The 100,000 genomes project set out to mainstream whole genome sequencing for treatment into the NHS. Genomics England, set up in 2013 to deliver the project, established sequencing and interpretation pipelines to enable whole genome sequences to be analysed for rare diseases and cancer patients with individual reports returned to clinicians. In parallel, NHS England set up a national network of NHS Genome Medicine Centres involving more than 80 hospitals to identify and consent eligible patients with unmet clinical need and delivering samples for sequencing with associated clinical data. Partnerships with the Scottish Genomes Partnership, NHS Wales and Health and Social Care in Northern Ireland have ensured patient access across the whole UK. The target of 100,000 genomes sequenced was reached in December 2018 at which point individual interpretation reports had been returned to the NHS for half of those genomes. Whole genome sequencing is now part of standard commissioned health care through the creation of the NHS Genome Medicine Service which is targeted to generate another 500,000 whole genomes for clinical care over the next 5 years. This is in addition to the 500,000 whole genomes of UK biobank participants planned over the same period.

The secure, scalable high performance-computing environment where all data processing takes place is located within the NHS firewall, but is also configured to support research. It is currently accessible by more than 1,500 researchers who are members of the Genomics England Clinical Interpretation Partnership (GeCIP). Researchers are organised into domains around disease or computational area. The environment contains a rich set of clinical data (more than 1 billion data points) including the longitudinal electronic health record of each participant, along side genome sequence and variant files with a full set of tools to enable research.

The construction of a dual use data environment within a health system provides a model for future translational human research. It allows researchers to move beyond analysis of cohorts of research subjects of limited size to analysis of patient data from whole health systems while respecting data privacy, allowing comorbidities and longitudinal health data to be better taken into account. It also provides a model for initiatives around other health data types, such as the newly announced InnovateUK Imaging, Pathology and AI centres and Health Data Research UK. I will discuss the progress of these projects and their impact on health research and personalised medicine in the UK.

Abstract: My lab is interested in learning how cells function and transmit signals. It turns out that many novel mechanisms can be discovered by analyzing virulence factors or toxins used by pathogens during infections to manipulate “normal” cells. We have found that these virulence factors or toxins many times mimic or capture an activity used by host cells. They then use this activity in clever ways during infection. For example, AMPylation (covalently attaching AMP to an amino acid side chain of a protein) is an ancient mechanism that we are re-discovering by studying pathogens. While bacterial pathogens hijacked this activity to shut down signaling in an infected host cell, the eukaryotic host, such as Drosophila, uses this same activity to maintain neuronal plasticity during chronic stress.  My lab uses many techniques including, biochemistry, microbiology, microscopy, yeast genetics, cell biology, proteomics, biophysics, etc, to uncover these ingenious molecular activities.

Abstract: New cryo-EM technologies enable to investigate protein structures in the native physiological context of the cell. We use these technologies to study the self-organized assembly of cilia, ubiquitous organelles of eukaryotic cells.
Assembly of the cilium requires the rapid bidirectional intraflagellar transport (IFT) of building blocks to and from the site of assembly at its tip. This bidirectional transport is driven by the anterograde motor kinesin-2 and the retrograde motor dynein-1b, which are both bound to a large complex of 25 IFT adaptor proteins. We have recently developed a millisecond resolution 3D correlative light and electron microscopy (CLEM) approach to show that anterograde and retrograde IFT trains use separated microtubule tracks along the microtubule doublets of the cilium (Stepanek & Pigino, 2016). With this method at hand we showed that the spatial segregation of oppositely directed trains ensures a collision free transport in the cilium. However, it remained to be explained how competition between kinesin and dynein motors, which are both found on the same anterograde trains, is avoided. In bidirectional transport systems in the cell, other than IFT, the presence of opposing motors leads to periodic stalling and slowing of cargos moving along the microtubule. No such effect occurs in IFT. To address these questions, we take advantage of the most advanced technologies in cryo-electron tomography and sub-tomogram averaging. After obtaining the 3D structure of IFT train complexes in the cilia of intact Chlamydomonas cells, we showed that a tug-of-war between kinesin-2 and dynein-1b is prevented by loading dynein-1b onto anterograde IFT trains in an inhibited conformation and by positioning it away from the microtubule track to prevent binding. These findings show how tightly coordinated structural changes mediate the behavior of such a complex cellular machine.

Eukaryotic genomes are pervasively transcribed, yielding a wealth of both functional and cryptic transcripts. We aim to understand how cells deal with such massive genomic output by studying the molecular machineries that sort RNA for function or decay. We are also interested in characterizing a possible functional impact of regulated RNA degradation. In my talk, I will describe our most recent efforts characterizing human nuclear RNA degradation complexes and discuss the molecular basis for cellular decision processes determining RNA fate.

Dr James Attwater (Laboratory of Molecular Biology): "Replication in the age of RNA"

Dr Lucy Young (AstraZeneca):"Differential activity of ATR and WEE1 inhibitors in a highly sensitive subpopulation of DLBCL linked to replication stress"


The two 15 minute talks by Cambridge-based speakers will be followed by a ~40 minute keynote talk. There’ll be drinks and pizza after!

Continuous developments in the electron microscopy (EM) field have led to a step change in our ability to solve the “high resolution” structure of challenging systems. Additionally, recent advances in the resolution obtainable by electron microscopy (EM) as well as the repertoire of samples available for study, make the method ideally suited for time-resolved studies. Unfortunately, there are constrains and bottlenecks that do not allow for this to be realised. Sample preparation is considered as one of the main bottlenecks that hinder EM and push it back from reaching its full potential.
In this talk a cryo-electron microscopy grid preparation device is introduced and described. This device permits rapid mixing, voltage assisted spraying, and vitrification of samples. Using the aforementioned apparatus, grids of sufficient ice quality are produced within a time frame of a few milliseconds (<10 ms). The produced samples enable sub 4 Å reconstructions, which are comparable to the traditional blotting approach for the same samples.
Rapid mixing and freezing is performed within time-frames that go below 10 ms, and thus provide greater temporal resolution from previously reported approaches. Additionally, fast sample preparation with spraying can address some of the currently unsolved problems in cryoEM, which are the problems associated with protein denaturation at the air-water interface, as well as the effects of shear forces produced by traditional blotting. Using this approach, short-lived conformational states of proteins and protein complexes that had previously not been determined by cryoEM approaches can be trapped and studied.

Gene transcription is a fundamental cellular process that is carried out by the multi-subunit RNA polymerase (RNAP), which is conserved from bacteria to human. Transcription is highly controlled and many regulatory factors/strategies act on initiation, which involves the opening up the double-strand DNA into single strands and the delivery of the DNA template into the RNAP active centre. Transcription initiation is a highly dynamic process, and has thus been difficult to be studied structurally. We use a special form of bacterial RNAP, which allows us to trap intermediate states. I will discuss our recent progress in unravelling the detailed molecular mechanism of transcription initiation process including how DNA is opened up and delivered into the active centre for transcription and the roles of specialised activator proteins that belong to the large AAA ATPase family.

Are you wondering how best to utilise your scientific skills? Are you planning your next step in academia or considering pursuing a career away from the bench? Would you like more information about different scientific careers from a diverse range of speakers?

Emma Gleave, Senior Scientist, AstraZeneca

Emma completed her PhD with Andrew Carter on the structure of dynein before working as a postdoc with Meindert Lamers studying DNA replication. She decided that life in academia was not for her and in 2017 joined AstraZeneca at Alderley Park where she is now a Senior Scientist working in the protein purification group of Discovery Sciences.


Rebecca Aarons, Senior Research Funding Coordinator, Research Strategy Office, University of Cambridge

Becky has a PhD in Chemistry from the University of Manchester and completed a successful postdoc at the Montreal Neurological Institute at McGill University. However, she decided to move away from the bench and spent 6 years at the Wellcome Trust at first managing grant applications, then a portfolio of strategic projects, including the Trust’s interests in chemical biology, advanced imaging and an international structural biology consortium. She decided to take a slight career break to avoid commuting to London while her children were young and joined the LMB in 2013 as a part-time governance assistant. She left in 2016 to take up a role in the University of Cambridge Research Strategy Office, one of a team running the new Strategic Research Reviews. She has since been promoted to Senior Research Funding Coordinator where she is now responsible for the University’s relationships with a number of research councils and charities, coordinating internal selection processes for funding and facilitation of funding bids. She has 3 children under 9 and is still managing to work part-time.

Jenny Gallop, Group Leader, Gurdon Institute

Jenny completed her PhD on endocytosis with Harvey McMahon at the LMB in 2005 before moving to Harvard Medical School with an EMBO fellowship in 2006 as a postdoc in Marc Kirschner's lab. She returned to Cambridge in 2011 to take up a Group Leader position at the Gurdon Institute where she was awarded a Wellcome Research Career Development Fellowship and ERC Starting Grant. She is a member of the Department of Biochemistry at the University of Cambridge. Her work asks how actin is regulated by signalling at membranes and the molecular mechanisms of filopodia formation during embryonic development. Jenny has two young children and has successfully used flexible working and maternity policies in running her group while they grow up.


Follow the link for more information: https://camawise.org.uk/

Not satisfied with nature’s vast catalyst repertoire, we want to create new protein catalysts and expand the space of genetically encoded enzyme functions. I will describe how we can use the most powerful biological design process, evolution, to optimize existing enzymes and invent new ones, thereby circumventing our profound ignorance of how sequence encodes function. Using mechanistic understanding and mimicking nature’s evolutionary processes, we can generate whole new enzyme families that catalyze synthetically important reactions not known in biology. Recent successes include selective carbene insertion to form C-Si and C-B bonds, and alkyne cyclopropanation to make highly strained carbocycles, all in living cells. Extending the capabilities and uncovering the mechanisms of these new enzymes derived from natural iron-heme proteins provides a basis for discovering new biocatalysts for increasingly challenging reactions. These new capabilities increase the scope of molecules and materials we can build using synthetic biology and move us closer to a sustainable world where chemical synthesis can be fully programmed in DNA.

The mammalian TMEM16 (TransMEMbrane proteins with unknown function 16) family has ten members with diverse functions, including calcium-activated chloride channels (TMEM16A/B), an auxiliary subunit of sodium-activated potassium channel (TMEM16C), and a calcium-activated cation channel and lipid scramblase (TMEM16F). I will present our recent studies of these TMEM16 family members.

Lily Jan went to California Institute of Technology (Caltech) for graduate school, after finishing her college study at National Taiwan University in 1968. She and her husband Yuh Nung Jan began their long-term collaboration when they were postdoctoral fellows, first with Seymour Benzer at Caltech and then with Steve Kuffler at Harvard Medical School. After joining the University of California, San Francisco (UCSF) faculty in 1979, Lily and Yuh Nung Jan began their ion channel studies with molecular identification of voltage-gated potassium channels, inward rectifier potassium channels, and calcium-activated chloride channels, in order to study these channels one at a time, to learn how they work and what they do in neurons and other cell types.

The talk will describe the evolutionary loss of a de novo cytosine DNA methyltransferse and its subsequent propagation for millions of years by a exquisitely specific maintenance methyltransferase in the lineage that gave rise to the human fungal pathogen Cryptococcus neoformans.