Research Themes

Neuroscience and Developmental Origins of Psychiatric Disease

Brain Injury, Neuroprotection and Psychiatry

This work has included developing an award-winning regional service for neonatal neuroprotection in the East of England. The Cambridge NeuroNICU, modelled on a service led by Professor Rowitch at UCSF, is a clinical and research platform for infants at risk of brain injury from across the region. This includes an infant brain functional imaging facility run by Professor Topun Austin that combines MRI with optical and electrophysiological technologies to identify infants at risk of brain injury through neoLAB, a joint venture with University College London. With Professor Ed Bullmore (Department of Psychiatry) we have a common interest in understanding the developmental origins of psychiatric disorders. We have plans to recruit a new Head of Children Psychiatry and build the MIND institute to expand research in psychiatry with focus on developmental and genetic origins of mental health disorders. There are active collaborations with Departments of Psychology (Dr. Vicky Leong), Department of Psychiatry (Professor John Suckling) and Autism Research Centre (Professor Simon Baron-Cohen).

Brain Development and Disease

Professor David Rowitch’s laboratory in the Cambridge Stem Cell Institute investigates diversity of glial cells and patient derived models of leukodystrophy. He is promoting new clinical research in precision medicine paediatrics with application of genomic technologies to diagnose and better understand the biological basis and rational treatment of neonatal neurological disorders, including encephalopathic seizures and cerebral palsy.

Top representative papers (w/impact factor, IF):

• Cooper RJ, Hebden JC, O’Reilly H, Mitra S, Michell A, Everdell NL, Gibson AP, Austin T. Transient haemodynamic events in neurologically compromised infants: A simultaneous EEG and diffuse optical maging study. Neuroimage 2011;55:1610-6. (IF = 9)
• Yuen TJ, Silbereis JC, Griveau A, Chang SM, Daneman R, Fancy SP, Zahed H, Maltepe E, Rowitch DH. Oligodendrocyte-encoded HIF function couples postnatal myelination and white matter angiogenesis. Cell. 2014 Jul 17;158(2):383-96. (IF = 28)
• Molofsky AV, Kelley KW, Tsai HH, Redmond SA, Chang SM, Madireddy L, Chan JR, Baranzini SE, Ullian EM, Rowitch DH. Astrocyte-encoded positional cues maintain sensorimotor circuit integrity. Nature. 2014 May 8;509(7499):189-94. (IF = 40)
• Gupta N, Henry RG, Strober J, Kang SM, Lim DA, Bucci M, Caverzasi E, Gaetano L, Mandelli ML, Ryan T, Perry R, Farrell J, Jeremy RJ, Ulman M, Huhn SL, Barkovich AJ, Rowitch DH. Neural stem cell engraftment and myelination in the human brain. Sci Transl Med. 2012 Oct 10;4(155):155ra137. (IF = 16.8)

Diabetes, Obesity and Endocrinology

Primary prevention and improved treatments for children

In 2008, Professor Dunger and his team launched the first international study of the use of ACE inhibitors and statins in adolescents with Type 1 diabetes (TID) based on extensive preliminary observational data involving over 10,500 young people with diabetes and their parents. Other on-going studies of TID include the role of the growth hormone – IGF1 axis in the development of insulin resistance, and the place of growth hormone inhibitors in preventing diabetic complications.

The clinical testing of closed-looped insulin delivery in T1D, using algorithms developed by Dr Roman Hovorka, (Institute for Metabolic Sciences, IMS) is showing promising results. Under free-living conditions, closed-loop reduced the risk of nocturnal hypoclycaemia and improved glucose control. World leading multicenter RCTs in newly diagnosed very young children with T1D are underway.  Dr Kathy Beardsall investigates continuous glucose monitoring and early insulin replacement in intensively ill preterm infants (NICU) and impact on long term outcomes through regional and international trial collaborations.

Top representative papers (w/impact factor, IF):

• Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, Vanhole C, Palmer CR, van Weissenbruch M, Midgley P, Thompson M, Thio M, Cornette L, Ossuetta I, Theyskens C, de Jong M, Ahluwalia JS, de Zegher F, Dunger DB. Early insulin therapy in very-low-birth-weight-infants.  N Engl J Med. 2008; 359(18):1873-84. (IF =  72)
• Thabit H, Tauschmann M, Allen JM, Leelarathna L, Hartnell S, Wilinska ME, Acerini CL, Dellweg S, Benesch C, Heinemann L, Mader JK, Holzer M, Kojzar H, Exall J, Yong J, Pichierri J, Barnard KD, Kollman C, Cheng P, Hindmarsh PC, Campbell FM, Arnolds S, Pieber TR, Evans ML, Dunger DB, Hovorka R; APCam Consortium and AP@home Consortium.  Home Use of an Artificial Beta Cell in Type 1 Diabetes.   N Engl J Med. 2015 Nov 26;373(22):2129-2140. doi: 10.1056/NEJMoa1509351. Epub 2015 Sep 17   PMID: 26379095. (IF =  72)

Genetics and pathophysiology of severe childhood obesity

Professor Sadaf Farooqi has recruited over 7000 children with severe obesity to the Genetics of Obesity Study (GOOS). She is using exome and genome sequencing to identify rare variants that are enriched in severely obese children as well as computational and molecular approaches to finding the mechanisms that are disrupted in severe obesity. She runs a programme of translational research looking into the complications of severe obesity in childhood.

Top representative papers (w/impact factor, IF):

• Ahmed RM, Irish M, Piguet O, Halliday GM, Ittner LM, Farooqi S, Hodges JR, Kiernan MC. Amyotrophic lateral sclerosis and frontotemporal dementia: distinct and overlapping changes in eating behaviour and metabolism. Lancet Neurol. 2016 Mar;15(3):332-42. doi: 10.1016/S1474-4422(15)00380-4. Epub 2016 Jan 26. (IF = 26).
• Klaauw A, Keogh J, Henning E, Stephenson C, Trowse VM, Fletcher P, Farooqi S. Role of melanocortin signalling in the preference for dietary macronutrients in human beings. van der Lancet. 2015 Feb 26;385 (IF = 44).
• Frank S, Heni M, Moss A, von Schnurbein J, Fritsche A, Häring HU, Farooqi S, Preissl H, Wabitsch M Leptin therapy in a congenital leptin-deficient patient leads to acute and long-term changes in homeostatic, reward, and food-related brain areas.. J Clin Endocrinol Metab. 2011 Aug;96(8):E1283-7. doi: 10.1210/jc.2010-2713. (IF = 5.5).

Reproductive development and behavior

Studies on mammalian sex development are applied to the management of infants with disorders of sex development (DSD), including the effects of environmental variants in genes controlling androgen production and action appear to affect normal development, including growth at puberty. Much of this research is underpinned by the Cambridge Baby Growth Study (CBGS) established by Professor Ieuan Hughes (emeritus) and Dr Carlo Acerini in 2001, with over 2000 families recruited. Recent study explores role of putative endocrine disruptors in the development of common DSD such as cryptorchidism and hypospadias.

Top representative papers (w/impact factor, IF) 

• Fisher BG, Thankamony A, Hughes IA, Ong KK, Dunger DB, Acerini CL. Prenatal paracetamol exposure is associated with shorter anogenital distance in male infants. Hum Reprod. 2016 Nov;31(11):2642-2650. PubMed PMID: 27609981. (IF = = 5.0)
• Hines M, Pasterski V, Spencer D, Neufeld S, Patalay P, Hindmarsh PC, Hughes IA, Acerini CL. Prenatal androgen exposure alters girls’ responses to information indicating gender-appropriate behaviour. Philos Trans R Soc Lond B Biol Sci. 2016 Feb 19;371(1688). pii: 20150125. doi: 10.1098/rstb.2015.0125. Epub 2016 Feb 1. PubMed PMID: 26833843. (IF = 8)
• Thankamony A, Lek N, Carroll D, Williams M, Dunger DB, Acerini CL, Ong KK, Hughes IA. Anogenital Distance and Penile Length in Infants with Hypospadias or Cryptorchidism: Comparison with Normative Data. Environ Health Perspect. 2014 Feb;122(2):207-11. doi: 10.1289/ehp.1307178. Epub 2013 Dec 6. (IF = 8)

Genomics, Epidemiology and Population Science

Early Growth and puberty timing as predictors of disease risk

Professor Ken Ong (MRC Epidemiology Unit) and Professor Dunger study genetic, environmental determinants of size at birth, future growth and risk for adult disease. Current studies include study of the role of imprinted genes led by Dr Clive Petry and detailed evaluation of the effects of nutrition during infancy on short term risk for obesity and insulin resistance.

Top representative papers (w/impact factor, IF)  :

• Ong KK, Northstone K, Wells JC, Rubin C, Ness AR, Golding J, Dunger DB. Earlier mother’s age at menarche predicts rapid infancy growth and childhood obesity. PLoS Medicine 4(4): e132 (2007) PMID: 17455989 (IF = 12)
• Elks CE, Loos RJ, Sharp SJ, Langenberg C, Ring SM, Timpson NJ, Ness AR, Davey Smith G, Dunger DB, Wareham NJ, Ong KK. Genetic markers of adult obesity risk are associated with greater early infancy weight gain and growth. PLoS Med. 2010;7(5):e1000284. PMID: 20520848 (IF =12)
• Perry JR, Day F, Elks CE, Sulem P,……., Stefansson K, Murabito JM, Ong KK. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature. 2014; 514(7520):92-7. PMID: 25231870 (IF = 40)

The POPS and Next Generation Children’s Projects: Early biomarker detection and long-term outcomes

With new funding from the NIHR Cambridge Biomedical Research Centre, we are collaborating with Professor Gordon Smith (Department of Obstetrics) to follow up growth and neurodevelopment of infants from Predictors of Pregnancy outcome study (POPS). The Decipher Developmental Disorders (DDD) project used whole exome sequencing for analysis and causative gene discovery of neurodevelopmental disorders in 14,000 probands and their parents (trios).  With Professor Lucy Raymond, Dr. Helen Firth and Dr Matthew Hurles (University of Cambridge Department of Clinical Genetics and Wellcome Trust Sanger Institute) we are investigating utility of whole genome sequencing for diagnosis with rapid turnaround time in the NICU and paediatric ITU. Moreover, we will use genotype-phenotype linkage to electronic health and educational records to assess long-term outcomes into adulthood.

Top representative papers (w/impact factor, IF):

• Sovio U, White IR, Dacey A, Pasupathy D, and Smith GC. (2015). Screening for fetal growth restriction with universal third trimester ultrasonography in nulliparous women in the pregnancy outcome prediction (POPs) study: a prospective cohort study. 386(10008): 2089-2097 (IF = 44)
• Wright CF, Fitzgerald TW, Jones WD, Clayton S, McRae JF, van Kogelenberg M, King DA, Ambridge K, Barrett DM, Bayzetinova T, Bevan AP, Bragin E, Chatzimichali EA, Gribble S, Jones P, Krishnappa N, Mason LE, Miller R, Morley KI, Parthiban V, Prigmore E, Rajan D, Sifrim A, Swaminathan GJ, Tivey AR, Middleton A, Parker M, Carter NP, Barrett JC, Hurles ME, FitzPatrick DR, Firth HV; DDD study. Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data. Lancet. 2015 Apr 4;385(9975):1305-14. doi: 10.1016/S0140-6736(14)61705-0. (IF = 44).
• Akawi N, McRae J, Ansari M, Balasubramanian M, Blyth M, Brady AF, Clayton S, Cole T, Deshpande C, Fitzgerald TW, Foulds N, Francis R, Gabriel G, Gerety SS, Goodship J, Hobson E, Jones WD, Joss S, King D, Klena N, Kumar A, Lees M, Lelliott C, Lord J, McMullan D, O’Regan M, Osio D, Piombo V, Prigmore E, Rajan D, Rosser E, Sifrim A, Smith A, Swaminathan GJ, Turnpenny P, Whitworth J, Wright CF, Firth HV, Barrett JC, Lo CW, FitzPatrick DR, Hurles ME; DDD studyDiscovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families. Nat Genet. 2015 Nov;47(11):1363-9. (IF = 28)

Meyer E, Carss KJ, Rankin J, Nichols JM, Grozeva D, Joseph AP, Mencacci NE, Papandreou A, Ng J, Barral S, Ngoh A, Ben-Pazi H, Willemsen MA, Arkadir D, Barnicoat A, Bergman H, Bhate S, Boys A, Darin N, Foulds N, Gutowski N, Hills A, Houlden H, Hurst JA, Israel Z, Kaminska M, Limousin P, Lumsden D, McKee S, Misra S, Mohammed SS, Nakou V, Nicolai J, Nilsson M, Pall H, Peall KJ, Peters GB, Prabhakar P, Reuter MS, Rump P, Segel R, Sinnema M, Smith M, Turnpenny P, White SM, Wieczorek D, Wiethoff S, Wilson BT, Winter G, Wragg C, Pope S, Heales SJ, Morrogh D; UK10K Consortium; Deciphering Developmental Disorders Study; NIHR BioResource Rare Diseases Consortium, Pittman A, Carr LJ, Perez-Dueñas B, Lin JP, Reis A, Gahl WA, Toro C, Bhatia KP, Wood NW, Kamsteeg EJ, Chong WK, Gissen P, Topf M, Dale RC, Chubb JR, Raymond FL, Kurian MA. Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. Nat Genet. 2017 Feb;49(2):223-237. (IF = 28)

Inflammatory bowel disease, allergy and gut barrier dysfunction

Another area of research is focused on epigenetics of the intestinal immune system in health and disease particularly inflammatory bowel diseases (IBD) led by Dr Matt Zilbauer. Specifically, we are currently exploring the impact of epigenetic mechanisms such as DNA methylation and histone modifications on regulating gene expression in purified cell subsets such as the intestinal epithelium as well as peripheral blood mononuclear cells (PBMCs). Dr Andrew Clark investigates serious childhood allergies and prevention strategies.

As part of a study to investigate pathophysiology of gut barrier dysfunction in critical illness, Dr Nazima Pathan and the PICU research group are undertaking research into how the gut-host homeostasis is altered in critical illness in children for insights into disease complications and therapy. The PICU team has an interest in genomic applications and neuro-intensive care.

Top representative papers (w/impact factor, IF):

• Kraiczy J, Nayak K, Ross A, Raine T, Mak TN, Gasparetto M, Cario E, Rakyan V, Heuschkel R, Zilbauer M. Assessing DNA methylation in the developing human intestinal epithelium: potential link to inflammatory bowel disease. Mucosal Immunol 2016;9:647-58. (IF = 7.5)
• Zilbauer M, Rayner TF, Clark C, Coffey AJ, Joyce CJ, Palta P, Palotie A, Lyons PA, Smith KG. Genome-wide methylation analyses of primary human leukocyte subsets identifies functionally important cell-type-specific hypomethylated regions. Blood 2013;122:e52-60. (IF = 11.8)
• Anagnostou K, Islam S, King Y, Foley L, Pasea L, Bond S, Palmer C, Deighton J, Ewan P, Clark A Assessing the efficacy of oral immunotherapy for the desensitisation of peanut allergy in children (STOP II): a phase 2 randomised controlled trial. Lancet. 2014 Apr 12;383(9925):1297-304. doi: 10.1016/S0140-6736(13)62301-6. (IF = 44).
• Pathan N, Ridout DA, Smith E, Goldman AP, Brown KL. Predictors of outcome for children requiring respiratory extra-corporeal life support: Implications for nclusion and exclusion criteria. Intensive Care Med. 2008 (IF = 125)

Paediatric Oncology

Genetics and development of paediatric cancers

The NHS paediatric haematology and oncology team is active in clinical research trials.  From a laboratory research perspective, Dr Matthew Murray’s translational programme involves the study of genetic changes in solid tumours of childhood, with a particular focus on germ cell tumours (both extracranial and intracranial). He has identified that the same genetic changes seen in germ cell tumours may also be found in patient bloodstream at the time of diagnosis, offering the potential to improve the accuracy of diagnosis, disease-monitoring and follow-up. Dr Suzanne Turner (Department of Pathology) investigates the pathogenesis of paediatric cancers, specifically Non-Hodgkin Lymphoma (NHL) and neuroblastoma She is co-chair of the paediatric programme of the CRUK Cambridge Cancer Centre. Professor Richard Gilbertson (Chair, Department of Oncology) directs the CRUK Cambridge Cancer Centre and investigates origins and treatment of paediatric brain tumours.  His lab has used next generation sequencing of patient samples to define some of the key driver mutations of paediatric brain tumours and mouse models to pin point the cells in the nervous system that give birth to these tumours.

Top representative papers (w/impact factor, IF):

• Palmer RD*, Murray MJ*, et al. Malignant Germ Cell Tumors Display Common MicroRNA Profiles Resulting in Global Changes in Expression of Messenger RNA Targets. Cancer Research, 2010;70:2911-23. *joint first authors
• Malcolm, T*, Villarese, P*, Fairbairn, C, Lamant, L, Trinquand, A, Hook, CE, Burke, GAA, Brugieres, L, Hughes K, Payet, D, Merkel, O, Schiefer, A, Ashankyty, I, Mian, S, Wasik, M., Turner, M, Kenner, L, Asnafi, V, Macintyre, E and Turner, SD (2016) NPM-ALK mimics beta selection enabling thymic escape and peripheral lymphoma development. Nature Communications, 7, Article number: 10087[IF 11.3]

 

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