Wellcome/ Cancer Research UK Gurdon Institute Prospectus 2020/2021

The Wellcome/ Cancer Research UK Gurdon Institute

Prospectus 2020/2021

Studying development to understand disease

25 YEARS

The Wellcome/ Cancer Research UK Gurdon Institute

Prospectus 2020/2021 E

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Contents Director’s welcome

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Emma Rawlins

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About the Institute

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Daniel St Johnston

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COVID stories

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Ben Simons

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Highlights in 2019/2020

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Azim Surani

44

Iva Tchasovnikarova

46

Fengzhu Xiong

48

Philip Zegerman

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Focus on research Group leaders Julie Ahringer

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Andrea Brand

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David Fernandez-Antoran

24

Martin Howard

52

Jenny Gallop

26

John Perry

54

John Gurdon

28

Facilities 56

Steve Jackson

30

Support staff

Tony Kouzarides

32

Hansong Ma

34

Eric Miska

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Associate group leaders

Seminars, events and publications in 2019/2020

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Acknowledgements 77

The Gurdon Institute

Welcome Welcome to our new Prospectus, where we highlight our activities for - unusually - two years: 2019 and 2020. The COVID-19 pandemic has made it an extraordinary time for everyone. I want to express my pride and gratitude for the exceptional efforts of Institute members, who have kept our building safe and our research progressing; this applies especially to our core team, whose dedication has been key to our continued progress. As you will see, there is much to be excited about in our research and activities.

Watermark, the first such award in the University. Special thanks for this achievement go to Hélène Doerflinger, Phil Zegerman and Emma Rawlins.

It was terrific to see Gurdon members receive recognition for their achievements. Steve Jackson received the Leopold Griffuel Award in Translational and Clinical Research, and the Royal Society Mullard Award. Hansong Ma was awarded a Philip Leverhulme Prize and selected as an EMBO Young Investigator, I received the Genetics Society of America's George W. Beadle Award, and Office Manager Lynda Lockey was named the Unsung Heroine of Professional Services. We are also excited that a major component of the Wellcome-funded Human Developmental Biology Initiative is based in the Institute, led by Emma Rawlins, Ben Simons and Azim Surani.

I'm delighted that Emma Rawlins was promoted to Senior Group Leader and that two new Group Leaders joined us in Autumn 2020. Iva Tchasovnikarova studies epigenetic pathway mechanisms and how they are disrupted in disease, while David FernandezAntoran's research is focused on cell competition and the impact of ionising radiation on selection.

I'm especially proud that our exceptional Public Engagement was recognised by a Silver Engage

After incubating Steve Jackson's company Adrestia in the Institute for two years, we wished them well as they moved to the Babraham Research Campus. We also sent our best wishes to Meri Huch and Rick Livesey and their labs, as they embarked on their new positions in Dresden and London, respectively.

Finally, I'm pleased to welcome two new Associate Group Leaders. John Perry (MRC Epidemiology Unit) uses human genetics to understand disease mechanisms, and Martin Howard (John Innes Centre) builds mathematical models of biological processes. We look forward to exciting and productive interactions with them.

Director February 2021

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About the Institute

About the Institute The Wellcome/ Cancer Research UK Gurdon Institute is a world-leading centre for research at the interface between developmental biology and cancer biology.

Our research is focussed in four overlapping areas:

our focus

Cell division, Function and regulation proliferation and of the genome and genome maintenance epigenome

We investigate these areas in both normal development and cancer using multiple model systems, from yeast to human organoids (pp.

20–50).

Since our formation in 1991, our research has led to major insights into the molecular and cellular defects that give rise to cancer and other diseases of ageing, and

Mechanisms of cell fate determination, multipotency and plasticity

findings have been successfully translated to drug discovery through spinout companies.

The Gurdon Institute’s principal sponsors are Wellcome and Cancer Research UK, who support our excellent infrastructure through core grants, and our research through direct grants to group leaders. Our research is also funded by other

Cell biological processes underlying organ development and function

sources including national and international governmental and charitable grants. Scientific progress and future plans are assessed at regular intervals by our International Scientific Advisory Board (p. 77) .

The Institute is embedded within the University of Cambridge, providing unparalleled opportunities for collaborations

and interactions across Cambridge’s vibrant research environment, including through department affiliations and teaching.

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We benefit from:

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Award-winning public engagement between our scientists and the wider public (pp. 16–17).

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An on-site canteen, social events and sports groups, which enhance our welcoming and inclusive environment.

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An Athena SWAN Bronze Award for promoting equality and diversity across our workforce.

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Core facilities with state-ofthe-art equipment and support including super-resolution microscopy, next-generation sequencing and bioinformatics (pp. 56–57) Central services providing administration, computing and IT, stores, media preparation and glass-washing.

A wealth of stimulating seminars and masterclasses, an annual Institute retreat, and Institute postdoc and PhD student groups (pp. 62–65)

Join us We have a thriving community of graduate students and postdocs who contribute to and benefit from our exciting research environment.

We welcome enquiries from those interested in joining us, which can be done by writing to the relevant group leader.

Find out about the latest opportunities on our website.

6

COVID stories

COVID stories What did we do during the coronavirus pandemic in 2020?

Along with institutions and businesses across England, the Institute shut its doors at 5pm on 20th March for Lockdown 1.0. Only minimal maintenance and technical staff remained, regularly checking the building and the fly stocks, while researchers could no longer access their benches and had to call a sudden halt to hundreds of experiments. Administrative staff took computers and files home.

Some of our scientists re-focussed their research Omer Ziv with Miska lab colleagues and collaborators at Justus Liebig University worked to produce a map and database of the short and long-range interactions of the SARS-CoV-2 RNA genome (details in ‘Research highlights 2020’). Ben Simons was involved in epidemiological modelling.

paediatrician at Addenbrooke’s Hospital from March to September.

It was actually quite nice to have something to do during that first lockdown, although being coughed on by feverish children all day wasn’t ideal!”

And that’s how it remained until 15th June when we re-opened at one quarter occupancy, slowly moving up to 50% occupancy by September. Many different staff, and especially researchers, were delighted to return once more to the building. Lockdown 2.0 in November sent some more staff back home again.

The core staff have done an incredible job to keep as much of the Institute open and functioning as possible (and legal) at all times, in terms of maintenance and safety in the building, supplying media, and enabling computing services for remote working. Meanwhile, other Institute members have contributed directly to fighting the pandemic:

Others intermitted from research and returned to the clinic: Ben Fisher (Miska lab) says “I returned to full-time clinical work as a

Five researchers worked shifts as volunteers at the Cambridge Testing Centre that ran seven days a week from 6am to midnight to support the national effort to boost COVID-19 testing capacity.

The Gurdon Institute

The roles taken by Weronika Fic, Dmitry Nashchekin, Helen Zenner and Mihoko Tame (St Johnston lab) and Paolo Amaral (Kouzarides lab) were in sample preparation, RT-PCR tests and data analysis, the full team eventually processing over 8000 nasopharyngeal swab samples daily.

Paolo recalls: “Volunteering at the centre felt like a call of duty. As the number of samples to be processed

quickly increased, with home tests arriving from all over the country, we were pushed to the limit and at one point caused a bottleneck of the whole pipeline. The solidarity and sense of responsibility of everyone in the team meant that we would ensure all the samples were processed each day, and we know we played an important part in helping contain the first COVID-19 wave.”

Core staff made Personal Protective Equipment: Alex Sossick and Charles Bradshaw of the Imaging and Bioinformatics teams each took home a 3D printer.

The machines were set up to run 24-hours a day, making in total 500 visor headbands, which were distributed locally to key workers in GP surgeries, hospitals and care homes. “The Institute had given a lot of our own PPE, especially visors, to Addenbrookes,” says Alex.

“Then, of course, there was the wider shortage across the country, so Charles and I looked at what we could do.”

Once our building opened again on 15th June under University guidance, the two set up a no-touch log-in log-out system allowing the Institute to track numbers of people on site in real time, ensuring we stuck to the strict rules on numbers in different lab spaces.

Family members sewed face coverings: The mother of a staff member sent about 600 of her hand-sewn, eco-friendly and washable face coverings all the way from her village in Italy, enough for everyone to have two each.

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About the Institute

The Gurdon Institute

Highlights in 2019/2020

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10 Awards

Awards Feb '19: Steve Jackson receives cancer research prize

The 47th ARC Foundation Léopold Griffuel Award in Translational and Clinical Research was presented to Steve Jackson at a ceremony in Paris on 10th April. The award was given "for his work on DNA damage repair and his role in the development of medicines such as PARP1 and 2 inhibitors used [for] cancer treatment."

May '19: Pisa Honorary Doctorate for John Gurdon

John Gurdon received a Doctorate Honoris Causa in Translational Medicine from the Scuola Superiore Sant’Anna of Pisa. He gave a lecture there and at Bologna University.

While in Bologna he was interviewed by national newspaper 'Il Resto del Carlino'.

Jul '19: Gurdon researchers in Wellcome’s new £10M project on human development

The Human Developmental Biology Initiative aims to provide insights into how humans develop – from one cell to billions of different cells that make up our tissues and organs.

Three of the Institute’s labs are among more than a dozen across the UK working together to generate data, develop new tools and build a ‘family tree’ of cell divisions during development, starting at fertilisation. Azim Surani is a co-lead for ‘cell lineage in human epiblast specification and early differentiation’; Emma Rawlins is a co-lead for ‘human lineage analysis in a 3D spatial context: cardiopulmonary system development’; and Ben Simons is a lead for one of three cross-cutting technology platforms – computational biology and data analysis.

Sep '19: Meri Huch wins BINDER Innovation Prize

The 2019 BINDER Innovation Prize was awarded to Group Leader Meri Huch for her research on liver organoids for the study of liver biology and disease. The award is given for "outstanding cell biological research with a focus on cell culture," and awarded by the German Society for Cell Biology.

Nov '19: Steve Jackson awarded ERC Synergy Grant Recipients of the ERC Synergy Grants were announced in

November and Steve Jackson is among them, awarded funding for a project on the DNA damage response in collaboration with partners in Switzerland and Austria.

This was the first of the new Horizon 2020 grants to come to Cambridge.

Dec '19: Song for the Unsung Heroine The Institute's Office Manager, Lynda Lockey, won the Unsung Heroine Award in the University of Cambridge Professional Services Recognition Scheme.

Institute Director Julie Ahringer said "Lynda is a very deserving recipient of the award...Her dedicated and understated work makes things run smoothly, and positively impacts everyone".

Jan ‘20: Ahringer honoured by Genetics Society of America Julie Ahringer was honoured with the Genetics Society of America's George W. Beadle Award "for outstanding contributions to the community of genetics researchers...beyond an exemplary research career".

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Aug ‘20: Award for research contributing to national prosperity

The Royal Society Mullard Award 2020 was awarded to Steve Jackson for his research that led to the discovery of the drug olaparib, which has reached blockbuster status for the treatment of ovarian and breast cancers.

Oct ‘20: Philip Leverhulme Prize for Ma Hansong Ma was awarded a prestigious Philip Leverhulme

Prize 2020 by the Leverhulme Trust. The prizes of £100,000 "recognise the achievement of outstanding researchers whose work has already attracted international recognition and whose future career is exceptionally promising".

Dec ‘20: Ma selected as EMBO Young Investigator Hansong Ma was selected as one of 30 new EMBO Young Investigators, judged to be "among the next generation of leading life scientists".

The awardees join a four-year programme that provides financial support, training and networking opportunities.

Dec ’20: Aztekin wins ELISIR scholarship at EPFL PhD student in the Gurdon lab, Can Aztekin, moves directly to an independent principal researcher position at the Swiss Federal Institute of Technology in Lausanne (EPFL), as an EPFL Life Sciences Independent Research (ELISIR) scholar.

12 Research highlights

Research in 2019

Fly gene provides clue to reversing mitochondrial disease The Ma lab have identified a protein in fruit flies (Drosophila) that can be targeted to reverse the effects of disease-causing mutations in mitochondrial genes.

The discovery could provide clues about how to counteract human mitochondrial diseases, for which there is currently no cure.

Chiang A C-Y et al. (2019) Current Biology 29: 1–7.

Alternative DNA repair pathway for MDC1 Salguero and colleagues in the Jackson lab have found an alternative pathway to elicit the DNA-damage response that

does not depend on the protein H2AX. They show that MDC1, which was previously believed to work only when interacting with phosphorylated H2AX, in fact retains its capacity to recruit repair factors to the site of DNA damage even when H2AX is absent. This may enable DNA repair in areas of the genome known to be depleted of H2AX. Salguero I et al. (2019) Nature Communications 10: 5191.

Don't get your DNA in twist The Zegerman lab’s new publication shows that limiting the rate of DNA duplication - by limiting the number of DNA replication initiation events - is important to prevent intertwining between the newly replicated chromosomes. This work may be relevant for the treatment of cancer cells, which are characterised by high rates of DNA duplication.

Morafraile EC et al. (2019) Genes & Development 33: 21–22.

New DNA stability genes uncovered in systematic study of Yeast Knockout Collection The Jackson lab applied next-

generation DNA sequencing to over 4500 yeast strains in the Gene Knockout Collection. The resulting comprehensive resource identifies new genes responsible for maintaining the stability of DNA in cells, and whose absence or mutation leads to a variety of effects, from changes in short sequence repeats to the loss of whole chromosomes. These 'mutational signatures' can now also be studied in human cells.

Puddu F et al. (2019) Nature 573: 416–420.

How to boost adult liver regeneration A paper from the Huch lab - with collaborators in the Gurdon Institute, UK and Germany - describes the molecular mechanism triggered by TET1 that allows damaged adult liver cells to regenerate. This paves the way for design of drugs to boost regeneration in conditions such as cirrhosis or other chronic

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liver diseases where regeneration is impaired.

Aloia L et al. (2019) Nature Cell Biology 21: 1321–1333.

an 'epitranscriptomic' pathway with effects on lung cancer cell behaviour in vitro. They developed a technique to precisely locate which guanosine on a micro RNA called let-7 was modified with a methyl group, regulating its processing and downstream action to suppress cell migration.

Pandolfini L, Barbieri I et al. (2019) Molecular Cell 74: P1278–1290.E9.

nucleocytoplasmic transport, uncovering new links between different forms of dementia.

Paonessa F et al. (2019) Cell Reports 26: P582–593.E5.

RNA uptake to the feeding glands

Jelly secretion with RNA Jelly with RNA

Brain location determines stem cell activation speed

New cell type in tail regeneration Researchers in the Gurdon and Simons labs working under Jerome Jullien identified a new cell type involved in regeneration of tadpole tails. They've named the Regeneration-Organizing Cells for their role in promoting and coordinating new tissue growth after amputation, and hope to find clues in these cells to inform new approaches to regeneration in mammals.

Aztekin C et al. (2019) Science 364: 653–658.

RNA modification pathway affects cancer cell migration Researchers in the Kouzarides lab and colleagues have characterised

Otsuki and Brand revealed that stem cells activate rapidly or slowly depending on where they reside in the brain. G2 quiescent stem cells, which activate first and have high regenerative potential, reside primarily in fruit fly ventral brain regions. G0 quiescent stem cells are more numerous in the dorsal brain.

This is an important consideration in designing regenerative therapies.

Otsuki L & Brand AH (2019) Developmental Cell 49: 1–8.

Nuclear membrane dysfunction underlying dementia The Livesey and Jackson groups pooled expertise, studying patientderived neurons in the lab to investigate how mutations in the tau gene cause frontotemporal dementia (FTD). They found that, in FTD neurons, microtubules deform the nuclear membrane and perturb

systemic RNA spread

RNA ingestion

RNA uptake to the hemolymph

Transmissible RNA pathway in honey bees The Miska lab's Eyal Maori along with colleagues in UK, Israel and the USA have discovered a pathway by which honey bees share RNA through secretion and ingestion of worker and royal jellies, offering a promising route for administering bee 'vaccines'. In addition, the researchers identified a specific protein in royal jelly that binds and protects the RNA in granules while outside the body.

Maori E et al. (2019) Molecular Cell 74: P598–608.E6.

14 Research highlights

Research in 2020 transcription factor Ascl1, which is a determinant for nerve, resides on chromatin to direct gene expression. While previous studies suggest that residency times are only seconds or minutes, this experiment showed a long-term association of hours or days, which could explain the stability of cell fate commitment.

Gurdon JB et al. (2020) Proc Natl Acad Sci 117 (26): 15075-15084.

How inflammation affects regeneration Why can regeneration-incompetent tadpoles not regenerate their tails? The Gurdon lab show that immune cells behave differently for regeneration-competent and -incompetent tadpoles. Successful suppression of inflammation is required for the multiple cellular mechanisms necessary for new tail growth.

Aztekin C et al. (2020) Development 147: dev.185496.

Is TF residency time the key to cell fate commitment?

The Gurdon lab used a competition assay to test how long the

Pancreas organoids to model disease Pancreas organoids can be successfully generated from single cells, or fresh and frozen tissue, then expanded and maintained long-term in culture, say the Huch

and Simons labs. These organoids grown in chemically defined culture medium provide an important model for research into the healthy and diseased pancreas, including conditions such as cystic fibrosis, pancreatitis, cancer and diabetes.

Georgakopoulos N et al. (2020) BMC Developmental Biology 20: 4.

Tailless/TLX directs cell fate change in tumourigenesis Hakes and Brand uncover the cell fate changes that occur during brain tumour initiation. They show that high levels of Tailless/ TLX, known to be associated with aggressive glioblastomas, revert intermediate progenitors to neural stem cells as a first step to tumourigenesis. Their findings also support enforced differentiation as an effective treatment for Tailless/ TLX-induced brain tumours.

Hakes AE & Brand AH. (2020) Elife 9: e53377.

How does stretching skin make it grow?

By tracing the dynamics of cells during stretch-mediated expansion of the mouse skin epidermis,

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collaborative studies by the Simons lab have shown - at single-cell resolution - how stem cells react to regenerate tissue and restore homeostasis. Stretching induces skin expansion by creating a transient bias in the renewal activity of epidermal stem cells, while a second subpopulation of basal progenitors remains committed to differentiation.

Aragona M et al. (2020) Nature 584: 268–273.

Cancer drug hope for genetic disease Berquez, Gadsby, Festa and Gallop lab colleagues discovered that adjusting membrane composition with the PI3K inhibitor alpelisib rebalances actin cytoskeletal organisation in cell culture and alleviates absorption defects in an in vivo mouse model of Lowe syndrome/Dent disease. Their findings provide proof-of-concept for the first disease-modifying treatment.

Berquez M et al. (2020) Kidney International 98 (4): 883-896.

Sperm populations show homogeneous epigenetic marks Gurdon lab and colleagues, led by Jerome Jullien, examined histones in sperm to uncover a conserved mechanism for transmission of epigenetic information to the embryo. As sperm develop they lose a large proportion of the histones found in somatic cells, but the remainder are retained in the same position across the sperm population, indicating the potential to prime transcription for embryonic development.

Oikawa M et al. (2020) Nat Comms 11: 349.

Embryo polarisation link to cell cycle The Zegerman lab, with Gurdon Institute colleagues, provided the first direct molecular mechanism through which polarisation of the embryo is coordinated with DNA replication initiation factors, linking developmental cues with changes in the cell cycle, in the nematode C. elegans.

Gaggioli V et al. (2020) PLoS Genetics 16 (12): e1008948.

Long-range interactions in SARSCoV-2 RNA Omer Ziv from the Miska lab, in collaboration with Justus-Liebig University colleagues, has revealed precise details of the base-pairing patterns formed by the long RNA genome of the SARS-CoV-2 virus, responsible for the COVID-19 pandemic. Ziv devised the method that takes a snapshot of both shortand long-range interactions in the RNA, which are essential for viral function and therefore present potential therapeutic targets.

Ziv O et al. (2020) Molecular Cell 80 (6): 1067-1077.E5

Gene regulatory architectures in germline and somatic tissues Jacques Serizay and Ahringer lab colleagues profiled and compared transcriptional and regulatory element activities across five tissues of the adult nematode worm, C. elegans. The results demonstrate fundamental differences in regulatory architectures of germline and somatic tissue-specific genes, and provide a tissue-specific resource for future studies.

Serizay J et al. (2020) Genome Res 30: 1752–1765.

16 Public engagement

Public engagement Mission: to make our fundamental biological research accessible and responsive to the public for the mutual benefits of inspiration, knowledge-exchange and trust.

Generate increased trust in fundamental research and ensure our research remains relevant to society

Public Public engagement Engagement strategy strategy

Embed public engagement in research culture

Our projects in 2019 to support the public engagement strategy included: Scientists' Collaborative Project with Educators (SCoPE) We aim to bring contemporary research into GCSE and A-level

classrooms with support for teachers and students to deepen their knowledge of fundamental biology and current research. Teachers and our scientists co-created four innovative teaching 'toolkits', free to use in classrooms across the UK: The Cell Explorer (online interactive 3D cell model), Explore Epigenetics (an online game about epigenetics), a kit for Fruit Fly Larvae Dissection Empower and inspire (teaching the next about the generation size and scale of cells, tissues and organs) and Unlocking Genetic Editing (a hands-on problemsolving game). The project was funded by Wellcome and evaluated by the University of Cambridge Faculty of Education. SCoPE website: https://scopegurdoninstitute.co.uk Tattoo My Science Our scientists created designs based on their biology research, and we turned these into fun,

temporary tattoos. Visitors to festivals and events could choose a tattoo from our collection of designs and then have a chance to discuss the research with the scientist applying their tattoo.

Afterwards, they could show off their new tattoo to friends and share their new science knowledge.

Thank you to the Wellcome Centre for Cell Biology in Edinburgh for sharing their idea!

Aspiring Scientists Training Programme Providing an inspiring, immersive experience to encourage groups that are underrepresented in science, we welcomed 11 Sixthform students for a week at the Institute. Students attended morning workshops about scientific topics or presentation skills. Then they spent the rest of the day in a lab to talk with lab members about their research and science careers.

The project was funded by the University of Cambridge Widening Participation Project. The Gurdon

Institute provided accommodation, travel expenses and food to all participants. Students told us "It gave me an experience hard to find elsewhere" and "I learned that I can become a scientist."

Stitching Science The Public Engagement Seed Fund Project for 2019 was devised and led by Stephanie Norwood, a former PhD student. The project aims to create an informal environment for scientists to interact with local communities and learn a new craft, disseminate information about research projects, and increase public trust in fundamental research. The project engaged crafters through a series of knitting workshops, craft fairs and other events. Participants create a detailed crochet cell containing various organelles (mitochondria, cytoplasm and membrane) and discuss the different parts of the cell with scientists as they knit. Website: https://bitly.com/StitchingSci

Sixth-form workshops Our Sixth-form workshops aim to inspire A-level biology students.

State schools from across the country can bring groups of Year 12 biology students to the Institute to learn about our research. The visit includes a tour of our facilities, a seminar about the history of science and the future of cancer research, a hands-on workshop where students can test their skills at identifying cancerous tissue with microscopes, and a Q&A with our PhD students.

Silver Engage Watermark The Gurdon Institute was awarded a Silver Engage Watermark in December 2020, the first such award at the University of Cambridge. The Silver Engage Watermark, awarded by the National Co-ordinating Centre for Public Engagement, recognises the Institute's “robust and committed approach to public engagement”.

18 Activities and impacts in 2019

The Gurdon Institute 19

Focus on research

20 Group leaders

JULIE AHRINGER Developmental regulation of chromatin structure and function How is chromatin regulated to direct correct gene expression programmes? Animal development is a remarkable process during which a single-celled totipotent zygote produces a myriad of different cell types. A driving force is the differential control of chromatin activity, which establishes gene expression programmes that drive cellular identity. Deciphering this control is necessary for understanding how the genome directs development and the diseases that result from chromatin dysregulation.

We study how cell-type specific gene expression and chromatin organisation are achieved using the simple C. elegans model, focusing on controls and interactions at regulatory elements, the formation and function of euchromatin and heterochromatin, and the regulation of 3D nuclear organization. Taking advantage of the experimental amenability and defined lineage of C. elegans, we apply high-throughput genomics, super-resolution microscopy, single-cell analyses, and computational approaches to understand core mechanisms of gene expression regulation in development.

Selected publications:

Co-workers: Alex Appert, Francesco Carelli, Marie de la Burgade, Yan Dong, Martin Fabry, Andrea Frapporti, Rhys McDonough, Arianna Pezzuolo, Roopali Pradhan, Anna Townley, Ser van der Burght, Connie Xiao

Serizay J et al. (2020) Tissue-specific profiling reveals distinctive regulatory architectures at ubiquitious, germline and somatic genes. BioRxiv DOI: 10.1101/2020.02.20.958579v1.

Janes J et al. (2018) Chromatin accessibility dynamics across C. elegans development and ageing. Elife 7:e37344.

McMurchy AN et al. (2017) A team of heterochromatin factors collaborates with small RNA pathways to combat repetitive elements and germline stress. Elife 6:e21666.

Evans KJ et al. (2016) Stable C. elegans chromatin domains separate broadly expressed and developmentally regulated genes. Proc Natl Acad Sci USA 113(45): E7020–7029.

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H3K9me2 2-cell

6-cell

32-cell

200-cell

DAPI

Heterochromatin in early development in C. elegans Embryonic nuclei imaged using STED super-resolution microscopy reveals that H3K9me2 is found in distinct foci.

22 Group leaders

ANDREA BRAND Time to wake up: regulation of stem cell quiescence and proliferation Stem cell populations in tissues as varied as blood, gut and brain spend much of their time in a mitotically dormant, quiescent, state.

A key point of regulation is the decision between quiescence and proliferation. The ability to reactivate neural stem cells in situ raises the prospect of potential future therapies for brain repair after damage or neurodegenerative disease. Understanding the molecular basis for stem cell reactivation is an essential first step in this quest.

In Drosophila, quiescent neural stem cells are easily identifiable and amenable to genetic manipulation, making them a powerful model with which to study the transition between quiescence and proliferation.

These stem cells exit quiescence in response to a nutrition-dependent signal from the fat body, a tissue that plays a key role in the regulation of metabolism and growth. My lab combines cutting-edge genetic and molecular approaches with advanced imaging techniques to study the reactivation of Drosophila neural stem cells in vivo. This enables us to deduce the sequence of events from the level of the organism, to the tissue, the cell, and finally the genome.

Selected publications:

Co-workers: Neha Agrawal, Diana Arman, Maire Brace, Catherine Davidson, Bernardo Delarue Bizzini, Alex Donovan, Amy Foreman, Thomas Genais, Leia Judge, Oriol Llorà Batlle, Anna Malkowska, Tara Srinivas, Jocelyn Tang, Christine Turner, Marloes van Wezel, Rebecca Yakob, Nemira Zilinskaite

Hakes AE & Brand AH (2020) Tailless/TLX reverts intermediate neural progenitors to stem cells driving tumourigenesis via repression of asense/ ASCL1. Elife 9:e53377.

Otsuki L& Brand AH (2019) Dorsal-ventral differences in neural stem cell quiescence are induced by p57KIP2/Dacapo. Dev Cell 49(2): 293-300.e3.

Otsuki L & Brand AH (2018) Cell cycle heterogeneity directs the timing of neural stem cell activation from quiescence. Science 360: 99–102.

Cheetham SW & Brand AH (2018) RNA-DamID reveals cell-type-specific binding of roX RNAs at chromatin-entry sites. Nat Struct Mol Biol 25:109–114.

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The developing visual system The Drosophila central brain (red and blue) and eye imaginal disc (green and red) with dividing cells labelled in white (van den Ameele and Brand).

24 Group leaders

DAVID FERNANDEZ-ANTORAN Radiation biology and cell competition How does ionising radiation affect tissue homeostasis? Healthy adult epithelial tissues progressively accumulate clones of cells carrying mutations implicated in cancer. Expansion of the clones follows Darwinian evolution rules, where some mutations can increase cell fitness and promote the growth of clones at the expense of the nonmutated normal adjacent cells, in a process of clonal competition.

Ionising radiation has long been studied as one of the most common environmental mutagenic agents that promotes tumour formation by damaging DNA and creating new oncogenic mutations. However, little is known about its effects on clonal evolution and tissue dynamics. We have recently shown that radiation can act as an environmental selective pressure, affecting cell competition mechanisms and promoting expansion of pre-existing oncogenic mutations, which might increase the risk of cancer development.

We use long-term human and mouse 3D primary epithelial cultures, in vivo cell lineage tracing, mathematical modelling, next generation sequencing methods and state-of-the-art confocal microscopy techniques to unravel the molecular responses and the cellular interactions that control normal and mutant cell behaviours after exposure to ionising radiation.

Our final aim is to set the basis for designing external interventions that can modulate cell competition outcomes during radiation exposure, eliminate oncogenic mutations and reduce the risk of cancer initiation and progression.

Co-workers: Inês Ferreira, Jose Antonio Valverde-Lopez

Selected publications: Fowler JC et al. (2020) Selection of oncogenic mutant clones in normal human skin varies with body site. Cancer Discov DOI: 10.1158/2159-8290.CD-20-1092.

Piedrafita G et al. (2020) A single-progenitor model as the unifying paradigm of epidermal and esophageal epithelial maintenance in mice. Nat Comms 11: 1429.

Fernandez-Antoran D et al. (2019) Outcompeting p53-mutant cells in the normal esophagus by redox manipulation. Cell Stem Cell, 25: 329–341.e6.

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The fight for space during ionising radiation exposure This rendered image shows an irradiated mouse oesophageal epithelium populated by fitter oncogenic mutant clones (green) that are expanding at the expense of non-mutated normal adjacent cells. Proliferation markers are shown in white and red; cell nuclei in blue.

26 Group leaders

JENNY GALLOP Signalling to the actin cytoskeleton How do cells control their movement? Cells move during embryonic development and throughout the life of an organism. When they move, cells reorganise a system of filaments - the actin cytoskeleton - that gives them their shape and exerts force on the surrounding tissues. When regulation of the actin cytoskeleton is disrupted it can lead to cancer metastasis, intellectual disability, kidney dysfunction and other problems.

We study how the actin cytoskeleton is assembled in different ways. The cell membrane is an important site of control of actin rearrangements because it is the boundary between the outside and inside of the cell and is responsible for initiating communication between and within cells, which is called signalling.

We have developed cell-free systems using phospholipid bilayers and frog egg extracts that allow us to find out how signalling lipids in the cell membrane precisely control the molecular events of actin assembly.

We use combine these cell-free systems with the use of fruit flies, frog embryos and cultured human cells to test and generate hypotheses about the molecular events underlying actin regulation during development and disease.

Selected publications:

Co-workers: Thomas Blake, Jonathan Gadsby, Pantelis Savvas Ioannou, Julia Mason, Kathy Oswald, Kazimir Uzwyshyn-Jones, Pankti Vaishnav

Berquez M et al. (2020) The phosphoinositide 3-kinase inhibitor alpelisib restores actin organization and improves proximal tubule dysfunction in vitro and in a mouse model of Lowe syndrome and Dent disease. Kidney Int. 98: 883–896.

Jarsch IK et al. (2020) A role for SNX9 in the biogenesis of filopodia. J Cell Biol 219(4): e201909178.

Richier B et al. (2018) Integrin signaling downregulates filopodia during muscle-tendon attachment. J Cell Sci 131: jcs21733.

Daste F et al. (2017) Control of actin polymerization via the coincidence of phosphoinositides and high membrane curvature. J Cell Biol 216: 3745–3765.

Watching filopodia grow Three-dimensional reconstruction of filopodia-like structures growing from a supported lipid bilayer. The structures were segmented based on fluorescent actin intensity in a stack of microscopy images of size 76.13 x 76.13 x 30 microns.

Colours were randomly assigned as a guide for the eye. The segmentation was performed using a custom image-analysis pipeline.

28 Group leaders

JOHN GURDON Nuclear reprogramming by oocytes and eggs Can we make cell reprogramming more efficient? Our group focuses on somatic cell nuclear transfer to amphibian eggs and oocytes from two complementary points of view. One aims to identify the molecules and mechanisms by which the cytoplasm of an egg or oocyte can reprogramme the nucleus of a differentiating somatic cell to behave like that of an embryo. From this state, many different kinds of cells for replacement can be generated.

The other aim is to identify the molecules and mechanisms that stabilise the differentiated state of somatic cells, as a result of which they resist reprogramming procedures. For these purposes we use single nuclear transfer to unfertilised eggs or multiple nuclear transfer to ovarian oocytes.

We make use of the special properties of an amphibian oocyte to inject messenger RNA that codes for a transcription factor protein. When this has been synthesised, it concentrates in the oocyte nucleus. The next day we inject plasmid DNA directly into the oocyte nucleus, where the factor causes transcription, and later expression, of a reporter gene in the plasmid.

Selected publications:

Co-workers: Hector Barbosa Triana, Dilly Bradford, Frances Connor, Nigel Garrett, Khayam Javed, Toshiaki Shigeoka, Ming-Hsuan Wen

Gurdon JB et al. (2020) Long-term association of a transcription factor with its chromatin binding site can stabilize gene expression and cell fate commitment. Proc Natl Acad Sci USA 117: 15075–15084.

Aztekin C et al. (2019) Identification of a regeneration-organizing cell in the Xenopus tail. Science 364: 653–658.

Hörmanseder E et al. (2017) H3K4 methylation-dependent memory of somatic cell identify inhibits reprogramming and development of nuclear transfer embryos. Cell Stem Cell 21: 135–143.e6.

The Gurdon Institute 29

Somatic cell nuclear transfer in Amphibia Nucleus of differentiated cell Transplanted nucleus and egg cytoplasm generate wide range of different cell types

1 year

2 days

unfertilised and enucleated egg

tadpole

frog

Nuclei of differentiated cells 1 day

Transplanted nuclei have changed donor gene expression

1 day

oocyte and its nucleus

injected nuclei enlarge

Design of competition experiments to analyse transcription factor action using Xenopus oocytes

24 hrs

mRNA for Ascl1

Plasmid DNA with an Ascl binding site and a Firefly reporter

1-24 hrs Freeze and assay for reporter expression

24 hrs

Plasmid DNA as competitor with an Ascl binding site and a Renilla reporter

Molecules and mechanisms Top: Two types of nuclear transfer experiments, with eggs or oocytes.

Bottom: The Xenopus oocyte can be used to provide a functional test for the binding of a cell-fatedetermining transcription factor, such as Ascl1 for nerve. Once expression of the first plasmid DNA is established, a second plasmid is not able to compete because of the stable binding of the factor.

30 Group leaders

STEVE JACKSON Maintenance of genome stability DNA is constantly damaged by environmental and endogenously arising agents. Cell survival and genome integrity are promoted by the DNA-damage response (DDR), which detects, signals the presence of and repairs DNA damage. DDR defects are associated with developmental disorders, immunodeficiencies, infertility, premature ageing and cancer. Our research aims to characterise the cell biology and mechanisms of established and new DDR pathways and components, and to apply this knowledge to better understand and treat human diseases.

We have taken the global approach of cataloguing the >4,500 knockout genes of the diploid yeast knockout collection, using next-generation sequencing to identify those genes that have an impact on genome stability. Analysing this dataset revealed genes affecting repetitive element maintenance, and nuclear and mitochondrial genome stability, and showed how strains adapt to loss of non-essential genes. At the other end of the scale spectrum, we determined what structural features of the DDR factors PALB2 and MDC1 associate with chromatin in ways that are crucial for effective DDR in the absence of BRCA1 and H2AX, respectively.

Selected publications: Co-workers: Samah Awad Diab, Rimma Belotserkovskaya, Ramsay Bowden, Chris Carnie, Julia Coates, Sabrina Collier, Giuseppina D'Alessandro, Muku Demir, Kate Dry, Yaron Galanty, Maryam Ghaderi Najafabadi, Nadia Gueorguieva, Vipul Gupta, Soren Hough, Rebecca Lloyd, Donna Lowe, David Morales, Francisco Muñoz Martinez, Domenic Pilger, Fabio Puddu, Helen Reed, Matylda Sczaniecka-Clift, Almudena Serrano Benitez, George Spooner, John Thomas, Andrea Voigt, Mike Woods, Guido Zagnoli-Vieira

Belotserkovskaya R et al. (2020) PALB2 chromatin recruitment restores homologous recombination in BRCA1-deficient cells depleted of 53BP1.

Nat Commun 11: 819.

Salguero I et al. (2019) MDC1 PST-repeat region promotes histone H2AXindependent chromatin association and DNA damage tolerance. Nat Commun 10: 5191.

Puddu F et al., (2019) Genome architecture and stability in the Saccharomyces cerevisiae knockout collection Nature 537:416-420.

The Gurdon Institute 31

MDC1 has H2AX-independent roles in the DNA damage response 100

Cell survival (%)

MDC1 recruitment of repair factors

H2AX ATM

P

IR

10 WT H2AX KO MDC1 KO H2AX/MDC1 KO

1

0.1 0

H2AX

1

2

3

IR dose (Gy)

4

Unexpectedly, eliminating MDC1 results in more DNA damage sensitivity than eliminating H2AX

After DNA damage, phosphorylated histone H2AX recruits MDC1, allowing the accumulation of additional repair factors

Repair factors, like 53BP1, accumulate at DNA damage sites even in the absence of H2AX, but this requires the PTS-repeat region of MDC1 MDC1 − wt

MDC1 − ∆PST H2AX-free genomic regions ATM

H2AX+/+

PST

recruitment of repair factors

H2AX

-/-

P 53BP1

5

MDC1

32 Group leaders

TONY KOUZARIDES Epigenetic modifications and cancer Do enzymes that modify chromatin and RNA offer therapeutic targets? DNA exists in the cell nucleus wrapped around histone proteins to form chromatin. The DNA and histones are decorated with many types of covalent chemical modifications, which can affect transcription and other cellular processes. In addition, non-coding RNAs that regulate chromatin function can be similarly chemically modified.

Our lab is involved in characterising the pathways that mediate and control DNA, RNA and histone modifications. We try to understand the cellular processes they regulate, their mechanism of action and their involvement in cancer.

Our focus at the moment is modifications of messenger RNA (mRNA) and non-coding RNA. There are very few modifications identified on these low-abundance RNAs, unlike on transfer RNA and ribosomal RNA, where there are many. We have been developing sensitive technologies to detect modifications, such as specific antibodies, chemical reactivity assays and mass spectrometry. Using these, we have been able to detect a number of novel modifications on mRNA and microRNA (short-length non-coding RNAs) and have shown that these function to regulate mRNA translation and microRNA processing. Furthermore, we have shown that the enzymes that mediate these modifications are implicated in cancer. We are developing small-molecule inhibitors against some of these enzymes in collaboration with STORM Therapeutics.

Selected publications: Co-workers: Minaam Abbas, Andrej Alendar, Andrew Bannister, Francisco José Campos Laborie, Alistair Cook, Elena Everatt, Marie Klimontova, Sri Lestari, Nikki Mann, Carlos Melo, Helena Santos Rosa, Konstantinos Tzelepis, Daniel Wing

Barbieri I & Kouzarides T (2020) Role of RNA modifications in cancer. Nat Rev Cancer 20, 303–322.

Pandofini L et al. (2019) METTL1 Promotes let-7 MicroRNA Processing via m7G Methylation. Mol Cell Bio 74(6): 1278-1290.

Barbieri I et al. (2017) Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control. Nature 552: 126–131.

The Gurdon Institute 33

Epigenetic targets for cancer therapy

RNA histone-modifying enzyme

RNA-modifying enzyme

Post-transcriptional control Transcriptional control DNA modification

Co-transcriptional control

The crucial role of modifications Gene expression can be regulated by chemical modifications before and during transcription, including of non-coding RNA.

34 Group leaders

HANSONG MA Mitochondrial DNA transmission and maintenance How mitochondrial genomes are transmitted and maintained. In addition to the nuclear genome, all animals have another genome packed inside the mitochondrion called mtDNA. This maternally inherited genome encodes important proteins for energy production.

During development and ageing, as mtDNA continues to replicate and turnover, mutations can occur to some of the copies. The subsequent prevalence of these mutants, which determines the progression and inheritance of the clinical abnormalities of mitochondrial disorders, depends on how they compete with the co-existing wild-type genomes for transmission. To date, over 50 mtDNA-linked disorders have been described in humans.

We have developed genetic systems in Drosophila to study the rules governing the transmission of mtDNA mutations. By creating fruit flies carrying both functional and pathogenic mitochondrial genomes, we reveal nuclear factors and mtDNA sequence polymorphisms that bias the transmission of one genome over the other. We also study repair mechanisms that safeguard the integrity of mtDNA during development and ageing.

Selected publications:

Co-workers: Ason Chiang, Ivy Di, Beitong Gao, Jan Jezek, Anna Klucnika, Andy Li, Eleanor McCartney, Matthew McCormack, Kathy Oswald, Sumaera Rathore, Ziming Wang

Chiang A et al. (2019) A Genome-wide screen reveals that reducing mitochondrial DNA polymerase can promote elimination of deleterious mitochondrial mutations. Curr Biol 29: 4330-36.

Klucnika A & Ma H (2019) A battle for transmission: the selfish and corporative animal mitochondrial genomes. Open Biol 9: 180267.

Ma H & O’Farrell PH (2016) Selfish drive can trump function when animal mitochondrial genomes compete. Nat Genet 48: 798–802.

The Gurdon Institute 35

wild type mtDNA

mutant mtDNA

maternal inheritance

mtDNA repair

heteroplasmic transmission

The maternally transmitted mitochondrial DNA (mtDNA) is a multi-copy genome that shows complex transmission patterns during developing and aging, and between generations due to relaxed replication, random segregation, and selection that favours the transmission of one genome over another in the pool. In addition to mitochondrial diseases caused by accumulation of a particular mutant, random mtDNA mutations have been shown to increase with age, contributing to mitochondrial dysfunction and various age-related conditions.

36 Group leaders

ERIC MISKA Non-coding RNA and genome dynamics What does non-coding RNA do in development and disease?

Most of the RNA transcribed from the DNA in our genome is not translated into protein but instead has direct functions in regulating biological processes. This paradigm shift in nucleic acid biology has been supported by technical advances in high-throughput sequencing, molecular genetics and computational biology, which can be combined with more traditional biochemical analyses.

Many species and roles of non-coding RNA have been identified. Our goal is to understand how non-coding RNAs regulate development, physiology and disease. We are exploring microRNA in the pathology of cancer and other diseases, RNA interference in viral immunity, Piwiinteracting RNA in germline development and genome integrity, and endogenous small interfering RNA in epigenetic inheritance – where we predict a big impact in understanding human health. Our model organisms are the nematode worm, the cichlid fishes of the Rift Lakes of East Africa, mouse, and human cell culture. More recently we have developed a technology to assess RNA structure and RNA–RNA interactions in living systems. We used this to uncover unexpected biology for the Zika virus, and key regulatory mechanisms for SARSCoV-2.

Selected publications: Co-workers: Harry Baird, Sarah Buddle, Nicholas Burton, Alexandra Dallaire, Benjamin Fisher, Giulia Furlan, David Jordan, Tsveta Kamenova, Joanna Kosalka, Lisa Lampersberger, Miranda Landgraf, Bethan Manley, Ragini Medhi, Narendra Meena, Harris Papadopoulou, Jon Price, Audrey Putman, Fu Xiang Quah, Navin Brian Ramakrishna, Cristian Riccio, Marc Ridyard, Miguel Vasconcelos Almeida, Gregoire Vernaz, Archana Yerra, Chengwei (Ulrika) Yuan, Omer Ziv

Ziv O et al. (2020) The Short- and Long-Range RNA–RNA Interactome of SARS-CoV-2. Mol Cell 80: 1067–1077.e5.

Maori E et al. (2019) A Secreted RNA Binding Protein Forms RNA-Stabilizing Granules in the Honeybee Royal Jelly. Mol Cell 74: 598-608.e6.

Ziv O et al. (2018) COMRADES determines in vivo RNA structures and interactions. Nat Methods 15: 785–788.

The Gurdon Institute 37

5′CS 5′ miR-21

5′

5′CS

V N

3′CS

M

3′ 5′

The Zika virus genomic structure inside human cells The Zika virus genome adopts alternating structures as the 5' cyclization sequence (CS) participates in interaction with host microRNA miR-21 (top), capsid translation (right), and genome cyclization (left).

5′CS

L

38 Group leaders

EMMA RAWLINS Stem and progenitor cells in the mammalian lung How do stem cells build and maintain the lung? The complicated three-dimensional structure of our lungs is essential for respiration and host defence. Building this structure relies on the correct sequence of division and differentiation events by lung progenitor cells, which also maintain the slowly turning-over airway epithelium in the adult.

How is the production of different cell types controlled in embryonic development and adult maintenance? We apply mouse genetics, live imaging, single-cell molecular analysis and mathematical modelling to understand lung stem cells, with a longer-term aim of directing endogenous lung cells to repair, or regenerate, diseased tissue.

In the adult lung we focus on the cellular mechanisms that maintain stem cell quiescence at steady-state, but allow a rapid repair response when needed. In the embryonic lung we study a population of multipotent progenitors that undergo steroid-induced changes in competence during development. In the embryo, we have recently switched our focus to normal human lung development, primarily using an organoid system that we developed. We combine the analysis of fresh human embryonic tissue with gene-targeting in the organoids, to determine the molecular and cellular mechanisms of normal human lung development. This will provide insights into conditions related to premature birth and into the possibility of therapeutic lung regeneration.

Selected publications: Co-workers: Ana Lucia Cabriales Torrijos, Ziqi Dong, Tessa Hughes, Quitz Jeng, Florence Leroy, Kyungtae Lim, Shuyu Liu, Vishal Menon, Ziming Shao, Vanesa Sokleva, Dawei Sun

Nikolic´ M et al. (2018) Human lung development: recent progress and new challenges. Development 145: dev163485.

Nikolic´ M et al. (2017) Human embryonic lung epithelial tips are multipotent progenitors that can be expanded in vitro as long-term self-renewing organoids. Elife 6: e26575.

Balasooriya GI et al. (2016) An FGFR1-SPRY2 Signaling Axis Limits Basal Cell Proliferation in the Steady-State Airway Epithelium. Dev Cell 37: 85–97.

How does the lung build itself?

In this 17-weeks-gestation human embryonic lung, the differentiating airway epithelium has been stained to visualise mRNA. Differentiating secretory cells (cyan) and ciliated cells (red) are visible. Cell nuclei in blue. (Credit: Dr Kyungtae Lim.)

40 Group leaders

DANIEL ST JOHNSTON Polarising epithelial cells and body axes How do cells know ‘up’ from ‘down’? Most cells in the body perform different functions at opposite sides of the cell. This cell polarity is essential in development, for example: in determining the head-to-tail axis of many animals, for cell migration and for asymmetric stem-cell divisions. Furthermore, loss of polarity is a hallmark of tumour cells and is thought to contribute to tissue invasion and metastasis. Our work focuses on epithelia, the sheets of polarised cells that form barriers between compartments and make up most of our organs and tissues.

We study the factors that mark different sides of epithelial cells and how these organise the internal cell architecture, using the Drosophila intestine and the follicle cell epithelium as models.

We have recently discovered that the gut epithelium polarises by a fundamentally different mechanism from other fly epithelia, and is much more similar to mammalian epithelia. We are now identifying new polarity factors in the fly gut and are testing whether these play similar roles in mouse intestinal organoids. We are also using live microscopy to visualise polarised secretion in epithelial cells, and quantitative superresolution microscopy to examine the clustering and co-localisation of polarity proteins.

Selected publications:

Co-workers: Edward Allgeyer, Jia Chen, Jin Mei Cheng, Helene Doerflinger, Weronika Fic, Xiao Li He, Nathan Hervieux, Florence Leroy, Dmitry Nashchekin, John Overton, Amandine Palandri, Jenny Richens, George Sirinakis, Mihoko Tame, Joseph Jose Thottachery, Helen Zenner, Xixi Zhu

Lovegrove H et al. (2019) The role of integrins in Drosophila egg chamber morphogenesis. Development 146: dev182774 Fic W et al. (2019) Drosophila IMP regulates Kuzbanian to control the timing of Notch signalling in the follicle cells. Development 146: dev168963.

Chen J et al. (2018) An alternative mode of epithelial polarity in the Drosophila midgut. PLoS Biol 16: e3000041.

domain

apical secretion

apical

lateral

basal

forming sheets that create a barrier loss of polarity in cancer

forming tubes

The special properties of epithelia A drawing showing how epithelial cells stick together to form epithelial sheets, with their free apical surfaces facing towards the outside or the lumen of an epithelial tube or gland. The lateral junctions (yellow) create a barrier between cells so that fluids, solutes and pathogens cannot leak across the epithelium. Most cancers arise from epithelial tissues and are characterised by a loss of apical–basal polarity (red cells).

42 Group leaders

BEN SIMONS Mechanisms of stem cell fate in tissue development, maintenance and disease How do stem and progenitor cells regulate their fate behaviour to specify and maintain tissues? During development, cell proliferation and differentiation must be coordinated with collective cell movements to specify organs of the correct size, pattern and composition. In the adult, stem cells must regulate a precise balance between proliferation and differentiation to maintain tissue homeostasis.

To address the mechanisms that regulate stem and progenitor cell fate, we combine cell lineage-tracing approaches and single-cell gene expression profiling with concepts and methods from statistical physics and mathematics. Applied to epithelial tissues, we have shown how common principles of self-organisation and emergence provide predictive insights into the cellular mechanisms that regulate tissue development, maintenance and repair. As well as questioning the nature of stem cell identity and function, these studies emphasize the role of cell fate stochasticity and state flexibility, and establish a quantitative platform to investigate pathways leading to cancer initiation and progression.

Selected publications:

Co-workers: Ignacio Bordeu, Lemonia Chatzeli, Catherine Dabrowska, Frances England, Adrien Hallou, Seungmin Han, Daniel Kunz, Jamie McGinn, Kathy Oswald, Bart Theeuwes, Yanbo Yin, Min Kyu Yum

Han S et al. (2019) Defining the identity and dynamics of adult gastric isthmus stem cells. Cell Stem Cell 25: 342–356.

Kitadate Y et al. (2019) Competition for mitogens regulates spermatogenic stem cell homeostasis in an open niche. Cell Stem Cell 24: 79–92.

Hannezo E et al. (2017) A unifying theory of branching morphogenesis. Cell 171: 242–255.

The Gurdon Institute 43

Cell lineage tracing in the stomach corpus Genetic lineage tracing using a multicolour confetti reporter system reveals the compartmentalisation of the mouse stomach corpus gland. (Credit: Juergen Fink and Seungmin Han.)

44 Group leaders

AZIM SURANI The human germline What makes a germline cell? We study primordial germ cells (PGCs), precursors to eggs and sperm, in the early embryo. We have established principles of early human development with a focus on human PGC (hPGC) specification. A unique epigenetic resetting follows in the germline after hPGC specification. Our work shows that SOX17 is the key regulator of human, but not mouse, germ cell fate. By developing in vitro models, and with authentic hPGCs from human embryos, we have also established how pluripotent stem cells gain competence for germ cell and somatic fates in human. These findings are important for studies on human pluripotent stem cells and regenerative medicine. The inheritance of genetic and epigenetic information from the germline through the totipotent state affects human development and disease for generations.

Whereas SOX17–BLIMP1 apparently initiate the epigenetic programme in early human germline, BLIMP1–PRDM14 play a similar role in mouse germline, resulting in the comprehensive erasure of DNA methylation (except for some resistant loci), X-reactivation and imprints erasure, followed by re-establishment of sperm- and oocyte-specific imprints.

Defects in these gamete-specific imprints lead to a variety of human disease syndromes. We have also examined mitochondrial DNA (mtDNA) in PGCs, showing evidence for selection against mitochondria that harbour mutations. This mechanism is imperfect and can account for inherited mtDNA disorders.

Selected publications: Co-workers: João Alves Lopes, Aracely Castillo, Lynn Froggett, Wolfram Gruhn, Mei Gu, Naoko Irie, Sun Min Lee, Jitesh Neupane, Marco Oechsner, So Shimamoto, Walfred Tang, Frederick Wong

Sybirna A et al. (2020) A critical role of PRDM14 in human primordial germ cell fate revealed by inducible degrons. Nat Commun 11: 1282.

Floros VI et al. (2018) Segregation of mitochondrial DNA heteroplasmy through a developmental genetic bottleneck in human embryos. Nat Cell Biol 20: 144– 151.

Kobayashi T et al. (2017) Principles of early human development and germ cell program from conserved model systems. Nature 546: 416–420.

Irie N et al. (2015) SOX17 Is a Critical Specifier of Human Primordial Germ Cell Fate. Cell 160: 253–268.

The Gurdon Institute 45

Germ cell development in vivo E6

E14

E16

E23 (week 4)

epiblast

primordial germ cells

E29 (week 5)

week 7-10

genital ridge

adults Reconstitution of cell fate transition in vitro BMP

WNT/BMP/ Activin

mesoderm conventional human pluripotent stem cells

pre-mesendoderm

mesendoderm

BMP

Activin SOX17

SOX17

primordial germ cells

definitive endoderm

What we know about primordial germ cell development Primordial germ cells are the first cell type to be specified in vivo in early human development. We have developed a protocol using specific signalling molecules to generate primordial germ cell-like cells in vitro from human pluripotent stem cells. We found that SOX17 is a critical determinant of human germ cell fate.

46 Group leaders

IVA TCHASOVNIKAROVA Genetic interrogation of epigenetic pathways How do changes in epigenetic pathways result in cancer? All DNA-templated processes occur in the context of chromatin, which is comprised of DNA and histone proteins. Epigenetic modifications of DNA and histones are important regulators of transcription, DNA repair and replication. Disruption of epigenetic processes can therefore result in malignant cellular transformation.

The overarching goal of our research is to use novel genetic approaches to study epigenetic pathways and the mechanisms through which these processes are corrupted by disease-associated mutations in chromatin regulators. We aim to (1) understand the molecular mechanisms used by chromatin regulators to exert their function in healthy human cells, and (2) examine how these mechanisms are altered in cancer.

Co-worker: Lynn Froggett

We leverage high-throughput genetic technologies, such as CRISPR/ Cas9 genetic screens, to discover novel factors involved in chromatin pathways. This approach has led to the identification of HUSH, a previously uncharacterised chromatin-modifying complex. In addition to mediating position-effect variegation in human cells, the HUSH complex also plays key roles in the silencing of retro-elements and unintegrated retroviral DNA, and as a restriction factor for Human Immunodeficiency Virus. Therefore, a major focus of our research is achieving a mechanistic understanding of HUSH-mediated repression. In parallel, we are developing novel genetic approaches that would allow us to interrogate other epigenetic pathways in an analogous manner.

Selected publications: Tchasovnikarova IA et al. (2015) Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells. Science 348: 1481–1485.

Tchasovnikarova IA et al. (2017) Hyperactivation of HUSH complex function

by Charcot-Marie-Tooth disease mutation in MORC2. Nat Genet 49: 1035–1044.

Timms RT et al. (2019) Differential Viral Accessibility (DIVA) identifies alterations in chromatin architecture through large-scale mapping of lentiviral integration sites. Nat Protoc 14: 153–170.

The Gurdon Institute 47

Left: A genome-wide CRISPR/Cas9 screen to identify genes required for transgene silencing.

Six genes are required for epigenetic silencing of a repressed GFP reporter: the three HUSH complex subunits TASOR, MPP8 and Periphilin; the H3K9 methyltransferase SETDB1 and its binding partner ATF7IP; and the chromatin remodeller MORC2.

H3K9me3

Right: Mechanism of HUSH-mediated repression.

The HUSH complex localises to genomic loci rich in the repressive histone modification H3K9me3.

Subsequent recruitment of the SETDB1/ ATF7IP complex and MORC2 is required for further H3K9me3 deposition and ATP-dependent chromatin compaction to instil epigenetic silencing.

Gene1

Gene 2

HUSH TASOR MPP8 PPHLN1

enriched in selected cells

GFP

H3K9me3 deposition

HUSH

Gene 2

chromatin compaction

SETDB1 Periphilin TASOR

Gene 1

MORC2

ATF7IP

chromatin compaction

SETDB1

ATF7IP

H3K9me3 deposition

MORC2 MPP8 GFP

all mutated genes

Gene 1

Gene 2

48 Group leaders

FENGZHU XIONG Tissue morphogenesis by mechanics and cell dynamics What forces drive tissue morphogenesis? Embryos are made of soft materials consisting of cells with limited mechanical capacities, yet they develop in a robust and coordinated manner and produce large-scale deformations (morphogenesis). We are interested in the ways in which developing tissues produce and respond to mechanical forces in order to achieve the correct shape and pattern. This knowledge is useful for understanding complex birth defects and engineering stem or reprogrammed cells into tissues, as well as interpreting the changes in diseased tissues such as tumours.

We use early avian embryos as a model system. The large size and accessibility of these embryos allow us to image cell and tissue dynamics, perform molecular genetic perturbations, and deploy novel mechanical tools such as soft gels and cantilevers to measure and apply forces. By integrating cell and tissue dynamics, we found that the paraxial mesoderm and axial tissues coordinate their elongation through mechanical feedback. We are currently investigating if the identified forces are also important for the straightness (bilateral symmetry) of the tissues and the folding of the neural tube.

Selected publications:

Co-workers: Christopher Chan, Ana Hernandez Rodriguez, Daniele Kunz, Yisha Lan, Lauren Moon, Kathy Oswald, Melinda Van Kerckvoorde, Anfu Wang, Melissa Yuan

Oginuma M et al. (2020) Intracellular pH controls WNT downstream of glycolysis in amniote embryos. Nature 584: 98–101.

Xiong F et al. (2020) Mechanical coupling coordinates the co-elongation of axial and paraxial tissues in avian embryos. Dev Cell 55: 354–366.

Mongera A et al. (2019) Mechanics of Anteroposterior Axis Formation in Vertebrates. Annu Rev Cell Dev Biol 35: 259–283

The Gurdon Institute 49

Naturally occurring twin chick embryo Bright-field image of a rare pair of well-formed separate embryos sharing one egg. The embryos show a head-to-head alignment. Body axis and somites are visible. (Credit: Daniele Kunz)

50 Group leaders

PHILIP ZEGERMAN The regulation of DNA replication initiation in eukaryotes How is DNA replication controlled? A fundamental requirement for all life on earth is that an exact copy of the entire genome must be made before cell division. DNA replication is therefore tightly regulated because failures in this process cause genomic instability, which is a hallmark of many diseases, most notably cancers. In addition, inhibition of DNA replication is the primary mode of action of many anti-tumour therapies. Therefore, investigating DNA replication control is important for finding new ways to diagnose and treat cancers. The evolutionary conservation of DNA replication mechanisms allows us to study this process in multiple systems, facilitating the translation of findings to humans.

We have shown that the levels of several key replication factors are critical to control the rate of genome duplication, not only in the single-celled organism, budding yeast, but also during vertebrate development in frog embryos. Our studies demonstrate that regulation of the levels of these factors is vital not only for normal cell division, but also for regulating the rate of cell proliferation in animal tissue. This has important implications for the deregulation of cell proliferation, which occurs in cancers.

Selected publications:

Co-workers: Andreas Hadjicharalambous, Fiona Jenkinson, Mark Johnson, Florence Leroy, Ivan Phanada, Miguel Santos

Morafraile EC et al. (2019) Checkpoint inhibition of origin firing prevents DNA topological stress. Genes Dev 33: 1539–1554.

Can G et al. (2019) Helicase Subunit Cdc45 Targets the Checkpoint Kinase Rad53 to Both Replication Initiation and Elongation Complexes after Fork Stalling. Mol Cell 73: p562–573.e3 Collart C et al. (2017) Chk1 Inhibition of the Replication Factor Drf1 Guarantees Cell-Cycle Elongation at the Xenopus laevis Mid-blastula Transition. Dev Cell 42: 82–96.

Collart C et al. (2013) Titration of four replication factors is essential for the Xenopus laevis midblastula transition. Science 341: 893–896.

The Gurdon Institute 51

origin of replication

two fully replicated DNA strands ready for cell division

incomplete replication

mutation

Studying life’s central process Regulation of replication initiation is critical for normal cell division.

replication initiation happens more than once before cell division

52 Associate group leaders

MARTIN HOWARD Building simple predictive models of complex biological processes How are cellular memory states switched and maintained? Our group combines simple, predictive mathematical modelling with longlasting experimental collaborations, to dissect biological mechanisms too complex to unravel by experiments alone. In many cases we are able to rationalise complex biological dynamics into simple underlying mechanisms, with few components and interactions. Our approach is highly interdisciplinary and relies heavily on the techniques of statistical physics and applied mathematics, as well as on close collaboration with experimental groups. This truly interdisciplinary approach allows us to get to the heart of biological mechanisms more speedily.

At present the main focus of the group is epigenetic dynamics, probing how epigenetic memory states are set up and then stably maintained.

In this context, we work with histone modification memory systems, as well as on DNA methylation, collaborating with experimentalists in systems ranging from plants to mammalian stem cells. A particular focus has been the Polycomb epigenetic system, where we have proposed an all-or-nothing epigenetic switching mechanism, with epigenetic gene silencing directly antagonised by transcription.

Overall, as epigenetic systems are central to health, understanding how they work at a fundamental level is of vital importance.

Selected publications: Zhao Y et al. (2020) Temperature-dependent growth contributes to longterm cold sensing. Nature 583: 825-829.

Yang H et al. (2017) Distinct phases of Polycomb silencing to hold epigenetic memory of cold in Arabidopsis. Science 357: 1142-1145.

Berry S et al. (2017) Slow chromatin dynamics allow polycomb target genes to filter fluctuations in transcription factor activity. Cell Systems 4: 445-457.e8.

The Gurdon Institute 53

KDM

Active Pol II

Pol II PRC2

PRC2

Repressed

Trans-regulators

me0

me1

me2

me3

Transcription

0

2

4 6 Time (cell cycles)

8

0 1

me3

me3

0

me0

0 1

Modification level

1

me0

Modification level

1

0 0

2

4 6 Time (cell cycles)

8

Modelling Polycomb epigenetic dynamics Top: schematic of chromatin state in active (upper) and repressed (lower) state. KDM: histone demethylase; Pol II: RNA Polymerase II; PRC2: Polycomb Repressive Complex 2; orange hexagons: histone H3K27 di- and trimethylation. Middle: key ingredients of a mathematical model for Polycomb dynamics; me0/1/2/3: methylation state of H3K27. Bottom: simulation of repressed state (high H3K27me3) (left) and of repressed state switching to an active state (right), both periodically perturbed by DNA replication. (Image credit: Dr Scott Berry).

54 Associate group leaders

JOHN PERRY Using human genetics to understand disease mechanisms What are the biological mechanisms that link patterns of growth and reproductive ageing to later life disease? Epidemiological studies have long linked patterns of early-life growth and reproductive ageing to later life diseases, yet the biological mechanisms underpinning these associations remain unclear. For example, what are the pathways that link variation in onset of puberty to risk of type 2 diabetes and cancer decades later? To explore this, we use large-scale human population studies to identify genetic variants that influence risk of disease or contribute to variation in quantitative traits. Through integration with transcriptomic and proteomic datasets we can then prioritise genes and pathways for evaluation with experimental collaborators using animal and cellular models.

Co-workers: Ken Ong, Felix Day, Hana Lango Allen, Yajie Zhao and Stasa Stankovic

My research is primarily based at the MRC Epidemiology Unit where I co-lead an MRC-funded programme with Professor Ken Ong. My Associate position at the Gurdon Institute focusses on one of the key biological mechanisms emerging from our population-based research: DNA damage response (DDR). Although often considered in the context of cancer susceptibility, it is now clear that DDR processes influence other complex diseases and traits. For example, our human genetics work has highlighted DDR as the major pathway governing reproductive ageing and fertility in women. We aim to better understand these processes, when they act over the life-course and how they might be modified to preserve fertility and prevent disease.

Selected publications: Ruth KS et al. (2020) Using human genetics to understand the disease impacts of testosterone in men and women. Nat Med 26: 252–258.

Thompson DJ et al. (2019) Genetic predisposition to mosaic Y chromosome loss in blood. Nature 575: 652–657.

Perry JRB et al. (2014) Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature 514: 92–97.

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Analysing genotypes and phenotypes in human populations phenotype

phenotype

genotype

Identifying genetic determinants of health and disease

1

2

3

4

5

6

7

8

9

10 11 12 chromosome

13

14

15

16

17

18

19

20

21

22

X

Understanding gene function and biological mechanisms functional models

transcriptome

epigenome

intervention/ therapeutics in vivo

proteome

metabolome

in vitro

Overview of process to identify disease- and trait-associated alleles, genes and biological pathways using large-scale human population studies. Genetic variation is measured genome-wide in populations of research participants. Individual genetic variants associated with diseases and traits can then be identified through computational approaches, linked to gene function through the integration of ‘omics’ resources and further evaluated in downstream experimental models.

56 Facilities

Facilities

Media/glasswashing service

Microscopy and image analysis

The media team provide quality-controlled buffers, growth media, worm plates, bacterial plates, fly vials and bottles, and standard and custom solutions. They collect and wash used glassware and provide sterile supplies.

The team run the technical support for a wide range of the latest imaging technologies, as well as providing training, research contributions and custom software development.

Typical annual production of media includes 400,000 vials and bottles of fly food; 300,000 nematode worm plates; and over 100 different recipes for buffers, media and solutions.

Find out more about the media team in the video for our YouTube series: ‘A Year in Institute Life’.

Researchers have access to confocal, light-sheet and super-resolution (STORM, PALM, STED, SIM) microscopes. We also have a cell-sorting core.

The duo building our new super-resolution microscopes describe their work in a video in our YouTube series: ‘A Year in Institute Life’.

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Next-generation sequencing and bioinformatics On-site sequencing allows researchers to access results with a quick turnaround. Bioinformatics expertise is provided by core posts as well as by research-group-based posts. A High Performance Computer cluster offers researchers the capability to process sequencing data in-house. These services are backed up by locally available courses in a variety of programming and analysis tools.

The sequencing service is featured in a video in our YouTube series: ‘A Year in Institute Life’.

IT/computing The computing team provides flexible and highquality IT infrastructure, services and support for all research and administrative computing activities within the Institute. We maintain high performance, high capacity and high bandwidth systems that are secure, resilient and highly available, ensuring the efficient movement, secure storage, and future accessibility and re-use of a very large volume of research data. We also strive to provide the very best levels of user support and engagement, responding rapidly to both problems and opportunities for new services.

58 Support staff

Support staff Sylviane Moss PhD Safety and Compliance Manager

Natalie Walls BSc Public Engagement Coordinator

Dermot Nolan Receptionist Samantha Wilson BSc Receptionist

Administration Bruce Daniels LLB DipLP BTh Administration and Operations Manager

Daniel Sargent HR Administrator Victoria Stubbs PhD Shared Facilities Manager

Alastair Downie Computer Systems Manager

Jane Course Finance Manager

Nigel Smith Computer Associate

Jayne Fisher Finance/ Accounts Assistant Diane Foster Deputy Administration and Operations Manager, Principal Technician Emma Gant BA PGCert Research Grants/ HR Coordinator Iolanda Guerra Health and Safety Adviser Lynda Lockey Office Manager

Computing/ IT

Peter Williamson BSc Computer Associate

Communications/ Public engagement

Bioinformatics Charles Bradshaw PhD Bioinformatician

Hélène Doerflinger PhD Public Engagement Manager

Sequencing

Claire O’Brien PhD Information and Communications Officer

Kevin (Kay) Harnish MSc Wellcome Research Assistant (Sequencing Facility)

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Miguel Leon Salvador Tracy Mitchell Nathy Villalobos Martinez MA

Imaging

Combined building & services group

Alexander Sossick BSc Head of Microscopy and Scientific Facilities Co-ordinator, Laser Safety Officer Richard Butler PhD Research Associate (Imaging) Nicola Lawrence PhD Microscopy Associate/ Deputy Head of Imaging, Laser Safety Officer

Media/ Glasswashing Juanita Baker-Hay Media/ Glasswashing Manager Lisa Baker Laura Carlton Vincent Dams Sandra Human

Alan Rix Building Services Manager

Accounts/ Purchasing/ Stores Ian Fleming Stores/ Purchasing Manager Simon Aldis Purchasing/ Accounts Assistant

Clive Bennett Custodian Katharine Bennett Custodian Paul Turrell Custodian

David Cooper Stores Technician

Regimantas Vysniauskas Senior Building Services Technician

Andrew Vincent Senior Stores Technician

Technical facilities

Super-resolution microscopy George Sirinakis PhD Wellcome Senior Research Associate Edward Allgeyer PhD Wellcome Senior Research Associate

Polly Attlesey RAnTech MIAT Facilities Manager Therese Jones-Green BSc Manager of Aquatic Services

Zest catering Amanda Harris Melissa Plowden Roberts

60 People in 2019

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Seminars, events and publications in 2019/2020

62 Seminars

Seminars The Gurdon Institute Seminar Series brings high-profile international scientists in front of an audience drawn from across the University biological sciences departments. Our speakers were: 5 March 2019 Yunsun Nam, The University of Texas Southwestern Medical Center, USA. Chemical regulation of functional RNAs 30 April 2019 Janet Rossant, Hospital for Sick Children, University of Toronto, Canada. The Anne McLaren Lecture: The blastocyst and its stem cells; from mouse to human relevance 16 May 2019 Cédric Feschotte, Cornell University, Ithaca, New York, USA. Transposable elements as catalysts of cellular innovation 21 May 2019 Philip W Ingham, Lee Kong Chian School of Medicine, Nanyang Technological University Singapore & Imperial College London. Spatiotemporal dynamics of cell fate specification and differentiation in the zebrafish embryo 29 October 2019 Arturo Londoño-Vallejo, Institut

Curie, Paris, France. Human Regulator of TElomere Length Helicase 1 (RTEL1) couples nuclear envelope stability and functions to genome replication 31 October 2019 Hiten Madhani, University of California, San Francisco, USA. Epigenetic memory over geological timescales 26 November 2019 Lori Passmore, MRC Laboratory of Molecular Biology, Cambridge, UK. Mechanistic insights into the mRNA poly(A) tail machinery and DNA repair 28 January 2020 Elaine Fuchs, Rockefeller University, New York, USA. Stem Cells: It’s All About the Neighborhood 28 January 2020 Eduardo Moreno, Champalimaud Centre for the Unknown, Lisbon, Portugal. Cell competition during development and disease Hosted by the Gurdon Institute PhD Society 04 February 2020 Naama Barkai, Weizmann Institute of Science, Rehovot, Israel.

Robustness and scaling in early

development: the “distal pinning” mechanism 30 June 2020 Fabian Theis, Institute of Computational Biology, Helmholtz Zentrum, Munich, Germany.

Model-based explanation of cellular response. Live webinar hosted by the Gurdon Institute Postdoc Association 27 July 2020 Nadine Vastenhouw, Max-Planck Institute of Molecular Cell Biology & Genetics, Dresden, Germany. Firing up the genome. Live webinar hosted by the Gurdon Institute Postdoc Association 13 October 2020 Titia de Lange, Anderson Center for Cancer Research, Rockefeller University, New York, USA. The Anne McLaren Lecture: How CST protects telomeres and double-strand breaks. Live webinar 17 November 2020 Martin Howard, John Innes Centre, Norwich. Mechanistic basis of epigenetic switching and memory.

Live webinar

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External events June ’19: The Milner Therapeutics Institute team officially moved out of their incubation space at the Gurdon Institute and into their new premises in the Jeffrey Cheah Biomedical Centre on the Cambridge Biomedical Campus, with a goodbye tea for colleagues.

22 Aug and 20 Sept ’19: East of England MEPs Catherine Rowett (UK Green Party) and Barbara Gibson (Liberal Democrat) visited the Institute to learn about who we are and what we do. Each was on a fact-finding mission to hear from group leaders and young researchers about the impact of the Brexit vote and continuing uncertainty about the future, on people's lives, career decisions and the UK science base.

14 Oct ’19: Artist Caroline Walker was commissioned by Cambridge University Library to capture images of women working in the lab at the Gurdon Institute. After shadowing researchers in the Rawlins lab and taking photographs, Caroline created a huge oil painting for the library’s entrance hall, on view to the public as part of the exhibition 'The Rising Tide: Women at Cambridge'. [You can see details from the preparatory oil sketches throughout this prospectus.]

Sept ‘19: Over 2000 cyclists from 184 organisations across Greater Cambridge took part in the Global Bike Challenge and clocked up 290,466 miles during Cycle September - and many of those were logged by Gurdon Institute staff. The Institute bagged 2nd place in the league tables for companies in our size range. Cycle September is run by cycling organisation Love to Ride.

Jan ’20: The newly launched Cambridge Centre for Physical Biology aims to support and facilitate multidisciplinary collaborations across the University of Cambridge. Gurdon Institute Group Leader Professor Ben Simons is one of the main leaders of the project.

Sept ’20: Adrestia Therapeutics, the latest biotech company to spin out from the Jackson lab, moved out of the Institute’s temporary incubation space and into new premises on the Babraham Research Campus. The company’s Disease Rebalancing Platform uses synthetic viability to identify phenotypic and molecular imbalances of disease as the basis of novel drug discovery.

In Dec ’20 GlaxoSmithKline and Ahren Innovation Capital co-led a substantial Series A investment in Adrestia.

Seminars for the local academic community Beyond the Gurdon Institute seminars, our members organise, host and support several other series: Developmental Biology Seminars, Cambridge RNA Club, Cambridge Epigenetics Club, Cambridge Fly Meeting, Cambridge 3Rs (replication, repair and recombination), Life Science Masterclasses and Worm Club.

64 Events

Institute events We hold regular social and sports activities, celebrations and specific events organised by our postdoc and PhD student associations. Here is a selection:

students to talk to each other, ask any questions, and raise concerns - basically get to know each other.

We plan to hold events throughout the year.”

17 Jan '19: A Fizz & Food party to celebrate Daniel St Johnston's 10 years as Director. Several past Group Leaders and our previous Institute Administrator attended.

Speeches were followed by an inspired song specially written and sung by Andrew Plygawko (St Johnston lab PhD student).

3 July '19: To celebrate LGBT STEM day we held a seminar by special guest Duncan Astle (Programme Leader, MRC Cognition and Brain Sciences Unit & member of Pride in STEM) talking about his research: Altering developing neurophysiology with training.

Feb '19: Launch of Climbing Club, organised by Miguel Leon Salvador from the Media team. Club sessions run on two evenings per week at the local sports hall.

June '19: Launch of the Gurdon Institute PhD Society. Vanesa Sokleva (Rawlins lab), the new President, says: "We want it to be a friendly and safe space for PhD

7 July '19: Our first Family Day, on a Sunday, featuring a walk, games and a picnic in Grantchester Meadows. Organised by Gurdon Institute Postdoc Association (GIPA) and the Wellbeing, Equality and Diversity (WED) Committee.

12 July '19: Our Gratitude Festival was the perfect moment to say Goodbye and a big Thank You to Suzanne (retiring long-serving HR & Grants Manager) and to the Huch and Livesey labs (moving to Dresden and London, respectively).

Activities included face painting, tie-dyeing, a bouncy castle and science tattoos.

3 & 4 Oct '19: Institute Retreat at Dunston Hall in Norfolk (see p.

76). The schedule had all the usual

Credit: Claudia Stocker

activities: Talks from all our group leaders, guest speaker Prof Anna Philpott (Stem Cell Institute and Head of School of the Biological Sciences), 'treasure hunt' games, poster session and plenty of fun on the dance floor after dinner.

Prizes announced at the Retreat: Three best posters (Rue JonesGreen, Leia Judge & Israel Salguero); Image competition (Andy Li); Video competition (Chufan Xu); Public Engagement Champion (Bernhard Strauss for many years running workshops for sixth formers, supporting work experience students, and taking part in numerous external events); Kathy Hilton Energy and Environment Champion (Kate Dry, for crisp

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packet recycling scheme); Ann Cartwright Good Citizen Award (the Maintenance Team for their unfailing brilliant work); Martin Evans Award for the greatest contribution to Institute social life (Miguel Salvador, for organising Climbing Club).

25 Oct '19: Halloween Happy Hour by the Jackson lab. The undisputed winner of the pumpkin carving competition was David Jordan (Miska lab).

22 Nov '19: GIPA Pub Quiz Happy Hour.

10 and 13 Dec '19: Children’s and Adults’ Christmas parties (the latter with Cartoon Character fancy dress).

6 Mar ’20: GIPA Carnival evening July ’20: The PE team supported one session of the Secret School for Curious Children. ‘Invisible Nature’ took place in the sunny outdoors with social distancing, and featured the popular Zoom boxes that create a microscope out of a mobile phone. Children scavenged for specimens and learnt about magnification.

1 & 2 Oct ’20: virtual Institute Retreat. We had two half days to hear the talks from researchers and core teams, and an evening session for the ‘treasure hunt/ quiz’. Awards went to those making exceptional contributions to the Institute

during the pandemic. For enabling lockdown and reopening: Fabian Braukmann, Chris Carnie, Andrea Frapporti and Roopali Pradhan.

For handmade masks: Carmen Calabrese. For bringing us through lockdown 1.0 and safely back to work: Di Foster, Sylviane Moss, Katherine Wallington and Arianna Pezzuolo.

The Public Engagement Champion Award 2020 goes to Edward Allgeyer, for creating a workshop enabling students to build simple microscopes for the CAST microscopy challenge, run in collaboration with our Imaging team and Zeiss.

66 Publications in 2019

Publications in 2019 Adashi EY, Cohen IG, Hanna JH, Surani AM, Hayashi K (2019) Stem Cell-Derived Human Gametes: The Public Engagement Imperative. Trends Mol Med 25: 165–167. DOI: 10.1016/j.molmed.2019.01.005.

Aztekin C, Hiscock TW, Marioni JC, Gurdon JB, Simons BD, Jullien J (2019) Identification of a regenerationorganizing cell in the Xenopus tail. Science 364: 653–658. DOI: 10.1126/science.aav9996.

Akay A, Jordan D, Navarro IC, Wrzesinski T, Ponting CP, Miska EA, Haerty W (2019) Identification of functional long non-coding RNAs in C. elegans. BMC Biol 17: 14. DOI: 10.1186/s12915-019-0635-7.

Baker A-M, Cereser B, Melton S, Fletcher AG, Rodriguez-Justo M, Tadrous PJ, Humphries A, Elia G, McDonald SAC, Wright NA, Simons BD, Jansen M, Graham TA (2019) Quantification of Crypt and Stem Cell Evolution in the Normal and Neoplastic Human Colon. Cell Rep 27: 2524. DOI: 10.1016/j. celrep.2019.05.035.

Allen F, Crepaldi L, Alsinet C, Strong AJ, Kleshchevnikov V, De Angeli P, Páleníková P, Khodak A, Kiselev V, Kosicki M, Bassett AR, Harding H, Galanty Y, MuñozMartínez F, Metzakopian E, Jackson SP, Parts L. (2019) Predicting the mutations generated by repair of Cas9induced double-strand breaks. Nat Biotechnol 37: 64–72. DOI: 10.1038/nbt.4317.

Aloia L, McKie MA, Vernaz G, Cordero-Espinoza L, Aleksieva N, van den Ameele J, Antonica F, FontCunill B, Raven A, Aiese Cigliano R, Belenguer G, Mort RL, Brand AH, Zernicka-Goetz M, Forbes SJ, Miska EA, Huch M (2019) Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration. Nat Cell Biol 21: 1321–1333.

DOI: 10.1038/s41556-019-0402-6.

Andersen MS, Hannezo E, Ulyanchenko S, Estrach S, Antoku Y, Pisano S, Boonekamp KE, Sendrup S, Maimets M, Pedersen MT, Johansen JV, Clement DL, Feral CC, Simons BD, Jensen KB (2019) Tracing the cellular dynamics of sebaceous gland development in normal and perturbed states. Nat Cell Biol 21: 924–932. DOI: 10.1038/s41556-019-0362-x.

Andrews TS, Hemberg M (2019) M3Drop: dropoutbased feature selection for scRNASeq. Bioinformatics 35: 2865–2867. DOI: 10.1093/bioinformatics/bty1044.

Baker A-M, Gabbutt C, Williams MJ, Cereser B, Jawad N, Rodriguez-Justo M, Jansen M, Barnes CP, Simons BD, McDonald SA, Graham TA, Wright NA (2019) Crypt fusion as a homeostatic mechanism in the human colon. Gut 68: 1986–1993. DOI: 10.1136/ gutjnl-2018-317540.

Balmus G, Pilger D, Coates J, Demir M, SczanieckaClift M, Barros AC, Woods M, Fu B, Yang F, Chen E, Ostermaier M, Stankovic T, Ponstingl H, Herzog M, Yusa K, Martinez FM, Durant ST, Galanty Y, Beli P, Adams DJ, Bradley A, Metzakopian E, Forment JV, Jackson SP (2019) ATM orchestrates the DNAdamage response to counter toxic non-homologous end-joining at broken replication forks. Nat Commun 10: 87. DOI: 10.1038/s41467-018-07729-2.

Beltran T, Barroso C, Birkle TY, Stevens L, Schwartz HT, Sternberg PW, Fradin H, Gunsalus K, Piano F, Sharma G, Cerrato C, Ahringer J, Martínez-Pérez E, Blaxter M, Sarkies P (2019) Comparative Epigenomics Reveals that RNA Polymerase II Pausing and Chromatin Domain Organization Control Nematode piRNA Biogenesis. Dev Cell 48: 793–810.e6. DOI: 10.1016/j. devcel.2018.12.026.

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Beurton F, Stempor P, Caron M, Appert A, Dong Y, Chen RA-J, Cluet D, Couté Y, Herbette M, Huang N, Polveche H, Spichty M, Bedet C, Ahringer J, Palladino F (2019) Physical and functional interaction between SET1/COMPASS complex component CFP-1 and a Sin3S HDAC complex in C. elegans.

Nucleic Acids Res 47: 11164–11180. DOI: 10.1093/ nar/gkz880.

Bezler A, Braukmann F, West SM, Duplan A, Conconi R, Schütz F, Gönczy P, Piano F, Gunsalus K, Miska EA, Keller L (2019) Tissue- and sex-specific small RNAomes reveal sex differences in response to the environment. PLoS Genet 15: e1007905. DOI: 10.1371/journal.pgen.1007905.

Chiang AC-Y, McCartney E, O’Farrell PH, Ma H (2019) A Genome-wide Screen Reveals that Reducing Mitochondrial DNA Polymerase Can Promote Elimination of Deleterious Mitochondrial Mutations.

Curr Biol 29: 4330–4336.e3. DOI: 10.1016/j. cub.2019.10.060.

Cornwell MJ, Thomson GJ, Coates J, Belotserkovskaya R, Waddell ID, Jackson SP, Galanty Y (2019) SmallMolecule Inhibition of UBE2T/FANCL-Mediated Ubiquitylation in the Fanconi Anemia Pathway.

ACS Chem Biol 14: 2148–2154. DOI: 10.1021/ acschembio.9b00570.

Elling U, Woods M, Forment JV, Fu B, Yang F, Ng BL, Vicente JR, Adams DJ, Doe B, Jackson SP, Penninger JM, Balmus G (2019) Derivation and maintenance of mouse haploid embryonic stem cells. Nat Protoc 14: 1991–2014. DOI: 10.1038/s41596-019-0169-z.

Erdmann RS, Baguley SW, Richens JH, Wissner RF, Xi Z, Allgeyer ES, Zhong S, Thompson AD, Lowe N, Butler R, Bewersdorf J, Rothman JE, St Johnston D, Schepartz A, Toomre D (2019) Labeling Strategies Matter for Super-Resolution Microscopy: A Comparison between HaloTags and SNAP-tags. Cell Chem Biol 26: 584–592. e6. DOI: 10.1016/j.chembiol.2019.01.003.

Fic W, Faria C, St Johnston D (2019) IMP regulates Kuzbanian to control the timing of Notch signalling in Drosophila follicle cells. Development 146: dev168963. DOI: 10.1242/dev.168963.

Gallop JL (2019) Filopodia and their links with membrane traffic and cell adhesion. Semin Cell Dev Biol DOI: 10.1016/j.semcdb.2019.11.017.

Gao X et al. (2019) Establishment of porcine and human expanded potential stem cells. Nat Cell Biol 21: 687–699. DOI: 10.1038/s41556-019-0333-2. [Surani lab] Gariboldi MI, Butler R, Best SM, Cameron RE (2019) Engineering vasculature: Architectural effects on microcapillary-like structure self-assembly. PLoS One 14: e0210390. DOI: 10.1371/journal.pone.0210390.

[Imaging group] Gervais L, van den Beek M, Josserand M, Sallé J, Stefanutti M, Perdigoto CN, Skorski P, Mazouni K, Marshall OJ, Brand AH, Schweisguth F, Bardin AJ (2019) Stem Cell Proliferation Is Kept in Check by the Chromatin Regulators Kismet/CHD7/CHD8 and Trr/MLL3/4. Dev Cell 49: 556–573.e6. DOI: 10.1016/j.devcel.2019.04.033.

Guiu J, Hannezo E, Yui S, Demharter S, Ulyanchenko S, Maimets M, Jørgensen A, Perlman S, Lundvall L, Mamsen LS, Larsen A, Olesen RH, Andersen CY, Thuesen LL, Hare KJ, Pers TH, Khodosevich K, Simons BD, Jensen KB (2019) Tracing the origin of adult intestinal stem cells. Nature 570: 107–111. DOI: 10.1038/s41586-019-1212-5.

Hakes AE, Brand AH (2019) Neural stem cell dynamics: the development of brain tumours. Curr Opin Cell Biol 60: 131–138. DOI: 10.1016/j.ceb.2019.06.001.

Han S, Fink J, Jörg DJ, Lee E, Yum MK, Chatzeli L, Merker SR, Josserand M, Trendafilova T, AnderssonRolf A, Dabrowska C, Kim H, Naumann R, Lee J-H, Sasaki N, Mort RL, Basak O, Clevers H, Stange DE, Philpott A, Kim JK, Simons BD, Koo B-K (2019) Defining the Identity and Dynamics of Adult Gastric Isthmus Stem Cells. Cell Stem Cell 25: 342–356.e7.

DOI: 10.1016/j.stem.2019.07.008.

68 Publications in 2019

Hannezo E, Simons BD (2019) Multiscale dynamics of branching morphogenesis. Curr Opin Cell Biol 60: 99–105. DOI: 10.1016/j.ceb.2019.04.008.

Hiscock TW (2019) Adapting machine-learning algorithms to design gene circuits. BMC Bioinformatics 20: 214. DOI: 10.1186/s12859-0192788-3. [Simons lab] Hoffman M, Gillmor AH, Kunz DJ, Johnston MJ, Nikolic A, Narta K, Zarrei M, King J, Ellestad K, Dang NH, Cavalli FMG, Kushida MM, Coutinho FJ, Zhu Y, Luu B, Ma Y, Mungall AJ, Moore R, Marra MA, Taylor MD, Pugh TJ, Dirks PB, Strother D, Lafay-Cousin L, Resnick AC, Scherer S, Senger DL, Simons BD, Chan JA, Morrissy AS, Gallo M (2019) Intratumoral Genetic and Functional Heterogeneity in Pediatric Glioblastoma.

Cancer Res 79: 2111–2123. DOI: 10.1158/0008-5472.

CAN-18-3441.

Howick VM, Russell AJC, Andrews T, Heaton H, Reid AJ, Natarajan K, Butungi H, Metcalf T, Verzier LH, Rayner JC, Berriman M, Herren JK, Billker O, Hemberg M, Talman AM, Lawniczak MKN (2019) The Malaria Cell Atlas: Single parasite transcriptomes across the complete Plasmodium life cycle. Science 365: eaaw2619. DOI: 10.1126/science.aaw2619.

Jadhav S, Avila J, Schöll M, Kovacs GG, Kövari E, Skrabana R, Evans LD, Kontsekova E, Malawska B, de Silva R, Buee L, Zilka N (2019) A walk through tau therapeutic strategies. Acta Neuropathol Commun 7: 22. DOI: 10.1186/s40478-019-0664-z. [Livesey lab] Jörg DJ, Caygill EE, Hakes AE, Contreras EG, Brand AH, Simons BD (2019) The proneural wave in the Drosophila optic lobe is driven by an excitable reaction-diffusion mechanism. Elife 8: e40919. DOI: 10.7554/eLife.40919.

Kiselev VY, Andrews TS, Hemberg M (2019) Challenges in unsupervised clustering of single-cell RNA-seq data. Nature Reviews Genetics 20: 273–282. DOI: 10.1038/s41576-018-0088-9.

Kitadate Y, Jörg DJ, Tokue M, Maruyama A, Ichikawa R, Tsuchiya S, Segi-Nishida E, Nakagawa T, Uchida A, Kimura-Yoshida C, Mizuno S, Sugiyama F, Azami T, Ema M, Noda C, Kobayashi S, Matsuo I, Kanai Y, Nagasawa T, Sugimoto Y, Takahashi S, Simons BD, Yoshida S (2019) Competition for Mitogens Regulates Spermatogenic Stem Cell Homeostasis in an Open Niche. Cell Stem Cell 24: 79–92.e6. DOI: 10.1016/j. stem.2018.11.013.

Klucnika A, Ma H (2019) A battle for transmission: the cooperative and selfish animal mitochondrial genomes. Open Biol 9: 180267. DOI: 10.1098/ rsob.180267.

Klucnika A, Ma H (2019) Mapping and editing animal mitochondrial genomes: can we overcome the challenges? Philos Trans R Soc Lond B Biol Sci 375: 20190187. DOI: 10.1098/rstb.2019.0187.

Krieger TG, Moran CM, Frangini A, Visser WE, Schoenmakers E, Muntoni F, Clark CA, Gadian D, Chong WK, Kuczynski A, Dattani M, Lyons G, Efthymiadou A, Varga-Khadem F, Simons BD, Chatterjee K, Livesey FJ (2019) Mutations in thyroid hormone receptor α1 cause premature neurogenesis and progenitor cell depletion in human cortical development. Proc Natl Acad Sci U S A 116: 22754– 22763. DOI: 10.1073/pnas.1908762116.

Kucab JE, Zou X, Morganella S, Joel M, Nanda AS, Nagy E, Gomez C, Degasperi A, Harris R, Jackson SP, Arlt VM, Phillips DH, Nik-Zainal S (2019) A Compendium of Mutational Signatures of Environmental Agents. Cell 177: 821–836.e16. DOI: 10.1016/j.cell.2019.03.001.

Lancaster MA, Huch M (2019) Disease modelling in human organoids. Dis Model Mech 12: dmm039347.

DOI: 10.1242/dmm.039347.

Lee JTH, Hemberg M (2019) Supervised clustering for single-cell analysis. Nature Methods 16: 965–966.

DOI: 10.1038/s41592-019-0534-4.

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Leger A, Amaral PP, Pandolfini L, Capitanchik C, Capraro F, Barbieri I, Migliori V, Luscombe NM, Enright AJ, Tzelepis K, Ule J, Fitzgerald T, Birney E, Leonardi T, Kouzarides T (2019) RNA modifications detection by comparative Nanopore direct RNA sequencing. bioRxiv DOI: https://doi. org/10.1101/843136.

Li Z, Solomonidis EG, Meloni M, Taylor RS, Duffin R, Dobie R, Magalhaes MS, Henderson BEP, Louwe PA, D’Amico G, Hodivala-Dilke KM, Shah AM, Mills NL, Simons BD, Gray GA, Henderson NC, Baker AH, Brittan M (2019) Single-cell transcriptome analyses reveal novel targets modulating cardiac neovascularization by resident endothelial cells following myocardial infarction. Eur Heart J 40: 2507–2520. DOI: 10.1093/eurheartj/ehz305.

Lovegrove HE, Bergstralh DT, St Johnston D (2019) The role of integrins in Drosophila egg chamber morphogenesis. Development 146: dev182774. DOI: 10.1242/dev.182774.

Maori E, Navarro IC, Boncristiani H, Seilly DJ, Rudolph KLM, Sapetschnig A, Lin C-C, Ladbury JE, Evans JD, Heeney JL, Miska EA (2019) A Secreted RNA Binding Protein Forms RNA-Stabilizing Granules in the Honeybee Royal Jelly. Mol Cell 74: 598–608.e6. DOI: 10.1016/j.molcel.2019.03.010.

Matsushima W, Brink K, Schroeder J, Miska EA, Gapp K (2019) Mature sperm small-RNA profile in the sparrow: implications for transgenerational effects of age on fitness. Environ Epigenet 5: dvz007. DOI: 10.1093/ eep/dvz007.

Matsushima W, Herzog VA, Neumann T, Gapp K, Zuber J, Ameres SL, Miska EA (2019) Sequencing cell-typespecific transcriptomes with SLAM-ITseq. Nat Protoc 14: 2261–2278. DOI: 10.1038/s41596-019-0179-x.

Michalak EM, Burr ML, Bannister AJ, Dawson MA (2019) The roles of DNA, RNA and histone methylation in ageing and cancer. Nat Rev Mol Cell Biol 20: 573–589.

DOI: 10.1038/s41580-019-0143-1. [Kouzarides lab]

Mongera A, Michaut A, Guillot C, Xiong F, Pourquié O (2019) Mechanics of Anteroposterior Axis Formation in Vertebrates. Annu Rev Cell Dev Biol 35: 259–283.

DOI: 10.1146/annurev-cellbio-100818-125436.

Morafraile EC, Hänni C, Allen G, Zeisner T, Clarke C, Johnson MC, Santos MM, Carroll L, Minchell NE, Baxter J, Banks P, Lydall D, Zegerman P (2019) Checkpoint inhibition of origin firing prevents DNA topological stress. Genes Dev 33: 1539–1554. DOI: 10.1101/gad.328682.119.

Otsuki L, Brand AH (2019) Dorsal-Ventral Differences in Neural Stem Cell Quiescence Are Induced by p57KIP2/Dacapo. Dev Cell 49: 293–300.e3. DOI: 10.1016/j.devcel.2019.02.015.

Pacini CE, Bradshaw CR, Garrett NJ, Koziol MJ (2019) Characteristics and homogeneity of N6-methylation in human genomes. Sci Rep 9: 5185. DOI: 10.1038/ s41598-019-41601-7. [Gurdon lab] Pandolfini L, Barbieri I, Bannister AJ, Hendrick A, Andrews B, Webster N, Murat P, Mach P, Brandi R, Robson SC, Migliori V, Alendar A, d’Onofrio M, Balasubramanian S, Kouzarides T (2019) METTL1 Promotes let-7 MicroRNA Processing via m7G Methylation. Mol Cell 74: 1278– 1290.e9. DOI: 10.1016/j.molcel.2019.03.040.

Paonessa F, Evans LD, Solanki R, Larrieu D, Wray S, Hardy J, Jackson SP, Livesey FJ. (2019) Microtubules deform the nuclear membrane and disrupt nucleocytoplasmic transport in tau-mediated frontotemporal dementia.

Cell Rep 26: 582–593. DOI: 10.1016/j.celrep.2018.12.085.

Parsons HT, Stevens TJ, McFarlane HE, Vidal-Melgosa S, Griss J, Lawrence N, Butler R, Sousa MML, Salemi M, Willats WGT, Petzold CJ, Heazlewood JL, Lilley KS (2019) Separating Golgi Proteins from Cis to Trans Reveals Underlying Properties of Cisternal Localization. Plant Cell 31: 2010–2034. DOI: 10.1105/ tpc.19.00081. [Imaging group] Pierson Smela M, Sybirna A, Wong FCK, Surani MA (2019) Testing the role of SOX15 in human primordial germ cell fate. Wellcome Open Res 4: 122. DOI: 10.12688/wellcomeopenres.15381.2.

70 Publications in 2019

Pijuan-Sala B, Griffiths JA, Guibentif C, Hiscock TW, Jawaid W, Calero-Nieto FJ, Mulas C, Ibarra-Soria X, Tyser RCV, Ho DLL, Reik W, Srinivas S, Simons BD, Nichols J, Marioni JC, Göttgens B (2019) A singlecell molecular map of mouse gastrulation and early organogenesis. Nature 566: 490–495. DOI: 10.1038/ s41586-019-0933-9.

Nielsen ML, Kouzarides T, Castelo-Branco G (2019) Interaction of Sox2 with RNA binding proteins in mouse embryonic stem cells. Exp Cell Res 381: 129–138. DOI: 10.1016/j.yexcr.2019.05.006.

Prior N, Hindley CJ, Rost F, Meléndez E, Lau WWY, Göttgens B, Rulands S, Simons BD, Huch M (2019) Lgr5+ stem and progenitor cells reside at the apex of a heterogeneous embryonic hepatoblast pool. Development 146: dev174557. DOI: 10.1242/ dev.174557.

Schiller HB, Montoro DT, Simon LM, Rawlins EL, Meyer KB, Strunz M, Vieira Braga FA, Timens W, Koppelman GH, Budinger GRS, Burgess JK, Waghray A, van den Berge M, Theis FJ, Regev A, Kaminski N, Rajagopal J, Teichmann SA, Misharin AV, Nawijn MC (2019) The Human Lung Cell Atlas: A High-Resolution Reference Map of the Human Lung in Health and Disease.

Am J Respir Cell Mol Biol 61: 31–41. DOI: 10.1165/ rcmb.2018-0416TR.

Prior N, Inacio P, Huch M (2019) Liver organoids: from basic research to therapeutic applications. Gut 68: 2228–2237. DOI: 10.1136/gutjnl-2019-319256.

Surani, MA (2019) Voices: The Importance of Fetal Tissue Research. Cell Stem Cell 24: 357–359. DOI: 10.1016/j.stem.2019.01.012.

Puddu F, Herzog M, Selivanova A, Wang S, Zhu J, KleinLavi S, Gordon M, Meirman R, Millan-Zambrano G, Ayestaran I, Salguero I, Sharan R, Li R, Kupiec M, Jackson SP (2019) Genome architecture and stability in the Saccharomyces cerevisiae knockout collection.

Nature 573: 416–420. DOI: 10.1038/s41586-019-1549-9.

Svardal H, Quah FX, Malinsky M, Ngatunga BP, Miska EA, Salzburger W, Genner MJ, Turner GF, Durbin R (2019) Ancestral hybridisation facilitated species diversification in the Lake Malawi cichlid fish adaptive radiation. Mol Biol Evol DOI: 10.1093/molbev/msz294.

Ramos-Ibeas P, Sang F, Zhu Q, Tang WWC, Withey S, Klisch D, Wood L, Loose M, Surani MA, Alberio R (2019) Pluripotency and X chromosome dynamics revealed in pig pre-gastrulating embryos by single cell analysis. Nat Commun 10: 500. DOI: 10.1038/ s41467-019-08387-8.

Rawlins, EL (2019) Voices: The Importance of Fetal Tissue Research. Cell Stem Cell 24: 357–359. DOI: 10.1016/j.stem.2019.01.012.

Salguero I, Belotserkovskaya R, Coates J, SczanieckaClift M, Demir M, Jhujh S, Wilson MD, Jackson SP (2019) MDC1 PST-repeat region promotes histone H2AX-independent chromatin association and DNA damage tolerance. Nat Commun 10: 5191. DOI: 10.1038/s41467-019-12929-5.

Samudyata, Amaral PP, Engström PG, Robson SC,

Sybirna A, Wong FCK, Surani MA (2019) Genetic basis for primordial germ cells specification in mouse and human: Conserved and divergent roles of PRDM and SOX transcription factors. Curr Top Dev Biol 135: 35–89. DOI: 10.1016/bs.ctdb.2019.04.004.

Thompson DJ et al. including Jackson SP (2019) Genetic predisposition to mosaic Y chromosome loss in blood. Nature 575: 652–657. DOI: 10.1038/s41586019-1765-3.

Tzelepis K, Rausch O, Kouzarides T (2019) RNAmodifying enzymes and their function in a chromatin context. Nat Struct Mol Biol 26: 858–862. DOI: 10.1038/s41594-019-0312-0. van den Ameele J, Brand AH (2019) Neural stem cell temporal patterning and brain tumour growth rely on oxidative phosphorylation. Elife 8: e47887. DOI: 10.7554/eLife.47887.

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van den Ameele J, Krautz R, Brand AH (2019) TaDa! Analysing cell type-specific chromatin in vivo with Targeted DamID. Curr Opin Neurobiol 56: 160–166.

DOI: 10.1016/j.conb.2019.01.021. van den Ameele J, Li AYZ, Ma H, Chinnery PF (2019) Mitochondrial heteroplasmy beyond the oocyte bottleneck. Semin Cell Dev Biol 97: 156–166. DOI: 10.1016/j.semcdb.2019.10.001.

Van Haute L, Lee S-Y, McCann BJ, Powell CA, Bansal D, Vasiliauskaitė L, Garone C, Shin S, Kim J-S, Frye M, Gleeson JG, Miska EA, Rhee H-W, Minczuk M (2019) NSUN2 introduces 5-methylcytosines in mammalian mitochondrial tRNAs. Nucleic Acids Res 47: 8720– 8733. DOI: 10.1093/nar/gkz559.

Weng C, Kosalka J, Berkyurek AC, Stempor P, Feng X, Mao H, Zeng C, Li WJ, Yan YH, Dong MQ, Morero NR, Zuliani C, Barabas O, Ahringer J, Guang S, Miska EA (2019) The USTC co-opts an ancient machinery to drive piRNA transcription in C. elegans. Genes Dev 33: 90–102. DOI: 10.1101/gad.319293.118.

Wiese M, Bannister AJ, Basu S, Boucher W, Wohlfahrt K, Christophorou MA, Nielsen ML, Klenerman D, Laue ED, Kouzarides T (2019) Citrullination of HP1γ chromodomain affects association with chromatin.

Epigenetics Chromatin 12: 21. DOI: 10.1186/s13072019-0265-x.

Publications in 2020 Albarnaz JD, Ren H, Torres AA, Shmeleva EV, Melo CA, Bannister AJ, Smith GL (2020) Viral mimicry of p65/RelA transactivation domain to inhibit NF-kB activation. bioRxiv DOI: 10.1101/2020.10.23.353060.

[Kouzarides lab] Aragona M, Sifrim A, Malfait M, Song Y, Van Herck J, Dekoninck S, Gargouri S, Lapouge G, Swedlund B, Dubois C, Baatsen P, Vints K, Han S, Tissir F, Voet T, Simons BD, Blanpain C (2020) Mechanisms of stretchmediated skin expansion at single-cell resolution.

Nature 584: 268–273. DOI: 10.1038/s41586-020-2555-7.

Aztekin C, Hiscock TW, Butler R, De Jesús Andino F, Robert J, Gurdon JB, Jullien J (2020) The myeloid lineage is required for the emergence of a regeneration-permissive environment following Xenopus tail amputation. Development 147: dev185496. DOI: 10.1242/dev.185496.

Aztekin C, Hiscock TW, Gurdon JB, Jullien J, Marioni JC, Simons BD (2020) Secreted inhibitors drive the loss of regeneration competence in Xenopus limbs. bioRxiv DOI: 10.1101/2020.06.01.127654.

Barbieri I, Kouzarides T (2020) Role of RNA modifications in cancer. Nat Rev Cancer 20: 303–322.

DOI: 10.1038/s41568-020-0253-2.

Belotserkovskaya R, Raga Gil E, Lawrence N, Butler R, Clifford G, Wilson MD, Jackson SP (2020) PALB2 chromatin recruitment restores homologous recombination in BRCA1-deficient cells depleted of 53BP1. Nat Commun 11: 819. DOI: 10.1038/s41467020-14563-y.

Berkyurek A, Furlan G, Lampersberger L, Beltran T, Weick E-M, Nischwitz E, Navarro IC, Braukmann F, Akay A, Price J, Butter F, Sarkies P, Miska E (2020) The RNA Polymerase II core subunit RPB-

72 Publications in 2020

9 directs transcriptional elongation at piRNA loci in Caenorhabditis elegans. bioRxiv DOI: 10.1101/2020.05.01.070433.

Berquez M, Gadsby JR, Festa BP, Butler R, Jackson SP, Berno V, Luciani A, Devuyst O, Gallop JL (2020) The phosphoinositide 3-kinase inhibitor alpelisib restores actin organization and improves proximal tubule dysfunction in vitro and in a mouse model of Lowe syndrome and Dent disease. Kidney Int 98: 883–896.

DOI: 10.1016/j.kint.2020.05.040.

Bista I, McCarthy SA, Wood J, Ning Z, Detrich Iii HW, Desvignes T, Postlethwait J, Chow W, Howe K, Torrance J, Smith M, Oliver K, Vertebrate Genomes Project Consortium, Miska EA, Durbin R (2020) The genome sequence of the channel bull blenny, Cottoperca gobio (Günther, 1861). Wellcome Open Res 5: 148. DOI: 10.12688/wellcomeopenres.16012.1.

Bottes S, Jaeger BN, Pilz G-A, Jörg DJ, Cole JD, Kruse M, Harris L, Korobeynyk VI, Mallona I, Helmchen F, Guillemot F, Simons BD, Jessberger S (2020) Longterm self-renewing stem cells in the adult mouse hippocampus identified by intravital imaging. Nat Neurosci DOI: 10.1038/s41593-020-00759-4.

Bowden AR, Morales-Juarez DA, Sczaniecka-Clift M, Agudo MM, Lukashchuk N, Thomas JC, Jackson SP (2020) Parallel CRISPR-Cas9 screens clarify impacts of p53 on screen performance. Elife 9: e55325. DOI: 10.7554/eLife.55325.

a036202. DOI: 10.1101/cshperspect.a036202.

Chauve L, Le Pen J, Hodge F, Todtenhaupt P, Biggins L, Miska EA, Andrews S, Casanueva O (2020) HighThroughput Quantitative RT-PCR in Single and Bulk C. elegans Samples Using Nanofluidic Technology. J Vis Exp (159): e61132. DOI: 10.3791/61132.

Cheetham SW, Brand AH (2020) Mapping RNAChromatin Interactions In Vivo with RNA-DamID. Methods Mol Biol 2161: 255–264. DOI: 10.1007/978-10716-0680-3_18.

Corominas-Murtra B, Scheele CLGJ, Kishi K, Ellenbroek SIJ, Simons BD, van Rheenen J, Hannezo E (2020) Stem cell lineage survival as a noisy competition for niche access. Proc Natl Acad Sci U S A 117: 16969– 16975. DOI: 10.1073/pnas.1921205117.

Dekoninck S, Hannezo E, Sifrim A, Miroshnikova YA, Aragona M, Malfait M, Gargouri S, de Neunheuser C, Dubois C, Voet T, Wickström SA, Simons BD, Blanpain C (2020) Defining the Design Principles of Skin Epidermis Postnatal Growth. Cell 181: 604–6.20E+24.

DOI: 10.1016/j.cell.2020.03.015.

Deng T, Stempor P, Appert A, Daube M, Ahringer J, Hajnal A, Lattmann E (2020) The Caenorhabditis elegans homolog of the Evi1 proto-oncogene, egl-43, coordinates G1 cell cycle arrest with pro-invasive gene expression during anchor cell invasion. PLoS Genet 16: e1008470. DOI: 10.1371/journal.pgen.1008470.

Braukmann F, Jordan D, Jenkins B, Koulman A, Miska EA (2020) SID-2 negatively regulates development likely independent of nutritional dsRNA uptake. RNA Biol DOI: 10.1080/15476286.2020.1827619.

Denoth-Lippuner A, Jaeger BN, Liang T, Chie SE, Royall LN, Kruse M, Simons BD, Jessberger S (2020) Visualization of individual cell division history in complex tissues. bioRxiv DOI: 10.1101/2020.08.26.266171.

Burton N, Riccio C, Dallaire A, Price J, Jenkins B, Koulman A, Miska E (2020) Cysteine synthases CYSL-1 and CYSL-2 mediate C. elegans heritable adaptation to P. vranovensis infection. Nat Commun 11:1741.

DOI: 10.1038/s41467-020-15555-8.

Fic W, Bastock R, Raimondi F, Los E, Inoue Y, Gallop J, Russell R, St Johnston D (2020) RhoGAP19D inhibits Cdc42 laterally to control epithelial cell shape and prevent invasion. bioRxiv DOI: 10.1101/2020.09.17.300145.

Chatzeli L, Simons BD (2020) Tracing the Dynamics of Stem Cell Fate. Cold Spring Harb Perspect Biol 12:

Foerster S, Neumann B, McClain C, Di Canio L, Chen C, Reich D, Simons B, Franklin RJM (2020) Proliferation is

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a requirement for differentiation of oligodendrocyte progenitor cells during CNS remyelination. bioRxiv DOI: 10.1101/2020.05.21.108373.

Gaggioli V, Kieninger MR, Klucnika A, Butler R, Zegerman P (2020) Identification of the critical replication targets of CDK reveals direct regulation of replication initiation factors by the embryo polarity machinery in C. elegans. PLoS Genet 16: e1008948.

DOI: 10.1371/journal.pgen.1008948.

Gal C, Carelli FN, Appert A, Cerrato C, Huang N, Dong Y, Murphy J, Ahringer J (2020) DREAM represses distinct targets by cooperating with different THAP domain proteins. bioRxiv DOI: 10.1101/2020.08.13.249698.

Gallop JL (2020) Filopodia and their links with membrane traffic and cell adhesion. Semin Cell Dev Biol 102: 81–89. DOI: 10.1016/j.semcdb.2019.11.017.

Georgakopoulos N, Prior N, Angres B, Mastrogiovanni G, Cagan A, Harrison D, Hindley CJ, Arnes-Benito R, Liau S-S, Curd A, Ivory N, Simons BD, Martincorena I, Wurst H, Saeb-Parsy K, Huch M (2020) Long-term expansion, genomic stability and in vivo safety of adult human pancreas organoids. BMC Dev Biol 20: 4. DOI: 10.1186/s12861-020-0209-5.

Gurdon JB, Javed K, Vodnala M, Garrett N (2020) Longterm association of a transcription factor with its chromatin binding site can stabilize gene expression and cell fate commitment. Proc Natl Acad Sci U S A 117: 15075–15084. DOI: 10.1073/pnas.2000467117.

Gurdon JB, Javed K, Wen MH, Barbosa Triana HM (2020) Injected cells provide a valuable complement to cellfree systems for analysis of gene expression. Exp Cell Res 396: 112296. DOI: 10.1016/j.yexcr.2020.112296.

Hakes AE, Brand AH (2020) Tailless/TLX reverts intermediate neural progenitors to stem cells driving tumourigenesis via repression of asense/ASCL1. Elife 9: e53377. DOI: 10.7554/eLife.53377.

Han N, Hwang W, Tzelepis K, Schmerer P, Yankova E, MacMahon M, Lei W, Katritsis N, Liu A, Schuldt

A, Harris R, Chapman K, McCaughan F, Weber F, Kouzarides T (2020) Identification of SARS-CoV-2 induced pathways reveal drug repurposing strategies. bioRxiv DOI: 10.1101/2020.08.24.265496.

Herzog M, Alonso-Perez E, Salguero I, Warringer J, Adams D, Jackson S, Puddu F (2020) Mutagenic mechanisms of cancer-associated DNA polymerase ε alleles. bioRxiv DOI: 10.1101/2020.09.04.270124.

Jarsch IK, Gadsby JR, Nuccitelli A, Mason J, Shimo H, Pilloux L, Marzook B, Mulvey CM, Dobramysl U, Bradshaw CR, Lilley KS, Hayward RD, Vaughan TJ, Dobson CL, Gallop JL (2020) A direct role for SNX9 in the biogenesis of filopodia. J Cell Biol 219: e201909178. DOI: 10.1083/jcb.201909178.

Johnson M, Can G, Santos M, Alexander D, Zegerman P (2020) Checkpoint inhibition of origin firing prevents inappropriate replication outside of S-phase. bioRxiv DOI: 10.1101/2020.09.30.320325.

Jörg DJ, Kitadate Y, Yoshida S, Simons BD (2020) Stem Cell Populations as Self-Renewing Many-Particle Systems. Ann Rev Con Mat Phys 12. DOI: 10.1146/ annurev-conmatphys-041720-125707.

Kouzarides T, Pandolfini L, Barbieri I, Bannister AJ, Andrews B (2020) Further Evidence Supporting N7-Methylation of Guanosine (m7G) in Human MicroRNAs. Mol Cell 79: 201–202. DOI: 10.1016/j. molcel.2020.05.023.

Lewis A, Berkyurek AC, Greiner A, Sawh AN, Vashisht A, Merrett S, Flamand MN, Wohlschlegel J, Sarov M, Miska EA, Duchaine TF (2020) A Family of ArgonauteInteracting Proteins Gates Nuclear RNAi. Mol Cell 78: 862–875.E8. DOI: 10.1016/j.molcel.2020.04.007.

Lewis SH, Ross L, Bain SA, Pahita E, Smith SA, Cordaux R, Miska EA, Lenhard B, Jiggins FM, Sarkies P (2020) Widespread conservation and lineage-specific diversification of genome-wide DNA methylation patterns across arthropods PLoS Genet 16: e1008864.

DOI: 10.1371/journal.pgen.1008864.

74 Publications in 2020

Lin Y, Yang J, Shen Z, Ma J, Simons BD, Shi S-H (2020) Behavior and lineage progression of neural progenitors in the mammalian cortex.

Curr Opin Neurobiol 66: 144–157. DOI: 10.1016/j. conb.2020.10.017.

Lloyd RL, Wijnhoven PWG, Ramos-Montoya A, Wilson Z, Illuzzi G, Falenta K, Jones GN, James N, Chabbert CD, Stott J, Dean E, Lau A, Young LA (2020) Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells. Oncogene 39: 4869–4883. DOI: 10.1038/ s41388-020-1328-y. [Jackson lab] Loeillet S, Herzog M, Puddu F, Legoix P, Baulande S, Jackson SP, Nicolas AG (2020) Trajectory and uniqueness of mutational signatures in yeast mutators. Proc Natl Acad Sci U S A 117: 24947–24956.

DOI: 10.1073/pnas.2011332117.

Lohoff T, Ghazanfar S, Missarova A, Koulena N, Pierson N, Griffiths JA, Bardot ES, Eng C-HL, Tyser RCV, Argelaguet R, Guibentif C, Srinivas S, Briscoe J, Simons BD, Hadjantonakis A-K, Göttgens B, Reik W, Nichols J, Cai L, Marioni JC (2020) Highly multiplexed spatially resolved gene expression profiling of mouse organogenesis. bioRxiv DOI: 10.1101/2020.11.20.391896.

Lowe DJ, Herzog M, Mosler T, Cohen H, Felton S, Beli P, Raj K, Galanty Y, Jackson SP (2020) Chronic irradiation of human cells reduces histone levels and deregulates gene expression. Sci Rep 10: 2200. DOI: 10.1038/ s41598-020-59163-4.

McCarthy DJ, Rostom R, Huang Y, Kunz DJ, Danecek P, Bonder MJ, Hagai T, Lyu R, HipSci Consortium, Wang W, Gaffney DJ, Simons BD, Stegle O, Teichmann SA (2020) Cardelino: computational integration of somatic clonal substructure and single-cell transcriptomes. Nat Methods 17: 414–421. DOI: 10.1038/s41592-020-0766-3.

Navarro IC, Tuorto F, Jordan D, Legrand C, Price J, Braukmann F, Hendrick A, Akay A, Kotter A, Helm M, Lyko F, Miska E (2020) Translational adaptation

to heat stress is mediated by 5-methylcytosine RNA modification in Caenorhabditis elegans. EMBO J e105496. DOI: 10.15252/embj.2020105496.

Neupane J, Wong FCK, Surani MA (2020) The unfolding body plan of primate embryos in culture. Cell Research 30: 103–104. DOI: 10.1038/s41422-0190269-x.

Ochi T, Quarantotti V, Lin H, Jullien J, Rosa E Silva I, Boselli F, Barnabas DD, Johnson CM, McLaughlin SH, Freund SMV, Blackford AN, Kimata Y, Goldstein RE, Jackson SP, Blundell TL, Dutcher SK, Gergely F, van Breugel M (2020) CCDC61/VFL3 Is a Paralog of SAS6 and Promotes Ciliary Functions. Structure 28: 674–689.E11. DOI: 10.1016/j.str.2020.04.010.

Oginuma M, Harima Y, Tarazona OA, Diaz-Cuadros M, Michaut A, Ishitani T, Xiong F, Pourquié O (2020) Intracellular pH controls WNT downstream of glycolysis in amniote embryos. Nature 584: 98–101.

DOI: 10.1038/s41586-020-2428-0.

Oikawa M, Simeone A, Hormanseder E, Teperek M, Gaggioli V, O’Doherty A, Falk E, Sporniak M, D’Santos C, Franklin VNR, Kishore K, Bradshaw CR, Keane D, Freour T, David L, Grzybowski AT, Ruthenburg AJ, Gurdon J, Jullien J (2020) Epigenetic homogeneity in histone methylation underlies sperm programming for embryonic transcription. Nat Commun 11: 3491–3491. DOI: 10.1038/s41467-020-17238-w.

Otsuki L, Brand AH (2020) Quiescent Neural Stem Cells for Brain Repair and Regeneration: Lessons from Model Systems. Trends Neurosci 43: 213–226. DOI: 10.1016/j.tins.2020.02.002.

Parada G, Munita R, Georgakopoulos-Soares I, Fernandez H, Metzakopian E, Andres ME, Miska E, Hemberg M (2020) MicroExonator enables systematic discovery and quantification of microexons across mouse embryonic development. bioRxiv DOI: 10.1101/2020.02.12.945683.

Q&A. A conversation with John Gurdon and Shinya Yamanaka (2020) Stem Cell Rep 14: 351–356. DOI: 10.1016/j.stemcr.2020.02.007

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Salvage SC, Rees JS, McStea A, Hirsch M, Wang L, Tynan CJ, Reed MW, Irons JR, Butler R, Thompson AJ, Martin-Fernandez ML, Huang CL-H, Jackson AP (2020) Supramolecular clustering of the cardiac sodium channel Nav1.5 in HEK293F cells, with and without the auxiliary β3-subunit. FASEB J 34: 3537–3553. DOI: 10.1096/fj.201701473RR. [Imaging group] Schon KR, Ratnaike T, van den Ameele J, Horvath R, Chinnery PF (2020) Mitochondrial Diseases: A Diagnostic Revolution. Trends Genet 36: 702–717.

DOI: 10.1016/j.tig.2020.06.009. [Brand lab] Scoones JC, Hiscock TW (2020) A dot-stripe Turing model of joint patterning in the tetrapod limb.

Development 147: dev.183699. DOI: 10.1242/ dev.183699. [Simons lab] Serizay J, Dong Y, Jänes J, Chesney M, Cerrato C, Ahringer J (2020) Distinctive regulatory architectures of germline-active and somatic genes in C. elegans. Genome Res 30: 1752–1765. DOI: 10.1101/ gr.265934.120.

Suen KM, Braukmann F, Butler R, Bensaddek D, Akay A, Lin C-C, Milonaitytė D, Doshi N, Sapetschnig A, Lamond A, Ladbury JE, Miska EA (2020) DEPS-1 is required for piRNA-dependent silencing and PIWI condensate organisation in Caenorhabditis elegans.

Nat Commun 11: 4242. DOI: 10.1038/s41467-02018089-1. [Miska lab] Sun D, Evans L, Rawlins E (2020) Organoid Easytag: an efficient workflow for gene targeting in human organoids. bioRxiv DOI: 10.1101/2020.05.04.076067.

Sungnak W, Huang N, Bécavin C, Berg M, Queen R, Litvinukova M, Talavera-López C, Maatz H, Reichart D, Sampaziotis F, Worlock KB, Yoshida M, Barnes JL, HCA Lung Biological Network (2020) SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med 26: 681–687. DOI: 10.1038/s41591-020-0868-6.

[Rawlins lab] Sybirna A, Tang WWC, Pierson Smela M, Dietmann S, Gruhn WH, Brosh R, Surani MA (2020) A critical role of

PRDM14 in human primordial germ cell fate revealed by inducible degrons. Nat Commun 11: 1282. DOI: 10.1038/s41467-020-15042-0.

Sznurkowska MK, Hannezo E, Azzarelli R, Chatzeli L, Ikeda T, Yoshida S, Philpott A, Simons BD (2020) Tracing the cellular basis of islet specification in mouse pancreas. Nat Commun 11: 5037. DOI: 10.1038/s41467-020-18837-3.

Than-Trong E, Kiani B, Dray N, Ortica S, Simons B, Rulands S, Alunni A, Bally-Cuif L (2020) Lineage hierarchies and stochasticity ensure the long-term maintenance of adult neural stem cells. Sci Adv 6: eaaz5424. DOI: 10.1126/sciadv.aaz5424. van den Ameele J, Fuge J, Pitceathly RDS, Berry S, McIntyre Z, Hanna MG, Lee M, Chinnery PF (2020) Chronic pain is common in mitochondrial disease.

Neuromuscul Disord 30: 413–419. DOI: 10.1016/j. nmd.2020.02.017. [Brand lab] van Steenwyk G, Gapp K, Jawaid A, Germain P-L, Manuella F, Tanwar DK, Zamboni N, Gaur N, Efimova A, Thumfart KM, Miska EA, Mansuy IM (2020) Involvement of circulating factors in the transmission of paternal experiences through the germline. EMBO J 39: e104579. DOI: 10.15252/embj.2020104579.

Venkataraman GG, Miska EA, Jordan DJ (2020) Geometric Requirements for Nonequilibrium Discrimination. arXiv:2001.11918v2 [physics.bio-ph].

Vernaz G, Malinsky M, Svardal H, Du M, Tyers A, Santos E, Durbin R, Genner M, Turner G, Miska E (2020) The methylomes of Lake Malawi cichlids reveal epigenetic variation associated with phenotypic diversification. bioRxiv DOI: 10.1101/2020.11.24.383034.

Wang J, Allgeyer ES, Sirinakis G, Zhang Y, Hu K, Lessard MD, Li Y, Diekmann R, Phillips MA, Dobbie IM, Ries J, Booth MJ, Bewersdorf J (2020) Implementation of a 4Pi-SMS super-resolution microscope. Nat Protoc DOI: 10.1038/s41596-020-00428-7. [St Johnston lab] Watson JK, Sanders P, Dunmore R, Rosignoli G, Julé Y, Rawlins EL, Mustelin T, May R, Clarke D, Finch DK (2020) Distal lung epithelial progenitor cell function

76 Publications in 2020

declines with age. Sci Rep 10: 10490. DOI: 10.1038/ s41598-020-66966-y.

Webber M, Jackson SP, Moon JC, Captur G (2020) Myocardial Fibrosis in Heart Failure: Anti-Fibrotic Therapies and the Role of Cardiovascular Magnetic Resonance in Drug Trials. Cardiol Ther 9: 363–376.

DOI: 10.1007/s40119-020-00199-y.

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The Gurdon Institute 77

Full staff lists for 2019 and 2020 can be found in the online supplement at www.gurdon.cam.ac.uk/about/prospectus International Scientific Advisory Board 2019 and 2020 Professor Sir Adrian Bird (Chair)

Professor Ken Zaret

Wellcome Trust Centre for Cell Biology, University of Edinburgh

Perelman School of Medicine, University of Pennsylvania

Professor Christine Mummery

CEO of LifeArc

Leiden University Medical Center

Professor Charles Swanton

Professor Peter Rigby

The Francis Crick Institute, London

Professor Emeritus of Developmental Biology Dr Sally Temple

Dr Melanie Lee CBE

Dr Pierre Léopold Institut Curie, Paris

Neural Stem Cell Institute, New York

Acknowledgements Photo and image credits Front cover image

By Andy Li (Ma lab), who says “This image shows the testis of Drosophila melanogaster expressing centrosominGFP (green) and tubulin-RFP (red) and stained to show cell nuclei (DAPI; blue), captured on the Leica SP8 confocal microscope at 630X magnification. The image has been processed to resemble a projection of the world map, to symbolise the international scientific community at the Gurdon Institute”.

Back cover image

By Oriol Llorà Batlle (Brand lab).

Drosophila melanogaster salivary glands, captured with an SP8 confocal

microscope at 10X magnification, visualised by staining cell nuclei (DAPI; cyan) and actin (Phalloidin; magenta).

labcoats & 76 by Peter Williamson; p 65 family day by Jelle van den Ameele, party costumes by Florence Leroy.

Portrait photos Group leaders by Chris Green, except: pp 3, 20 & 30 by James Smith; p 28 by Eva Hörmanseder; p 44 by brandAnonymous; pp 22, 24, 46, 48, 52 & 54 unknown.

Other images Research illustrations pp 4, 16 (l), 29, 31, 33, 35, 37, 41, 45, 47, 51, 53 & 55: by Claudia Flandoli; pp 6-7 coronavirus by Onisha Patel; p. 16 (r): Damla Sarac; p.64 Claudia Stocker.

Research group and support staff photos

by Chris Green except pp 24 & 54.

Section-headers pp 8-9, 18-19 & 60-61: details from oil sketches by Caroline Walker.

Other photos P 5 (l) and p 63 (MEP) James Smith; p 5 (mid and r) Natalie Glasberg; p 17 (l) Naomi Clements-Brod, (r) Stephanie Norwood; p 56 Sylviane Moss; p 57 (r) Al Downie; p 64 Miguel Salvador; pp 65

Production Edited and produced by Claire O’Brien, with thanks to Emma Gant, Daniel Sargent, Hélène Doerflinger and Kathy Oswald.

Wellcome/ Cancer Research UK Gurdon Institute The Henry Wellcome Building of Cancer and Developmental Biology University of Cambridge Tennis Court Road Cambridge CB2 1QN, UK Tel: +44 (0)1223 334088 Fax: +44 (0)1223 334089 www.gurdon.cam.ac.uk contact@gurdon.cam.ac.uk @GurdonInstitute