̽��ֱ�� of Cambridge - Synthetic Biology Strategic Research Initiative

‘Programmable molecular scissors’ could help fight COVID-19 infection

cjb250 — Wed, 16 Nov 2022 10:00:18 +0000

Enzymes are naturally occurring biological catalysts, which enable the chemical transformations required for our bodies to function – from translating the genetic code into proteins, right through to digesting food. Although most enzymes are proteins, some of these crucial reactions are catalysed by RNA, a chemical cousin of DNA, which can fold into enzymes known as ribozymes. Some classes of ribozyme are able to target specific sequences in other RNA molecules and cut them precisely.

In 2014, Dr Alex Taylor and colleagues discovered that artificial genetic material known as XNA – in other words, synthetic chemical alternatives to RNA and DNA not found in nature – could be used to create the world’s first fully-artificial enzymes, which Taylor named XNAzymes.

At the beginning, XNAzymes were inefficient, requiring unrealistic laboratory conditions to function. Earlier this year, however, his lab reported a new generation of XNAzymes, engineered to be much more stable and efficient under conditions inside cells. These artificial enzymes can cut long, complex RNA molecules and are so precise that if the target sequence differs by just a single nucleotide (the basic structural unit of RNA), they will recognise not to cut it. This means they can be programmed to attack mutated RNAs involved in cancer or other diseases, leaving normal RNA molecules well alone.

Now, in research published today in Nature Communications, Taylor and his team at the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), ̽��ֱ�� of Cambridge, report how they have used this technology to successfully ‘kill’ live SARS-CoV-2 virus.

Taylor, a Sir Henry Dale Fellow and Affiliated Researcher at St John’s College, Cambridge, said: “Put simply, XNAzymes are molecular scissors which recognise a particular sequence in the RNA, then chop it up. As soon as scientists published the RNA sequence of SARS-CoV-2, we started scanning through looking for sequences for our XNAzymes to attack.”

While these artificial enzymes can be programmed to recognise specific RNA sequences, the catalytic core of the XNAzyme – the machinery that operates the ‘scissors’ – does not change. This means that creating new XNAzymes can be done in far less time than it normally takes to develop antiviral drugs.

As Taylor explained: “It’s like having a pair of scissors where the overall design remains the same, but you can change the blades or handles depending on the material you want to cut. ̽��ֱ��power of this approach is that, even working by myself in the lab at the start of the pandemic, I was able to generate and screen a handful of these XNAzymes in a matter of days.”

Taylor then teamed up with Dr Nicholas Matheson to show that his XNAzymes were active against live SARS-CoV-2 virus, taking advantage of CITIID’s state-of-the-art Containment Level 3 Laboratory – the largest academic facility for studying high risk biological agents like SARS-CoV-2 in the country.

“It's really encouraging that for the first time – and this has been a big goal of the field – we actually have them working as enzymes inside cells, and inhibiting replication of live virus,” said Dr Pehuén Pereyra Gerber, who performed the experiments on SARS-CoV-2 in Matheson’s lab.

“What we’ve shown is proof of principle, and it’s still early days,” added Matheson, “It’s worth remembering, however, that the amazingly successful Pfizer and Moderna COVID-19 vaccines are themselves based on synthetic RNA molecules – so it’s a really exciting and rapidly developing field, with enormous potential.”

Taylor checked the target viral sequences against databases of human RNAs to ensure they were not present in our own RNA. Because the XNAzymes are highly specific, this should in theory prevent some of the ‘off-target’ side-effects that similar, less accurate molecular therapeutics may cause, such as liver toxicity.

SARS-CoV-2 has the ability to evolve and change its genetic code, leading to new variants against which vaccines are less effective. To get around this problem, Taylor not only targeted regions of the viral RNA that mutate less frequently, but he also designed three of the XNAzymes to self-assemble into a ‘nanostructure’ that cuts different parts of the virus genome.

“We’re targeting multiple sequences, so for the virus to evade the therapy it would have to mutate at several sites at once,” he said. “In principle, you could combine lots of these XNAzymes together into a cocktail. But even if a new variant does appear that is capable of getting round this, because we already have the catalytic core, we can rapidly make new enzymes to keep ahead of it.”

XNAzymes could potentially be administered as drugs to protect people exposed to COVID-19, to prevent the virus taking hold, or to treat patients with infection, helping rid the body of the virus. This sort of approach might be particularly important for patients who, because of a weakened immune system, struggle to clear the virus on their own.

̽��ֱ��next step for Taylor and his team is to make XNAzymes that are even more specific and robust – “bulletproof,” he says – allowing them to remain in the body for longer, and work as even more effective catalysts, in smaller doses.

̽��ֱ��research was funded by the Wellcome Trust, the Royal Society, the Medical Research Council, NHS Blood and Transplant, and Addenbrooke’s Charitable Trust.

Reference
Pereyra Gerber, P, Donde, MJ, Matheson, NJ and Taylor, AI. XNAzymes targeting the SARS-CoV-2 genome inhibit viral infection. Nature Communications (2022). DOI: 10.1038/s41467-022-34339-w

Cambridge scientists have used synthetic biology to create artificial enzymes programmed to target the genetic code of SARS-CoV-2 and destroy the virus, an approach that could be used to develop a new generation of antiviral drugs.

XNAzymes are molecular scissors which recognise a particular sequence in the RNA, then chop it up

Alex Taylor

Jordan Siemens (Getty Images)

A 3d animation of the COVID-19 Virus or Coronavirus being broken apart

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New legal tool aims to increase openness, sharing and innovation in global biotechnology

cjb250 — Thu, 11 Oct 2018 18:56:48 +0000

̽��ֱ��OpenMTA is a Material Transfer Agreement (MTA) designed to foster a spirit of openness, sharing and innovation in global biotechnology. MTAs provide the legal frameworks within which research organisations lay down terms and conditions for sharing their materials - everything from DNA to plant seeds to patient samples.

Use of the OpenMTA allows redistribution and commercial use of materials, while respecting the rights of creators and promoting safe practice and responsible research. ̽��ֱ��new standardised framework also eases the administrative burden for technology transfer offices, negating the need to negotiate unique terms for individual transfers of widely-used material.

̽��ֱ��OpenMTA launches today with a commentary published in the journal Nature Biotechnology. It provides a new way to openly exchange low level “nuts and bolts” components for biological research and engineering, complementing existing, more restrictive arrangements for material transfer.

̽��ֱ��OpenMTA was developed through a collaboration, led by the San Francisco-based BioBricks Foundation and UK-based OpenPlant Synthetic Biology Research Centre. OpenPlant is a joint initiative between the ̽��ֱ�� of Cambridge, John Innes Centre and the Earlham Institute, which aims to develop open technologies and responsible innovations for industrial biotechnology sustainabile agriculture.

Professor Jim Haseloff, ̽��ֱ�� of Cambridge, UK, said: “ ̽��ֱ��OpenMTA provides a new pathway for open exchange of DNA components - the basic building blocks for new engineering approaches in biology. It is a necessary step towards building a commons [commonly owned resource] that will underpin and democratise access to future biotechnological advances and sustainable industries.”

̽��ֱ��collaboration brought together an international working group comprising researchers, technology transfer professionals, social scientists and legal experts to inform the creation of a legal framework that could improve sharing of biomaterials and increase innovation. ̽��ֱ��team identified five design goals on which to base the new agreement: access, attribution, reuse, redistribution and non-discrimination. Additional design goals included issues of safety and, in particular, the sharing of biomaterials in an international context.

Dr Linda Kahl, Senior Counsel of the BioBricks Foundation, said: “We encourage organisations worldwide to sign the OpenMTA Master Agreement and start using it. In five years’ time my ideal is for the OpenMTA to be the default option for the transfer of research materials within and between academic research institutions and companies.

“Instead of automatically placing restrictions on materials, people will ask whether restrictions on use and redistribution are appropriate and instead use this tool to promote sharing and innovation in a way that does not compromise safety.”

Dr Colette Matthewman, Programme Manager for the OpenPlant Synthetic Biology Research Centre, said: “We hope to see the OpenMTA enable an international flow of non-proprietary tools between academic, government, NGO and industry researchers, to be used, reused and expanded upon to develop new tools and innovations.”

̽��ֱ��agreement will facilitate the use, modification and redistribution of tools for innovation in academic and commercial research, and promote access for researchers in less privileged institutions and world regions.

Dr Fernán Federici, Millennium Institute for Integrative Biology (iBio), Santiago, Chile, said: " ̽��ֱ��OpenMTA will be particularly useful in Latin America, allowing researchers to redistribute materials imported from overseas sources, reducing shipping costs and waiting times for future local users. We are implementing it in an international project that requires sharing genetic tools among labs in four different continents. We believe, the OpenMTA will support projects based on community-sourced resources and distributed repositories that lead to more fluid collaborations."

̽��ֱ��OpenPlant Synthetic Biology Research Centre is funded by the UK Biotechnology and biological Sciences Research Council and the Engineering and Physics Council as part of the UK Synthetic Biology for Growth programme.

Adapted from a press release from the John Innes Centre.

Reference
Kahl, L et al. Opening options for material transfer. Nature Biotechnology; 11 Oct 2018

A new easy-to-use legal tool that enables exchange of biological material between research institutes and companies launches today.

̽��ֱ��OpenMTA provides a new pathway for open exchange of DNA components - the basic building blocks for new engineering approaches in biology

Jim Haseloff

Geralt

DNA

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Report highlights opportunities and risks associated with synthetic biology and bioengineering

cjb250 — Tue, 21 Nov 2017 11:50:43 +0000

Rapid developments in the field of synthetic biology and its associated tools and methods, including more widely available gene editing techniques, have substantially increased our capabilities for bioengineering – the application of principles and techniques from engineering to biological systems, often with the goal of addressing 'real-world' problems.

In a feature article published in the open access journal eLife, an international team of experts led by Dr Bonnie Wintle and Dr Christian R. Boehm from the Centre for the Study of Existential Risk at the ̽��ֱ�� of Cambridge, capture perspectives of industry, innovators, scholars, and the security community in the UK and US on what they view as the major emerging issues in the field.

Dr Wintle says: “ ̽��ֱ��growth of the bio-based economy offers the promise of addressing global environmental and societal challenges, but as our paper shows, it can also present new kinds of challenges and risks. ̽��ֱ��sector needs to proceed with caution to ensure we can reap the benefits safely and securely.”

̽��ֱ��report is intended as a summary and launching point for policy makers across a range of sectors to further explore those issues that may be relevant to them.

Among the issues highlighted by the report as being most relevant over the next five years are:

Artificial photosynthesis and carbon capture for producing biofuels

If technical hurdles can be overcome, such developments might contribute to the future adoption of carbon capture systems, and provide sustainable sources of commodity chemicals and fuel.

Enhanced photosynthesis for agricultural productivity

Synthetic biology may hold the key to increasing yields on currently farmed land – and hence helping address food security – by enhancing photosynthesis and reducing pre-harvest losses, as well as reducing post-harvest and post-consumer waste.

Synthetic gene drives

Gene drives promote the inheritance of preferred genetic traits throughout a species, for example to prevent malaria-transmitting mosquitoes from breeding. However, this technology raises questions about whether it may alter ecosystems, potentially even creating niches where a new disease-carrying species or new disease organism may take hold.

Human genome editing

Genome engineering technologies such as CRISPR/Cas9 offer the possibility to improve human lifespans and health. However, their implementation poses major ethical dilemmas. It is feasible that individuals or states with the financial and technological means may elect to provide strategic advantages to future generations.

Defence agency research in biological engineering

̽��ֱ��areas of synthetic biology in which some defence agencies invest raise the risk of ‘dual-use’. For example, one programme intends to use insects to disseminate engineered plant viruses that confer traits to the target plants they feed on, with the aim of protecting crops from potential plant pathogens – but such technologies could plausibly also be used by others to harm targets.

In the next five to ten years, the authors identified areas of interest including:

Regenerative medicine: 3D printing body parts and tissue engineering

While this technology will undoubtedly ease suffering caused by traumatic injuries and a myriad of illnesses, reversing the decay associated with age is still fraught with ethical, social and economic concerns. Healthcare systems would rapidly become overburdened by the cost of replenishing body parts of citizens as they age and could lead new socioeconomic classes, as only those who can pay for such care themselves can extend their healthy years.

Microbiome-based therapies

̽��ֱ��human microbiome is implicated in a large number of human disorders, from Parkinson’s to colon cancer, as well as metabolic conditions such as obesity and type 2 diabetes. Synthetic biology approaches could greatly accelerate the development of more effective microbiota-based therapeutics. However, there is a risk that DNA from genetically engineered microbes may spread to other microbiota in the human microbiome or into the wider environment.

Intersection of information security and bio-automation

Advancements in automation technology combined with faster and more reliable engineering techniques have resulted in the emergence of robotic 'cloud labs' where digital information is transformed into DNA then expressed in some target organisms. This opens the possibility of new kinds of information security threats, which could include tampering with digital DNA sequences leading to the production of harmful organisms, and sabotaging vaccine and drug production through attacks on critical DNA sequence databases or equipment.

Over the longer term, issues identified include:

New makers disrupt pharmaceutical markets

Community bio-labs and entrepreneurial startups are customizing and sharing methods and tools for biological experiments and engineering. Combined with open business models and open source technologies, this could herald opportunities for manufacturing therapies tailored to regional diseases that multinational pharmaceutical companies might not find profitable. But this raises concerns around the potential disruption of existing manufacturing markets and raw material supply chains as well as fears about inadequate regulation, less rigorous product quality control and misuse.

Platform technologies to address emerging disease pandemics

Emerging infectious diseases—such as recent Ebola and Zika virus disease outbreaks—and potential biological weapons attacks require scalable, flexible diagnosis and treatment. New technologies could enable the rapid identification and development of vaccine candidates, and plant-based antibody production systems.

Shifting ownership models in biotechnology

̽��ֱ��rise of off-patent, generic tools and the lowering of technical barriers for engineering biology has the potential to help those in low-resource settings, benefit from developing a sustainable bioeconomy based on local needs and priorities, particularly where new advances are made open for others to build on.

Dr Jenny Molloy comments: “One theme that emerged repeatedly was that of inequality of access to the technology and its benefits. ̽��ֱ��rise of open source, off-patent tools could enable widespread sharing of knowledge within the biological engineering field and increase access to benefits for those in developing countries.”

Professor Johnathan Napier from Rothamsted Research adds: “ ̽��ֱ��challenges embodied in the Sustainable Development Goals will require all manner of ideas and innovations to deliver significant outcomes. In agriculture, we are on the cusp of new paradigms for how and what we grow, and where. Demonstrating the fairness and usefulness of such approaches is crucial to ensure public acceptance and also to delivering impact in a meaningful way.”

Dr Christian R. Boehm concludes: “As these technologies emerge and develop, we must ensure public trust and acceptance. People may be willing to accept some of the benefits, such as the shift in ownership away from big business and towards more open science, and the ability to address problems that disproportionately affect the developing world, such as food security and disease. But proceeding without the appropriate safety precautions and societal consensus—whatever the public health benefits—could damage the field for many years to come.”

̽��ֱ��research was made possible by the Centre for the Study of Existential Risk, the Synthetic Biology Strategic Research Initiative (both at the ̽��ֱ�� of Cambridge), and the Future of Humanity Institute ( ̽��ֱ�� of Oxford). It was based on a workshop co-funded by the Templeton World Charity Foundation and the European Research Council under the European Union’s Horizon 2020 research and innovation programme.

Reference
Wintle, BC, Boehm, CR et al. A transatlantic perspective on 20 emerging issues in biological engineering. eLife; 14 Nov 2017; DOI: 10.7554/eLife.30247

Human genome editing, 3D-printed replacement organs and artificial photosynthesis – the field of bioengineering offers great promise for tackling the major challenges that face our society. But as a new article out today highlights, these developments provide both opportunities and risks in the short and long term.

Susanne Nilsson

Reaching for the Sky

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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