We are Genomics

Author: Dr. George Busby* / Edited by: Luiz Guidi

There is a smart cafe at the top of Oxford’s Ashmolean Museum, the sort of place undergraduates take their visiting grandparents to wash down a round of cucumber sandwiches with a pot of Earl Grey tea. On a warm spring day in 2014, Peter Donnelly was sitting on the outside terrace, catching up with an old friend, John Colenutt.

Over the course of their tea, Donnelly, currently Director of the Wellcome Trust Centre for Human Genetics in Oxford, told Colenutt, an investment banker who had switched to the charity sector, of his new commercial venture, Genomics plc. The company had started on the back of a 2013 collaborative academic research project (called the WGS500 project) between Donnelly’s Oxford research institute, the NIHR Biomedical Research Centre, and the genetic sequencing behemoth Illumina.

The WGS500 project was set up to assess the role that whole genome sequencing could have in identifying the causes of diseases in patients thought to be genetic. By finding novel, rare mutations involved with these diseases, the project had been a success. As a direct result of this project, David Cameron and George Osborne released money for Genomics England, a new government-backed initiative. Genomics England would be a company wholly owned by the Department of Health and charged with delivering the 100,000 Genomes Project, an ambitious mass genome sequencing project for the NHS.

To encourage innovation, the Conservative government made it a precondition of the incorporation of Genomics England that it could only work with commercial entities. Donnelly, together with his Oxford colleague Gil McVean were both motivated by a strong belief that genomics could be an essential tool in healthcare, and so were interested in getting involved with the data. However, to do so, Donnelly and McVean would need to start a company.

The pair wanted to bring in some additional expertise to found their company so they asked Chris Spencer and Gerton Lunter if they were interested in the idea. Spencer, a colleague with years of experience doing large-scale disease genomics analyses, and Lunter, an expert in algorithmic and computational methods, were interested indeed. With the founding team now in place, Genomics plc was incorporated in early 2014.

The masterminds behind Genomics plc: Dr. Chris Spencer, Prof. Peter Donnelly, Dr. Gerton Lunter and Prof. Gil McVean. (Photo credit: John Cairns Photography)

The masterminds behind Genomics plc: Dr. Chris Spencer, Prof. Peter Donnelly, Dr. Gerton Lunter and Prof. Gil McVean.

(Photo credit: John Cairns Photography)

 

Developing ideas and understanding the market

After their initial discussions with Genomics England, with Spencer and Lunter now on board, Donnelly and McVean realised that their ambitions were far broader than just servicing the 100,000 Genomes Project. As they built their business plan, they identified additional opportunities. For example, they were well placed to get involved with the collection and curation of a spectrum of heterogeneous public genomic data sources, which were stored in various formats and places.

There were also other genomics projects on the horizon, like the UK Biobank, where genomic data would be available to both universities and companies, which would also be tied to dense and detailed phenotypic measurements. Centralising these sequencing datasets would be the key to unlocking the potential of genomics in healthcare.

 

Defining the core business

Amassing enormous datasets is only part of the story of Genomics plc. If Colenutt was not sold on the potential of the company by this aspect alone, his interest must have been piqued when Donnelly told him about the analytical capabilities of their team. In the words of Colenutt, "if you're not doing good analysis, then the rest of it is a waste of time". And “good analysis” of these data would naturally lead to a wide variety of outputs, from drug discovery to personalised medicine. Solid analysis of substantial datasets is difficult, however, therefore, being able to carry it out would provide real value to the company.

Along with curating data and its analysis, the final element of Genomics plc’s business strategy “core trinity is the insight into human biology that comes from the deep analysis of well-maintained data. In fact, this is the central drive behind the company. "If this company succeeds, the world will be a better place", says Colenutt. By the time only the crumbs of their mille-feuille remained on their plates at the Ashmolean Museum terrace café, Donnelly had managed to convince Colenutt not just of the potential of the company, but also to be its CEO.

 

Getting the company going

Not yet three years old, Genomics plc has grown to a thriving start-up with over 30 full-time employees. “The nice thing about biotech is that it’s for profit,” says Colenutt, “which provides a clarity of thinking and purpose, and there’s a clear barometer on whether you should do things or not, which you don’t get in the charity sector.”

During my interviews, McVean told me that to get to where they are now, they needed to speak to as many people as possible in the early days. For example, they met with Oxford University Innovation, got legal advice from lawyers who worked with spinouts, and spoke with academics from Oxford with experience in starting businesses. He also suggested that budding entrepreneurs should not be afraid to ask around; there is a lot of help out there and plenty of people to talk to. “There is, within the UK and internationally, actually a very mature ecosystem of investors looking for university spinouts who are in it for the long term. They’re taking bets, obviously, and they expect most of their bets to fail, but they do typically have a reasonably good track history of sniffing out things that are likely to be successful.”

One crucial early interaction of Genomics plc in 2014 was with Dave Norwood and IP Group, one of the two main investment firms that put money into UK university start-ups (the other being Imperial Innovations). Norwood, a chess grandmaster, had been involved with a number of successful spinouts, including local unicorn Oxford Nanopore Technology. Norwood agreed to chair the board, and business administrative help was provided by IP Group. “Lots of young companies fall over because they just don’t do basics right” Colenutt tells me. “Filing tax returns when they need to and stuff like that, which may not the most exciting task, but can really catch you out. So you can basically outsource all of that in the early days so you can concentrate on what you’re trying to do, which is growing the business…”, says Colenutt.

 

Finding investment

The second key benefit that Norwood brought was introducing Genomics plc to potential investors. “Every new company has to raise money, otherwise it’s all talk”, Colenutt remarks. “Dave can’t get those guys to invest, but he can help get us in front of people. We’re incredibly lucky that we’ve got him involved in the company, it’s a real differentiating factor for us.”

When Colenutt and his team started talking to investors “it was an open door, really. One of the easiest things we’ve done”, says McVean. “We told them of our track record in statistics and genomics, and this ambition. I think we spoke to five people and four of them wanted to invest in us”. In November 2014, Genomics plc announced a successful first funding round of £10.3 million.

 

Keeping a fluid business strategy
McVean is confident that in the future, Genomics plc will deploy their services in a whole variety of settings. However, at the moment, their business strategy mainly involves working with pharmaceutical companies for drug target identification and validation, and working in partnership with Genomics England. In every case, having a powerful platform that enables analysis to be done in an efficient and scalable way is key to the company’s offer.

According to McVean, it’s clear that their current success is built on an ability to be fluid and flexible. “You have a big team of people who need to pull together to do a ‘thing’. And in a start up, that ‘thing’ may be poorly defined to start with and may change, and is constantly challenged and revisited and chewed over. That means that we’ve had changes of direction. For example, early on, we thought that we’d release software for the clinical interpretation of whole genomes, but after a while we realised that that was never going to be big for us”, he says.

 

Building the best team
Finding and looking after the best people have been key focus points for the company but also the challenges. “You’ve got to make sure you’ve got the structures, command chains and feedback loops right, so that you can do what it is you are trying to do in an effective way. There’s a lot of potential manpower, and if it’s not well organised, it can go in an awful lot of different directions. So that organisation of activity has been a challenge… The people that you employ are the most important thing. Get that wrong, and you’re in trouble”, says McVean.

The team brings a variety of skills to Genomics plc, from genomics to computer science and software engineering. Scaling up to millions of genomes is truly a big data problem. “We need to listen to people who know how to build and run software infrastructure at scale and those who understand and care about the legal frameworks around these datasets”, Spencer tells me. “There’s a huge challenge ahead, but for us the potential is clear. Having the right people, working together, to do science, is what is going to make the difference.”

 

Advice for entrepreneurs
For those thinking about starting a company, McVean has some clear advice. “There’s real value in doing things really well. Google and Apple weren’t the first to do what they do, but they do it really well. Do something that people want, even if they don't know it yet, that will generate insight that is not just focused in one direction. Do something that opens up a whole load of other stuff.”

At the top of McVean’s list of areas with potential is measuring things. “I get incredibly frustrated that there’s not enough stuff measured. You can measure disease endpoints well, but we want to understand what’s going on in organisms at a much finer resolution. That’s an area where there’s a lot of room for new technologies.” He also offers a reminder that whatever you do, you need to define what your market would look like: “remember that you've got to sell.”

Despite having a unique birth story, Genomics plc is a great example of how a group of scientists are exploiting their expertise to take advantage of a new opportunity that appeared in front of them. It is also clear that they are having fun and enjoying the ride. A key theme of their life so far is  adaptability and fluidity. And by positioning themselves as a genome analysis company with the aim of understanding human biology, they are allowing themselves to be flexible in the future. It will be interesting indeed to watch how Genomics plc evolves over the coming years.

 

(Article reposted from the Science Innovation Union website, with permission by the author)

*Dr. George Busby is a Research Associate in statistical genomics at the Wellcome Trust Centre for Human Genetics. He is currently working with Dr. Chris Spencer. E-mail contact: george@well.ox.ac.uk 

The Evolving Role of the PhD, Academia and Industry

Author: Marianthi Tatari

 

According to reports from the Higher Education Statistics Agency (HESA) in the U.K. 80% of postgraduate students complete their PhD while only 7% of all full time entrants drop off after their 1st year. Moreover, according to other reports, there is an overall increase in enrolments in both undergraduate and postgraduate students of 11% and 7% respectively in biological sciences alone (chart 5). However, despite the ever increasing number of PhD graduates the availability of academic positions remains static at best with many online articles ruminating on the lack of opportunity for PhD holders, many of which get trapped in a perpetual PostdDoc cycle.

This overproduction of PhDs is not a new phenomenon, in fact it goes back as long as 1978. While Universities spend a lot of effort to promote their graduate programs, they do very little to incorporate “employability” in their PhD-level courses. A few such multi-disciplinary programs have started to emerge which promote highly interdisciplinary PhDs but there is certainly room for the list to grow at least outside the U.K.. At the same time the topic of “alternative careers for PhD graduates” gains more and more interest with only half of the PhD graduates following an academic research or teaching path and a 20% turning to research in the industry, while some institutions and individuals are rethinking the overall concept of the PhD and its usefulness.

This increase in PhD holders who “escape” academia and turn to pharma poses the question: why not adjust the PhD program to fit the needs of the biotech industry and give companies a more active role in the process? This question has been in the mind of both students and Universities for some time now and some graduate schools, realizing the big role biotech companies play in applied research, have tried to address it by incorporating placements in industry and the media into their PhD programs. Not so long ago this need for research that has direct relevance for the biotech industry has been the basis for a platform trying to bridge academia and industry through PhD degrees. These so-called industrial-PhDs (iPhDs) were the result of a high demand from PhD students and young scientists who wanted to see their career moving out of the lab and into the clinic. Since 2009 several such iPhD programs have been launched throughout Europe while other joint programs are organized by innovation centres early on at the level of a Masters degree. Such PhD programs include research on a specific topic of common interest for both the schools and the companies and are jointly supervised. Through them the students not only perform research but also gain a better understanding of the challenges and opportunities that exist within the company environment and build their network of collaborators, helping to shape their future career.

Although these iPhD programs are rapidly increasing in numbers, there are still many PhD students who can’t join them although they still envision their transition to pharma but are unsure how to do that. The reality is that it’s within every student’s power to reach out and make connections with people from both academia and industry who can help them. There are already a few platforms formed by such young entrepreneurs who aim to bridge the gap between academia and industry. By exploring all the available options graduate students will become more aware of their own aspirations and limitations and will not consider academia as a one-way road after their PhD and this is exactly what Oxford Biotech is trying to build.

Artificial Intelligence, Machine Learning and Biotech

There is no doubt that we live in the time of smart devices. From the simplest everyday items, like a coffee maker which can be programmed to have your coffee ready the moment you get out of bed, to the smartphone in your hand. When people talk about artificial intelligence (AI) though, their minds go a lot further than that. They seem to think of evil robots with the desire to take over the world. But is that even possible? And what exactly can be done with AI?

AI is the term computer scientist John McCarthy used to describe “the science and engineering of making intelligent machines”. There is no denial that computers nowadays can perform a large number of tasks better and faster than any human could and in fact they are improving at rates that humans simply can’t match. The immense power of computers to analyze large amounts of data, identifying patterns and finding connections, has an obvious application in fields such as the stock market and economics, but it has also been invaluable in biomedical sciences. Ever since whole genome sequencing jumped from being an expensive 10-year long experiment to a relatively cheap everyday technique in the lab, scientists found themselves with a plethora of data in need of analysis. As a result, high-power computers and machine learning (ML) methods have found new applications in biomedicine as a way to analyze complex datasets to predict the outcome of deadly diseases.

This can be an invaluable diagnostic tool and the number of studies using ML techniques has increased over the last decade, however there is still a major caveat. Trying to identify the patterns and key factors involved in a disease, such as cancer, is like trying to reverse engineer a highly complex system whose detailed functions are not yet fully understood and are certainly not always based on Boolean logic, but rather manifest in shades of grey. Additionally, the applicability and precision of ML techniques in interrogating diseases depends a lot on the quality of the collected data, which in turn means that if biomedical scientists plan to include such methods in their experiments there will need to be guidelines and quality criteria if they are ever going to be useful as a diagnostic/therapeutic tool.

In the meantime, the current definition of AI lacks one very important aspect of human intelligence, namely the cognitive skills. Naturally the notion of transferring consciousness to a machine has gathered the interest of different scientific fields and huge strides of progress have been made. From Google’s DeepMind self-learning algorithms to the development of an artificial DNA-computer which can give the correct answers to a series of questions an interesting question arises: can we grow AI? Spoiler-alert: we probably can. Recently a passionate computer scientist (Toni Westbrook) did just that. Synthnet is a virtual brain, a virtual neuronal network formed by virtual DNA, which can learn through trial and error process, essentially recreating intelligence. Also very recently a non-invasive brain-to-brain interface (BBI) was published whereby a functional link between the brains of a human and a rat was established through a computer, successfully transferring thoughts into motions from one brain to the other.

It is clear that AI is the new kid on the block, a kid that is growing at a really fast pace and it is also safe to say that its place in the future is guaranteed. However, when facing a better, faster and smarter computer it is not good enough only to ask: what can we do that a computer can’t? We need to ask what activities will humans always insist be performed by other humans. The answer to this question is rather simple: relational tasks, tasks that include empathy, function in a group and social awareness. Until we are able to solve the ethical dilemma of algorithmic morality or to put it simply: ‘what should a self-driving car be programmed to do in the event of an unavoidable accident’, or until we reach a point where we can fully transfer consciousness to a machine, we humans are going to stick around for a while.

Written by: Mara Tatari

Mobile Health

Author: Jamiu Aderonmu

In addition to patient monitoring devices and other mobile telemedicine (providing health care from a distance) devices, these days, smart phones, and tablets play a major role in mobile health (mHealth). mHealth can be described as medical and public health that is supported by mobile devices. But what are the potential and actual roles of mHealth in the healthcare delivery process?

mHealth has the potential to play a role in all phases of the healthcare process: prevention, diagnosis, decision-making, treatment, and follow-up. Since it can support data collection, monitoring and new care models, mHealth can contribute to the creation of value if it is involved in the entire health care process.

The prevention phase can use mobile apps for promoting healthy habits by scheduling reminders, and for mLearning activities aimed at teaching people about diseases. In the diagnosis phase, mobile technology can help with remote access to patient information, but it can also help to carry out more complex processes like telediagnosis.

After the diagnosis has been made, the clinician has to make decisions, for example, are additional tests needed? Or does the patient’s condition require specific therapy? mHealth can be helpful in several ways for the decision-making phase; from automated mobile libraries with clinical descriptions of diseases, to the use of mobile technologies for shared decision making by health care professionals.

During treatment, mobile technology can be used to manage a patient’s symptoms/condition or to allow the patient to do this themselves (self-management), but it can also be helpful for treating patients at remote locations by means of tele-health and tele-surgery equipment.

After a patient has been treated, fundamental follow-up activities need to be put in place and these can be supported by mobile technology. For example, the real-time measuring of a patient’s vital signs, or achieving better and ongoing quality communication between patients and health care professionals. With these things in mind, mHealth has the potential to make a difference in terms of better quality of life, and more appropriate care, for the patient, and freeing up time for medical staff.

Whilst mHealth is mainly used via text messaging/SMS in less economically developed healthcare infrastructures, wealthier countries have found more of a role for mHealth in supporting activities of daily living, such as preparing food or eating/drinking. [While patients carry on with their usual daily activities, clinical data can still be collected.] In addition to smartphones and laptops, specialized health-related software applications are currently being developed, tested, and marketed for use in mHealth. Many of these technologies are developing primarily in high-income countries. Other examples include Sproutling’s Baby MonitorLiftware, Netatmo’s June, and Spire. This contrast in technologies being used can be attributed to cost differences. Nowadays, cheap mobile phones are readily available. For example, in 2011 Huawei partnered with Safaricom to unveil an $80 Android phone. On the other hand, in higher income countries, some healthcare professionals are using a wireless video otoscope that cost almost $3,000. In addition to self-management activities carried out by patients, mHealth seems to assist physicians with deciding how and when to treat patients.

Different adaptations to mobile devices and remote monitoring devices will be very important for the improvement of mHealth in the future. In addition to text messaging/SMS, these are very important for Diabetes care (management of insulin dosages, control of blood sugar levels). With a reported 357 million people living with Diabetes, it is one of the major chronic diseases worldwide.

mHealth products (considered Diagnostic Medical Devices by European Commission) are part of the Medical Device Industry. The EU Regulatory Framework (which was revised) for this industry is very supportive of innovation, is SME’s friendly, and helps provide rapid access to the market. The promising and attractive nature of the framework has increased investments in European medical device SME’s from U.S. venture capitalists. This innovative aspect is very important, considering that the life cycle for development on average is 18 months, which is much shorter than pharmaceutical drugs (4-10 years). The relatively short time for getting a product on the market is encouraging for investors who are more likely to see a faster return on their investments, as the market looks promising.

This has spurred innovation and development in Europe, with Germany, France and UK being the main markets. The majority (about 95%) of these companies are SME’s. This can be seen as welcoming news for those looking to get involved in a biotech start-up company.

Building successful partnerships between academia and industry

By Marilynn Larkin

Summary

In a recent presentation held at the German Center for Research and Innovation in New York City, experts from academia provided insights into their institutions’ efforts to ensure that promising research has at least some chance of being “translated” into useful products, and an industry expert discussed some of the hurdles and solutions. 

Dr. Jörn Erselius, Managing Director at Max Planck Innovation (MI) in Munich, Germany, gave an overview of the organization’s success in bringing research to market. MI undertook several initiatives to bring promising projects to the point that they could be considered for collaborations and also launched a Life Science Inkubator, specifically to catalyze startups. Selected team members receive education on business and entrepreneurship, as well as assistance in putting together a business plan and fundraising.

Dr. Teri Willey, VP of Business Development & Technology Transfer at Cold Spring Harbor Laboratory (CSHL) in New York, said the small life sciences organization is an incubator for more than 20 biotechnology spinoffs and has 605 active patent cases pending for 280 technologies and 872 technology transfer agreements of various sorts (as of April 2014). CSHL  takes a stepwise approach to collaboration, starting with “great science and great scientists” and then helping scientists select the right partner, execute a contract and follow through post deal.

Dr. Barbara Dalton, Director at Pfizer Ventures Investments Team in New York City, praised the strategies and successes of both MI and CSHL, but emphasized that many more such efforts by academia are needed to bring basic research projects to the point where they are actually fundable businesses. “Big wins…are extremely rare,” she said. “Institutions probably have to spin out 100 companies to get one or two that might result in a successful partnership and product, and so for the most part, these ventures are really, really risky.” 

How can academic institutions leverage their assets to secure funding in a tight economy and also deliver ROI? “For a venture capitalist, it all comes down to the people — that’s really what we invest in,” Dr. Dalton said. 

Read the entire article, which includes a section on “Traits a scientist needs to get funding,” here: https://www.elsevier.com/connect/building-successful-partnerships-between-academia-and-industry

NEIL WOODFORD ON INVESTMENT IN THE BIOTECH WORLD

The most accomplished and recognised fund manager in the UK, Neil Woodford, talks to us about the value of investing in emerging start-up and biotech companies.

After graduating in 1981 with a degree in Economics, Neil Woodford joined a small fund management company in London, thereafter working in several larger firms until moving to Perpetual in 1989. He remained with the fund management business Perpetual, later acquired by Invesco, for 26 years, noting their unconstrained and active management style. As Head of Investment he was a driving force for the company’s success and profitability. In April 2014 Neil left Invesco in order to set up his own fund management company, where he is now able to implement his own vision and style of investment.

Around 30% of the total funds Neil invests are within the pharmaceutical industry, from small spinouts to larger companies like AstraZeneca and Roche. However, Neil explains that all investments in his portfolio have to pass the same filter: “everything that is in the fund is there because I believe it to be an undervalued asset.” When building the best investment portfolio for a client, the pharmaceutical and biotechnology industries offer opportunity to adopt a patient long term approach, a style that Neil favours, with capital supply to companies which are not only successful, but also likely to deliver better results than market expectations, thus making them good investments. Neil believes this sector will offer opportunity for investment going forward, as research and development productivity continues to improve despite a fall in recent years.

Part of this R&D recovery can be attributed to the industry recognising what it does well, and what it does not do well. Whilst the pharmaceutical industry is effective at later stage development and can utilise a global infrastructure to deliver, they have under-performed in early stage development. Collaboration with academia has afforded a valuable opportunity to make improvements in this area, exemplified by the calls for innovative ideas by Roche with their extended innovation approach and GSK’s One Start competition. As Neil mentions, “collaboration is really important in the early stage of scientific development, it’s about bringing brilliant individuals together, and when scientists get together, typically you get better outcomes.”

Of course Neil also has a reputation of investing in smaller biotechnology and start-up companies; an area that has been under-exploited by his competitors. He affirms that the UK has an excellent track record of outstanding scientific innovation, yet a poor record of converting these ideas into commercial successes. Often this commercialisation has fallen to the United States, where there is a greater supply of accessible capital. However, Neil believes there is an obligation to take the great innovations fostered in the UK’s further education system and convert them into domestically based commercial successes. In addition to the altruistic appeal of this attitude, investments in this area have the potential to deliver substantial returns to potential investors. Neil says, “We are seeing in this portfolio some unbelievably exciting opportunities and some are not far from IPOs (Initial Public Offerings).”

A combination of recent biotech company successes, and an increasing drug approval rate – the FDA approved 41 in 2014 – has started to get the attention of other investors, creating a more supportive environment for biotechnology firms, with an accordingly increased supply of funds to the sector. Public figureheads in the wider technology world are also pushing for more investment into biotech, epitomised by the new Breakthrough Prize with several being awarded every year since its inception in 2013.

In performing the necessary due diligence when choosing the right investment for a portfolio, Neil points out that judgments are made about the people running the business, with regard to both heir competencies and their leadership. Additionally, assessments are made in conjunction with a team of collaborators about the technology and market opportunity to help inform the investment. With that in mind, we asked Neil about what advice he would give to young entrepreneurs and students seeking to establish their own company. He stresses that putting the right team together is essential: “At the start of a project students must realise it’s a tough road converting a great idea into a successful business, it’s a tough road, but it’s not impossible.” It is therefore crucial to bring the right people and different skills together, and to develop a useful network of contacts. Neil emphasises that in order to achieve this budding entrepreneurs must be willing to part with equity in order to ensure the right team is brought on board; to have a little of something that is very successful is better than to have a lot of something that is unsuccessful.

Neil Woodford’s success is recognised the world over and the faith he places in the future of the UK pharmaceutical industry, reflected in his investments, is a source of hope of and incentive for young and ambitious scientists.

Interview run by: Mina Bekheet
Written by: Fatemeh Ghari
Edited by: Oliver Coleman

THE SGC STORY – AN INTERVIEW WITH CHAS BOUNTRA

Chas is a Professor of Translational Medicine in the Nuffield Department of Clinical Medicine and Associate Member of the Department of Pharmacology at the University of Oxford. He is also a Visiting Professor in Neuroscience and Mental Health at Imperial College, London. Chas is an invited expert on several government and charitable research funding bodies, and an advisor for many academic, biotech and pharma drug discovery programmes. He was voted ‘one of the top innovators in the industry’ in 2012. Previously, Chas was Vice President and Head of Biology at GlaxoSmithKline. He was involved in the identification of more than 40 clinical candidates for many gastro-intestinal, inflammatory and neuro-psychiatric diseases.

Support for open innovation in research is increasing across technology sectors around the world. In June 2014 Tesla boldly released their patents on electric vehicle technology to accelerate its development. Research companies, both large and small, can waste resources and time when investigating the same targets behind closed doors and patents, when talking to each other would better target their focus elsewhere to quicken advancements and avoid repeat failure.

One institution shaking things up in the pharmaceutical industry and doing things a bit differently is the Structural Genomics Consortium (SGC) in Oxford.

The SGC is a dedicated example of the open innovation model, as their stated mission is to focus on less well explored areas of the human genome and share their results freely and openly with the scientific community and collaborators. This approach has already led to the sharing of over 1200 new protein structures online and the development of over 30 high quality small molecule chemical probes being made available for epigenetic proteins.

The story of the SGC began 10 years ago, when it was established to produce openly accessible academic research to support the drug discovery process. A process that, a decade later, SGC Chief Scientist Professor Chas Bountra reflects on:

“We [the industry] don’t know how to do target discovery, we still don’t understand human disease well enough”.

A surprising statement in the face of the overwhelming success that the SGC has seen, yet it bears a serious point when one considers that despite the sequencing of the human genome, no revolutionary advance in drug discovery has come; we are still searching for ‘cures’ for cancer, diabetes, chronic inflammatory conditions and a multitude of others. Nonetheless the progress made towards these laudable goals has been considerable, and the SGC has played a major role in advancing the burgeoning field of epigenetics.

The SGC’s small molecule probe project targeting epigenetic proteins was initiated in 2008, initially just with financial support and expertise from GSK, now with nine other pharmaceutical companies and the Wellcome Trust, to the combined tune of over £135m in funding together signalling a “paradigm shift in the industry” according to Professor Bountra. Put simply, the project aimed to provide tools to interrogate biology where before there were none. Professor Bountra continues: “A useful chemical probe must be potent, selective and cell active”. That is to say research with ‘dirty’ (off-target effecting) and in-vitro only activity probes is not acceptable in the face of exquisitely complex systems which we must go after, such as the CNS for Alzheimer’s. In delivering probes meeting these criteria for under-researched targets, including target verification through use of different chemotype probes and inactive control testing, the SGC serves as a bridge between the worlds of academia and industry. This bridge is vital to rebuild confidence between the two when, Professor Bountra tells us,

“Industry feels that up to 50% of the academic literature is not reproducible when they come to test it”

creating an unsustainably low level of trust that can only be repaired through closer collaboration.

Global and local collaborations form a key part of the SGC’s strategy, one of which has borne a game changing small molecule for targeting cancer. The story of JQ1 is an excellent example of what open innovation between scientists across disciplines in the clinic and the lab can achieve, and in a space of time that no other approach could. Jay Bradner’s research group at Dana-Farber worked with the SGC to publish on the inhibition of BET bromodomains, which on discovery of their importance to the function of oncogenic MYC protein, led to a resurgence in interest targeting this previously elusive functionality. In particular, a candidate drug spawned from this research, OTX-015, being developed by OncoEthix in phase 1 trials led to a buyout from Merck in late 2014 for $375 million. The valuable promise shown by this class of inhibitors against cancer has led to other pharmaceutical companies beginning research on them, and in the ensuing 4 and a half years Professor Bountra informs us there have been 6 new companies established, with 6 new molecules and 12 clinical studies and hundreds of academic publications across the globe – a huge achievement. Moreover, these quality probes are enabling precise interrogation of their target proteins to discover new biology, particularly relating to inflammation. Even deciding which assays to perform to find this new biology is itself a huge challenge.

Professor Bountra also says that the “interest from patients has never been higher”, to the extent that they and their relatives have been in his office offering their tissue for study, and setting up foundations – an extraordinary show of support and source of motivation for the science. Much of this remarkable story has stemmed from the 2010 Nature publication of the BET target validation and the decision to share JQ1 openly as a tool for research. It is fantastic progress in just five years of research and this ‘crowdsourced science’ looks set to continue producing more exciting results.

Panacea Innovation’s Biostars competition provides a superb opportunity for applicants to exploit this way of doing science, by either: developing their own ideas, or utilising scientific output and mentorship from the SGC in order to turn science into commercial reality.

 

Written by Oliver Coleman, Editor-in-Chief

CRISPR-CAS9 THERAPEUTICS: A TECHNOLOGY OVERVIEW

Author: Alfred Chin, Johns Hopkins University

In a controversial paper published in the journal Protein & Cell earlier this year, Chinese scientists at Sun Yat-sen University reported the world’s first genomic editing of human embryos (1). Using genomic editing technology known as CRISPR-Cas9, the researchers edited the β-globin gene in human ‘non-viable’ embryos to correct β-thalassemia, a genetic blood disorder. Far from being clinically applicable, the results of the study shed light on the myriad of complications the team encountered in harnessing CRISPR-Cas9 as a therapeutic agent. The study came at a time of intense debate among the scientific community over the ethics of genomic editing. Some leading biologists have called for a moratorium on human genome editing (2), while other researchers believe that withholding technology that can eliminate crippling genetic diseases such as cystic fibrosis is unethical (3). Because of the rapid advancement of CRISPR-Cas9 technology, discussion on the science, legality, and ethics of therapeutic genome editing has never been more pertinent.

 

 Origins and Biology

The CRISPR-Cas system was first described as a bacterial adaptive defense mechanism against foreign invaders such as plasmids or viruses. CRISPRs, ‘clustered regularly interspaced short palindromic repeats’, are short DNA repeats of viral origin found in the genomes of bacteria, and Cas (CRISPR-associated) refers to proteins with nuclease domains that can recognize and cut DNA (4). Upon viral infection, CRISPR loci are transcribed to form mature CRISPR RNAs. Complexed with Cas proteins, the mature CRISPR RNA recognizes the foreign nucleic acid and guides the Cas protein to cleave and disable the invading virus.

In a Science paper published in June 2012, American RNA biologist Jennifer Doudna and French microbiologist Emmanuelle Charpentier capitalized on the bacterial defense mechanism by engineering a novel, programmable CRISPR/Cas system that was site-specific (5). Doudna and Charpentier’s method was the first demonstration of site-specific DNA cleavage using the Cas9 protein in vitro. However, it was not until 2013 – when MIT bioengineer Feng Zhang engineered a novel version of CRISPR-Cas9 to edit genomes in human cells (6) – did genomic editing become a therapeutic possibility.

 

Therapeutic Applications

CRISPR-Cas9’s ability to correct genetic defects presents an effective solution for individuals afflicted with incurable genetic disorders. Researchers are racing to optimize CRISPR-Cas9 for specific genetic disorders as proof-of-concepts that may eventually lead to clinical applications, and landmark advancements in correcting hereditary diseases are made every year. In 2013, Breakthrough Prize in Life Sciences winner Hans Clevers and his colleagues corrected the CFTR (cystic fibrosis transmembrane conductor receptor) locus in intestinal stem cells of cystic fibrosis patients (7). In 2014, Daniel Anderson and his group at MIT successfully corrected the Fah mutation responsible for hereditary tyrosinemia type I – a fatal genetic disease characterized by an inability to metabolize amino acid tyrosine – in liver cells (8). In 2015, a team from Duke University led by Charles Gersbach restored proper dystrophin expression in human cells with Duchenne muscular dystrophy (9).

Realizing that CRISPR-Cas9 offers unparalleled genetic specificity, researchers are using the genomic editing technology to facilitate discoveries in cancer biology. Representative animal models are integral in medical research, and CRISPR-Cas9 has led to cancer models that better reflect the disease in humans. Last October, Feng Zhang and Nobel laureate Phillip Sharp successfully engineered a CRISPR-Cas9 system that is easily delivered into mice to model the deleterious effects of mutations in cancer, facilitating “rapid screening of causal genetic mutations in a variety of biological and disease applications” (10). This was possible due to the ability of their system to introduce loss-of-function mutations in tumor suppressor genes and gain-of-function mutations in proto-oncogenes. Earlier this year, Christopher Vakoc and his team at Cold Spring Harbor Laboratory extended CRISPR-Cas9 technology to comprehensively identify protein domains that sustain cancer cells (11). The broad screening capabilities of Vakoc’s approach may help identify novel cancer drug targets, which are of great interest to drug discovery efforts led by pharmaceutical companies.

 

Addressing Challenges and Limitations

Before CRISPR-Cas9 can modify the genome of patients, it needs to be efficiently delivered into the nucleus. Traditionally, the Cas9 protein used by researchers comes from Streptococcus pyogenes, but the protein’s large size limits its use in therapeutic applications. In a paper published in Nature earlier this year, Feng Zhang and Phillip Sharp discovered that Cas9 from Staphylococcus aureus – which is more than one kilobase shorter – can edit the genome with similar efficiency to the S. pyogenes Cas9 protein (12). Aside from employing a smaller Cas9 protein, CRISPR-Cas9 delivery can be enhanced further by attaching the system to molecules that facilitate uptake. David Liu and his group at Harvard University complexed CRISPR-Cas9 with cationic lipids, resulting in higher potency and specificity of genomic editing in vivo than conventional delivery methods (13).

Whether it is drug dosage or radiotherapy duration, effective therapeutic applications require precise control. Methods to temporally and spatially regulate CRISPR-Cas9 are an emerging focus of research in 2015, and they provide researchers with greater flexibility and options. Scott Lowe and colleagues at Memorial Sloan Kettering Cancer Center developed an inducible CRISPR (iCRISPR) system that can be activated by administering doxycycline in vivo, allowing researchers to activate CRISPR-Cas9 at will in mouse models (14). In a groundbreaking paper published in Nature Biotechnology earlier this month, Moritoshi Sato’s lab at The University of Tokyo combined CRISPR-Cas9 with another revolutionary genetic research method – optogenetics (15). Heralded as “Method of the Year” by Nature Methods in 2010, optogenetics refers to the ability to control cellular activity by light. Sato’s photoactivatable Cas9 protein comprises of fragments that activate and assemble when exposed to blue light. Not only is light non-invasive, but it also renders extremely high spatial, temporal, and reversible control.

While CRISPR-Cas9 is highly site-specific, off-target cleavages can occur. Understandably, genomic editing accuracy is a paramount concern because of the devastating effects of any unintended edits in humans, and methods to detect off-target cleavages are needed. J. Keith Joung’s lab at Massachusetts General Hospital developed a method called GUIDE-seq to identify errors in CRISPR-Cas9 edits across the entire human genome in living cells, and the method remains the most rigorous and sensitive in the field to date (16). In addition to allowing researchers to assess the accuracy of future CRISPR-Cas9 systems, error-checking tools such as GUIDE-seq may be used by clinicians in the future to verify successful therapeutic genome editing in patients.

 

Intellectual Property

Given that CRISPR-Cas9 has fundamentally changed the way biologists around the world approach genetics, it is no surprise that the patent office is flooded with CRISPR-Cas9 patents. Patent applications for CRISPR-Cas9 technologies in 2014 more than quadrupled those in 2013, and MIT, Broad Institute, and Feng Zhang collectively command a majority of filed CRISPR-Cas9 patents (17). Currently, Feng Zhang – a cofounder of CRISPR-Cas9 startup Editas Medicine – holds the first US patent for CRISPR-Cas9 editing of eukaryotic genomes, which has been licensed to several biotech and pharmaceutical companies (18). However, Jennifer Doudna and Emmanuelle Charpentier – cofounders of Caribou Biosciences and CRISPR Therapeutics respectively – believe that they should own the rights to CRISPR-Cas9 and have requested the US Patent & Trademark Office to reconsider the patents owned by Feng Zhang and Broad Institute.  With billions of dollars at stake, legal fights over CRISPR patents may prevent commercialization of CRISPR-Cas9 and reflect badly on the universities involved (19).

 

Ethical and Legal Concerns

The primary ethical concern for CRISPR-Cas9 therapeutics pertains to the prospect of human germline engineering. Last month, Nature Biotechnology published a feature article with inputs from researchers, ethicists, and business leaders around the world on the ethical issues raised by CRISPR germline engineering (20). The general consensus seems to be that germline engineering is inevitable because researchers will successfully troubleshoot any technical barriers sooner or later. However, one thing remains unanimously agreed – germline engineering must be carefully regulated. While the medical benefits of germline engineering are clear, many experts foresee societal risks. One obvious concern is that only rich families may be able to afford genomic editing, conferring an inherent advantage to babies born in wealthier countries. Another long-term concern is a genomic editing slippery slope that may lead to ‘designer babies.’  Where is the line drawn between therapeutics and enhancement?

In terms of the legality of germline engineering, most experts are in favor of a temporary moratorium to foster discussion since an international ban is unlikely to be entirely enforced. While researchers in China have already published studies on germline engineering, US National Institutes of Health director Francis Collins issued a statement earlier this year that banned NIH-funded research into genomic editing of human embryos (21). Due to the divergent medical research policies around the world, the issue of whether germline engineering should be regulated internationally or domestically has also been raised in the scientific community.

Perhaps the biggest biomedical discovery in decades, CRISPR-Cas9 holds enormous prospects for therapeutic intervention to cure devastating genetic diseases. It also allows humans to permanently change the course of evolution. The decisions made by governments, researchers, and biotech companies on the use of therapeutic gene editing in the next decade will undoubtedly change science and medicine forever.

 

References

 

1. Liang, P. et al. CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein & Cell 6, 363-372 (2015).

2. Wade, N. Scientists seek ban on Method of Editing the Human Genome. The New York Times (2015). at <http://www.nytimes.com/2015/03/20/science/biologists-call-for-halt-to-gene-editing-technique-in-humans.html?_r=0>

3. Gallagher, J. Embryo engineering a moral duty, says top scientist. BBC (2015). at <http://www.bbc.com/news/uk-politics-32633510>

4. Doudna, J. & Charpentier, E. The new frontier of genome engineering with CRISPR-Cas9. Science346, 1258096-1258096 (2014).

5. Jinek, M. et al. A Programmable Dual-RNA-Guided DNA Endonuclease in Adaptive Bacterial Immunity. Science 337, 816-821 (2012).

6. Cong, L. et al. Multiplex Genome Engineering Using CRISPR/Cas Systems. Science 339, 819-823 (2013).

7. Schwank, G. et al. Functional Repair of CFTR by CRISPR/Cas9 in Intestinal Stem Cell Organoids of Cystic Fibrosis Patients. Cell Stem Cell 13, 653-658 (2013).

8. Yin, H. et al. Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype.Nat Biotechnol 32, 551-553 (2014).

9. Ousterout, D. et al. Multiplex CRISPR/Cas9-based genome editing for correction of dystrophin mutations that cause Duchenne muscular dystrophy. Nat Comms 6, 6244 (2015).

10. Platt, R. et al. CRISPR-Cas9 Knockin Mice for Genome Editing and Cancer Modeling. Cell 159, 440-455 (2014).

11. Shi, J. et al. Discovery of cancer drug targets by CRISPR-Cas9 screening of protein domains. Nat Biotechnol 33, 661-667 (2015).

12. Ran, F. et al. In vivo genome editing using Staphylococcus aureus Cas9. Nature 520, 186-191 (2015).

13. Zuris, J. et al. Cationic lipid-mediated delivery of proteins enables efficient protein-based genome editing in vitro and in vivo. Nat Biotechnol 33, 73-80 (2014).

14. Dow, L. et al. Inducible in vivo genome editing with CRISPR-Cas9. Nat Biotechnol 33, 390-394 (2015).

15. Nihongaki, Y., Kawano, F., Nakajima, T. & Sato, M. Photoactivatable CRISPR-Cas9 for optogenetic genome editing. Nat Biotechnol (2015). doi:10.1038/nbt.3245

16. Tsai, S. et al. GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases. Nat Biotechnol 33, 187-197 (2014).

17. Ledford, H. CRISPR, the disruptor. Nature (2015). at <http://www.nature.com/news/crispr-the-disruptor-1.17673>

18. Rood, J. Who Owns CRISPR?. The Scientist Magazine (2015). at <http://www.the-scientist.com/?articles.view/articleNo/42595/title/Who-Owns-CRISPR-/>

19. Regalado, A. Battle over CRISPR Gene Editing Patents. MIT Technology Review (2015). at <http://www.technologyreview.com/news/536736/crispr-patent-fight-now-a-winner-take-all-match/>

20. Bosley, K. et al. CRISPR germline engineering–the community speaks. Nat Biotechnol 33, 478-486 (2015).

21. Collins, F. Statement on NIH funding of research using gene-editing technologies in human embryos - The NIH Director - National Institutes of Health (NIH). nih.gov (2015). at <http://www.nih.gov/about/director/04292015_statement_gene_editing_technologies.htm

BREAKING BOTTLENECKS IN DRUG DISCOVERY AND DEVELOPMENT

By Marilynn Larkin 

Despite years of effort and advances in technology and data mining, bringing a drug from bench to bedside remains a costly, complex and time-consuming process with no guarantee of success. According to a recent report by Pharmaceutical Research and Manufacturers of America, “Biopharmaceutical Research & Development: The Process behind new Medicines,” it takes on average at least 10 years for a drug to make the journey from discovery to the marketplace at an average cost of $2.6 billion. And the likelihood that a drug entering clinical testing will eventually be approved is estimated to be less than 12 percent.

Researchers have begun testing ways to overcome bottlenecks in drug discovery and development, thereby streamlining the process involved in selecting a candidate drug, developing it, getting it into the clinic and then to the public. They’re becoming more proactive about identifying and investigating potential adverse effects before the clinical trial phase;  using stem cells and in silico (computer) modeling to gain insights earlier into how a promising compound might react in the human body; and changing how they select and work with animal models, thereby reducing the amount of animal testing required for a new drug approval.

In a recent symposium for pharmaceutical industry thought leaders, “Preclinical Safety Strategies to Impact Early Decision-Making,” experts in pharmacokinetics/pharmacodynamics, safety pharmacology and toxicology explained how these approaches are enabling drug developers to predict sooner and with more accuracy whether a candidate drug has a chance of success.

Read the entire article, which includes a link to the webinar, here:

https://www.elsevier.com/connect/breaking-bottlenecks-in-drug-discovery-and-development

BioStars 2015-2016 Grand Finale - Oxford, LMH 16.03.16

The Grand Finale of the BioStars 2015 edition, hosted at the spectacular Deneke Hall of Lady Margaret Hall, University of Oxford, had more than 150 guests, among which the shorlisted teams. The judging panel included Paul-Peter Tak (Senior Vice President R&D Pipeline at GSK), Graeme Martin (President and CEO of Takeda Ventures), Andrea Mica (Managing Partner at Oxford Technologies), Shaun Grady (Vice President - Strategic Partnering & Business Development at AstraZeneca), Ruth Mckernan (CEO of Innovate UK) and Erik Nordkamp (Director and Head of Global Innovative Pharmaceutical business at Pfizer).