Crystallography: From Chocolate to Drug Discovery

This post was contributed by Dr Clare Sansom, senior associate lecturer in the Department of Biological Sciences. Dr Sansom attended inaugural Rosalind Franklin Lecture during Birkbeck Science Week 2016.

Rosalind Franklin - slide

Birkbeck has already established lecture series in honour of some of its most distinguished alumni. Until 2016, however, Rosalind Franklin – co-discoverer of the DNA structure and perhaps the most widely recognisable of its ‘famous names’ – was missing from the list of honourees. This gap has now been filled; the annual Rosalind Franklin lecture forms part of the college’s Athena SWAN programme and will always be given by a distinguished woman scientist.

And fittingly, the inaugural lecture, which was part of Science Week 2016, was devoted to Rosalind Franklin’s own discipline, crystallography. Elspeth Garman, Professor of Molecular Biophysics at Oxford University, gave an entertaining and illuminating lecture to a large audience that included Rosalind’s sister, the author Jenifer Glynn.

Exploring crystals

Garman began her lecture by showing a short video that she had produced for OxfordSparks.net that used a ‘little green man’ to illustrate the method of X-ray crystallography that is used to obtain molecular structures from crystals. The rest of the lecture, she said, would simply go through that process more slowly. She started by showing some beautiful examples of crystals. All crystals are formed from ordered arrays of molecules. They can be enormous, such as crystals of the mineral selenite in a cave in Mexico that measure over 30’ long or too small to be visible with the naked eye.

In the early decades of crystallography, structures could only be obtained from crystals of the smallest, simplest molecules: the first structure of all, published in 1913 by the father-and-son team of W.H. and W.L. Bragg, was of table salt. When they were jointly awarded the Nobel Prize for Physics in 1915, the younger Bragg was a 25-year-old officer in the trenches on the Western Front. His record as the youngest Nobel Laureate was unbroken until Malala Yousafzai’s Peace Prize in 2014.

The Braggs’ discoveries paved the way for studies of the structures of many, many substances: including the chocolate of the lecture title. Few of the audience can have known that chocolate exists in six different crystal forms, or that only one of these (Form V) is good to eat. The process of ‘tempering’ – a series of heating and cooling steps – is used to ensure that it solidifies in the correct form.

Professor Nick Keep and Professor Elspeth Garman at the inaugural Rosalind Franklin lecture

Professor Nick Keep and Professor Elspeth Garman at the inaugural Rosalind Franklin lecture

Protein crystallography

Garman then moved on to talk about her own field of protein crystallography. Proteins are the ‘active’ molecules in physiology, and they are formed from long, linear strings of 20 different ‘beads’ (actually, small organic molecules known as amino acids). Chemists can quite easily find out the sequence of these beads in a protein, but it is impossible to work out from this the way that the string will fold up into a definite structure ‘like a piece of wet spaghetti’. And it is this structure that places different units with different chemical properties on the surface or in the interior of the protein, or near each other, and that therefore determines what the protein will do.

Protein crystallography only became technically possible in the mid-twentieth century, and even then it was a painfully slow and complex process that could only be used to study the smallest, simplest proteins. Dorothy Hodgkin, also a professor at Oxford, won her Nobel Prize in Chemistry in 1964 for the structures of two biologically important but fairly small molecules: penicillin, with 25 non-hydrogen atoms and vitamin B12, with 80. She is perhaps better known for solving the structure of insulin, the protein that is missing or malfunctioning in diabetics. This has 829 non-hydrogen atoms; in contrast, the 2009 Chemistry Nobel Prize was awarded for the structure of the ribosome, the large (by molecular standards) ‘molecular machine’ that synthesises proteins from a nucleic acid template. The bacterial ribosome used for the Nobel-winning structural studies is well over 300 times larger than insulin, with over a quarter of a million atoms.

Real world applications

Dr Rosalind Franklin

Dr Rosalind Franklin

Protein structures are not only beautiful to look at and fascinating to study, but they can be useful, particularly for drug discovery. Many useful drugs have already been designed at least partly by looking at a protein structure and working out the kinds of molecule that would bind tightly to it, perhaps blocking its activity. Some viral proteins have been particularly amenable to this approach.

Rosalind Franklin did some of the first research into virus structure when she was based at Birkbeck, towards the end of her tragically short life, and her student Aaron Klug cited her inspiration in his own Nobel lecture in 1982. X-ray crystal structures were used in the design of the anti-flu drugs Relenza™ and Tamiflu™ and of HIV protease inhibitors, and more recently still structures of the foot and mouth virus are helping scientists develop new vaccines for tackling this potentially devastating animal disease. The foot-and-mouth virus structure even made the front page of the Daily Express.

The equipment that Dorothy Hodgkin and her contemporaries used to solve protein structures in the 1960s and 1970s looks primitive today. Now, almost every step of protein crystallography has been automated. Powerful beams of X-rays generated by synchrotron radiation sources, such as the UK’s Diamond Light Source in Oxfordshire, allow structures to be determined quickly from the smallest crystals. It is even possible to control some of these machines remotely; Garman has operated the one at Grenoble from her sitting room. Yet there is one step that has changed remarkably little. It is still almost as difficult to get proteins to crystallise as it was in the early decades. Researchers have to select which of a large number of combinations of conditions (temperature, pH and many others) will persuade a protein to form viable crystals. Guesswork still plays a large part and some researchers seem to be ‘better’ at this than others: Garman adds the acronym ‘GMN’ or ‘Grandmother’s maiden name’ to her list of conditions to reflect this.

Yet, with every step other than crystallisation speeded up and automated beyond recognition, the trickle of new structures in the 70s and even 80s has become a torrent. Publicly available structures are stored online in the Protein Data Bank, which started in 1976 with about a dozen structures: it now (May 2016) holds over 118,000. Protein crystallography as a discipline is thriving, but there are many challenges ahead. We are only now beginning to tackle the 70% or so of human proteins that are only stable when embedded in fatty cell membranes and are therefore insoluble in water. It is possible to imagine a time when it is possible to solve the structure of a single molecule, with no more need for time-consuming crystallisation. And, hopefully, women scientists will play at least as important a role in the second century of crystallography as they – from Quaker Kathleen Lonsdale, who developed important equations while jailed for conscientious objection during World War II, through Franklin and Hodgkin to Garman and her contemporaries – have in the first.

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Growing Your Ecosystem

This post was contributed by Miranda Weston-Smith, who on 10 March was a guest speaker at an event hosted by the Transforming Institutions by Gendering contents and Gaining Equality in Research (TRIGGER) team – a research project in Birkbeck’s Department of Management.

biobeat-brandingAt a joint Birkbeck School of Science and TRIGGER event, Miranda Weston-Smith discussed her experiences in founding BioBeat together with opportunities for scientists and business graduates in bio-sciences. Miranda helps early stage biomedical businesses attract investment and develop their business strategies.

Miranda has worked with many entrepreneurs and is experienced in fundraising, business planning and technology transfer. She is a long standing Mentor for Cambridge Judge Business School’s Entrepreneurship Centre, contributes to the University of Cambridge Masters in Bioscience Enterprise course and is a member of the St John’s Innovation Centre Training Team.

Miranda studied Natural Sciences at the University of Cambridge and has a Diploma from the Chartered Institute of Management Accountants.

 

She brings experience as a Technology Manager at Cambridge Enterprise, where she assessed and marketed life science technologies, negotiated licences and spun-out companies. She was responsible for technology transfer at the University of Cambridge for the Cambridge-MIT Institute. In her five years at the seed capital firm, Cambridge Research and Innovation, she invested in early stage technologies. Miranda co-founded Cambridge Network with Hermann Hauser.

 

As a result of working with researchers, Miranda founded and runs BioBeat, a programme to inspire the next wave of bio-entrepreneurs and business leaders. It is a way to engage with successful women entrepreneurs and she explained that in her experience women adopt different strategies to issues such as working in teams, risks, and raising finance. Doctor Helen Lee, Director of Research, Department of Haematology, University of Cambridge and Founder, Diagnostics for the Real World, and Dr Jane Osbourn, Vice President Research and Development, MedImmune and Head of Site MedImmune Cambridge were hugely important catalysts for BioBeat getting underway and for the first Bio Beat conference in 2013, with an all-female panel.

Introducing the Cambridge bio cluster

Miranda introduced the Cambridge bio cluster that involved a range of organisations involved in medicines, R&D Support, clinical diagnostics and consumer health. Many of the companies involved in these areas have connections with Cambridge University. Those involved in medicines may have direct intellectual property (IP) relationships with University. For others, the relationships may be more indirect through networking between individuals and groups.

Miranda discussed the differences between the Cambridge biocluster of 2010 and of 2015. Lines are much tighter and investment has significantly increased through a range of funders. For example, Axol Bioscience after setting out to obtain £600,000 through a crowdfunding campaign, managed to bring in £1 million.

On advice for entrepreneurs, Miranda stressed that it is Important to find out where strengths of a company lie. The company needs to find where it sits in the market – where its customers are – and then funding can speed-up. For example, one company set out to exploit exhalation technology through non-invasive equipment that was developed as a veterinary product for horses and other animals. However, having discovered that managing severe breathing attacks such as asthma costs the NHS over £1 billion per year, the company is now developing the technology for human patients. The approval procedure, finances and returns are completely different in these two sectors.

Another aspect stressed by Miranda is linking-up the product and the market with the financial details. Investors are really interested in the two aspects of market and finance as well as the product, so providing projections of three-year cash-flows can be very important. Investors will be seeking creativity in potential problem-solving from an early stage.

Q&A

Miranda then took questions in a lively session during which most delegates to the seminar participated by asking specific questions or joining in the discussion that ensued.

The first question related to the institutional anchors that underpin the bio-science cluster. Miranda said that Cambridge University provided local industry links and was there as a strong, constant presence. The corporates that are present are a mainstay that can provide sponsorship as well as international connections and perspectives. BioBeat is also a way of opening up fresh energies and a way of encouraging people to do more.

In answer to later questions about the university’s role, Miranda confirmed that the institution does not usually seek absolute control of enterprises, but tries to support incubate, and accelerate ideas. Cambridge University’s IP policy is that of retention of the first right to file patent applications; but copyright rests with the researchers. This means that there are many ways to exploit the ideas and not just go through the University. In addition, Cambridge Enterprises puts in seed money, but this is generally done in a low key way. Generally the University sees itself as an enabler and incubator.

A series of questions and some discussion followed about how to get involved in networking from a student business perspective, rather than as a scientific researcher. Miranda suggested that the first thing to do is to just try it after scoping-out what events are going on. Miranda candidly admitted that when she first started, she didn’t really understand what networking was all about and that you have to learn on the job. Porosity and being interested in what others are doing are important. Also, if you go out with one or two colleagues, it is important not just to stand together; just go up to people and start talking to them.

In the discussion it was mentioned that potential entrepreneurs could attend interesting networking events. Such events are regularly attended by service providers, head-hunters, institutions and sometimes investors. In London, One Nucleus holds regular events. Miranda confirmed the value of attending them.

Asked about how the Cambridge bio-cluster compared with others in Europe, Miranda suggested that one of ways is to look at companies that are moving into the area, such as   Ilumina. Microsoft has its European R&D office in Cambridge. Astra Zeneca (AZ) already has various laboratories around Cambridge, but eventually some 1600 – 2000 people will move in to their new building. The impact on the cluster will be for example, there will be opportunities for sub-contracting work and for early stage collaborative projects.

Finally, on the subject of how Miranda saw the cluster evolving, she said she expected Cambridge University to continue to spin-out biotech companies, and with spin-outs from other companies, the cluster will grow further. Spin-outs will also come from Barbaham Institute and Addenbrookes Hospital and from companies such Illumina.

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The importance of Web Science

Richard has a BSc in Physics from University of Leicester and an
MSc in 
Advanced Richard Brownlow copyInformation Systems from Birkbeck. He has over 20 years’ experience in industry as a Software Engineer and Software Project Manager and is currently studying for a PhD at the London Knowledge Lab where he is a member of the Weaving Communities of Practice Project. His research is in the design of tools to help domain experts integrate heterogeneous data sets.This post was contributed by PhD student Richard Brownlow. 

 

Annually at Birkbeck, the Department of Computer Science and Information Systems celebrates the work of its founder, the late Dr Andrew Booth, who was a pioneer in computer hardware and machine translation. Hosting this year’s Andrew Booth Memorial Lecture was the London Knowledge Lab, a unique interdisciplinary collaboration between two of the UK’s most prominent centres of research – Birkbeck and the UCL Institute of Education.

This year, we were honoured to have Professor Dame Wendy Hall present. She has played a foundational role in the development of the Web, the Semantic Web and Web Science, with her current research focussed in applications of the Semantic Web and in exploring the interface between the life and physical sciences. Along with being the first person outside of North America to be elected to the post of President of the Association for Computing Machinery (ACM), she has also been hugely influential and inspirational in promoting women’s careers in computer science.

Along with Professor Hall’s lecture, a broad range of London Knowledge Lab research was on show in the Department, for staff, students, alumni and guests from other institutions and across the industry. Opportunities for future collaborations and research were discussed. Some of the research demos included projects relating to Learning Technologies, such as LIBE which supports literacies through lifelong learning with inquiry based education. Other research demos were in the areas of ontology querying and mobile location analytics. I was also given the opportunity to demonstrate some of my own research interests including the knowledge base developed for the Weaving Communities of Practice project.

The importance of Web Science

The magnificent Keynes Library in Gordon Square was the setting as Professor Hall kindly delivered her lecture, captivating the audience with her insight on what the discipline of Web Science means in the context of the history of the World-Wide-Web. This was especially interesting given the foundational role she played in the development of the Web, including her collaborations with other giants of the sector such as Sir Tim Berners-Lee.

internet

Discussing the role of the Web in knowledge creation and sharing and the need to understand it in terms of both its technical and its social aspects, she also spoke on how this multidisciplinary field has come to be known as Web Science and the establishment of the Web Science Trust (WST) in 2006. She went on to describe how Web Science encompasses the theory and practice of Social Machines and how such machines are quite different from Turing Machines, which lie at the heart of every computer.

Professor Hall described the establishment of the Web Science Trust Network of Laboratories (WSTNet), an initiative furthering academic excellence in the field. There are currently fifteen such labs, including two in the UK. She then went on to describe a new exciting initiative called the Web Observatory, through which global partnerships are established to share data sets (both open and closed) along with associated Metadata and Analytics tools. Through these initiatives, Professor Hall described how Web Science aims to understand the origins, current state and possible futures of the Web, and to further the development of new research methodologies.

It is just over 10 years since Professor Hall delivered one of the inaugural talks at the London Knowledge Lab. In her vote of thanks, Professor Alex Poulovassilis – one of the two Co-Directors of the London Knowledge Lab – drew links to that inaugural lecture, firstly in the role of the Web in knowledge acquisition, sharing and dissemination, and secondly in the need to keep historical “memories” of the Web in order to enable the longitudinal analyses required for understanding its evolution and future.

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Academia’s gender inequality problem

This post was contributed by Professor Helen Lawton-Smith of Birkbeck’s Department of Management. Professor Lawton-Smith is organising Improving gender equality in work – what can we learn from London’s business and policy organisations? on Wednesday 18 March, 2pm-5pm.

laboratoryWomen are under-represented in senior positions in science, engineering, maths and medicine disciplines at UK universities. Initiatives including Athena SWAN and the Aurora Women’s leadership programme have been set up to address this problem, yet such initiatives by themselves are not enough to tackle the problem of the current gender bias. What is needed is institutional embedding, so that gender and other diversity issues are integrated into an equality framework of decision-making processes and structures within organisations, which cannot be side-stepped by those in positions of power.

The four-year Transforming Institutions by Gendering contents and Gaining Equality in Research (TRIGGER) project at Birkbeck is championing the role of female academics in scientific subjects as part of a five-country European project. This initiative is testing a blueprint designed to raise the status of women in scientific and technological organisations such as universities. The nine action areas are designed to identify barriers to equality in the workplace, including the impact of research. The project builds on Birkbeck’s existing commitment to promoting female academics. Results and reactions have been very interesting.

Equality issues have been tackled in a variety of ways by companies and by policy making bodies such as local authorities and government agencies. According to the New York Times in October 2014, Silicon Valley also has a diversity problem – one which is being tackled head on by companies such as Google and Facebook.

Academia has a lot to learn from how other kinds of large organisation have identified the nature and causes of gender inequality. On Wednesday 18 March the TRIGGER project and the BEI School are hosting a networking event designed to explore which institutional changes work best in supporting gender equality in large organisations. The panel’s speakers will reflect on why changes were necessary, what changes have been introduced, the outcome of those changes, and what still needs to happen to improve gender equality. The diversity of speakers will ensure there are opportunities for learning for all.

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