Anil Mehta

I was a clinical academic undertaking international research into the children’s disease cystic fibrosis whilst working 50% of his time as a consultant paediatrician with a neonatal medicine/paediatric cardiology interest. His focus is on EU-wide patient care, health outcomes, rare disease policy and better informed policy making. I retired recently.

My background lies in the biological Bermuda Triangle that occupies the treacherous sea between physics (Oxford) medicine (University College London) and molecular biology (Kings College London). Gordon Stewart has a similar but more advanced background in the same disciplines. We met at UCL and trained together at KCL.

After retiring, I was recruited to the post of Scientific Director for a charity focusing on the overlapping cellular pathways common to two separate inherited human diseases (phaeochromocytoma-PPGL and cystic fibrosis-CF). The strategy is to apply knowledge gained from human cell biopsies to test hypotheses in tractable animal models such as the worm C. elegans and the social amoeba Dictyostelium. Our approach leverages latent commonality via human biopsy analysis through RNA sequencing and informatics using an approach pioneered by an SME in Dundee (MicroMatrices). That data informs animal disease modelling by PIs in Universities and Research Institutes in Budapest (worm), Melbourne (amoeba) and Singapore (bioinformatics/structure).

To perform these tasks I set up the charity with a Dundee family who are prone to a familial cancer that arises in a highly conserved succinate dehydrogenase (SDH) protein. SDH lies at the interface between the TCA cycle and mitochondrial electron transport that act in concert to control energy metabolism. Our data in press suggest that the subtle defect found in cancer-affected members of this family is a gain of function mutation resulting from an Arg-His missense mutant in the SDHB subunit. Because the SDH tetramer has been highly conserved over millennia across species, we have created novel SDHB mutated worms and are now further characterising the phenotype using amoebae. The overlap with CF arises because both diseases manifest unusual cancers of the young and we have discovered that both diseases utilise the same pathway involving energy synthesis via a process that controls the level of phosphorylated histidine. Disrupted phosphohistidine alters signalling to pathways in energy balance, endocytosis, autophagy, Ras activation/ERK scaffolding, inflammation resolution and succinate to fumarate ratio balance. All these are linked to multiple metabolite dysfunctions across the mitochondrion. The CF work takes place in Leeds/Sheffield and centres on drugs that suppress excess inflammation and restore mitochondrial function in CF-monocytes derived from CF patients. The latter collaboration is new and follows my work as an advisor to another charity focussing on CF. From the latter, I have currently directed around £60K to Leeds to drive seed corn work working closely with Professor Peckham with whom I share a long term collaboration in CF (see Lancet papers).

He has tried to improve the welfare of Europeans who suffer because their diseases are very rare in a given hospital setting. This area is a priority for the EU through their Rare Disease Directive that will require the NHS to plan care for all rare disease patients (UK to launch end 2013).

Past work: Dr Mehta implemented the first comprehensive UK-wide CF patient registry of ~ 7000 patients across 60 NHS CF clinics between 1995 and 2006 and recently developed the first 30,000 patient, 35-country pan-European demographic CF registry, with EU FP6 funding (2006-2009). His translational science focuses on two areas: (1) discovery of a new pathway in CF disease through collaborations He developed the European Demographic CF Registry (2006-2009) and was Scientific Lead on European Registry Executive of the European CF Society (2010-16).

IMPACT:

UK CF Database protocols are used by others to improve NHS efficiency: For example, Registry data from UK CF Centres are used by the CF Trust for (i) NHS resource allocation (patients banded by disease severity – banded between £5K & £40K p.a.) (ii) CF-Centre audit by NHS-commissioner-led peer review and (iii) EMA approved phase-IV studies are followed by the registry for new CF drugs.

Citations: Lancet cover (2007)/editorials/podcasts(2007/10); commentaries in leading specialist journals such as Pediatrics and in annual Scottish and UK audit reports for Government to calculate costs/centre re-imbursement (1995-2006); 23 peer-reviewed research publications impacted beyond academia by describing, inter alia, remote monitoring of toxic drug doses specified by the Committee on Safety of Medicines, reduced therapies following neonatal screening, cited by CDC Atlanta in Newborn Screening Recommendations Reports: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5313a1.htm and therapeutic windows to address the worse outcomes for CF females with diabetes (guidelines of the American Diabetes Association, doi: 10.2337/dc10-1768, 2010).

European CF Registry impacts: The published research findings created part of the evidence base that, after recent comment on disparities of care from the European Commission, are helping facilitate the lobby to drive the implementation of a recent decision by the European Council of Ministers to ratify the European Rare Disease Directive This has led to unsolicited invitations to influence European policy debate as follows:

Policy Appointments to Advisory Board of the EPIRARE Consortium of meta-registries funded by EU DG Sanco. Further impact on policy is on-going through membership of in two key ECFS committees and EURORDIS/EPIRARE (2012) to intensify lobbying at the European Commission, the European Council of Ministers and with MEPs to implement the policy changes needed to improve outcomes.

Political Presentations of the findings at the European Parliament (2009, 2010, 2013 on file Peter Liese MEP Bonn and in CF Europe office files and MEP Bart Staes Office ) and;

Keynote Address Invitations from CF Europe to influence CF care policy in Italy/Slovakia/Serbia (2013); Chaired an Irish Governmental Panel for rare disease research funding (Health Research Board, Dublin 2013).

In the period since 2008, these impacts can be classified into the following groups:

Impacting public policy and services. Through the European Commission, European Parliament and committee work in DG Sanco, EURORDIS, the European Cystic Fibrosis Society (ECFS) and CF-Europe.

Impacting health and welfare. The beneficiaries are health service / regulatory authorities across rare diseases by demonstrating the poor quality of CF health in low-income EU member states drawing the attention of their respective governments through the Commissionv and at the European Parliament in November on CF days (2009, 2010; 2013;CF-Europe web site). Quantifying disparities in care between member states creates a benchmark for disease survival (current political addresses in the Balkans (2013) and Slovakia (2013). These invitations follow transactions with 20 MEPs after presentations in 2009 to alert their national governments about their relative performances. Translations of the Lancet work into native languages (e.g. Polish, Slovakian) facilitated lobby activity (evidence available in the CF-Europe and Polish and Slovakian CF Association files).

Impacting rare disease practitioners and services outside CF. Other rare diseases share the same implementation challenges; countries such as Argentina, Brazil, Mexico, India etc. who are at the start of their rare disease implementation strategy. The European Rare Disease Organisation (EURORDIS) highlighted the utility of the Dundee rare disease protocols through the award of a EURORDIS prize (Krakow meeting, 2010) and the appointment as EURORDIS Registry Tutor (2011-12) where AM led a symposium for 16 country representatives to advise on the implementation of a registry applicable to any rare disease (Annual Eurordis meeting, Brussels 2012: where AM delivered templates for consent with confidentiality, procedures for quantitative data handling). AM’s RD blogs led to his invitation to join the scientific board of a new Findacure Foundation for Fundamental Diseases (see Guardian news, august 2013), who wish to conjoin rare disease researchers with altruistic funders in order to improve research and care across the rare disease spectrum.

Impacts on society. The evidence has been presented in a user-friendly manner (most recently at the Italian National CF delegate meeting in Rome, September 7th 2013). This impact includes patient-friendly European registry audit reports (2012; www.ecfs.eu) and AM-initiated patient poster campaigns across Europe explaining the origins of current CF medicines to patients to improve recruitment into clinical trials (from 2010; available from I Fajac and the ECFS office in Leuven: https://www.ecfs.eu/ctn/my-current-medication).

Research
Background: CMO-Donaldson’s report (2009, ‘rare is common’) commented that millions suffering from rare diseases (RD) remain inadequately treated because healthcare is hospital-centred where RD-patients are too few for large-scale evidence generation. Registries underpinning research are an important part of the solution, and in cystic fibrosis (CF), no comprehensive UK- or Europe-wide clinical registry existed prior to my team’s work (a post-doctoral scientist Dr E. Sims and MD student J McCormick. Throughout, project manager G. Mehta supervised/trained UK-European hospital administrative staff including the EU CF Society registry group).

Screening for Cystic Fibrosis: The prior research demonstrating benefit vs. cost of new born CF screening (Lancet 2007) was incorporated into international screening guidelines of European Governments (e.g. Sweden 2010, Netherlands (2009-10), Germany), CDC Atlanta (US) and those of the European CF Society (ECFS, 2009). My parallel research demonstrating poorer outcomes for female patients with CF diabetes was cited in the clinical care guidelines if the American Diabetes Association (doi: 10.2337/dc10-1768, 2010) and recently, in the Lancet (2010), we reported better CF patient survival in established vs. new EU member states.

UK CF Database (1995-2007; UKCF-Trust Registry thereafter): ~2 million UK-carriers of the CF genetic defect randomly generate thousands of geographically-dispersed CF patients. My team designed and implemented the UK-CF-Database (UKCFD), engineering robust data protection & management protocols ensuring anonymity that drove the research described herein. 7000 CF patients (>40 CF-clinics) were registered at handover to the UK CFTrust. The underpinning research publications facilitated the case to Government for neonatal CF screening by calculating cost-benefit ratios demonstrating less intense drug therapy for a given FEV1 in screened cohortsi. The UKCFD was also applied by others to remotely measure CF-drug toxicities (gut/kidney). In 2007, the UKCFD-data and structure/protocols were embedded into a new registry (www.cftrust.org.uk); now used in NHS commissioning. This registry matches patient disease severity against CF-centre reimbursement for ~10,000 UK patients in 2013 and, its design tracks new, expensive therapies (>£100K p.a. per-patient).

CF Pathogenesis: In CF science, a key unanswered question is the pathway by which the CF gene, through defective encoding of the normal version of its protein (called CFTR), causes disease in the human cell membrane. My work proposes a new pathway that lies at the interface of phospho-histidine and phospho-serine, that has implications for cell growth, cell specialisation and nutrient uptake in cells (see Annesley S et al. 2011). My collaborators and I hypothesised that the missing amino acid Phe508, deleted from the normal CFTR protein, did not just destroy the misfolded Phe508delCFTR (as is well established), but additionally, pressed a new ‘switch’. This proposed switch is being researched through collaborations in Italy, Portugal and Hungary in 2014 where new grants have been funded for postdoctoral staff scientists to unravel this complex scenario.

PhD supervision
In addition to the members in group alumni, Dr Mehta now focuses on supervision/examination of external students across the EU.

Lectures and conferences
Since 2005 Dr Mehta has been invited to give >50 lectures/seminars (>40 international invitations) with ~20 invitations in epidemiology (>15 international) and 31 invitations in basic science (23 international
EU Parliament, three speeches of disparities of CF care over 5 years (latest in 2013)
Disparities in CF Care Keynote Lectures (Serbia/Slovakia) 2013
Symposium Convenor/Moderator/Co-chair & Speaker CK2 & CFTR, at European CF Society
Frontiers in CF Science each year between 2006 and 2012.
Speaker/Chair/Co-chair on NDPK, CK2 and CFTR, 8th & 9th International NDPK Conferences
Seminars on CK2 and CFTR, Universities of Pittsburgh and North Carolina, 2010
Invited opponent 2 hour lecture on CF screening, Karolinska Institute, Sweden, 2010
Invitation to lecture at International Neonatal Update Conference, London 2010
Magistral lecture European Registry, Croatian Cystic Fibrosis Association, Zagreb, 2007
Protein kinases and ion channel function in CF. EMBL Heidelberg, 2007
Impact
Peak Flow Meter

BBC Radio Four: Explanation of the Peak Flow Meter