Monday, October 27, 2014

Synthetic Biology on Ordinary Paper

Synthetic biology on ordinary paper, results off the page

By combining efforts and innovations, Wyss Institute scientists develop synthetic gene controls for programmable diagnostics and biosensors, delivered out of the lab on pocket-sized slips of paper



New achievements in synthetic biology announced today by researchers at the Wyss Institute for Biologically Inspired Engineering, which will allow complex cellular recognition reactions to proceed outside of living cells, will dare scientists to dream big: there could one day be inexpensive, shippable and accurate test kits that use saliva or a drop of blood to identify specific disease or infection — a feat that could be accomplished anywhere in the world, within minutes and without laboratory support, just by using a pocket–sized paper diagnostic tool.

[caption id="attachment_231" align="aligncenter" width="635"]Synthetic Biology on Ordinary Paper Wyss Institute scientists have embedded effective synthetic gene networks in pocket-sized slips of paper. An array of RNA–activated sensors uses visible color changing proteins to indicate presence of a targeted RNA, capable of identifying pathogens such as antibiotic–resistant bacteria and strain–specific Ebola virus. Credit: Harvard's Wyss Institute[/caption]

That once far–fetched idea seems within closer reach as a result of two new studies describing the advances, published today in Cell, accomplished through extensive cross–team collaboration between two teams at the Wyss Institute headed by Wyss Core Faculty Members James Collins, Ph.D., and Peng Yin, Ph.D..

Wyss Institute scientists discuss the collaborative environment and team effort that led to two breakthroughs in synthetic biology that can either stand alone as distinct advances – or combine forces to create truly tantalizing potentials in diagnostics and gene therapies. Credit: Harvard’s Wyss Institute

"In the last fifteen years, there have been exciting advances in synthetic biology," said Collins, who is also Professor of Biomedical Engineering and Medicine at Boston University, and Co–Director and Co–Founder of the Center of Synthetic Biology. "But until now, researchers have been limited in their progress due to the complexity of biological systems and the challenges faced when trying to re–purpose them. Synthetic biology has been confined to the laboratory, operating within living cells or in liquid–solution test tubes."

The conventional process can be thought of through an analogy to computer programming. Synthetic gene networks are built to carry out functions, similar to software applications, within a living cell or in a liquid solution, which is considered the "operating system".

"What we have been able to do is to create an in vitro, sterile, abiotic operating system upon which we can rationally design synthetic, biological mechanisms to carry out specific functions," said Collins, senior author of the first study, "Paper–Based Synthetic Gene Networks".

Leveraging an innovation for chemistry–based paper diagnostics previously devised by Wyss Institute Core Faculty Member George Whitesides, Ph.D. , the new in vitro operating system is ordinary paper.

"We've harnessed the genetic machinery of cells and embedded them in the fiber matrix of paper, which can then be freeze dried for storage and transport — we can now take synthetic biology out of the lab and use it anywhere to better understand our health and the environment," said lead author and Wyss Staff Scientist Keith Pardee, Ph.D.

Biological Programs on Paper

Using standard equipment at his lab bench and commercially–available, cell–free systems, Pardee designed and built a wide range of paper–based diagnostics and biosensors. He also used commonly–used fluorescent and color–changing proteins to provide visible indication that the mechanisms were working. Once built, the paper–based tools can be freeze dried for safe room–temperature storage and shipping, maintaining their effectiveness for up to one year. To be activated, the freeze–dried paper need simply be rehydrated with water.

The paper–based platform can also be used in the lab to save a huge amount of time and cost as compared to conventional in vivo methods of validating tools for cell–based research. "Where it would normally take two or three days to validate a tool inside of a living cell, this can be done using a synthetic biology paper–based platform in as little as 90 minutes," Pardee said.

As proof of concept, Collins and Pardee demonstrated a variety of effective paper–based tools ranging from small molecule and RNA actuation of genetic switches, to rapid design and construction of complex gene circuits, to programmable paper–based diagnostics that can detect antibiotic resistant bacteria and even strain–specific Ebola virus.

The Ebola sensor was created by using the paper–based method and utilized a novel gene regulator called a "toehold switch", a new system for gene expression control with unparalleled programmability and flexibility reported in the second study inCell. Although its inventors had designed the toehold switch to regulate genes inside living cells, its function was easily transferred to the convenience of ordinary freeze–dried paper, showcasing the true robustness of both the freeze–dried paper technique and the toehold switch.

The Ebola sensor was conceived by Wyss Institute Postdoctoral Fellow Alex Green, Ph.D., co–inventor of the toehold switch regulator and lead author of its report, after the ongoing West Africa crisis brought the deadly pathogen to global spotlight. Due to its easy assembly and fast prototyping ability, Green was eager to test the paper–based platform as an operating system for the toehold switch, which he had initially developed for programming gene expression in living cells. Green reached out to Pardee and together they assembled the prototype Ebola sensor in less than a day and then developed an assay that can differentiate between Sudan and Zaire virus strains within an hour of exposure.

Putting the 'Synthetic' in 'Synthetic Biology'

The toehold switch works as such an accurate biosensor because it can be programmed to only react with specific, intended targets, producing true "switch" behavior with an unprecedented ability to turn on targeted gene expression. It can be programmed to precisely detect an RNA signature of virtually any kind and then turn on production of a specific protein.

Reported in the paper "Toehold Switches: De–Novo–Designed Regulators of Gene Expression", Green developed the toehold switch gene regulator with senior author Yin, who is Associate Professor in the Department of Systems Biology at Harvard Medical School in addition to being a Wyss Core Faculty Member.

"While conventional synthetic biology complicates accuracy and functionality because it relies on re–purposing and re–wiring existing biological parts, the toehold switch is inspired by Nature but is an entirely novel, de–novo–designed gene expression regulator," said Yin.

"We looked at our progress to rationally design dynamic DNA nanodevices in test tubes and applied that same fundamental principle to solve problems in synthetic biology," said Yin. The resulting toehold switch, an RNA–based organic nanodevice, is a truly "synthetic" synthetic gene regulator with 40–fold better ability to control gene expression than conventional regulators.

The toehold switch functions so precisely that many different toehold switches can operate simultaneously in the same cell. This allows several toehold switches to be linked together, creating a complex circuit, which could be programmed to carry out multiple–step functions such as first detecting a pathogen and then delivering an appropriate therapy.

"Instead of re–purposing an existing part that was evolved by Nature, we wanted to change our way of thinking, leverage naturally–occurring principles, and build from scratch," Green said. His Ph.D. in materials science and strong computer programming skills allowed him to approach biology with a fresh perspective and start from the ground up to engineer the toehold switch, rather than merely rewiring existing natural parts.

Wyss Institute scientists discuss the collaborative environment and team effort that led to two breakthroughs in synthetic biology that can either stand alone as distinct advances – or combine forces to create truly tantalizing potentials in diagnostics and gene therapies. Credit: Harvard’s Wyss Institute

By combining forces, the two Wyss Institute teams showed that the toehold switch, so effective in living cells for its dynamic control of in vivo gene expression, is also fully capable of functioning in vitro on freeze–dried paper. With its impressive gene regulation functions able to be transported out of the lab for easy delivery of diagnostics and gene therapies, paper–based toehold switches promise a profound impact on human and environmental health.

"Whether used in vivo or in vitro, the ability to rationally design gene regulators opens many doors for increasingly complex synthetic biological circuits," Green said.

The Wyss Effect

Standing on their own, both paper–based synthetic gene networks and toehold switch gene regulators could each have revolutionary impacts on synthetic biology: the former brings synthetic biology out of the traditional confinement of a living cell, the latter provides a rational design framework to enable de–novo design of both the parts and the network of gene regulation. But combining the two technologies together could truly set the stage for powerful, multiplex biological circuits and sensors that can be quickly and inexpensively assembled for transport and use anywhere in the world.

"The level of idea sharing and collaboration that occurred to achieve these results is evidence of the teamwork that is the lifeblood of the Wyss," said Institute Founding Director Don Ingber, M.D., Ph.D., Professor of Vascular Biology at Harvard Medical School and Boston Children's Hospital, and Professor of Bioengineering at Harvard School of Engineering and Applied Science. "But we go beyond collaboration, to ensure that these great ideas are translated into useful technologies that can have transformative impact in the real world."


Images and video are available.

The Wyss Institute for Biologically Inspired Engineering at Harvard University uses Nature's design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world. Working as an alliance among all of Harvard's Schools, and in partnership with Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Boston Children's Hospital, Dana Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Boston University, Tufts University, and Charité - Universitätsmedizin Berlin, and the University of Zurich, the Institute crosses disciplinary and institutional barriers to engage in high-risk research that leads to transformative technological breakthroughs. By emulating Nature's principles for self-organizing and self-regulating, Wyss researchers are developing innovative new engineering solutions for healthcare, energy, architecture, robotics, and manufacturing. These technologies are translated into commercial products and therapies through collaborations with clinical investigators, corporate alliances, and new start-ups.

News Release Source :  Synthetic biology on ordinary paper, results off the page

194 Countries Urged to Regulate Synthetic Biology Now

Regulate Synthetic Biology Now: 194 Countries

SynBio industry’s wild west days are numbered


In a unanimous decision of 194 countries, the United Nation's Convention on Biological Diversity (CBD) today formally urged nation states to regulate synthetic biology (SynBio), a new extreme form of genetic engineering. The landmark decision follows ten days of hard-fought negotiations between developing countries and a small group of wealthy biotech-friendly economies. Until now, synthetic organisms have been developed and commercialized without international regulations; increasing numbers of synthetically-derived products are making their way to market. The CBD’s decision is regarded as a "starting signal" for governments to begin establishing formal oversight for this exploding and controversial field.

[caption id="attachment_226" align="aligncenter" width="477"]194 Countries asked Regulate Synthetic Biology Now 194 Countries asked Regulate Synthetic Biology Now[/caption]

"Synthetic Biology has been like the wild west: a risky technology frontier with little oversight or regulation,” Jim Thomas of ETC Group explained from CBD negotiations in Korea. “At last the UN is laying down the law."

"This international decision is very clear,” Thomas added. “Not only do countries now have to set up the means to regulate synthetic biology, but those regulations need to be based on precaution and not harming the environment. The good news is that precaution won the day."

This decision comes at a critical time. The SynBio industry is bringing some of its first products to market, including a vanilla flavour produced by synthetically modified yeast and specialized oils used in soaps and detergents derived from synthetically modified algae. In December, bay area SynBio firm Glowing Plants Inc. intends to release synthetically-engineered glow-in-the-dark plants to 6,000 recipients without government oversight. The United States is not a signatory to the CBD, making it one of only three countries that will not be formally bound by this decision (the other 2 are Andorra and the Holy See).

Compared to conventional genetic engineering, synthetic biology poses serious risks to the environment, biodiversity and health as well as to the cultures and livelihoods of Indigenous peoples and local communities. Scientists warn that modified algae and yeast could have unpredictable effects if they escape. New applications could also disrupt the behaviour of plants, insects and potentially whole ecosystems. For example, dsRNA crop sprays[1] disrupt the action of genes, which may kill targeted pest, but will also affect other organisms in unpredictable ways by silencing genes.

"The multibillion-dollar SynBio industry has been slipping untested ingredients into food, cosmetics and soaps; they are even preparing to release synthetically modified organisms into the environment,” said Dana Perls of Friends of the Earth-U.S. “This decision is a clear signal that synthetic biology urgently needs to be assessed and regulated. “Governments need to step in to do that."

Many of the diplomats negotiating at the UN Convention had instructions to establish a complete moratorium on the release of synthetically modified organisms. However, they faced stiff opposition from a small group of wealthy countries with strong biotech industries, particularly Brazil, Canada, New Zealand, Australia and the UK.

After a week of negotiations, battle lines were drawn between the pro-SynBio states on one side and African, Asian, Caribbean and Latin American countries on the other side. Notable among the latter group were: Malaysia, Bolivia, Philippines, Saint Lucia Antigua, Ethiopia, Timor Leste and Egypt.

Global South representatives raised concerns that synthetic biology products intended to replace agricultural commodities could devastate their economies and degrade biodiversity. Many delegates were also concerned that synthetically modified organisms could create biosafety risks – e.g. the possibility of synthetic algae escaping into waterways, producing a solar-powered oil spill.

A network of international organizations including Friends of the Earth, ETC Group, Econexus and the Federation of German Scientists had been closely monitoring the negotiations and providing input for over 4 years. Civil society groups first raised the topic of synthetic biology at the CBD in 2010.

“It was good to see delegates of the South stand up for the interests of their farmers, peasants and biodiversity here in Pyeongchang," said Neth Dano, Asia Director of ETC Group. "This is not the moratorium many of us wanted, but it’s a good step in the right direction."

“Synthetic biology involves many novel, experimental, little understood techniques and outcomes, and this greatly increases the risks involved to the environment, human health, food security and livelihoods,” said Helena Paul of EcoNexus. “Our technical cleverness tends to blind us to our ignorance; the UK wishes to play a leading role in synthetic biology and does not seem to want precaution to stand in the way, so this COP decision is a helpful corrective to that dangerous policy.”

What’s in the CBD decision?

The CBD’s three-page decision outlines its recommendations for member countries’ approaches to synthetic biology. The CBD urges all member countries to:

  • Follow a precautionary approach to synthetic biology.

  • Set up systems to regulate the environmental release of any synthetic biology organisms or products. These regulations must ensure that activities in one country cannot harm the environment of another. (Article 3 of the CBD)

  • Ensure that no synthetic biology organisms are released for field trials without a process of formal prior risk assessment.

  • Submit synthetic biology organisms, components and products to scientific assessments that consider risks to conservation and sustainable use of biodiversity as well as human health, food security and socio-economic considerations.

  • Encourage research funds to assess the safety of synthetic biology as well the socio-economic impacts of the technology.

  • Support developing countries to develop their capacity to assess synthetic biology.

The decision also:

  • Establishes an ongoing process within the Convention on Biological Diversity, including an expert group which will establish a definition of synthetic biology and identify whether existing governance arrangements are adequate.

  • Invites other UN bodies to consider the issue of synthetic biology as it relates to their mandates.

Notes to Editors:

The full text of the decision agreed by COP 12 of the CBD is available here.

Synthetic biology covers a range of new genetic engineering techniques that either build from scratch or “edit” the genetic code of living organisms. It’s a rapidly expanding industry that re-engineers microbes and other organisms to produce industrially useful compounds. For more information about, visit


1. dsRNA stands for double stranded RNA. These molecules are a part of the finely tuned gene regulation of an organism. They will switch of specific genes, but their mode of action and interaction is not well understood.

News Release Source : Regulate Synthetic Biology Now: 194 Countries

Prof. James Collins to Receive The 2015 HFSP Nakasone Award

James Collins to receive the 2015 HFSP Nakasone Award

The 2015 HFSP Nakasone Award

The Human Frontier Science Program Organization (HFSPO) has announced that the 2015 HFSP Nakasone Award has been conferred upon James Collins of Boston University and Harvard's Wyss Institute for his innovative work on synthetic gene networks and programmable cells which launched the exciting field of synthetic biology.

[caption id="attachment_222" align="aligncenter" width="640"]James Collins to receive the 2015 HFSP Nakasone Award James Collins to receive the 2015 HFSP Nakasone Award[/caption]

The HFSP Nakasone Award was established to honour scientists who have made key breakthroughs in fields at the forefront of the life sciences. It recognizes the vision of former Prime Minister Nakasone of Japan in the creation of the Human Frontier Science Program. James Collins will present the HFSP Nakasone Lecture at the 15th annual meeting of HFSP awardees to be held in La Jolla, California, in July 2015.

James Collins was one of the first to show that one can engineer biological circuits out of proteins, genes and other bits of DNA. He designed and constructed a genetic toggle switch - a bistable gene circuit with broad implications for biomedicine and biotechnology. This work represents a landmark in the beginnings of synthetic biology. He showed that synthetic gene networks can be used as regulatory modules and interfaced with the cell's genetic circuitry to create programmable cells for biomedical and biotech applications. Along these lines, Collins has developed whole-cell biosensors to detect various stimuli (chemicals, pathogens, heavy metals, explosives), as well as synthetic probiotics to detect and treat infections (e.g., cholera). Collins has also designed and constructed RNA switches, genetic counters, programmable microbial kill switches, synthetic bacteriophages to combat bacterial infections, genetic switchboards for metabolic engineering, synthetic mRNA for stem cell reprogramming, and tunable mammalian genetic switches.

Collins' innovative work in synthetic biology is impacting the biosciences and the biotech industry in providing one of the key enabling technologies of the 21st century. His engineered gene circuits and synthetic biology technology have been utilized by multiple companies in diverse fields ranging from agriculture to drug discovery. His work has inspired scientists around the world and enabled multiple biomedical applications, including in vivo bio-sensing, antibiotic potentiation, biofilm eradication, drug target identification and validation, microbiome reengineering, and efficient stem cell reprogramming and differentiation. Collins' mammalian switch technology is being used by research groups worldwide and his programmable microbial kill switch was highlighted by President Obama's Bioethics Commission as a much-needed safeguard for real-world applications of synthetic biology.

The work of James Collins is advancing, if not defining, the emerging discipline of synthetic biology, and his path-blazing research on synthetic gene networks and programmable cells is transforming the life sciences and expanding our ability to study and harness complex mechanisms of living organisms.

The HFSP Nakasone Award was established in 2010. Previous recipients have been Karl Deisseroth (2010), Michael Elowitz (2011), Gina Turrigiano (2012), Stephen Quake (2013), and Uri Alon (2014).

The Human Frontier Science Program Organization was founded in 1989 to support international research and training at the frontier of the life sciences. It is supported by contributions from the G7 nations, together with Switzerland, Australia, India, New Zealand, Norway, Singapore, Republic of Korea and the European Union. With its collaborative research grants and postdoctoral fellowship programs, the program has approved over 4000 awards involving more than 6600 scientists from all over the world during the 25 years of its existence. The HFSPO supports research at the interface between life sciences and the natural sciences and engineering and places special emphasis on creating opportunities for young scientists.

News Release SourceJames Collins to receive the 2015 HFSP Nakasone Award

For more detail of the award :

More information on Prof. James Collins and his work is available

at (Boston University) and

at (Wyss Institute).