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Biological production by human design

8 Jul 2014 by qmtbqdmdjq.d qmtbqdmdjq.d

Rapid advances in synthetic biology have made it possible to convert biomass to chemicals, fuels and materials, and produce new therapeutic drugs, all of which promise significant economic growth. Richard Kitney, Professor of BioMedical Systems Engineering at Imperial College considers the opportunities The recently proposed takeover of Astra Zeneca by Pfizer has placed the importance of the UK’s knowledge base under the spotlight once more. This made Synthetic Biology a particularly fitting focus for my recent Institution of Engineering and Technology (IET) Prestige Lecture. Synthetic biology was listed second in the top new technologies likely to have major impact on the future world economy at Davos 2012 by the World Economic Forum’s Global Agenda Council on Emerging Technologies. The UK Government has also placed synthetic biology amongst the UK Government’s ‘eight great technologies.’ with the potential to propel the UK to future growth. It has committed £88m of £600m in extra science funding to the field, most recently awarding £10m for the establishment of five centres for DNA synthesis across the UK. Many of the critical discoveries related to the study of DNA which is at the core of synthetic biology were made in Cambridge in the UK where Francis Crick and James Watson used results from previous studies and X-ray diffraction data to help determine DNA’s molecular structure. By 1953, Crick and Watson had built a model that incorporated all known features of DNA, and created the ‘Watson-Crick model of DNA’. At around the same time, two key publications in the US paved the way for the digital revolution. In 1948, Cybernetics or Control and Communication in the Animal and the Machine by Norbert Weiner, professor of mathematics at the Massachusetts Institute of Technology (MIT), discussed the mathematics of biological systems. Using the tools in probability theory developed by Wiener, Claude Shannon then published A Mathematical Theory of Communication, a revolutionary paper considered as the foundation of information theory. By the 1990s, DNA sequencing had yielded the genome sequences of a handful of important species, culminating in the initial sequencing of the human genome in 2001. This marked the beginning of the field of synthetic biology that we know today. Following the initial sequencing of the human genome, there has been huge efficiency gains, with next-generation sequencing opening up nature’s vast reservoir of biological information and, with it, identification of novel biological parts. In parallel, there has been rapid progress in the development of reliable, chemically-based DNA synthesis – i.e. the ability to write DNA. We now have the ability to both read and write DNA in long strands in just a few seconds, which allows the alteration and construction of DNA sequences and the possibility of building whole genomes from scratch. Biological production by human design In synthetic biology, the cell is effectively a manufacturing unit called the ‘chassis’ or the ‘host’, which like a computer-controlled machine can be programmed using software. In a biological context, the DNA is the software telling the cell what to produce. The cell acts as an extremely flexible machine, and is able to produce various biological parts, such as skin, liver cells, or cartilage. Synthetic biology now makes it possible for scientists to design sections of DNA that produce other types of biological parts (or ‘bio parts’), devices and even systems, according to human design. Bio parts are functional pieces of DNA designed to be easily assembled and to interact predictably when made part of a larger structure. Each bio part is a module that is combined to create the overall strand of DNA that is put it into a cell to produce a device. Bio parts make the construction of novel biological systems considerably easier, while gradually reducing the time, expense and skill level required in doing so (much like what happened with the industrial revolution). Ultimately, this model makes it possible to produce human-designed sections of DNA capable of carrying out virtually any type of industrial or chemical process. It is achieved through:

Modularisation – the process of breaking down a biological system into a series of well-defined, standard parts or components (for example, a gene, protein, a pathway, a microbe in a culture)
Characterisation – defining the behaviour and function of these parts in particular contexts in order to understand how they can be used in human-defined design
Standardisation – where the design process is based on well-defined standard modules that can be interfaced to produce a device or system.

The process of characterising human-designed sections of DNA is ongoing. The results are entered into a universal registry that serves as a computing database where bio parts are comprised of data, plus metadata. The data is a description of how the bio part works in a particular cell type from a biological point of view. Metadata describes the experimental conditions required to support the synthesis process and produce a specific outcome – typically, a bio synthetic device. One example of bio synthetic devices is the biosensors developed to support medical applications such as the detection of MRSA infection in the respiratory or urinary tract. This is an extremely important advancement, given that urinary tract infection is a serious issue in hospitals where patients use catheters. Researchers at Imperial College have developed a three-stage bio synthetic device that when injected into someone, is able to travel round the body to detect AHL (the chemical emitted by pathogenic bacteria when colonising a host). The device uses a biological amplifier to transmit to a ‘reporter’, a GFP protein that when stimulated by the bio amplifier fluoresces green, allowing doctors to physically observe a build-up of pathogenic bacteria such as MRSA. The GFP protein is based on DNA taken from a jellyfish, and has been re-engineered using synthetic biology to act as a reporter. The fluorescent protein is now commercially available, and is also used to verify that a bio device is working correctly. It is even possible to envisage the use of a cell itself as a biosensor to detect a biomarker for a disease and then, from within the same cell, to switch on the production of a desired drug. If brought to fruition, this could revolutionise the treatment of chronic illness. Another real-world application in the medical field is a device combining a biosensor and protein nanocage therapy unit. This device carries a psycho-toxic drug that would otherwise be metabolised by the body before reaching the diseased area. The device travels around the body, detects infected cells (e.g. those that are cancerous), which the nanocage then latches on to and releases the psycho-toxic drug. This enables diseased cells to be treated in a highly-targeted way. Nanocage therapy units can also be used to treat arterial diseases that can lead to strokes, by using a biosensor to detect the presence of arterial plaque (disease tissue) that builds up in the lumens of arteries and then fluoresces to identify large instances of build-up. Researchers at Imperial College London have successfully demonstrated that they can build some of the basic components for digital devices out of harmless gut bacteria and DNA. This includes logic gates or switches, which are used for processing information in computers and microprocessors. Although still some way off from commercialisation, these biological logic gates or switches could one day lead to micro processors so tiny they can interoperate at an inter-cellular level. This would make it possible to superimpose human design mechanisms onto the cell itself rather than injecting DNA strands into the cell. The most important aspect of synthetic biology however, is that it represents a ‘Platform Technology’ that can be applied time and again across a whole range of fields – including vaccines, pharmaceuticals, healthcare, and bio energy materials. Bioethanol for example, is the product of fermentation by yeast. In addition to yeast, a variety of different micro-organisms, including bacteria and cyanobacteria, are being investigated for fuel component production capabilities. Modification of such organisms to improve production economics or to produce different fuel or chemical component characteristics is being explored by many scientists. In addition, the technology has the potential to produce many of the chemicals or materials currently derived from petrochemical feedstock using fermentation or industrial biotechnology routes and renewable feedstock. Industrial biotechnology could be a key application area for synthetic biology, providing the platform to deliver benefits to many different sectors, such as cosmetics, lubricants, biopharmaceuticals and detergents. With the UK’s long tradition of scientific discovery and intellectual activity (second only to the US), it is vital to the future of our economy that we maintain our world-leading status. This was acknowledged recently by the business secretary Vince Cable, who said that he was “committed to ensuring that the UK continues to be a world-leader in science and pharmaceuticals research and development”. It is telling that Cable’s comments came in response to the mooted takeover of pharmaceutical firm AstraZeneca by US rival Pfizer. Given that our medical technology sector consists of some 2,800 companies employing 52,000 people and generating around £10.6bn of turnover a year, and with the global value of the market for synthetic biology forecasted to reach $10.8 bn in 2016 by analysts at BCC Research, the stakes are high. Unsurprisingly, substantial government investment is being made to support the research base. Total public investment, through the research councils and the Higher Education Funding Council for England (HEFCE) is around £6bn a year. The Technology Strategy Board, the UK’s innovation agency, invests a further £350m a year, helping 4,000 companies across all technology domains and business sectors develop new products, processes and services. Crucially, the capital funds for the DNA synthesis centres being established across the UK are part of £50m allocated to realise the ‘Roadmap for Synthetic Biology’ in the UK. Together with the Engineering and Physical Sciences Research Council (EPSRC) Centres for Doctoral Training (CDTs), which provide world-leading training environments for students of synthetic biology, these will build bridges between academic and embryonic synthetic biology companies, helping to nurture the UK’s growing synthetic biology industry, create jobs and drive economic growth. Author Professor Richard Kitney is Chairman of the Institute of Systems and Synthetic Biology; and Co-Director of the EPSRC National Centre for Synthetic Biology and Innovation and The UK National Industrial Translation Centre for Synthetic Biology – both based at Imperial College London. About the IET Kelvin Lecture Synthetic Biology – “One of the eight great technologies” was this year’s Kelvin Lecture, which was set up to commemorate the life of three time president, Lord Kelvin, as part of the Prestige Lecture Series run by The Institution of Engineering and Technology (IET). To view the webcast go to: http://conferences.theiet.org/kelvin/