Synthetic biology is a new area of
biologicalBiology is the natural science concerned with the study of life and living organisms, including their structure, function, growth, origin, evolution, distribution, and taxonomy...
research that combines
scienceScience is in its broadest sense to any systematic knowledge-base or prescriptive practice that is capable of resulting in a prediction or predictable type of outcome...
and
engineeringEngineering is the discipline, art and profession of acquiring and applying technical, scientific and mathematical knowledge to design and implement materials, structures, machines, devices, systems, and processes that safely realize a desired objective or inventions.The American Engineers' Council...
in order to design and build ("synthesize") novel biological functions and systems.
History of the term
In 1974, the Polish geneticist
Waclaw SzybalskiWacław Szybalski is a Professor of Oncology at the McArdle Laboratory for Cancer Research, University of Wisconsin–Madison Medical School....
introduced the term "synthetic biology", writing: Let me now comment on the question "what next". Up to now we are working on the descriptive phase of molecular biology. ... But the real challenge will start when we enter the synthetic biology phase of research in our field. We will then devise new control elements and add these new modules to the existing genomes or build up wholly new genomes. This would be a field with the unlimited expansion potential and hardly any limitations to building "new better control circuits" and ..... finally other "synthetic" organisms, like a "new better mouse". ... I am not concerned that we will run out exciting and novel ideas, ... in the synthetic biology, in general. When in 1978 the
Nobel Prize in Physiology or Medicine was awarded to Arber, Nathans and Smith for the discovery of
restriction enzymeA restriction enzyme is an enzyme that cuts double-stranded or single stranded DNA at specific recognition nucleotide sequences known as restriction sites. Such enzymes, found in bacteria and archaea, are thought to have evolved to provide a defense mechanism against invading viruses...
s, Waclaw Szybalski wrote in an editorial comment in the journal Gene:
The work on restriction nucleases not only permits us easily to construct recombinant DNADeoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms and some viruses. The main role of DNA molecules is the long-term storage of information...
moleculeA molecule is defined as an electrically neutral group of at least two atoms in a definite arrangement held together by very strong chemical bonds. Molecules are distinguished from polyatomic ions in this strict sense...
s and to analyze individual genes, but also has led us 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.
However, synthetic biology is a term that has also been used to describe an approach to biology that attempts to integrate different areas of research in order to create an holistic understanding. There is significant controversy over whether synthetic biology as currently practiced is in accordance with this holistic approach, which was associated with the anti-reductionist movements within biology during the late twentieth century (More references needed here).
Biology
Biologists are interested in learning more about how natural living systems work. One simple, direct way to test our current understanding of a natural living system is to build an instance (or version) of the system in accordance with our current understanding of the system.
Michael Elowitz's early work on the
RepressilatorThe repressilator is a synthetic genetic regulatory network reported in a paper by Michael B. Elowitz and Stanislas Leibler. This network was designed from scratch to exhibit a stable oscillation which is reported via the expression of green fluorescent protein, and hence acts like an electrical...
is one good example of such work. Elowitz had a model for how gene expression should work inside living cells. To test his model, he built a piece of DNA in accordance with his model, placed the DNA inside living cells, and watched what happened. Slight differences between observation and expectation highlight new science that may be well worth doing. Work of this sort often makes good use of mathematics to predict and study the dynamics of the biological system before experimentally constructing it. A wide variety of mathematical descriptions have been used with varying accuracy, including
graph theoryIn mathematics and computer science, graph theory is the study of graphs: mathematical structures used to model pairwise relations between objects from a certain collection. A "graph" in this context refers to a collection of vertices or 'nodes' and a collection of edges that connect pairs of...
,
BooleanBoolean , as a noun or an adjective, may refer to:* Boolean algebra , a logical calculus of truth values or set membership* Boolean algebra , a set with operations resembling logical ones...
networks,
ordinary differential equationIn mathematics, an ordinary differential equation is a relation that contains functions of only one independent variable, and one or more of its derivatives with respect to that variable....
s,
stochastic differential equationA stochastic differential equation is a differential equation in which one or more of the terms is a stochastic process, thus resulting in a solution which is itself a stochastic process...
s, and
Master equationIn physics, a master equation is a phenomenological set of first-order differential equations describing the time evolution of the probability of a system to occupy each one of a discrete set of states:...
s (in order of increasing accuracy). Good examples include the work of
Adam Arkin,
Jim Collins and
Alexander van Oudenaarden. See also the
PBS Nova special on artificial life.
Chemistry
Biological systems are
physical systemIn physics the word system has a technical meaning, namely, it is the portion of the physical universe chosen for analysis. Everything outside the system is known as the environment, which in analysis is ignored except for its effects on the system. The cut between system and environment is a free...
s that are made up of chemicals. Around 100 years ago, the science of
chemistryChemistry is the science concerned with the composition, behavior, structure, and properties of matter, as well as the changes it undergoes during chemical reactions...
went through a transition from studying natural chemicals to trying to design and build new chemicals. This transition led to the field of synthetic chemistry. In the same tradition, 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 biochemicals to studying the origins of life.
Eric Kool's group at
StanfordThe Leland Stanford Junior University, commonly referred to as Stanford University or Stanford, is a private research university located in Stanford, California, United States...
,
Steven Benner's group at
FloridaThe University of Florida is a public land-grant, sea-grant, space-grant major research university located on a campus located in Gainesville, Florida, in the United States. The university traces its origins to 1853, and has continuously operated on its present Gainesville campus since the fall...
,
Carlos Bustamante's group at
BerkeleyThe University of California, Berkeley is a public research university located in Berkeley, California, United States. The oldest of the ten major campuses affiliated with the University of California, Berkeley offers some 300 undergraduate and graduate degree programs in a wide range of disciplines...
, and
Jack Szostak's group at
HarvardHarvard University is a private university located in Cambridge, Massachusetts and a member of the Ivy League. Founded in 1636 by the colonial Massachusetts legislature, Harvard is the oldest institution of higher learning in the United States and currently comprises ten separate academic units...
, David McMillen's group at University of Toronto are good examples of this tradition. Much of the improved economics and versatility of synthetic biology is driven by ongoing improvements in
gene synthesisGene synthesis is the process of synthesizing an artificially designed gene into a physical DNA sequence.Gene synthesis was first demonstrated by Har Gobind Khorana in 1970 for a short artificial gene. Nowadays, commercial gene synthesis services are available from hundreds of companies worldwide,...
.
Engineering
Engineers view biology as a
technology. 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 . A good example of these technologies include the work of
Chris VoigtChristopher Voigt is an American synthetic biologist, molecular biophysicist, and engineer. He is currently an assistant Professor in the of the with appointments in the and the graduate student programs. His research interests focus on the reprogramming of bacterial organisms to perform...
, who redesigned the Type III
secretionSecretion is the process of elaborating, releasing, and oozing chemicals from a cell, a secreted chemical substance or amount of substance. In contrast to excretion, the substance may have a certain function, rather than being a waste product....
system used by
SalmonellaSalmonella is a genus of rod-shaped, Gram-negative, non-spore forming, predominantly motile enterobacteria with diameters around 0.7 to 1.5 µm, lengths from 2 to 5 µm, and flagella which project in all directions...
typhimurium to secrete spider silk proteins, a strong elastic biomaterial, instead of its own natural infectious proteins. One aspect of Synthetic Biology which distinguishes it from conventional
genetic engineeringGenetic engineering, recombinant DNA technology, genetic modification/manipulation and gene splicing are terms that apply to the direct manipulation of an organism's genes. Genetic engineering is different from traditional breeding, where the organism's genes are manipulated indirectly...
is a heavy emphasis on developing foundational technologies that make the engineering of biology easier and more reliable. Good examples of engineering in Synthetic Biology include the pioneering work of Tim Gardner and
Jim CollinsJames J. Collins is an American bioengineer, Professor of Biomedical Engineering at Boston University, and a Howard Hughes Medical Institute Investigator...
on an
engineered genetic toggle switch, the
Registry of Standard Biological Parts, and the International Genetically Engineered Machine competition
(iGEM).
Re-writing
Re-writers are Synthetic Biologists who are interested in testing the idea that since natural biological systems are so complicated, we would be better off re-building the natural systems that we care about, from the ground up, in order to provide engineered surrogates that are easier to understand and interact with. Re-writers draw inspiration from
refactoringCode refactoring is the process of changing a computer program's internal structure without modifying its external functional behavior or existing functionality, in order to improve internal quality attributes of the software...
, a process sometimes used to improve computer software.
Drew EndyDrew Endy is a synthetic biologist.He was a junior fellow for 3 years and later an assistant professor in the Department of Biological Engineering at MIT. In September 2008, he moved to Palo Alto to become an assistant professor in the Department of Bioengineering at Stanford University...
and his
group have done some preliminary work on re-writing (e.g.,
Refactoring Bacteriophage T7). Oligonucleotides harvested from a photolithographic or inkjet manufactured DNA chip combined with DNA mismatch error-correction allows inexpensive large-scale changes of codons in genetic systems to improve
gene expressionGene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as rRNA genes or tRNA genes, the product is a functional RNA...
or incorporate novel amino-acids (see
George ChurchGeorge Church is an American molecular geneticist. He is currently Professor of Genetics at Harvard Medical School and Professor of Health Sciences & Technology at Harvard and MIT....
's and Anthony Forster's lab
synthetic cell projects. As in the T7 example above, this favors a synthesis-from-scratch approach.
Safety and Security
In addition to numerous scientific and technical challenges, synthetic biology raises questions for ethics, biosecurity, biosafety, health, energy and intellectual property. To date, key stakeholders have focused primarily on the so-called dual-use challenge. For example, while the study of synthetic biology may lead to more efficient ways to produce medical treatments (e.g. against malaria), it may also lead to synthesis or redesign of harmful pathogens (e.g., smallpox) by malicious actors. . Proposals for
licensing and monitoring the various phases of gene and
genomeIn modern molecular biology the genome refers to all of its hereditary information encoded in DNA .The genome includes both the genes and the non-coding sequences of the DNA. The term was adapted in 1920 by Hans Winkler, Professor of Botany at the University of Hamburg, Germany...
synthesis began to appear in 2004. A 2007
study by the
J. Craig Venter InstituteThe J. Craig Venter Institute is a non-profit genomics research institute founded by J. Craig Venter, Ph.D. in October 2006. The Institute was the result of consolidating four organizations: the Center for the Advancement of Genomics, The Institute for Genomic Research, the Institute for...
, MIT, and CSIS compared several policy options for governing the safety risks associated with synthetic biology. Other initiatives, such as
OpenWetWare,
diybio,
biopunk,
biohack, and possibly others, have attempted to integrate self-regulation in their proliferation of
open sourceOpen source is an approach to the design, development, and distribution of software, offering practical accessibility to a software's source code. Some consider open source as one of various possible design approaches, while others consider it a critical strategic element of their operations...
synthetic biology projects. However the distributed and diffuse nature of open-source biotechnology may make it more difficult to track, regulate, or mitigate potential biosafety and biosecurity concerns. An initiative for self-regulation has been proposed by the International Association Synthetic Biology, which held a workshop on technical solutions for biosecurity in synthetic biology. The report emerging from the workshop proposes a set of measures to be implemented by the synthetic biology industry for improved biosecurity and biosafety. Deliberate misuse aside, harm to human health or the environment could potentially result from error (e.g. failure to follow standard laboratory containment protocols).
Social and Ethical
Online discussion of so-called “societal issues” online at
OpenWetWare, at the
SYNBIOSAFE forum on issues regarding ethics, safety, security, IPR, governance, and public perception
(background document).
Some efforts have been made to engage social issues "upstream" focus on the integral and mutually formative relations among scientific and other human practices. These approaches attempt to invent ongoing and regular forms of collaboration among synthetic biologists, ethicists, political analysts, funders, human scientists and civil society activists. These collaborations have consisted either of intensive, short term meetings, aimed at producing guidelines or regulations, or standing committees whose purpose is limited to protocol review or rule enforcement. Such work has proven valuable in identifying the ways in which synthetic biology intensifies already-known challenges in rDNA technologies. However, these forms are not suited to identifying new challenges as they emerge, and critics worry about uncritical complicity. An example of efforts to develop ongoing collaboration is the "human practices" component of the Synthetic Biology Engineering Research Center
(SynBERC), an NSF funded collaboration among a number of leading research universities. In Europe, the multi-partner project
SYNBIOSAFE, coordinated by IDC, is investigating the biosafety, biosecurity and ethical aspects of synthetic biology. The International Consortium for Polynucleotide Synthesis was formed in 2006 to encourage sharing of ideas and resources for pro-actively monitoring synthetic gene orders and enforcing safe practices,
(ICPS). The recently formed Industry Association Synthetic Biology
(IASB) has also started to tackle open biosecurity problems for biotech companies doing gene synthesis.
A report from the
Hastings CenterThe Hastings Center, founded in 1969, is an independent, non-partisan, non-profit bioethics research institute based in the United States. It is dedicated to the examination of essential questions in health care, biotechnology, and the environment...
and Woodrow Wilson Center found that non-physical moral concerns in synthetic biology have received scant attention.
Distributive justiceDistributive justice concerns what some consider to be socially just with respect to the allocation of goods in a society. Thus, a community in which incidental inequalities in outcome do not arise would be considered a society guided by the principles of distributive justice...
and our relationship with nature are two such concerns. The authors suggest that what is needed most is a better understanding of precisely what values are considered at play in the context of synthetic biology.
In January 2009, the
Alfred P. Sloan FoundationThe Alfred P. Sloan Foundation is a philanthropic non-profit organization in the United States. It was established in 1934 by Alfred P. Sloan, Jr., then-President and Chief Executive Officer of General Motors....
funded the Woodrow Wilson Center, the
Hastings CenterThe Hastings Center, founded in 1969, is an independent, non-partisan, non-profit bioethics research institute based in the United States. It is dedicated to the examination of essential questions in health care, biotechnology, and the environment...
, and the
J. Craig Venter InstituteThe J. Craig Venter Institute is a non-profit genomics research institute founded by J. Craig Venter, Ph.D. in October 2006. The Institute was the result of consolidating four organizations: the Center for the Advancement of Genomics, The Institute for Genomic Research, the Institute for...
to examine the public perception, ethics, and policy implications of synthetic biology.
Key enabling technologies
There are several key enabling technologies that are critical to the growth of synthetic biology. The key concepts include standardization of biological parts and hierarchical abstraction to permit using those parts in increasingly complex synthetic systems. . Achieving this is greatly aided by basic technologies of reading and writing of DNA (sequencing and fabrication), which are improving in price/performance exponentially
(Kurzweil 2001). Measurements under a variety of conditions are needed for accurate modeling and computer-aided-design (CAD).
Sequencing
Synthetic biologists make use of
DNA sequencingThe term DNA sequencing refers to sequencing methods for determining the order of the nucleotide bases—adenine, guanine, cytosine, and thymine—in a molecule of DNA....
in their work in several ways. First, large-scale genome sequencing efforts continue to provide a wealth of information on naturally occurring organisms. This information provides a rich substrate from which synthetic biologists can construct parts and devices. Second, synthetic biologists use sequencing to verify that they fabricated their engineered system as intended. Third, fast, cheap and reliable sequencing can also facilitate rapid detection and identification of synthetic systems and organisms.
Fabrication
A critical limitation in synthetic biology today is the time and effort expended during fabrication of engineered genetic sequences. To speed up the cycle of design, fabrication, testing and redesign, synthetic biology requires more rapid and reliable
de novo DNA synthesisOligonucleotide synthesis is the chemical synthesis of relatively short fragments of nucleic acids with defined chemical structure . The technique is extremely useful in current laboratory practice because it provides a rapid and inexpensive access to custom-made oligonucleotides of the desired...
and assembly of fragments of DNA, in a process commonly referred to as
gene synthesisGene synthesis is the process of synthesizing an artificially designed gene into a physical DNA sequence.Gene synthesis was first demonstrated by Har Gobind Khorana in 1970 for a short artificial gene. Nowadays, commercial gene synthesis services are available from hundreds of companies worldwide,...
.
In 2002 researchers at SUNY Stony Brook succeeded in synthesizing the 7741 base
poliovirusPoliovirus, the causative agent of poliomyelitis, is a human enterovirus and member of the family of Picornaviridae. Poliovirus is composed of a RNA genome and a protein capsid. The genome is single-stranded positive-sense RNA genome that is about 7500 nucleotides long. The viral particle is about...
genome from its published sequence, producing the first synthetic organism. This took about two years of painstaking work. In 2003 the 5386 bp genome of the
bacteriophageA bacteriophage is any one of a number of viruses that infect bacteria. Bacteriophages are among the most common organisms on Earth. The term is commonly used in its shortened form, phage....
Phi X 174 was assembled in about two weeks. In 2006, the same team, at the
J. Craig Venter InstituteThe J. Craig Venter Institute is a non-profit genomics research institute founded by J. Craig Venter, Ph.D. in October 2006. The Institute was the result of consolidating four organizations: the Center for the Advancement of Genomics, The Institute for Genomic Research, the Institute for...
, has constructed and patented a synthetic genome of a novel minimal bacterium,
Mycoplasma laboratoriumMycoplasma laboratorium is a planned partially synthetic species of bacterium derived from the genome of Mycoplasma genitalium. This effort in synthetic biology is being undertaken at the J. Craig Venter Institute by a team of approximately twenty scientists headed by Nobel laureate Hamilton Smith,...
and is working on getting it functioning in a living cell.
In 2007 it was reported that several companies were offering the
synthesis of genetic sequencesGene synthesis is the process of synthesizing an artificially designed gene into a physical DNA sequence.Gene synthesis was first demonstrated by Har Gobind Khorana in 1970 for a short artificial gene. Nowadays, commercial gene synthesis services are available from hundreds of companies worldwide,...
up to 2000 bp long, for a price of about $1 per base pair and a turnaround time of less than two weeks.
As of the present date, September 2009, the price has dropped to less than $0.50 per base pair with some improvement in turn around time. Not only is the price judged lower than the cost of conventional cDNA cloning, the economics make it practical for researchers to design and purchase multiple variants of the same sequence to identify genes or proteins with optimized performance.
Modeling
Models inform the design of engineered biological systems by allowing synthetic biologists to better predict system behavior prior to fabrication. 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. Recently, multiscale models of gene regulatory networks have been developed that focus on synthetic biology applications. Simulations have been used that model all biomolecular interactions in transcription, translation, regulation, and induction of gene regulatory networks, guiding the design of synthetic systems.
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. Technologies which allow many parallel and time-dependent measurements will be especially useful in synthetic biology.
MicroscopyMicroscopy is the technical field of using microscopes to view samples or objects. There are three well-known branches of microscopy, optical, electron and scanning probe microscopy....
and
flow cytometryFlow cytometry is a technique for counting and examining microscopic particles, such as cells and chromosomes, by suspending them in a stream of fluid and passing them by an electronic detection apparatus. It allows simultaneous multiparametric analysis of the physical and/or chemical...
are examples of useful measurement technologies.
See also
- Angela Belcher
Angela M. Belcher is a material scientist, biological engineer, and professor at the Massachusetts Institute of Technology in , United States...
- BioBrick
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 such as E. coli to construct new biological systems. BioBrick parts represent an effort to introduce the...
- Bioengineering
- Biohacking
- Computational biology
Computational biology is an interdisciplinary field that applies the techniques of computer science, applied mathematics and statistics to address biological problems. The main focus lies on developing mathematical modeling and computational simulation techniques...
- Computational biomodeling
- IGEM
The International Genetically Engineered Machine competition is the premiere undergraduate Synthetic Biology competition.- Competition details :...
- List of emerging technologies
- Synthetic genomics
Synthetic genomics is a nascent field of synthetic biology that uses aspects of genetic modification on pre-existing life forms with the intent of producing some product or desired behavior on the part of the life form so created....
- Synthetic morphology
Synthetic morphology is a sub-discipline of the broader field of synthetic biology.In standard synthetic biology, artificial gene networks are introduced into cells, inputs are applied to those networks, and the networks perform logical operations on them and output the result of the operation as...
- Systems biology
Systems biology is a biology-based inter-disciplinary study field that focuses on the systematic study of complex interactions in biological systems, thus using a new perspective to study them. Particularly from year 2000 onwards, the term is used widely in the biosciences, and in a variety of...
- Nucleic acid analogues
Nucleic acid analogues are compounds structurally similar to naturally occurring RNA and DNA, used in medicine and in molecular biology research....
- Expanded genetic code
An expanded genetic code refers to an artificially modified genetic code in which one or more specific codons have been allocated to encode an amino acid which is not among the twenty/twentytwo found in nature.-Introduction:...
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