicator and make diagnostic decision. This decision is then translated into drug activation in diseased condition.

(9) Complex molecular devices for tissue repair/regeneration: One of the most fascinating possibilities for synthetic biology could be the development of small macromolecular assemblies composed of a sensor and a group of enzymes, which could be used to sense damage in blood vessels and proceed to repair them by dissolving plaques and stimulating endothelial regeneration. Similarly, it may be possible to re-establish the integrity of the collagen network. This will require a combination of protein design with good physiological knowledge of the systems to be repaired. While the assembly of such complex tasks is impossible with our current understanding, such an assembly could be achieved once the synthetic biology design principles are consistently applied to adapt all the participating units.

(10) Cells involved in the immune response may be programmed to recognize specific viruses or bacteria and target them in a more efficient way than our existing immune system does.

(11) Gene therapy would be easier because with applications of synthetic biology (owing to advances in DNA synthesis) it will be possible to design and modify viruses to deliver healthy genes to the target tissue in an efficient way, promoting specific recombination and integration of synthetic genes with the existing genome. Similarly, viruses that can recognize specific cells and target them for destruction will fall into this category.

(12) Smart materials: Synthetic biology will expand the range of potential target materials. Engineered cells will make polypeptides with non-natural amino acids that have good materials properties such as cross-linking ability and useful electrical or optical behaviour. Proteins with artificially evolved recognition properties can provide the ‘glue’ for binding other materials together in highly selective ways.

Conferences Held on Synthetic Biology

Today, synthetic biology is at roughly the same level of development as molecular genetics was in the mid- to late 1970s, some five years after the invention of recombinant-DNA technology.

International Notable conferences, workshops, competitions held so far are:

(1) Synthetic Biology 1.0 Massachusetts Institute of Technology (MIT), Cambridge, MA (June 2004)

(2) Synthetic Biology 2.0 University of California, Berkeley, CA (May 20-22, 2006)

(3) Synthetic Biology 3.0 ETH Zurich, Switzerland, from June 24-26 2007

(4) Based on the groundbreaking research in Synthetic Biology, iGEM is a high profile international competition, which gives students the great opportunity to design novel engineered parts, model biochemical reactions and then implement these designs in the laboratory. iGEM workshop was organized in China by TianjinUniversity on 16, 17 April 2007.

(5) QB3 synthetic biology symposium organized by California Institute of Quantitative Biosciences was held on August 19-20, 2007 at UC San Francisco’s MissionBay campus to explore current research and issues in the emerging field of synthetic biology. Symposium topics included the use of DNA as a programmable substrate, the design of synthetic bacteria to produce malaria drugs and fight cancer, programming of stem cells, and engineering signaling proteins to control cell morphology. In addition, computer scientists and electrical engineers shared research on biologically-based robotics systems.

They were all fundamentally interested in being able to engineer cellular behavior, so as to be able to program cells. Engineering life forms is like engineering a computer, namely it will require the correct assembly of individual modules.

Researchers who participated in the symposium came from universities and institutes from around the United States and other parts of the world.

Advances in Synthetic Biology conference is planned on March 6-7, 2008 at Cambridge, UK.

Players of Synthetic Biology

Although much of the current work on synthetic biology is taking place in the United States, research groups are also active in Europe, Israel, and Japan, and the technology will surely spread to other countries. Over the next decade, synthetic biology is likely to enter a phase of exponential growth.

Institutions active in synthetic biology are

  • MIT
  • University of California (Jay Keasling’s pioneering work)
  • California Institute of Technology
  • University of Cambridge
  • KEIO University, Japan (Mitsuhiro Itaya)
  • Swiss Federal Institute of Technology, Zurich
  • National Centre for Biological Sciences, Bangalore

National Science Foundation is investing $17 million over the next five years to open the SyntheticBiologyEngineeringResearchCenter (SynBERC): Five MIT researchers are among the pioneers behind a new research center in synthetic biology.

The BioBricks Foundation (BBF) is the non-profit organization that is working to enable the development of open commons of basic biological functions (BioBricks) that can be freely used, shared and improved. BBF is also working to promote constructive development and application of next generation biological technologies.

Companies with Synthetic Biology Activities

 

No. Company Synthetic Biology business area
     
1 Ambrx, La Jolla, CA, USAwww.ambrx.com Develops biopharmaceuticals utilizing artificial amino acids
2 Amyris Biotechnologies, Emeryville, CA, USAwww.amyrisbiotech.com Developing synthetic microbes to produce pharmaceuticals, fine chemicals, nutraceuticals, vitamins, flavors and biofuels
3 Egea Biosciences, San Diego, CAUSAwww.egeabiosciences.com

www.centocor.com

Now wholly owned by Johnson & Johnson.Develops innovative genes, proteins and biomaterials for J&J medical immunology subsidiary Centocor; Egea holds broad patent on genome synthesis
4 Codon Devices, Cambridge,MA, USAwww.codondevices.com Describes itself as a ‘Bio Fab’ able to design and construct engineered genetic devices for partners in medicine, biofuels, agriculture, materials and other application areas
5 Diversa, San Diego, CA, USAwww.diversa.com Diversa adds new codons to ‘optimize’ enzymes taken from natural bacteria to apply to industrial processes
6 DNA 2.0, ww.dna20.com  
7 DuPont, Wilmington,Delaware, USAwww.dupont.com DuPont is partnering with Genencor, BP, Diversa and others to develop microbesthat will produce fibers (Sorona) and biofuels
8 EngeneOS, Waltham, MA, USAwww.engeneOS.com Designs and builds programmable biomolecular devices from both natural and artificial building blocks
9 EraGen Biosciences, Madison, WI, USAwww.eragen.com Develops genetic diagnostic tech-nologies based on expanded genetic alphabet
10 Firebird BiomolecularSciences, Gainesville, FL, USAwww.firebirdbio.com Supplies nucleic acid components, libraries, polymerases, and software tosupport synthetic biology
11 Genencor, Palo Alto, CA, USAwww.genencor.com Develops and sells biocatalysts and other biochemicals. Undertakes pathwayengineering
12 Genomatica, San Diego, CA, USAwww.genomatica.com Designs software that models genetic network for synthetic biology applications
13 LS9, San Francisco, CA, USAwww.LS9.com Designs microbial factories that produce biofuels and other energy related compounds
14 Mascoma, Cambridge, MA, USAwww.mascoma.com Developing microbes to convert agricultural feedstock into cellulosic ethanol
15 Protolife, Venice, Italywww.protolife.net Developing artificial cells and synthetic living systems
16 Sangamo Biosciences, Richmond, CA, USAwww.sangamo.com Produce engineered ‘zinc finger’ proteins for controlling gene regulation
17 Synthetic Genomics, Rockville, MD, USAwww.syntheticgenomics.com Developing minimal genome as chassis for energy applications

 

Synthetic biology in India

National Centre for Biological Sciences (NCBS), Bangalore is perhaps the only place where synthetic biology projects are going on in India. Mukund Thattai’s lab in NCBS, Bangalore is working on synthetic biology. One can see DNA plates consisting all the standard biological parts in NCBS laboratory. Standard biological parts have reduced the pain of finding and cloning the desired gene. This laboratory is involved in three projects as far as synthetic biology is concerned:

1) Trying to make cell cycle synchronous in a population of bacterial cells

2) Re-engineering chemotaxis in bacteria

3) Observing the cell-communication in UV radiated bacterial cells (meaning how well they can communicate this message to their peers)

These projects made use of biological parts and the design part did not take more than 2-3 weeks. They just combined parts, made a circuit and then cloned the circuit into cells. The cloning part is the slowest step as it takes a large amount of the time (3 months approx).

Genomics research is on at full swing at institutes like the Center for Cellular and Molecular Biology (CCMB), Indian Institute of Science (IISc), Institute for Genomics and Integrative Biology (IGIB) and the Centre for DNA Fingerprinting and Diagnostics (CDFD).

Imperial Bio-Medic, Chandigarh, India, MWG, Bangalore, India, Bioserve Biotechnologies, Hyderabad, India are the centers which support synthetic biology work in India.

Challenges before Synthetic Biology

In natural systems, evolution has already optimized the regulatory interactions between network elements in cascades and other network motifs to work cohesively towards achieving a particular behavior. In synthetic biology, networks are typically assembled from unrelated elements that have not been optimized by this evolutionary process. Hence, one of the main challenges in engineering synthetic circuits is altering the kinetics of individual elements until they are impedance-matched such that they function correctly within the context of the new network. The challenge is also to decide on laws that govern research and applications of synthetic biology.

Potential dangers and Obstacles

The criteria that apply for the risk assessment of gene technology also apply to synthetic biology. As with any powerful new technology, synthetic biology is likely to create new risks for society, including possible unintended harmful consequences for human health or the environment, or deliberate misuse for hostile purposes. The technology of synthetic biology provides a new set of tools. Any ethical challenges come from the way we use the tools and not from the tools themselves.

(a) The accidental release of an unintentionally harmful organism or system,

(b) The purposeful design and release of an intentionally harmful organism or system, synthesis or redesign of harmful pathogens (e.g., smallpox, Ebola virus), bioterrorism,

(c) A future over-reliance on our ability to design and maintain engineered biological systems in an otherwise natural world,

(d) Damage of ecosystem or habitat by genetically engineered organisms when released in environment

(e) Extreme posssibilities are biosynthesized systems may also not survive in the wild because of their special nutritional and environmental needs or there may be uncontrolled spreading of genetically modified organisms. Researchers are proposing to include a DNA watermark in engineering biological systems so that their spread can be tracked,

(f) Ethical objections can be on man’s attitude to play ‘God’,

(g) Synthetic biology is still considered to be expensive and still unreliable research process,

(h) Biological systems are too complex to engineer,

(i) Evolution of man developed (synthesized) organisms would be undesirable (functionality introduced may be lost) but unavoidable.

 

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