Making Platelets in vitro: an environmental question and making it count.

10th April 2017.  
Cédric Ghevaert, Wellcome Trust - MRC Stem Cell Institute, Cambridge

The production of megakaryocytes (MKs)--the precursors of blood platelets--from human pluripotent stem cells (hPSCs) offers exciting clinical opportunities for transfusion medicine. Here we describe an original approach for the large-scale generation of MKs in chemically defined conditions using a forward programming strategy relying on the concurrent exogenous expression of three transcription factors: GATA1, FLI1 and TAL1. The forward programmed MKs proliferate and differentiate in culture for several months with MK purity over 90% reaching up to 2 × 10(5) mature MKs per input hPSC. Functional platelets are generated throughout the culture allowing the prospective collection of several transfusion units from as few as 1 million starting hPSCs. The high cell purity and yield achieved by MK forward programming, combined with efficient cryopreservation and good manufacturing practice (GMP)-compatible culture, make this approach eminently suitable to both in vitro production of platelets for transfusion and basic research in MK and platelet biology.

After completing his MD at the Universite Libre de Bruxelles (which also included a whole year studying at the University of Bristol, UK) in 1997, Dr Ghevaert started his career training in Internal Medicine in the United Kingdom and became a member of the Royal College of Physicians in 2000. He went on to specialize in Haematology (completing his training in 2005). His intention was always to have an academic career and he therefore started a PhD at the University of Cambridge. He completed his PhD in 2008 and moved on as a post-doctoral clinical fellow to Prof Steve Watson laboratory at the University of Birmingham where he obtained a personal Intermediate Clinical Fellowship from the British Heart Foundation. This programme of research allowed him to further his knowledge of platelet and megakaryocyte biology. In 2010 he obtained a tenure post as Senior Lecturer in Transfusion Medicine in the Department of Haematology at the University of Cambridge where he now runs a research group with a special interest in two main fields of research: 1. production in vitro of blood cells for transfusion in humans using pluripotent stem cells technologies and 2. in vitro modelling of inherited platelet disorders. His research is supported by various funding bodies including NHS Blood and Transplant, the British Heart Foundation, National Institute for Health and Research.

[1] Moreau T, Evans AL, Vasquez L, Tijssen MR, Yan Y, Trotter MW, Howard D, Colzani M, Arumugam M, Wu WH, Dalby A, Lampela R, Bouet G, Hobbs CM, Pask DC, Payne H, Ponomaryov T, Brill A, Soranzo N, Ouwehand WH, Pedersen RA, Ghevaert C. Large-scale production of megakaryocytes from human pluripotent stem cells by chemically defined forward programming. Nat Commun. 2016 Apr 7;7:11208.

[2] Guerrero JA, Bennett C, van der Weyden L, McKinney H, Chin M, Nurden P, McIntyre Z, Cambridge EL, Estabel J, Wardle-Jones H, Speak AO, Erber WN, Rendon A, Ouwehand WH, Ghevaert C. Gray platelet syndrome: proinflammatory megakaryocytes and α-granule loss cause myelofibrosis and confer metastasis resistance in mice. Blood. 2014 Dec 4;124(24):3624-35.

Image: A drawing by G Bizzozero describing a platelet rich thrombus. Giulio Bizzozero, although not the first to observe 'blood corpuscles' later known as platelets, was the scientist who defined their role in coagulation adn thrombosis. Original reference: G Bizzozero. Ueber einen neuen Forrnbestandteil des Blutes und dessen Rolle bei der Thrombose
und Blutgerinnung.  Archiv fur pathologische Anatomie und Physiologie und fur klinische Medicin 90: 261–332 (1882)

All College students are warmly encouraged to participate. The poster of the seminar can be downloaded here





A Life Passion for Vaccines. How the Vaccines for Pertussis and Meningitis Were Developed.

21th March 2017.  
Mariagrazia Pizza, GSK Vaccines, Siena

Since the beginning of human evolution, approximately 3 million years ago to the mid 1700’s, life expectancy has been between 25 and 35 years. Today is more than 80 years. One of the major contributors in the increase in life expectancy has been the use of vaccines in preventing infectious diseases. However, most of the vaccines available today, although very effective, have been developed at the end of last century using conventional technologies. The vaccinology field is evolving very rapidly, with the modern technologies providing alternative ways in designing improved vaccines or novel vaccines against infections for which preventive measures do not exist. Today is possible to identify new antigens directly from the genome (Reverse Vaccinology), and apply a structure-based design to deliver more stable and more immunogenic antigens (Structural Vaccinology). The Reverse Vaccinology approach has been instrumental for the development of a new vaccine against Neisseria meningitidis serogroup B, a bacterium causing a devastating disease characterized by meningitis and sepsis.

Mariagrazia Pizza was educated as a pharmaceutical chemist at the University of Naples, Italy. After a fellowship at the EMBL laboratories in Heidelberg, Germany, she moved to Siena, Italy, where she stayed ever since as a scientist and Project leader, responsible for many bacterial projects. During this period, she has contributed to the discovery and licensure of two innovative bacterial vaccines, against pertussis and meningococcus B. She is currently a Discovery Project Leader at the Research and Development Centre of GSK Vaccines, in Siena. During her career, she received many scientific awards. She is co-author of over 180 publications in International peer-reviewed journals and over 150 patents.

All College students are warmly encouraged to participate. The poster of the seminar can be downloaded here

Image: Scanning electron micrograph of N meninigitidis, a bacterium causing meninigitis.




Genome Editing: its Promise for Society and Some Potential Perils

13th March 2017.  
John Parrington University of Oxford

Since the birth of civilisation, human beings have manipulated other life-forms. The ability to directly engineer the genomes of organisms first became possible in the 1970s, when the gene for human insulin was introduced into bacteria to produce this protein for diabetics. At the same time, mice were modified to produce human growth hormone, and grew huge as a result. But these were only our first tottering steps into the possibilities of genetic engineering. In the past few years, the pace of progress has accelerated enormously. We can now cut and paste genes using molecular scissors with astonishing ease, and the new technology of genome editing can be applied to practically any species of plants or animals. These new technologies hold much promise for improving lives. Genome editing may soon be used to treat rare genetic disorders, but also diseases like AIDS, by genetically modifying patients’ white blood cells to be resistant to HIV. In agriculture, genome editing could be used to engineer species with increased food output, and the ability to thrive in challenging climates. But these powerful new techniques also raise important ethical dilemmas and potential dangers, pressing issues that are already upon us given the speed of scientific developments.
To what extent should parents be able to manipulate the genetics of their offspring - and would designer babies be limited to the rich? Can we effectively weigh up the risks from introducing synthetic lifeforms into complex ecosystems? John Parrington explains the nature and possibilities of these new scientific developments, which could usher in a brave, new world. We must rapidly come to understand its implications if we are to direct its huge potential to the good of humanity and the planet.

John Parrington is an Associate Professor in Molecular and Cellular Pharmacology at the University of Oxford, and a Tutorial Fellow in Medicine at Worcester College, Oxford. He has published over 90 peer-reviewed articles in science journals including Nature, Current Biology, Journal of Cell Biology, Journal of Clinical Investigation, The EMBO Journal, Development, Developmental Biology, and Human Reproduction. He has extensive experience writing popular science, having published articles in The Guardian, New Scientist, Chemistry World, and The Biologist. He has also written science reports for the Wellcome Trust, British Council, and Royal Society. He is the author of The Deeper Genome, (Oxford University Press, 2015) and Redesigning Life (Oxford University Press, 2016).

All College students are warmly encouraged to participate. The poster of the seminar can be downloaded here.




Evolution of Research Assessment in the UK

6th March 2017.  
Steven Hill, Higher Education Funding Council for England

Periodic national research assessments of universities have been a feature of the United Kingdom's research policy landscape for more than 3 decades. In this talk I will chart the development and evolution of the approaches to research assessment, focusing on debates about the role of peer review and metrics, and examining the introduction of societal impact assessment in the most recent exercise, the Research Excellence Framework 2014 (REF2014). Finally, I will outline the plans for the next exercise, REF2021, and the current areas of debate and discussion.

Steven Hill is Head of Research Policy at the Higher Education Funding Council for England. At HEFCE Steven is responsible for research funding and assessment, open research, public engagement and impact. He is the chair of the steering group for the 2021 Research Excellence Framework, that is currently under development. Prior to joining HEFCE Steven was Head of the Strategy Unit at Research Councils UK, and had several roles in the Department for Environment, Food and Rural Affairs, working on evidence-based policy making. Earlier in his career Steven was a university lecturer at the University of Oxford where his research focused on plant biology.

All College students are warmly encouraged to participate. The poster of the seminar can be downloaded here.

Image: A portrait of English natural scientist C Darwin.



How to Succeed at University

5th October 2016.  
Bob Smale and Julie Fowlie, Brighton University 

The authors of the highly acclaimed and successful book How to Succeed at University will present the book to College students at 5.00 pm on October 5th in the College lecture thatre.  B Smale and J Fowlie will highlight the key factors that enable a University student to achieve his/her full potential at University and in later life. The book, now its 2nd edition, has been read and put to use by a number of University students in the UK and other countries since the 1st edition was released in 2009. Collegio Volta is particularly interested in introducing personal development plans and this is one of several areas in which B Smale and J Fowlie's book will provide significant guidance. 

All College students are warmly encouraged to participate. The poster of the seminar can be downloaded here. A synopsis of the talk can be downloaded here.

Image: students attending a degree ceremony t the University of Pavia (2nd July 2016).



Admission to Medical Schools

30th June 2015.  
Andy Chamberlain, Cambridge Assessment. 

On June 30th Andy Chamberlain of Camridge Assesment will give a seminar on Admission Tests for Medicine fit for the Future. The seminar will discuss several of the tests in common use (BMAT, IMAT, etc) and the evolution of these tests in order to improve performance and ensure that the best students are admitted,  The poster of the seminar can be downloaded here.  All medical students are encouraged to attend.

Image: Cardiff University


Making molecular tools out of DNA

15th February 2017. 
Björn Högberg, Karolinska Institute, Stockholm. 

The 3rd College C Milstein lecture and the Annual lecture of the Department of Molecular Medicine will be presented at the 2017 Life Science Symposium on February 15th by Björn Högberg a scientist at the Karolinsla Institute (Stockholm) and is entitled Building Molecular Tools out of DNA. The poster of the lecture can be downloaded here.

Lecture Synopsis. DNA is not only a carrier of genetic information but also an excellent building material for nanoscale engineering. I will present our recent work on ‘3D-printing’ DNA origami, a method that allows full computer aided design and provides a way to make DNA origami nanostructures more accessible to experiments in physiological conditions. The last part is important, because not only are DNA origami structures cool in themselves, they can help us learn important lessons about how biology works on the nanoscale. In my talk I will go through how we use these nanostructures to look at cell-cell signaling and how nanoscale clustering of ligands affects receptor signaling. I will show you how these DNA origami techniques are currently forming the basis for what might possibly become a new era of precise spatial control in biology.

Biographical Sketch.. Björn Högberg is an Associate professor of nanomedicine at the Medical Biochemistry and Biophysics Department at the Karolinska Institute. He got his PhD in physics from Mid Sweden University in 2007 and did his post-doc at the Harvard Mecial School in Boston the following years. Since late 2010 he has been leading a research group at the Karolinska in Stockholm. He is a leader in the field of DNA nanotechnology and in particular their biological research applications. Since starting his own lab he has consistently published with high impact and was recently awarded with several prestigious grants including a Knut and Alice Wallenberg Foundation Academy Fellows and an ERC consolidator.

Selected publications
[1] Benson E, Mohammed A, Gardell J,  Masich S, Czeizler E, Orponen P and Högberg B, DNA rendering of polyhedral meshes at the nanoscale,  Nature, 523 p. 441 (2015)

[2] Shaw A, Lundin V, Petrova E, Fördős F, Benson E, Al-Amin A, Herland A, Blokzijl A, Högberg B* and  Teixeira A*, Spatial control of membrane receptor function using ligand nanocalipers, Nature Meth, 11 p. 841 (2014) [3] Ducani C, Kaul C, Moche M, Shih WM and Högberg B, Enzymatic production of ‘monoclonal stoichiometric’ single-stranded DNA oligonucleotides, Nature Meth, 10, p. 647 (2013)



The long journey of mitochondrial medicine

2nd May 2016. 
Massimo Zeviani,
MRC Mitochondrial Biology Unit, Cambridge

The 2nd College C Milstein lecture and 2015/16 Annual lecture of the Department of Molecular Medicine will be given by Massimo Zeviani of the MRC Mitochondrial Biology Unit and University of Cambridge, UK on the 29th of April 2016 at 5.30 pm at Collegio A Volta (17 via A Ferrata, Pavia). The lecture is entitled Mitochondrial medicine: a long journey through the magic circle and beyond and the poster of the lecture can be found here. All members of the Department and other members of the academic community in Pavia, students and staff, are welcome to attend. The abstract of the lecture and a short biographical sketch are enclosed below, as supplied by the speaker.

Mitochondria are the major source of ATP that is synthesized by the respiratory chain through the process of oxidative phosphorylation (OXPHOS), a complex biochemical process carried out through the dual control of physically separated, but functionally interrelated, genomes, nuclear and mitochondrial DNAs. The genetic and biochemical intricacy of mitochondrial bioenergetics explains the extreme heterogeneity of mitochondrial disorders, a group of highly invalidating human conditions, for which no effective treatment is nowadays available. In addition to bioenergetic failure, other mechanisms are probably predominant in the pathogenesis of specific syndromes, such as alterations of cellular redox status, the production of reactive oxygen species, compromised Ca2+ homeostasis, mitochondrial protein and organelle quality control, and mitochondrial pathways of apoptosis. By investigating selected families and patients, we have identified several new disease genes, each responsible of distinct defects in the respiratory chain, mtDNA metabolism, or both, associated with paediatric or adult-onset clinical presentations. I will focus this lecture on an expanding group of disorders characterized by mtDNA instability, either sporadically occurring in critical tissues (e.g. muscle and brain) or caused by mutations in a number of different nucleus encoded genes that directly control mtDNA maintenance and replication, or are involved in the mitochondrial quality control system.

Massimo Zeviani graduated cum laude in Medicine at the University of Padua. He specialised in Endocrinology and Neurology, and obtained a PhD in Genetics at the University René Descartes in Paris. In 1984, he moved to Columbia University, New York, where he worked as a post-doc for five years with Billi Di Mauro on the biochemical and molecular definition of respiratory chain disorders.  In 1990, he became Assistant and then Associate in Neurology at the Department of Biochemistry and Genetics of the Istituto Neurologico “C. Besta” in Milan where he organized a laboratory of molecular biology on mitochondrial disorders. In 2001 he became the director of the Unit of Molecular Neurogenetics and, in 2011 he became the director of the Department of Molecular Medicine of the same Institute. In January 2013, he was appointed Director of the MRC Mitochondrial Biology Unit in Cambridge, UK.  In June 2013, he was awarded the Grand Prix of the NRJ Foundation, Paris, for “Genetics of degenerative diseases”.  Author of ≈300 scientific publications in peer-reviewed journals (H index 70), he has identified and characterized numerous disease genes associated with OXPHOS defects, contributing to the elucidation of the molecular pathogenesis of mitochondrial disorders. More recently he focused on the development of therapeutic approaches to treat these conditions in experimental models and, eventually, patients.


Iron-Sulphur Cluster Biogenesis

2nd May 2016.  
Salvatore Adinolfi, King's College London

On Monday the 2nd of May 2016, Salvatore Adinolfi, a Senior Lecturer and Group Leader at the Maurice Wohl institute for Neuroscience of King’s College London will give a seminar entitled Fe-S cluster biogenesis. A complex issue in the Unit of Immunology and General Pathology on the ground floor of the Golgi/Spallanzani Building (9, via Ferrata). The poster of the seminar can be downloaded here. All interested participants are welcome.

Abstract. Friedreich’s ataxia is the most common inherited recessive ataxia. It is associated with reduced levels of frataxin, a small mitochondrial protein of still unclear function. Independent reports have linked frataxin to iron-sulphur cluster assembly through interactions with the two central components of this machinery, the desulphurase Nfs1/IscS and the scaffold protein Isu/IscU. We have characterized the interaction of CyaY (the bacterial orthologue of frataxin) with the IscS/IscU complex and studied the effect on the enzymatic kinetics of cluster formation on the scaffold protein IscU. A single molecule of CyaY binds IscS in a pocket between the active site and the IscS dimer interface through electrostatic interactions of complementary charged residues. Cyay binding leads to a regulation of the desulfurase activity of IscS. We propose that frataxins act as sensors in the regulation of iron-sulfur cluster formation to fine-tune the quantity of cluster formed to the concentration of the available acceptors.

Biography.  S Adinolfi graduated at the “Federico II” University in Naples where he started his career with the Centro Nazionale Ricerche (CNR). Subsequently he won a Postdoc fellowship to learn molecular biology techniques at the EMBL in Heidelberg and then moved to UK with a position at the National Institute for Medical Research in London where he was involved meanly in investigating the molecular mechanism underlying genetic diseases. Recently has been granted an independent position at the King’s College London at the Maurice Wohl institute for Neuroscience.

Reference. Adinolfi S et al. Bacterial frataxin CyaY is the gatekeeper of iron-sulfur cluster formation catalyzed by IscS. Nat Struct Mol Biol 16:390-6 (2009) doi:10.1038/nsmb.1579.

Image courtesy of The image shows the major proteins of the bacterial Isc operon involved in iron-sulphur biogenesis. A similar system builds iron-sulfur clusters in the mitochondria of eukaryotic cells.


Medical Training in the United Kingdom

15th October 2015.  
Wendy Reid, Health Education England

Wendy Reid, Director of Health Education England will give a seminar at 6.00 pm on October 15th on Working and Training as a Doctor in the United Kingdom (UK). The poster of the seminar can be downloaded here. 

The aging of the population and an increase in the resources available to the National Health Service has meart that the UK has recently attracted a significant number of young medical graduates.  In her talk W Reid will explain the procedures for admissiont of foreign medical graduates to UK hospital for training and work. All interested medical students are invited to participate.

Image: Hammersmith Hospital in London, the site of a distinguished postgraduate medical school, now part of Imperial College



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