Scientists produce beneficial natural compounds in tomato – with potential for industrial scale up

From the John Innes Centre news feed and featuring OpenPlant scientists Professor Cathie Martin and Dr Yang Zhang.

Given the opportunity to drink fifty bottles of wine or eat one tomato, which would you choose?

Scientists at the John Innes Centre have found a way to produce industrial quantities of useful natural compounds efficiently, by growing them in tomatoes.

The compounds are phenylpropanoids like Resveratrol, the compound found in wine which has been reported to extend lifespan in animal studies, and Genistein, the compound found in soybean which has been suggested to play a role in prevention of steroid-hormone related cancers, particularly breast cancer. 

As a result of the research led by Dr Yang Zhang and Dr Eugenio Butelli working in Professor Cathie Martin’s lab at the John Innes Centre, one tomato can produce the same quantity of Resveratrol as exists in 50 bottles of red wine. One tomato has also produced the amount of Genistein found in 2.5kg of tofu.

Drs Zhang and Butelli have been studying the effect of a protein called AtMYB12 which is found in Arabidopsis thaliana, a plant found in most UK gardens and used as a model plant in scientific investigation. 

The protein AtMYB12 activates a broad set of genes involved in metabolic pathways responsible for producing natural compounds of use to the plant. The protein acts a bit like a tap to increase or reduce the production of natural compounds depending on how much of the protein is present. 

What was interesting about the effect of introducing this protein into a tomato plant was how it acted to both increase the capacity of the plant to produce natural compounds (by activating phenylpropanoid production) and to influence the amount of energy and carbon the plant dedicated to producing these natural compounds. In response to the influence of the AtMYB12 protein, tomato plants began to create more phenylpropanoids and flavanoids and to devote more energy to doing this in fruit.

Introducing both AtMYB12 and genes from plants encoding enzymes specific for making Resveratrol in grape and Genistein in legumes, resulted in tomatoes that could produce as much as 80mg of novel compound per gram of dry weight –demonstrating that industrial scale up is possible. 

Tomatoes are a high yielding crop - producing up to 500 tonnes per hectare in countries delivering the highest yields (FAOSTAT 2013) and require relatively few inputs. Production of valuable compounds like Resveratrol or Genistein in tomatoes could be a more economical way of producing them than relying on artificial synthesis in a lab or extracting them in tiny quantities from traditional plant sources (e.g., grapes, soybeans, etc.). The tomatoes can be harvested and juiced and the valuable compounds can be extracted from the juice. The tomatoes themselves could potentially become the source of increased nutritional or medicinal benefit. 

Professor Cathie Martin said:

"Our study provides a general tool for producing valuable phenylpropanoid compounds on an industrial scale in plants, and potentially production of other products derived from aromatic amino acids. Our work will be of interest to different research areas including fundamental research on plants, plant/microbe engineering, medicinal plant natural products, as well as diet and health research.”

Dr Yang Zhang, said:

"Medicinal plants with high value are often difficult to grow and manage, and need very long cultivation times to produce the desired compounds. Our research provides a fantastic platform to quickly produce these valuable medicinal compounds in tomatoes. Target compounds could be purified directly from tomato juice. We believe our design idea could also be applied to other compounds such as terpenoids and alkaloids, which are the major groups of medicinal compounds from plants.”

This research was strategically funded by the BBSRC, the EU ATHENA collaborative project, the Major State Basic Research Development Program (973 Program) of China, the John Innes Foundation, and the DBT-CREST Fellowship.

Source: Scientists produce beneficial natural compounds in tomato – with potential for industrial scale up

2015 Nobel prize recognises importance of research into medicinal compounds made by plants and microbes.

From the John Innes Centre

Earlier this month the Nobel Prize for physiology and medicine was awarded to three scientists who pioneered the development of new drugs from plants and microbes, and in doing so, went on to save millions of lives.

Chinese scientist, Professor Youyou Tu, received half the Nobel prize for developing artemisinin, a drug from the wormwood plant which gave the world a desperately needed new therapy for treatment of malaria.

Professors Satoshi Omura and William Campbell received a quarter of the prize each for the development of ivermectin, a drug made by a bacterium called Streptomyces avermitilis. Ivermectin was originally intended to tackle parasitic infections in animals, but it also proved to be extremely effective as a simple and life-changing treatment for the human parasitic infections which cause river blindness and elephantiasis.

The John Innes Centre is a world leader in this area of science. Scientists in the Plant and Microbial Metabolism programme aim to understand how plants and microbes make diverse natural compounds, and to apply this knowledge to develop new therapeutics that can improve human and animal health. Two relevant examples of current JIC research are the continuing discovery of potential new antibiotics made by species of the bacterium Streptomyces, and the discovery of how the anti-cancer drug vincristine is made by the Madagascar periwinkle plant.

Streptomycetes and antibiotics

Streptomycetes are soil-dwelling bacteria that give rise to half of the antibiotics used in human and veterinary medicine and agriculture. Ivermectin is one of the best known examples; another is streptomycin for which Professor Selman Waksman was awarded the Nobel Prize for Medicine in 1952. Streptomycetes also produce compounds that are used as anti-cancer agents, herbicides and other pharmacologically active chemicals such as immuno-suppressants, and several enzymes that are important to the food industry. 

Following the huge advances in understanding antibiotic production by Streptomyces species stemming from the research of Professor David Hopwood at JIC from the 1960s onwards, Professor Merv Bibb and Dr Barrie Wilkinson and Dr Andy Truman are working to discover new compounds made by Streptomyces and related bacteria. Their discoveries build on the pioneering work of Omura, Campbell, Waksman, Hopwood and others, and are needed more urgently than ever in the face of the dwindling effectiveness of current antibiotics for many major diseases.

Fortunately, advanced methods of sequencing bacterial genomes have now revealed that these bacteria have the genetic capacity to make many diverse compounds with unexplored structures and properties. There is thus huge untapped potential for the discovery of new antibiotics. The John Innes researchers are using combinations of genetics, bioinformatics, chemistry and molecular biology to pinpoint and characterise new compounds of potential value, and to engineer the production of large amounts of these compounds for tests of their antibiotic properties. The researchers collaborate with other organisations and pharmaceutical companies to ensure that new compounds can be rapidly developed into drugs if they show therapeutic potential. 

The Madagascar Periwinkle (Catharanthus Roseus) - The plant that makes vincristine

Madagascar periwinkle and anti-cancer drugs

The Madagascar periwinkle plant produces rare complex compounds that are used as anticancer therapies. Vincristine, for example, is important for the treatment of several cancers. The drug has to be purified from the plant, and as a result it is very expensive and in short supply. Professor Sarah O’Connor is working with collaborators in Europe and the USA to discover how this and related compounds are made in the plant. Her discoveries will lead to better production methods for the anticancer compounds, and the development of novel, related compounds which may have new or enhanced therapeutic properties. She recently engineered yeast cells to produce a precursor to vincristine, using genes from the periwinkle plant. This development opens up the possibility of cheap, large scale production of vincristine in the future.

Many species of plants in addition to the Madagascar periwinkle produce valuable drugs. The antimalarial drug artemisinin discovered by Professor YouYou Tu in the wormwood plant is an outstanding example. Quinine, the original antimalarial therapy, comes from a South American tree, and plants also produce morphine, atropine and a host of other drugs in common use. JIC makes major contributions to the discovery of new therapeutic compounds from plants. As for bacteria, new information about plant genomes shows us that plants have a huge capacity for the production of potentially valuable molecules that have not yet been characterised. Genomic information also helps us to discover the compounds responsible for the therapeutic properties of plants used in traditional medicines. The research of Professors Sarah O’Connor, Anne Osbourn, Cathie Martin, Rob Field and George Lomonossoff and Dr Paul O’Maille is leading to the discovery of new compounds and how they are made in plants, to the synthesis of altered versions of therapeutic compounds expected to have novel properties, and to methods for engineering large scale production of plant-derived therapeutic compounds.

EU Workshop on Access and Benefit Sharing under Nagoya Protocol

More info and registration here

Context

The EU is a Party to the Nagoya Protocol on Access to Genetic Resources and the Fair and Equitable Sharing of Benefits Arising from their Utilisation. The EU ABS Regulation, which transposes into the EU legal order the compliance pillar of the Protocol, became applicable as of 12 October 2014. The principal obligations of the Regulation – i.e. Article 4 on due diligence, Article 7 on monitoring user compliance and Article 9 on checks on user compliance – will become applicable as of 12 October 2015. In this context it is important that those who utilise genetic resources (i.e. conduct research and development on the genetic and/or biological composition of genetic resources, including through the application of biotechnology) are aware of the obligations arising from the Regulation, and that they can take the necessary measures to ensure their activities are compliant.

Workshop presentation

The workshop aims at providing the participants with knowledge about their obligations under the EU ABS Regulation and what they practically imply for their everyday work. In the first part of the workshop, the new legal framework will be explained, providing insight into the main provisions of the EU ABS Regulation. In the second part of the workshop, participants will have a chance to put the knowledge gained into practice through interactive case studies, based on real-life examples and realistic scenarios. The workshop should allow participants to better understand their obligations under the EU law, and to establish which steps they need to follow and which practical measures they should take when dealing with genetic resources originating from Parties to the Nagoya Protocol.

Target group

The workshop is targeted at senior academics and experienced researchers conducting research and development on genetic resources who have an interest in gaining an essential understanding of the new legal framework in the EU, in view of the ABS Regulation becoming fully operational later this year.

Scientists with an expertise in the ABS regulation are not targeted by this basic training workshop

Event on writing for The Conversation (23 Nov 2015)

The Conversation is a website aimed at providing expert opinion and comment from academics across the UK:Articles on the site are regularly carried on other sites, including The Guardian, Independent, CNN and IFLscience.

The site is a great opportunity to share your science with a wider audience and contribute commentary on synthetic biology and related fields.

The Office of External Affairs and Communications at the University of Cambridge is hosting an event on 23 November with Jonathan Este, Associate Editor at The Conversation.

"The University of Cambridge is now a member of the Conversation, meaning that our researchers have greater opportunity to write stories for the site, and will also be able to benefit from training sessions in writing opinion pieces for a general audience. This can benefit early-career as well as more established researchers.

Jonathan Este will give a short talk covering the following: · What is The Conversation?

· How can researchers get involved in writing features?

· What are the benefits?

· What training and support is available?

Professor Simon Redfern from the Department of Earth Sciences who is a regular columnist on the Science & Technology page of The Conversation will also talk about his experiences.

After the presentations there will be an opportunity to network with colleagues over tea, coffee and biscuits."

There are a limited number of places, so please do book your place here.

5 Independent Research Career Development Fellowships at WISB (deadline 2 Dec)

Warwick Integrative Synthetic Biology Centre (WISB) is looking for ambitious postdoctoral researchers who wish to begin development of an independent career in synthetic biology. Five independent Research Career Development Fellowships are offered for 4 years. For more information, please see attached poster and More info and applications on the University of Warwick HR website (vacancy ref: 76911-105 - deadline 2 Dec) Information Flyer (PDF)

High-frequency, precise modification of the tomato genome (open access)

Čermák, T., Baltes, N. J., Čegan, R., Zhang, Y., & Voytas, D. F. (2015). High-frequency, precise modification of the tomato genome. Genome biology, 16(1), 1-15. doi:10.​1186/​s13059-015-0796-9 The use of homologous recombination to precisely modify plant genomes has been challenging, due to the lack of efficient methods for delivering DNA repair templates to plant cells. Even with the advent of sequence-specific nucleases, which stimulate homologous recombination at predefined genomic sites by creating targeted DNA double-strand breaks, there are only a handful of studies that report precise editing of endogenous genes in crop plants. More efficient methods are needed to modify plant genomes through homologous recombination, ideally without randomly integrating foreign DNA.

Plant synthetic promoters and transcription factors

Liu, W., & Stewart, C. N. (2016). Plant synthetic promoters and transcription factors. Current opinion in biotechnology, 37, 36-44. doi:10.1016/j.copbio.2015.10.001 Synthetic promoters and transcription factors (TFs) have become incredibly powerful and efficient components for precise regulation of targeted plant transgene expression. Synthetic promoters can be rationally designed and constructed using specific type, copy number and spacing of motifs placed upstream of synthetic or native core promoters. Similarly, synthetic TFs can be constructed using a variety of DNA binding domains (DBDs) and effector domains. Synthetic promoters and TFs can provide tremendous advantages over their natural counterparts with regards to transgene expression strength and specificity. They will probably be needed for coordinated transgene expression for metabolic engineering and synthetic circuit applications in plants for bioenergy and advanced crop engineering. In this article we review the recent advances in synthetic promoters and TFs in plants and speculate on their future.

OpenPlant ERASynBio Summer School in New Phytologist

New Phytologist have published a report on the OpenPlant ERASynBio Summer School in plant synthetic biology authored by Nicola Patron, Colette Matthewman and collaborators at BBSRC.

European science policy is reflecting the increasing importance of synthetic biology as a tool to drive cutting-edge scientific developments. Significant strategic investment has been made, coordinated by the European Research Area Network for synthetic biology (ERASynBio), to ensure European synthetic biology research is coherent and world-leading. Strategies to achieve this include providing high-quality training for the next generation of synthetic biologists, and fostering international collaborations across a range of disciplines (ERASynBio, 2014). To realize these aims, ERASynBio has funded annual summer schools to bring together early career researchers from across ERASynBio partner countries for world-class synthetic biology training and networking. The second of these summer schools, which ran on 14–20 September 2014 at the John Innes Centre, Norwich, UK, was designed to provide the participants with ‘An introduction to synthetic biology in plant systems’ in conjunction with OpenPlant, a collaborative plant-focussed Synthetic Biology Research Centre linking the University of Cambridge, John Innes Centre and The Sainsbury Laboratory.

‘… an invaluable and enjoyable opportunity for early career researchers to learn from and engage with world-leading experts in plant synthetic biology.’

Read more via New Phytologist
Carmichael, R. E., Boyce, A., Matthewman, C., & Patron, N. J. (2015). An introduction to synthetic biology in plant systems. New Phytologist, 208(1), 20-22. DOI: 10.1111/nph.13433

OpenPlant at the UK Synthetic Biology 2015 Conference

Three OpenPlant group leaders spoke at the recent UK Synthetic Biology Conference:

Nicola Patron (The Sainsbury Laboratory)
Development and Application of Standards for Plant Synthetic Biology

Anne Osbourn (John Innes Centre)
Making new molecules

Alison Smith (University of Cambridge)
Using synthetic biology approaches to allow predictable metabolic engineering in algae

The full conference schedule can be found here and there are plans for a 2016 conference in Edinburgh with more involvement from PhD students and postdocs. You can see some highlights from #SBUK2015 below!

OpenPlant ERASynBio Summer School in New Phytologist

New Phytologist have published a report on the OpenPlant ERASynBio Summer School in plant synthetic biology authored by Nicola Patron, Colette Matthewman and collaborators at BBSRC.

European science policy is reflecting the increasing importance of synthetic biology as a tool to drive cutting-edge scientific developments. Significant strategic investment has been made, coordinated by the European Research Area Network for synthetic biology (ERASynBio), to ensure European synthetic biology research is coherent and world-leading. Strategies to achieve this include providing high-quality training for the next generation of synthetic biologists, and fostering international collaborations across a range of disciplines (ERASynBio, 2014). To realize these aims, ERASynBio has funded annual summer schools to bring together early career researchers from across ERASynBio partner countries for world-class synthetic biology training and networking. The second of these summer schools, which ran on 14–20 September 2014 at the John Innes Centre, Norwich, UK, was designed to provide the participants with ‘An introduction to synthetic biology in plant systems’ in conjunction with OpenPlant, a collaborative plant-focussed Synthetic Biology Research Centre linking the University of Cambridge, John Innes Centre and The Sainsbury Laboratory.

‘… an invaluable and enjoyable opportunity for early career researchers to learn from and engage with world-leading experts in plant synthetic biology.’

Read more via New Phytologist Carmichael, R. E., Boyce, A., Matthewman, C., & Patron, N. J. (2015). An introduction to synthetic biology in plant systems. New Phytologist, 208(1), 20-22. DOI: 10.1111/nph.13433

Plant Methods Thematic Series on Gene Editing

The sponsor of the upcoming CRISPR workshop, Plant Methods, is inviting submissions to its new thematic series on Plant Genome Editing.

The series is being launched in conjunction with the GARNet-OpenPlant CRISPR-Cas Workshop to be held at the JIC Norwich on 7-8 September 2015.

The exciting field of genome editing is advancing rapidly and precise genome editing techniques have already become an important tool for both fundamental research and plant biotechnology.

The thematic series, which will include invited reviews by Holger Puchta (Karlsruher Institut für Technologie), Sandeep Kumar (Dow AgroSciences) and Carolyn Lawrence-Dill (Iowa State University), will cover all aspects of genome editing technologies as applied to plant research (both for crop plants and model organisms). GARNet will also collaborate with Nicola Patron to produce a commentary article from the CRISPR workshop.

Potential topics include, but are not limited to:

• Alternative methods for targeted genome editing (including CRISPR-Cas and zinc finger nickases)

• New technologies for synthetic biology

• Computational tools for genome editing

Manuscripts in the categories of Review, Methodology, Research Article, Software or Databases will be considered.

Find out more via GARNet

Job: Lectureship in Synthetic Biology

The Centre for Bacterial Cell Biology and Interdisciplinary Computing and Complex BioSystems (ICOS) research group are recruiting a tenured track Lectureship/Senior Lectureship (Assistant or Associate Professor in the American system) in

Synthetic Biology/Nanotechnology. Early applications are encouraged.

For informal enquires please contact the CSBB director, Professor Natalio Krasnogor.

Read more details about and how to apply for this exciting post.

Algae Biotech Experience at Cambridge

On the 25^th of July, fifteen 6^th form students selected from sevens schools across East Anglia were invited to spend the day at University of Cambridge to learn about algae research and biotechnology. The event was hosted by PhD students Anthony Riseley, Dept of Biochemistry and Johan Ulrich Kudahl, Dept of Plant Sciences and with support from the Biochemical Society, Dept. of Biochemistry and the Marie Curie training network, Photo.Comm.

The Algae Biotech Experience (ABE) was an event which aimed to:

1. Engage the students into the importance and relevance of microbiology in the 21^st century;
2. Challenge the students to conducting real scientific experiments and molecular techniques such as PCR and phycobilisome extractions and;
3. Help the students to discover the importance of algae science in our daily life and its relevance to helping solve problems such as the energy crisis and food security.

The day included wet lab practicals (PCR, phycobilisome extractions), computational projects (bioinformatics/protein structure visualisation), a lecture from a Cambridge scientist, a lab tour and microscopy of various algae species.

OpenPlant at the UK Synthetic Biology 2015 Conference

Three OpenPlant group leaders spoke at the recent UK Synthetic Biology Conference: Nicola Patron (The Sainsbury Laboratory) Development and Application of Standards for Plant Synthetic Biology

Anne Osbourn (John Innes Centre) Making new molecules

Alison Smith (University of Cambridge) Using synthetic biology approaches to allow predictable metabolic engineering in algae

The full conference schedule can be found here and there are plans for a 2016 conference in Edinburgh with more involvement from PhD students and postdocs. You can see some highlights from #SBUK2015 below!

OpenPlant Forum 2015: blog by Dr Colette Matthewman

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A number of events took place in Cambridge as part of Cambridge Open Technology Week. At the heart of the activities was the OpenPlant Forum a two-day meeting bringing together experts from a range of sectors to discuss developing open technologies for plant synthetic biology.

What was remarkable about the Forum was the strikingly varied and multi-disciplinary agenda covering intellectual property, policy and regulation, responsible research and innovation and open science as well as an excellent scientific programme.

The first day of the Forum focussed on foundational technologies that facilitate exchange and freedom to operate in research environments. The second day concentrated on application of these technologies to trait engineering, and open source routes to innovation and industry.

In between talks, Dr Jenni Rant showcased outputs from Science Art Writing (SAW) Trust synthetic biology public engagement workshops, including a Marchantia themed game.

Kicking off events, Tom Knight, a computer engineer now widely considered the ‘father of synthetic biology’, talked about how synthetic biology aims to make an engineering discipline of biology. He commented that “biologists tend to like complexity, while engineers like it simple”.

Dr Nicola Patron described her recent efforts with OpenPlant and the international community, to bring together a common standard for the assembly of plant DNA parts. Many of the scientific talks described DNA parts collections for gene regulation or for producing high value chemicals in plants.

Professor Anne Osbourn highlighted the value of genetic and chemical diversity in plants, explaining for example that plant P450 enzymes can achieve things that test-tube chemistry can’t. Further examples were seen in talks by Dr Yang Zhang and Dr Stephanie Brown who are exploiting this plant natural diversity for production of heath promoting and anti-cancer compounds in tomato and yeast.

Openness was a running theme across the two days with social scientist Dr Jane Calvert emphasizing how open biology, open innovation and opening up are all critical to the future of synthetic biology. Professor Chas Bountra talked about his ground-breaking work in novel drug discovery, explaining that drug discovery is too expensive, risky and slow, and open science and pooling of resources can speed up research and share the risks. Dr Linda Kahl outlined the need for new legal tools to improve freedom to operate for researchers in both academia and industry, and her work to create an Open Material Transfer Agreement in collaboration with OpenPlant.

Next year the OpenPlant Forum comes to the Norwich Research Park, from 25 – 27 July 2016.

OpenPlant is funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and the Engineering and Physical Sciences Research Council (EPSRC).

Source: OpenPlant Forum 2015: blog by Dr Colette Matthewman

SBOL 2.0 Specification Released

The SBOL editors are pleased to announce the official release of the next major version of the Synthetic Biology Open Language (SBOL). The SBOL 2.0 specification is available online at: http://sbolstandard.org/downloads/specification-data-model-2-0/ Major new capabilities of SBOL version 2.0 over the prior 1.x include: - Beyond DNA, designs can include RNA, proteins, and other components - Designs can associate function with structure and link to external models - Rich annotation of biological designs, for integration with non-SBOL design information

This specification is complemented by the 2.0 beta release of libSBOLj (available at: https://github.com/SynBioDex/libSBOLj/releases), a library implementing the SBOL 2.0 specification in order to allow simple integration of the new SBOL capabilities into software tools.

Thanks, -Jake Beal (SBOL Editor, on behalf of the SBOL community)

First common standard for assembly of DNA parts in plant SynBio published

Dr Nicola Patron

Supported by OpenPlant, Dr Nicola Patron of The Sainsbury Laboratory, Norwich, has led development of the first common standard for the assembly of DNA parts for plant synthetic biology.

Published today in New Phytologist as a Viewpoint article, this standard has been agreed between the inventors and developers of several Type IIS cloning technologies, the leaders of numerous plant bioengineering consortia and leaders of international plant science.

In the article, Nicola and her co-authors describe a common syntax of twelve fusion sites to enable the facile assembly of eukaryotic transcriptional units.

The manuscript received favourable support in the peer review process. One reviewer commented that “ …this is somewhat of a landmark publication that will massively influence all plant synthetic biology to come and shows the community in this field to be ahead of their colleagues in other areas.” Another remarked that “this paper will be a catalyst for further discussion around standardization not only in plants but in synthetic biology in general.”

By establishing a standard for the wider plant community Nicola and her colleagues will facilitate the sharing of standard parts for plants between scientists. It also sets a basis for the development of software and hardware that will support accelerated design and automated assembly. Their vision is to develop an extensive catalogue of standardised, characterised DNA parts to accelerate plant bioengineering.

The establishment of a DNA assembly standard for plants is an important and timely step in plant synthetic biology.

Dr Jim Haseloff at the University of Cambridge said: “The publication of a common syntax for plant DNA parts is a landmark for the adoption of engineering principles in multicellular organisms. It is the result of wide cooperation between researchers across the plant biology field, and sets the scene for greater scientific exchange and innovation in crop improvement.”

Read the paper: ‘Standards for plant synthetic biology: a common syntax for exchange of DNA parts’

Edited from the post Dr Nicola Patron establishes first common standard for assembly of DNA parts in plant SynBio which appeared first on The Sainsbury Laboratory.

Source: Dr Nicola Patron establishes first common standard for assembly of DNA parts in plant SynBio