Synthetic Biology and the Omics Revolution by John Dalton of CICM johnd@issue-crisis.com www.issue-crisis.com 1
Synthetic Biology and the Omics Revolution By John Dalton of CICM Biology and many of its sub-disciplines, in particular those related to molecular biology, have become vibrant and complex areas of research. As molecular medicine and bioengineering continue to develop in their subject knowledge and application, the gap between the ability of scientists to communicate their findings and the ability of the educated non-scientific public to comprehend their relevance broadens. Accordingly, some level of biological literacy is required to grasp many of the issues that frequently fill our media, such as the Human Genome Project, personalised medicine and now, synthetic biology. Equally important is the need for many stakeholders to appreciate their medical, commercial and possible ecological applications. We are witnessing a new bioeconomy emerging that will not only transform how many commercial sectors operate and their efficiency, but also provide complex new challenges to our ethical and legal systems. What is particularly exciting is the potential that genomics and synthetic biology have to tackle complex issues, such as climate change and the growth of antibiotic resistance. The implications for commerce are huge as many processes will be significantly altered through the applications of engineered microbes with novel functions that can improve efficiency, reduce waste and pollution. Medicine will be transformed and many diseases that where previously thought to be incurable may be tackled and suffering and pain reduced or eliminated. In 1977, the scientist Fred Sanger and his team started the field of biology that was to become known as genomics when he successfully managed to sequence the genome of a virus. A genome is a complete set of genes carried by an organism or virus. The term genomics was actually adapted by Professor Hans Winkler1 1 in 1920, but became more familiar with the publicity surrounding the Human Genome Project. Genes are specific segments of DNA that code for a polypeptide (protein) or RNA product. Sanger s work laid the pathway for the sequencing of more complex organisms, leading ultimately to the sequencing of the human genome. The Human Genome Project marked a major development in our understanding of how genes encoded proteins and the link between our genome and many diseases and medical conditions. For those with a basic grounding in science, in particular biology, it is generally understood that our DNA contains genes that code for proteins. How exactly genes coded for the proteins and how these proteins interacted with each other in cells and tissues remained somewhat obscure until the 1990s. All of these new areas of study, based on the genomics revolution, will certainly produce some fascinating and useful insights and applications for humans and other species.. Given that genes give rise to polypeptides or proteins, a second important field of study is called proteomics, which attempts to identify all the proteins present in a cell under various conditions, functions and interactions. The ability to sequence a genome based on the pioneering work of scientists like Sanger back in 1977 led to the Omics revolution, which emerged during the 1990s and is to this date producing more and more exciting areas of research. Some examples of Omics, other than genomics, include: Proteomics - (the study of the proteome): the analysis of all cellular proteins* Transcriptomics - the analysis of all expressed RNA molecules produced in a cell Metabolomics the study of the metabolic networks in a cell or tissue Glycomics (the study of glycomes): the analysis of all the carbohydrate molecules that can be produced by a cell, tissue or organism Toxicogenomics the analysis of the effects of toxic chemicals on genes and gene expression Pharmacogenomics the development of customised medicine based on an individual s specific genetic profile for a specific condition Metagenomics the analysis of genomics collectively from the environment Nutrigenomics the analysis of interactions between diet and genes 1 Winkler, HL (1920). Verbreitung und Ursache der Parthenogenesis im Pflanzen- und Tierreiche. Jena: Verlag Fische www.issue-crisis.com 2
* Proteomics is of clinical interest because it allows scientists to compare proteins from normal and diseased tissues, which in turn can help identify proteins and specific biomarkers for disease. What is especially noticeable is the pace of change and development that has occurred since the 1990s, catalysed largely by the sequencing of the Human Genome. The Human Genome Project was started in 1990 under the direction of James Watson and was completed in 2003; President Clinton had announced the completion at the White House in June 2000, but this referred only to a draft sequence. What exactly has been achieved by sequencing a complete human genome? Well, in short, something quite remarkable. By sequencing and understanding the order of base sequences that make up human DNA, the international project has transformed our understanding of how genes work, their numbers, their interaction with each other, mutations and many other factors, including our evolutional origins. It has also produced some very significant findings, which surprised some scientists. For example: that we have about 20,000 protein-coding genes, which is far fewer than the numbers predicted (between 80,000-100,000 genes) less than 2 % of the genome actually codes for proteins the vast majority of the genome is made of noncoding DNA that is essential for the regulation and expression of the coding (exons) regions less than 2 % of the genome actually codes for proteins the vast majority of the genome is made of non-coding DNA that is essential for the regulation and expression of the coding (exons) regions 50% of all human genomes show sequence similarity with other organisms Human genomes are 99.9% similar in sequence diversity from one person to another is due to copy number variations and single-nucleotide polymorphisms 2 For those in medical research, the sequencing of the human genome opened a new, fascinating era of discovery that enable scientists to target genes and help bring under control the damage caused by numerous genetic disorders. As a result of these developments in genomics, biology has increasingly become a more computational science. Known as bioinformatics, computational biology uses biological data to develop algorithms and understand relations within biological systems. The discipline of bioinformatics allows scientists to understand gene structure and sequence as well as protein structure and function. A puzzle for biologists has always been, why are there far more gene products (proteins) transcribed than can be explained by the 20,000 protein-encoding genes identified thus far? Today scientists are only beginning to unravel the complexities of how proteins are produced and how genes are regulated. What has become clear is that proteins have complex interactions with each other: the proteome is far more complex than the genome. Bioinformatics and molecular modelling are necessary to understand the relationship between genomics, proteomics and metabolomics and how these interactions relate to physiology and the development and treatment of specific diseases. 2 A single-nucleotide polymorphism is any position in the genome where there is a difference in a single nucleotide between two unrelated members of the same species www.issue-crisis.com 3
One of the most interesting developments to arise from the growth in research about the basis of disease is our understanding of how microbes interact with each other and their capacity to cause disease. For years it was thought that many microbes were independent functioning organisms, yet research based on what is now called the Human Microbiome Project 3 suggests that microbes are far more commensal and mutualistic than previously considered. The Human Microbiome Project has certain specific objectives, including determining whether changes in the human microbiome can be correlated with specific diseases and health, and if individuals share a common microbiome. The project relies heavily on the sequencing techniques of genomics to explore keys areas of the microbiome: oral, nasal, skin, conjunctival, urogenital and gastrointestinal. What are the benefits of Genomics? Personalised Medicine One of the principal benefits that will emerge from genomics is personalised medicine. This medical model seeks to customise healthcare by targeting drugs and therapies to treat not just patients within a population, but more importantly, individuals. The ability to determine an individual s unique molecular characteristics and use this information to more accurately predict susceptibility to disease, treat outcomes, and reduce the likelihood of adverse effects of drugs are all potential benefits from what is termed personalized medicine. In essence, personalised medicine is a model that seeks to customise healthcare by removing the traditional one size fits all approach. If you are ill with a condition then it very likely that someone else with the same condition will receive the same treatment, albeit a different dosage. Using each person s unique genetic basis, personalised medicine hopes to provide more targeted and effective treatments. Currently, genetic analysis of patients has already improved targeted therapies for blood clots, colorectal cancer and breast cancer. The opportunities for further more accurate and targeted therapies are significant once the price and availability of sequencing improves and our understanding of biomarkers develops. For it to become clinically effective, personalised medicine requires human genomes to be sequenced at relatively low cost, and to identify gene polymorphisms (genetic changes that are responsible for human disease). The race is currently on to sequence a human genome for less than $1000 in order to stimulate technological innovation to bring down the cost of sequencing, making it accessible and economically viable. To understand the genetic basis of many complex diseases, biologists are now using rapid genotyping technologies that create haplotype maps, which in turn, are used to identify single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) that are linked to genes involved in disease. The key benefits of personalised medicine can be summarised thus: Develop more effective and targeted drug therapies (pharmacogenomics and toxicogenomics) * Customise disease prevention strategies Reduce or eliminate costly drug trials Help in the prediction of diseases and disease detection *By understanding the unique sequences in our DNA and the genetic variation that they imply, scientists will be more able to develop drugs that are specific to biomarkers. Personalised medicine may also reduce the side effects of drugs and other toxins in the body. Many people suffer severe sideeffects from certain drugs, while others within the population suffer limited or no side-effects. 3 A microbiome is a totality of microbes, their genomes and environmental interactions in a specific environment www.issue-crisis.com 4
Personalised medicine represents a real paradigm shift in medicine by focusing on prevention rather than reaction. In particular, personalised medicine is well suited to tackle complex diseases such as cancer, heart disease, neurodegenerative conditions and diabetes, more than, for examples, genetic diseases such as cystic fibrosis, which come under the umbrella of genetic medicine. A disease such as cancer has numerous gene and environmental interactions and is therefore best studied at the genome level. The Omics Revolution is not just about Molecular Medicine Metagenomics or environmental genomics is a fascinating field of study that involves analysing DNA samples from environmental samples without isolating intact organisms. This discipline was heavily influenced by J. Craig Venter and his expedition called Sorcerer II Global Ocean, in which Venter and his researchers sampled oceans in various parts of the world during 2009. The results produced numerous new microbial sequences not previously known to science whose protein use and function is still to be determined. For example, from the expedition, one kilogram of marine sediment contained a million different viruses, most of them new to science. The sequencing of bacterial and viral genomes has numerous potential benefits. Sequencing of organisms, such as Streptomyces coelicolor (source of genes for many natural antibiotics), E coli (strain 0157:H7 (pathogenic bacterium) Mycobacterium tuberculosis (causes tuberculosis) and Rickettsia prowazekii (causes typhus) provides useful insights into how these organisms may exchange genes with other microbes and cause superbugs. Indeed, the growth of antibiotic resistance has become a major threat to public health, with the possibility of making many current routine operations life threatening within 20 years of something is not done to combat the resistance. In March 2013, the government s Chief Medical Officer for England went as far to state that the threat posed by antibiotic resistance should be ranked alongside terrorism as a risk to the UK security. In addition to functional genomics, there is comparative genomics, which compares genomes of different species. Comparative genomics is important in the understanding of evolution and the function of multi-gene families as well as the mechanisms of action of many microbes and how their genetic systems bring about diseases. Currently, the following other genomes, other than Man s have been sequenced: dog Canis familiaris; chimpanzee Pan troglodytes; Rhesus macaque monkey Macaca mulatta, and the sea urchin, Strongylocentrotus purpuratus. Synthetic Biology Synthetic biology is the result of the confluence of a number of different scientific disciplines: molecular biology, physical science and engineering. The term synthetic biology means the re-engineering of biological components to provide new design functions. In essence, it is the engineering of biology and the synthesis of complex, biologically-based systems, which display functions that may not exist in nature. n 1995 J. Craig Venter and his team determined the genomic sequence of a free-living cellular organism, the bacterium, Haemophilus influenza, which can cause meningitis. After the completion of the Human Genome Project in 2003, Venter announced in 2007 the completion of a single human s genome (his own). Then in May 2010, Venter announced to the world that his team had successfully produced the first man-made bacterium Mycoplasma mycoides JCVIsyn.1.0. This was according to Venter the first synthetic organism ever. The cell became known as Synthia and its genome had been compiled inside a computer. www.issue-crisis.com 5
Synthia was clear evidence that it was possible to artificially construct a genome and, furthermore, possible to place this synthetic genome inside a recipient cell, so that the cell functions and reproduces like any other bacterium. Responsibly, Vender s team ensured that Synthia was incapable of infection and could only be grown in a highly specific form of lab media. The ultimate question for most people is, did Venter and his team really create life? The best answer is that he re-created a life form synthetically using a computer-generated genome, which was placed inside an existing recipient cell. Whatever way one looks at the situation, it certainly was unique and such a life form had not previously existed. The experiment relied upon other pre-existing life forms to become a reality, for example the host cell. What is clear is that the experiment will certainly go down in science history as the start of a new revolution in biological sciences, making synthetic biology a multidisciplinary science. Synthetic biology can be distinguished from systems biology 4 in a number of ways. First, systems biology attempts to quantify biological systems by incorporating data from genomics, transcriptomics, proteomics and various other sub disciplines, plus engineering applications. In synthetic biology the principal focus is on the rationale engineering of organisms to produce useful, novel functions. What are the Implications of Synthetic Biology? Although it is early days, there is no doubt that synthetic biology will go on to produce some very useful benefits to Mankind and other organisms. In particular, at this stage it is suggested that synthetic biology will have an important role to play in: Disease prevention, drug design, and clinical therapies Bio-energy and synthetic fuels Environmental protection and remediation Agriculture and food production; in particular novel agrochemicals Consumer and chemical production; e.g. synthetic rubber or less toxic biodispersants Development of highly adaptive antibiotics Development of highly effective biosensors Using the techniques of synthetic biology the chemical industry will witness a fundamental transformation from oil-based chemicals towards fuels based on biomass, owing to developments in synthetic biology. Synthetic biology also promises vaccine development and better understanding of viruses, such as the Bluetongue virus (BTV), which has the capacity to inflict serious damage on livestock, in particular sheep, globally. Currently, synthetic biology is not a reality and is a very nascent discipline. But just like so many other technological or other biological revolutions, synthetic biology clearly has sound scientific logic behind it and it is merely a matter of time and innovation for it to become a reality and its products and actions to transform our lives. Fears over Synthetic Biology Many of the fears and issues raised over synthetic biology are exaggerated, in particular the threat from biological terrorism. Advocates for synthetic biology are quick to point out that any attempt to manipulate the genome of a microbe to create a weapon of terror would take much time, effort, scientific know-how and investment of resources and finances. 4 Systems biology is a discipline that seeks to determine how complex biological systems function by integrating experimentally derived information through mathematical and computing solutions www.issue-crisis.com 6
Weaponising engineered life forms has been a fear since the advancement of genetic engineering and the issue of GM microbes stockpiles developed during the Cold War. A further issue that has been consistently raised by many is the availability of genome sequences online, such as the smallpox genome. Despite all the rhetoric, it is still difficult to engineer life and create or manipulate a microbe for dissemination for the purposes of terrorism. That said, it is also fair to be cautious. As technologies improve this will enhance the ease with which synthetic biology can be conducted by gifted amateurs and PhD terrorists (a termed coined by John Dalton). There is a case for monitoring developments outside of regulated scientific research. A well-resourced and funded laboratory, possibly under the guidance or direction of an anti-western power or group, might conceivably be able to engineer a deadly virus or bacterium for terrorists purposes. Many important questions have arisen regarding genomics and synthetic biology. Should pathogenic viral and bacterial genomes be available online for all to see and access? Should researchers make available to the general public research material that shows how they made a strain? In 2002 scientists at Stony Brook University in the US recreated a polio virus based on its genetic sequence. Scientists have also recreated the highly pathogenic flu virus that killed millions in 1918 in order to gain insight into what part of its genetic makeup made it so pathogenic. One of the dangers is that synthetic biology might become de-skilled and made more open with time and this has obvious bio-security implications. Fears over so-called garage biologists is growing although little evidence to-date suggests that they will become a significant threat, but as with any new technology it makes perfect sense to keep a close eye on developments and regulate and restrict its use and applications so as to prevent the release of dangerous synthetic genomes into nature. This is likely to happen at some stage, either through an accident or via a deliberate release. Although the threat of misuse of synthetic biology to the public or from determined terrorists may not be that great, what is clear is that bioterrorism, if it did occur, would have devastating consequences as a weapon of terror. If, for whatever reason, a biological weapon was released inside an airport, at a large sporting event or in a shopping mall, how well prepared are our governments and authorities to deal with the matter? Furthermore, in relation to a bioterrorism attack, however unlikely, how many of our health workers have been vaccinated against pathogenic organisms? Complexity and Business implications Investors and venture capitalists are showing increased interest in the potential applications of the genomics revolution and synthetic biology. Issues relating to intellectual property, in particular patenting organisms, as well as ethical arguments, are just the tip of a very large iceberg. As bioengineering becomes ever more specialised, business people who do not have a grounding in science, will have to work harder to keep up-to-date with developments and potential commercial applications. The gap between science and business in many ways grows wider every day as the pace of discovery and hyper-specialisation of scientific knowledge increases. It is therefore vital that complex scientific advances are broken down and communicated to non-scientists in a way that allows the business community to absorb and assimilate developments, their significance and potential, without being bogged down in scientific terminology or convoluted detail. In an emerging bioeconomy, a confluence of disciplines is inevitable, which in turn must be reflected through our education and training systems, arguing for a more multidisciplinary approach. www.issue-crisis.com 7
A typical MBA student may be able to read a balance sheet and understand the concept of applied strategy in a commercial context, but just learning about pure business may lead to serious deficiencies of knowledge and application in a rapidly emerging bioeconomy. Will this result in a change in how business students are taught or lead to the demise of the current MBA dominance in education? Will it result in more postgraduate courses that are multidisciplinary in their approach, bridging the artificial gap between science and business? The trend towards multidiscipline postgraduate courses has already started, reflecting this very need, but the number and diversity of courses is low. Investors and those who are prepared to take risks in new ventures need to understand what exactly it is they are investing in and the associated risks. In some ways disruptive technology developments are often easier to explain to investors than significant developments in biology or engineering. This is the essence of the problem modern biology and genetics when combined with engineering becomes incredibly complex and is difficult to easily comprehend. This in turn may result in journalists and bloggers miscommunicating outcomes and generating unnecessary fears. Risk management relies upon decision-makers taking risks, but in an environment where the risk exposure is not too great and where the risks by and large are understood and manageable. In the case of genomics and its related fields of synthetic biology, the risks become ever more complex and interdependent, making it harder for business executives and investors to take a view. Many business executives are informed by the general and business media: Financial Times, Bloomberg, The Economist, or investor bulletins or trade journals. All of these are written by business and financial journalists who, despite being extremely able in their own right, may not adequately convey risks in context or may report uncorroborated claims made by campaigning NGOs or activists who may have motives that are against the use of the technology. If the nanotechnology revolution is a guide, then genomics and synthetic biology will not have such a tough time but when one starts to play with nature, far more irrational fears surface, fuelled by well meaning, but often misguided or ill-informed activists. by John Dalton www.issue-crisis.com 8