Annual Scientific Report 2015

findings regarding association were intriguing, the
direction of effect required experimental validation.
In collaboration with the Institute of Healthy Ageing
at UCL, we tested the effect of manipulating 10 of the
genes most significantly associated with lifespan, using
Drosophila strains available from public stock centres.
We tested RNAi knock-down and UAS over-expression
lines using a ubiquitous adult-onset driver system
(da-GS). Preliminary results suggest that a proportion
of the genes significantly reduced lifespan. Moreover,
over-expression of one of the tested genes significantly
increased lifespan as compared to control.
Allergy: the price of immunity?
Allergy is an increasingly widespread clinical problem
that leads to various conditions such as allergic
asthma and susceptibility to anaphylactic shock.
These conditions arise from exposure to a range of
environmental and food proteins (‘allergens’) that
are recognised by a form of immune system antibody
called IgE. This part of the immune system is thought
to have evolved to provide mammals with additional
rapid-response mechanisms to combat metazoan
parasites. In this study, we addressed the pertinent
question, ‘what makes an allergen an allergen?’ Although
they constitute a very small percentage of known
proteins, they appear to be diverse and unrelated.
Janet Thornton
PhD King’s College & National Institute for Medical
Research, London, 1973. Postdoctoral research,
University of Oxford, NIMR & Birkbeck College,
London. Lecturer, Birkbeck College 1983-1989.
Professor of Biomolecular Structure, University
College London since 1990. Bernal Professor
at Birkbeck College, 1996-2002. Director of the
Centre for Structural Biology at Birkbeck College
and University College London, 1998-2001.
Director of EMBL-EBI 2001-2015, EMBL Senior
Scientist since 2001.
Future plans
In our quest to understand enzymes and their
mechanisms using structural and chemical information,
we will explore how enzymes, their families and
pathways have evolved. We will continue our study
of reactions and use this new knowledge to improve
chemistry queries across our databases. We will study
sequence variation in different individuals and explore
how genetic variations impact on the structure and
function of a protein, and sometimes cause disease.
Using evolutionary approaches, we hope to improve
our prediction of protein function from sequence and
structure. We will continue our ageing studies, exploring
longevity sub-phenotypes, identifying small molecules
that might modulate lifespan in model organisms, and
validating and characterising the effects of a small set of
genes on lifespan in Drosophila.
Selected publications
Cuesta SM, Rahman SA, Thornton JM (2016) Exploring
the chemistry and evolution of the isomerases. Proc Nat
Acad Sci (in press); doi:10.1073/pnas.1509494113
Furnham N, et al. (2015) Large-scale analysis exploring
evolution of catalytic machineries and mechanisms in
enzyme superfamilies. J. Mol. Biol. 428:253-267
Ivanov DK, et al. (2015) Longevity GWAS using the
Drosophila genetic reference panel. J. Gerontol Series A:
Biol. Sci. Med. Sci. glv047
Thornton group research in 2015 showed that the off-target effects
of the immune system in allergy are due to the significant molecular
similarities they identified between environmental allergens and
parasitic worm proteins. The findings demonstrate that allergy in
humans is a trade-off for immunity to parasites.
Using computational studies (Tyagi et al., 2015), we
established molecular similarity between parasite
proteins and allergens that affect the nature of immune
response and are able to predict the regions of parasite
proteins that potentially share similarity with the
IgE-binding region(s) of the allergens. Our experimental
studies supported the computational predictions, and
we presented the first confirmed example of a plantpollen-like
protein in a worm that is targeted by IgE.
The results of this study will enable us to predict likely
allergens in food and environmental organisms and help
in the design of protein molecules to treat allergy in
the future.
Tyagi N, et al. (2015) Comparisons of allergenic
and Metazoan parasite proteins: allergy the price of
immunity. PLoS Comput. Biol. 11:e1004546
2015 EMBL-EBI Annual Scientific Report 148