WIMM PI
CURRICULUM VITAE
Personal data
Name:
Nationality :
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Current Position
2005- present
2008-present
July 2012
Katja Simon
German
katja.simon@ndm.ox.ac.uk
Independent grant funding
Head of the Translational Immunology Laboratory, Biomedical Research
Centre, NIHR
Awarded open-end contract by Oxford University, Associate Professor
Previous Positions
1994-1998
Postdoc 1 Centre d'Immunologie Marseille Luminy, France, Signalling and
cell death in the thymus, A-M. Schmitt-Verhulst
1999- 2005
Postdoc 2 Weatherall Institute of Molecular Medicine (WIMM), Oxford,
Death receptors in immunity, Gavin Screaton
1999-2004
Organiser and Lecturer of " Methods and Techniques" course for first
year DPhil students, WIMM
2000-2007
Tutor in Immunology and Cell Death to Undergraduate students
2005-2008
Lecturer for the Final Honour School of Medicine and MsC Integrated
Immunology, University of Oxford
2007-2010
Examiner of the MsC course Integrated Immunology
2006-present
Supervision of 4 PhD students (one was Departmental Graduate Prize
winner in 2010)
Research Achievements
In my PhD, I described a Th1 cytokine pattern in patients with rheumatoid arthritis, an
achievement for which I received the EULAR Award. As a postdoctoral fellow, I identified key
molecules signalling for thymocyte death and ruled out that TRAIL, a cell death receptor,
mediates thymic cell death. I also demonstrated that the expression of Fas ligand by tumours
breaks tolerance and induces an innate inflammation leading to tumour rejection, followed by a
powerful antibody response (Isis patent 2002). The tumour-rejecting monoclonal antibodies that
I generated cleared murine melanoma.
In 2005, I obtained my first independent grant, and I started to build my research group around
the role of autophagy in the immune and hematopoietic system. Autophagy is the major cellular
lysosomal catabolic process that degrades damaged organelles and cytoplasmic bulk material.
Molecular tools to study autophagy were just becoming available. At the time it was thought that
autophagy was a cell death mechanism. We, and others subsequently demonstrated that in vivo
autophagy is primarily a survival and cytoprotective pathway.
We demonstrated that mice lacking an essential autophagy gene in the haematopoietic system
(VavAtg7-/-) develop severe lethal anaemia due to dying red blood cells (RBCs). Autophagy is
essential for the selective removal of mitochondria from maturing RBCs. Furthermore VavAtg7-/mice develop myelodysplasia with myeloid proliferation and malignancy. Blast cells from bone
marrow from AML patients show decreased levels of autophagy. Low autophagy levels lead to
increased proliferation rate in a MLL-ENL leukemic line, possibly because of a switch to
glycolysis due to deficient mitophagy.
In addition VavAtg7-/- show a prematurely aged immune system, with malfunctioning stem cells,
inflamm-ageing, lymphopenia and other hallmarks of an ageing innate and adaptive immune
system. Mice with a T cell specific deletion of autophagy are unable to mount a T cell memory
response to MCMV and Influenza. We found a rejuvenating drug that can increase T cell
responses in an autophagy dependent fashion.
Using multispectral imaging analysis we found that autophagy levels fall with age in human T
lymphocytes, correlating with mitochondrial damage, increased reactive oxygen species and
increased double strand DNA breaks, typical signs of replicative senescence. Taken together,
we postulate that age-related decline of autophagy contributes to immune senescence and
myeloid proliferation. Interestingly MDS is prevalent in the elderly.
What are the Future Aims of Your Current Group?
The interplay between autophagy, cell cycle control and malignancy is emerging as a key
feature in tumour development, which we will be investigating over the next five years in the
haematopoietic system. Our tools, conditional Atg7 and Atg5 mouse models, autophagy
detection techniques in human primary cells, as well as state-of-the-art immunological and
haematological techniques, make us highly competitive in this field.
The pathways that lead to division and growth in multicellular organisms have been conserved
from single to multi-cellular organisms. One such conserved pathway is autophagy. Autophagy
is the major lysosomal mechanism to degrade macromolecules in the cell. Cell growth in
response to environmental conditions is regulated by two antagonistic processes: protein
synthesis (anabolism) and autophagy (catabolism), integrating signals from growth factors,
amino acids and energy status through the TOR complex. mTOR signaling inhibits autophagy
while it positively regulates protein synthesis. Autophagy can also respond directly
independently of mTOR to the cellular milieu.
Under certain environmental or developmental conditions, cells leave the cell cycle to enter one
of three types of cell cycle arrest (G0) namely quiescence, senescence or terminal
differentiation. While mTOR activation has been shown to activate cell growth and cycling in
hematopoietic cells, our results indicate that autophagy directly inhibits proliferation and exit of
the cell cycle. Understanding the control of TOR signaling and autophagy in this process is
relevant to disease, in particular malignancy. Our previous work shows that autophagy is
required in the maintenance of quiescence in hematopoietic stem cells (HSC) and terminal
differentiation of neutrophils, both critical events in myeloid malignancy.
The hematopoietic system provides an ideal physiological system to study the interplay between
cell cycle and autophagy and a typical quiescent cell is the HSC. The hematopoietic system
develops in a hierarchical fashion; a small number of long-term stem cells that are quiescent
divide to become progenitors that proliferate and differentiate into mature blood cell lineages
produced in large numbers.
A second more mature hematopoietic stem-like cell type is the memory T cell. Like HSCs
memory T cells have to exit cell cycle to enter quiescence. Immunological memory is a
hallmark feature of the adaptive immune system to fight recurring pathogens. After an infection
has been resolved, a few of the specific T lymphocytes are retained in a resting pre-terminally
differentiated state known as memory cells. It is thought that immunological memory depends on
a stem-cell-like, self-renewing population of lymphocytes with the multipotent ability to derive
central memory, effector memory and effector T cells.
Thirdly our data shows that the terminal differentiation of neutrophils is controlled by
autophagy. After their terminal differentiation, neutrophils have a finite lifespan of a few days.
Neutrophils are well characterised by surface markers, functional features and morphologically
by granules and nuclear shape. Only differentiated neutrophils undergo cell death, immature
neutrophils accumulate and cause disease, in particular myeloid malignancy (ref).
Over the next five years, we are setting out to understand the role of autophagy in cell cycle exit
and maintenance of quiescence and terminal differentiation in hematopoietic cells, in both
physiological and pathological settings.
We will be addressing 3 main questions:
Can immune senescence be reversed by modulation of autophagy?
Some infectious diseases such as seasonal influenza mostly affect the aged, while only 1 in 3
elderly respond to the annual flu vaccination. We will correlate vaccination efficiency with
autophagy levels and modulate autophagy while vaccinating mice. We will attempt to improve
memory T cell responses by increasing autophagy genetically and pharmacologically
How does autophagy contribute to myeloid proliferation and malignancy?
Preliminary data in the myeloid lineage suggests that (1) autophagy deficiency leads to a
change in metabolism by proteomics (Warburg effect), (2) neutrophils remain undifferentiated
and immature, a hallmark of myeloid mailgnancy, and (3) inflammasome activity is increased.
Are these findings linked and do they contribute to enhanced proliferation and transformation of
this lineage? Does autophagy induction lead to differentiation and death of transformed myeloid
cells?
How does autophagy regulate stem cell differentiation and quiescence?
From our data that autophagy is highly active in hematopoietic stem cells (HSCs) and other
data, we postulate that autophagy contributes to the longevity of HSCs while avoiding ageing
and differentiation. Telomere length and damage will be monitored in HSCs and autophagy will
be increased genetically. Is autophagy needed for remodelling during differentiation, and
remaining in a state of quiescence? Describing a role for autophagy in hematopoietic stem cellness is an entirely novel concept applicable to other stem cells and cancer.
How do These Aims Contribute to the Understanding and/or Management of Human
Disease?
Aged individuals are less efficient at fighting off infections, with the consequence that some
infectious diseases such as seasonal influenza mostly affect the aged. As we are facing new
emerging infectious diseases and some vaccinations are likely to be administered at a more
advanced age, this has become a substantial health and socio-economic problem that needs
addressing urgently. Myeloid malignancies and proliferation are another contributing factor to
morbidity in the aged. Chloroquine, an autophagy inhibitor is currently being tested in over 40
trials for cancer. With our experimental systems we will elucidate its precise mechanism of
action. We are planning to undertake a small molecule library screen for autophagy modulators.
Our work will address how to enhance healthy life span, while contributing to the elucidation of
basic concepts in autophagy, senescence and cancer biology.
As autophagy is impinging on many areas of biomedical research, interdisciplinary research is
necessarily part of my programme. We have a network of collaborators across the medical
division (P Klenerman NDM, M Tarsounas Gray Institute, D Ferguson NDCLS, E Soilleux
NDCLS) and in the WIMM (SE Jacobsen, P Vyas, A Townsend) making this programme
successful. Other national and international collaborators will also help us to elucidate basic as
well translational aspects in this field.
In 2008, we founded the Translational Immunology Lab (JRH, Oxford BRC, NIHR) as part of the
Immunity theme, an "Immunology hub" where we give advice, train scientists and perform stateof-the-art flow cytometry-based immunological assays for translational studies. In addition, we
set up a high throughput and objective statistically rigorous quantification of autophagic flux
using the Image stream, with concomitant surface marker detection, essential for the study of
autophagy in clinical samples. Over 30 groups across the Medical Science Division are using
this assay, which has led to 3 publications with 4 more in revision, and 4 grants awarded so far.
We are currently setting up a FlowFish protocol on telomere length for the ImageStream.
Lay Summary of Research
Due to medical progress and improved hygiene, the population of the developed world is ageing,
with the number of people aged over 65 in the UK expected to rise dramatically, from 600 million
to nearly 2 billion in 2050. The elderly population is facing increased morbidity and mortality.
One of the contributing factors is the ageing of the immune system termed immune senescence.
Aged individuals are less efficient at fighting off infections, with the consequence that some
infectious diseases such as seasonal influenza mostly affect the aged. Crucially the elderly also
take longer to recover from infections and do not respond to vaccinations, such as the annual flu
vaccination, thus reducing the impact of preventive medicine. As we are facing new emerging
infectious diseases and some vaccinations are likely to be administered at a more advanced
age, this has become a substantial health and socio-economic problem that needs addressing
urgently.
Autophagy is a major cellular pathway responsible for the degradation of cellular toxic waste and
recycling. It is known that calorie restriction, exercise and certain drugs turn autophagy on,
maintaining a healthy status in aged cells, preventing the onset of age-related diseases like
Parkinson’s, Alzheimer’s, muscle wasting and osteoporosis.
We have shown that autophagy is declining with age in human immune cells, contributing to
failure to fight off infections, and responding to vaccinations. With our research we are aiming to
reverse this decline, at least temporarily, for example during flu vaccination of the elderly.
Furthermore our previous research also shows that certain blood cancer types (myeloid
dysplasia and myeloid malignancies), prevalent in the aged, develop when autophagy is
deficient. Understanding the process of autophagy and how it contributes to ageing and agerelated diseases will help to design therapies and life style changes that will prevent these
diseases.
All Publications Over the Past 5 Years
Simon AK*, Jones E*, Richards H*, Wright K, Godkin A, Screaton G and Gallimore A. (2007)
Regulatory T cell inhibit Fas ligand induced innate and adaptive immunity. Eur J Immunol
37, 758-767.
Simon AK, Newsom-Davis T*, Frayne MEF*, Ch’en PF-T*, McMichael AJ and Screaton GRS
(2008) Generation of tumour-rejecting anti-carbohydrate monoclonal antibodies using
melanoma modified with Fas Ligand, Int Immunol 20: 525-34
Arsov I, Li X, Matthews G, Coradin J, Hartmann B, Simon AK, Sealfon SC and Yue Z. (2008)
BAC-mediated transgenic expression of fluorescent autophagic protein Beclin 1 reveals a
role for Beclin 1 in lymphocyte development, Cell Death Diff 15 : 1385-95
Gallimore AM and Simon AK (2008) Positive and Negative influences of regulatory T cells on
tumour immunity, Oncogene 27: 5886-93
Newsom-Davis TE, Wang D, Steinman L, Chen PF, Wang LX, Simon AK and Screaton.GR
(2009) Enhanced immune recognition of cryptic glycan markers in human tumours, Cancer
Research, 69, 2018-25
Hong H, Gu Y, Zhang, H, Simon AK, Chen X, Wu C, Xu X-N, and Jiang S, (2009) Depletion of
CD4+CD25+ regulatory T cells enhances natural killer T cell-mediated anti-tumour immunity
in a murine mammary breast cancer model, Clin Exp Immunol, 159:93-9
Mortensen M, Ferguson DJP, Edelmann M, Kessler B, Morten KJ, Komatsu M and Simon AK
(2009) Loss of autophagy in erythroid cells leads to defective removal of mitochondria and
lethal anaemia in vivo. Proc Natl Acad Sci 107 :832-837
Mortensen M and Simon AK (2010) Nonredundant role of Atg7 in mitochondrial clearance
during erythroid development. Autophagy, 6 : 423-5.
Krashias G, Simon AK , Wegmann F, Kok WL, Ho LP, Stevens D, Skehel J, Heeney JL,
Moghaddam AE, Sattentau QJ. (2010) Potent adaptive immune responses induced against
HIV-1 gp140 and influenza virus HA by a polyanionic carbomer. Vaccine 28:2482-9
Mortensen M, Ferguson, D and Simon AK (2010) Mitochondrial clearance by autophagy in
developing erythrocytes: clearly important, but just how much so? Cell Cycle, 9:1901-6
Richards H, Williams A, Jones J, Hindley J, Godkin A, Simon AK and Gallimore, A (2010) Novel
role of regulatory T cells in limiting early neutrophil responses in skin, Immunology, 131:
583-592
Mortensen, M, Soilleux EJ, Tripp R, Stranks AJ, Djordjevic G, Kranc KR* and Simon AK*
(2011) The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance and
leukemia prevention. J Exp Med 208:455–67
Mortensen M*, Watson AS* and Simon AK (2011) Lack of autophagy in the hematopoietic
system leads to loss of hematopoietic stem cell function and dysregulated myeloid
proliferation Autophagy 7: 9:1-2
Watson AS*, Mortensen M* and Simon AK (2011) Autophagy in the pathogenesis of
myelodysplastic syndrome and acute myeloid leukemia, Cell Cycle 10:11, 1-7
Sood A, Salih S, Roh D, Lacharme-Lora L, Parry M, Hardiman B, Keehan R, Grummer R,
Winterhager F, Gokhame P, Andrews P, Abbott C, Forbes K, Westwood M, Aplin J, Ingham
E, Papageorgiou I, Berry M, Liu J, Dick A, Garland RJ, Williams N, Singh R, Simon AK,
Lewis M, Ham J, Roger L, Baird DM, Crompton LA, Caldwell MA ,Swallwell H, Machlin MB,
Lopez-Castejon G, Randall A, Lin H, Suleiman M-S, Evans H, Newson R, Case CP (2011)
Signalling of DNA damage and cytokines across cellular barriers exposed to nanoparticles
depends on barrier thickness. Nature Nanotechnology, 6 (12), 824-833.
Kwok AS, Phadwal K, Turner1 BJ, Oliver PL, Raw A, Simon AK, Talbot K and Agashe VR (2011)
HspB8 Mutation Causing Hereditary Distal Motor Neuropathy Impairs Lysosomal Delivery of
Autophagosomes, Journal of Neurochemistry, 187 (10) 5268-76.
Phadwal K, Alegre Abarrategui J, Watson A, Pike L, Anbalagan S, Hammond EM, WadeMartins R, McMichael A, Klenerman P and Simon AK (2012) Autophagic flux measurement
in primary cells: Impaired levels of macroautophagy in immunosenescent T cells
Autophagy, 8 (4).
+
Medullary
Epithelium (2012) Roberts A, White AJ, Jenkinson, WE, Turchinovich G, Nakmura K,
Withers DR, McConnnell FM, Desanti GE, Benezech C, Pamell SM, Cunningham AF,
Paolino M, Penninger J, Simon AK, Nitta T, Ohigashi I, Takaham Y, Casamano JH, Hayday
H, Lane PJL, Jenkinson EJ, Anderson G, Immunity 36 (4) 427-437
Träger U, Sierro S, Djordjevic G, Bouzo B, Khandwala S, Meloni A, Mortensen M and Simon AK
(2012) The immune response to melanoma is limited by thymic selection of self-antigens.
PlosOne, 7 (4): e35005
Lopez-Herrera G, Tampella G, Pan-Hammarström Q, Herholz P, Trujillo-Vargas CM, Phadwal
K, Simon AK, Moutschen M, Etzioni A, Mory A, Srugo I, Melamed D, Hultenby K, Liu C,
Baronio M, Vitali M, Philippet P, Dideberg V, Aghamohammadi A, Rezaei N, Enright V, Du L,
Salzer U, Eibel H, Pfeifer D, Veelken H, Stauss H, Lougaris V, Plebani A, Gertz EM,
Schäffer AA, Hammarström L and Bodo Grimbacher (2012) Deleterious LRBA mutations in a
novel syndrome of immune deficiency and autoimmunity, Am J Hum Gen, Jun 8;90(6):9861001. Epub May 17
Klionsky DJ et al (1400 authors)(2012) Guidelines for the Use and Interpretation of Assays for
Monitoring Autophagy in Higher Eukaryotes, Autophagy Apr;8(4):445-544
Phadwal K, Watson AS and Simon AK (2012) Tightrope Act : Autophagy in stem cell renewal,
differentiation, proliferation and aging, Cell and Mol Life Sciences, June 5
Pike LR, Singleton DC, Buffa F, Abramczyk O, Phadwal K, Li JL, Simon AK, Murray JT, Harris
AL (2012) Transcriptional upregulation of Ulk1 by ATF4 contributes to cancer cell survival.
Biochem J. Oct 18
Pike LR, Phadwal K, Simon AK, Harris AL (2012) ATF4 orchestrates a program a BH3-only
protein expression in severe hypoxia (2012) Mol Biol Rep. 2012 Dec;39 (12):10811-22
Guan,JL, Simon AK, Prescott M, Menendez JA, Liu F, Fen Wang F, Wang C, Wolvetang A,
Vazquez-Martin A and Zhang J (2013) Autophagy in Stem Cells Autophagy, 13, 9 (6)
Simon AK and Ballabio A (2013) T.rex attacks the lysosome, Nature Immunology 14 (1)
Puleston D and Simon AK (2013) Autophagy in the Immune system, Immunology, Aug 31
Pienaar IS, Harrison IF, Elson JL, Bury A, Woll P, Simon AK, Dexter DT (2013) An animal
model mimicking pedunculopontine nucleus cholinergic degeneration in Parkinson's disease,
Brain Struc Funct, in press
Puleston D, Phadwal K, Watson AS, Soilleux EJ, Chittaranjan, S, Bortnik SB, Ktistakis TK,
Gorski SM*, Simon AK* (2013) Autophagy detection techniques in primary mammalian cells,
Cold Spring Harbor Protocols, in press
Ten Key Publications Throughout your Career
Simon AK, Seipelt E, Sieper J (1994). Divergent T cell cytokine patterns in inflammatory
arthritis. Proc Natl Acad Sci 91, 8562-8566
Simon AK, Auphan N, Schmitt-Verhulst AM (1996). Developmental control of antigen-induced
thymic transcription factors. Int Immunol 9, 1421-1428
Simon AK, Auphan N, Pophillat M, Boyer C, Ghosh S, Rincon M, Flavell RA, Schmitt-Verhulst
AM. (2000) The lack of NF-kappaB transactivation and PKCepsilon expression in
CD4+CD8+ thymocytes correlates with negative selection. Cell Death Differ 12, 253-62
Simon AK, Williams O, Mongkolsapaya, J, Boquan J, Xu X, Walczak H, Screaton GR. (2001)
TRAIL in T cell development: sensitivity of human thymocytes. Proc Natl Acad Sci 98,
5150-5163
Simon AK*, Gallimore A*, Jones E, Cerundolo V, Screaton GR (2002). Fas ligand breaks
tolerance to self-antigens and induces tumour immunity mediated by antibodies. Cancer
Cell 2 , 315-322.
Simon AK*, Jones E*, Richards H*, Wright K, Godkin A, Screaton G and Gallimore A. (2007)
Regulatory T cell inhibit Fas ligand induced innate and adaptive immunity. Eur J Immunol
37, 758-767.
Simon AK, Newsom-Davis T*, Frayne MEF*, Ch’en PF-T*, McMichael AJ and Screaton GRS
(2008) Generation of tumour-rejecting anti-carbohydrate monoclonal antibodies using
melanoma modified with Fas Ligand, Int Immunol 20: 525-34
Mortensen M, Ferguson DJP, Edelmann M, Kessler B, Morten KJ, Komatsu M and Simon AK
(2009) Loss of autophagy in erythroid cells leads to defective removal of mitochondria and
lethal anaemia in vivo. Proc Natl Acad Sci 107 :832-837
Mortensen, M, Soilleux EJ, Tripp R, Stranks AJ, Djordjevic G, Kranc KR* and Simon AK*
(2011) The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance and
leukemia prevention. J Exp Med 208:455–67
Phadwal K, Alegre Abarrategui J, Watson A, Pike L, Anbalagan S, Hammond EM, WadeMartins R, McMichael A, Klenerman P and Simon AK (2012) Autophagic flux measurement
in primary cells: Impaired levels of macroautophagy in immunosenescent T cells
Autophagy, 8 (4).
Markers of Esteem
1994
European award for young investigators in Rheumatology research
Current Grant Support
2008-2017
Biomedical Research Centre, my salary funded by NIHR
(consumables £50,000/year for 1 postdoc + 1 RA)
Immunity Theme leader: Paul Klenerman
2010-2014
DPhil studentship: funded by council NSERCanada and Lady Tata Trust
2011-2014
Wellcome Trust Project Grant, Developing treatments for mitochondrial
DNA diseases £251,826 Co-applicant with J Poulton and K Morten
0948685/Z/10/Z
2012-2015
2012-2015
MRC project grant, Developing Induced pluripotent stem cells as a model
to investigate tissue specific mitochondrial disease, appprox £250, 000,
Co-applicant with J Poulton, F Brook, K Morten, N Ashley, R WadeMartins, S Cowley
Kidney Research UK, Mechanism of interstitial nephritis, fibrosis and renal
failure due to Uromodulin mutations, £235,920, Co-applicant with Raj
Thakker