Stephen T Holgate, Faculty of Medicine,

University of Southampton

sth@soton.ac.uk

New inroads into understanding the

mechanisms of CFS and M.E.

Chronic Fatigue Syndrome

Research Foundation

Importance of CFS/ME

• Common: – 0.4% - 1% (240,000 – 600,000 people

UK) – 0.76% meta-analysis → 450,000 in UK

• Disabling

– Specialist services: 50% cannot work – And 10% housebound

• Treatment only moderately effective

– Adults: 22% recover with best treatment

• Research difficult – Different sub-groups – We don’t know causes or pathology

It would seem that conditions similar to CFS/ME have been around for

considerably longer than is generally assumed. The mixture of a broad array of

neurological and muscular symptoms that can occur after an infective illness

can be traced back into history.

In the case of Florence Nightingale, her illness began after she returned from

the Crimean War and spent years housebound, too fatigued to talk to more than

one visitor at a time.

M.E. Time to deliver – May 2014

M.E. Time to deliver – May 2014

Severe M.E./CFS • The impact of severe M.E./CFS can be devastating and long-

lasting. Two thirds of people with severe M.E./CFS had been ill for 10 years or more.

• Nearly half had seen their GP once or not at all in the past 12 months, and more than half had not visited a specialist NHS M.E./CFS clinic at all in the past five years.

• Nearly two thirds of people with severe M.E./CFS had not had a social care assessment in the past five years.

• More than a quarter (27%) of people with severe M.E./CFS who had applied for Employment and Support Allowance in the past year had had their level of benefit reduced or removed altogether.

M.E. Time to deliver – May 2014

Categorised ratings of nature of CFS/ME

Hossenbaccus Z, White PD. J R Soc Med. 2013;4:4.

Disagreements still remain over definitions, causes, mechanisms and diagnostic criteria of CFS/ME

Annual Report 2012-13

We asked people with M.E. to let us know what their research priorities were. We received more than 1,000 replies. Here’s just a few:

“I think we need to have more biomedical research to understand what is actually going wrong in order to find treatments. It’s the only way forward.”

“I’d first support research which aims to prove once and for all that this is a real, physical illness, which we are not fabricating.”

“I would like to see a cure in my lifetime. I would also like to see more understanding of the illness and effective treatments created. Thank you for working hard on our behalf.”

“I need a cure and/or the ability to prove that this condition exists and how debilitating it is. Being judged because you don’t look ill is the final slap in the face.”

“I just would like a cure – I have suffered 21 years now”

Why is a Research Collaborative needed in CFS/ME?

Difficulties in getting the condition recognised by the medical profession (despite estimates of illness prevalence ranging from 240,000-600,000).

Likely to be more than one disease with multiple causative pathways and levels of severity.

Disagreement over mechanisms A complex disorder requiring careful phenotyping and different

scientific methods. Very few new treatments available. Quality of research very variable with much speculation and

conjecture based on poor evidence. Breakdown in trust between patients, clinicians, researchers and

funders. Low level of research funding which is fragmented. Lack of industry interest.

Chronic Fatigue

Syndrome

Research Foundation

Chronic Fatigue

Syndrome

Research Foundation

So how can inroads be made into

what causes these complex symptoms?

William Osler: the Father of modern medicine 1849-1919

William Osler at Work in the Blockley Mortuary, Philadelphia General Hospital, 1886

The practice of modern medicine: Johns Hopkins

The Four Doctors by John Singer Sargent, 1905 The 4 physicians who founded Johns Hopkins Hospital. From left to right: William Henry Welch, William Stewart Halsted, Osler, Howard Kelly

Johns Hopkins Hospital's First Interns, April 1889

The Principles and Practice of Medicine: 1892

“Medicine became a science by combining clinical observation

with pathology and function and through the application of

chemical, biological and physical sciences”.

William Osler: the Father of modern medicine But we now face very serious and intractable problems in health: Reductionist models of disease fail to account for much of the

chronic inflammatory and degenerative conditions facing society.

These non-communicable diseases are increasing as we survive longer and as developing nations adopt aspects of the Western lifestyle.

After years of improvement in public health, lifestyle influences (sedentary, smoking, diet, “recreational” drugs, stress ), especially on the young are creating a health “time-bomb” in e.g. cancer, obesity, diabetes, hypertension, COPD, asthma.

Drug development industry based on “blockbuster, one size fits all” model is failing.

R&D for a New Medicine: 10+ years, $1 bn+

Source: Drug Discovery and Development: Understanding the R&D Process, www.innovation.org;

Indefinite

Drug Discovery Preclinical Clinical Trials

Regulatory Review

Scale-Up to Manufacture

Post-Marketing Surveillance

1 Approved

New Medicine

0.5 – 2 Years 6 – 7 Years 3 – 6 Years

Number Of Patients / Subjects

Phase I

Phase II

Phase III

5 250 ~ 5,000 – 10,000

Compounds

Pre-

Disc

over

y

20 – 100 100 – 500 1,000 – 5,000

IND

Subm

itted

NDA

Sub

mitt

ed

Drug discovery: a big challenge for addressing both developed and developing world diseases

Set against this is:

The explosion of new technology to interrogate complex cellular processes – the ‘omics (genomomics, transcriptomics, proteomics, epigenomics, microbiomics, metabolomics) and the exposome.

New statistical approaches to identifying subtypes of complex disease (e.g. cluster analyses, machine learning).

Applications of informatics (mathematics) to interrogate large data-sets from biological collections, clinical trials and linked population-based case records and prescribing practice.

“Nearly 400 jobs are at risk as pharmaceutical giant Novartis consults on plans to close its Horsham site, off

Parsonage Road, it has been revealed today”

(Tuesday November 5, 2013).

Pfizer take over bid of Astra Zeneca

The Changing Focus of Healthcare

Information and knowledge Health practitioner Patient

Information and knowledge Patient Health practitioner

Massive cultural change to shift focus to pulling patients through whole pathways not just

managing stages of diagnosis and treatment

The nature of medical research

• Observational studies in specific disease • Hypothesis generation • Targeted application of “science” to the problem • Abnormal pathway identified and validated • New therapy directed at the abnormal pathway • Randomised clinical trial • Introduction into clinical practice

But a new approach is needed

The emergence and rapid developmental evolution of ‘omics technology platforms

Next “Genomics” The ’omics cascade What can happen

What appears to be happening

What makes it

Happen

What has happened

& is happening

genome

chromosome cell

Genes contain instructions for making proteins

DNA

proteins

Proteins act alone or in complexes to perform many cellular functions

genome

From Genes to Proteins

The plummeting cost of complete genome sequencing

Towards the $1000 genome

How do these developments impact upon healthcare and drug development?

Stratified or personalised medicine

“the tailoring of medical treatment to the individual characteristics of each patient …. involves the use of companion diagnostics to achieve the best outcomes in the management of a patient's disease or disease predisposition. Preventive or therapeutic interventions can then be concentrated on those who will benefit, sparing expense and side effects for those who will not”. “A form of medicine that uses information about a person's genes, proteins, and environment to prevent diagnose, and treat disease." Adapted from: “Priorities for Personalized Medicine” by the US President’s Council of Advisors on Science and Technology (PCAST), 2008

• Personalised based on the genome of each person; • Predictive to determine the risk for a disease in each individual • Preventative prophylactic measures will be able to be taken to

decrease risk also with accent on awareness in each individual case • Participative; prophylactic interventions will require the

participation of the patient

P4 medicine combines Personalised, Predictive, Preventive, and Participatory elements.

Descriptive Pathology of Diseases In the past decade, our understanding of the molecular mechanisms that underlie breast cancer pathology and

progression has dramatically improved.

Significant progress has been made in the development of molecular markers that can predict response to anticancer drug therapy.

The goal is to design a therapy that is effective, less toxic, and personalised for each individual.

The illustration on the left shows the way we understood breast cancer in the past. All breast cancers were the same. One size fits all. Every patient essentially was treated in a similar fashion. All cancers are not the same and each one has its own characteristics. Molecular markers on each tumour have been identified that distinguish it from others. These tumour biomarkers are used to tailor specific therapies for each type of breast cancer

Hormone Positive Breast Cancer

Hormone therapy works on hormone positive breast cancer. Tamoxifen is a selective oestrogen modulator that acts by

blocking the oestrogen receptor in both normal breast cells and cancer cells. It prevents hormones from fuelling the

growth of breast cancer.

Hormone Therapy for Breast Cancer

Hormone therapy is effective in tumours that have either oestrogen or progesterone receptors, or both to block the effect of oestrogen in the

breast cancer cell. These include selective oestrogen-receptor modulators (SERM's), aromatase inhibitors (AI's), and oestrogen

receptors down-regulators.

HER2-positive Breast Cancer

“HER2 expressing tumours over-express the HER2 protein. Herceptin attaches to the breast cancer cell. The patient's own

immune system targets the cancer cell and prevents it from growing

Killed

Stratified medicine for cancer therapy: cancer of the pancreas

Shaw EC & Johnson PWM. Drug Discovery Today 2012; 17: 261–26

A summary of the major

disrupted cellular pathways in a series of pancreatic cancers, according to data on genetic abnormalities detected by sequencing, microarrays and transcriptomics: (a), with the specific gene alterations discovered in two of the cases mapped in detail (b), case Pa14C (c), case Pa10X).

Abbreviations: JNK: Jun N-terminal kinases; TGF-β: transforming growth factor-beta

(a) (b)

(c)

Signatures of mutational processes in multiple different human cancers

Alexandrov LB et al. Nature 2013: 500; 415-21

ESF 2013: Personalised Medicine for the European Citizen: Towards more precise medicine for the diagnosis, treatment

and prevention of disease

Medicine will move from a reactive to a proactive discipline over the next decade;

one that is predictive, personalised, preventive and participatory

ESF Forward Look launch Brussels 28 January 2013

Forward Look on Personalised Medicine

80 recommendations

…

resulting in a

Personalised Medicine “Target”

The promise of personalised medicine

• More effective medicines • Safer medicines • Cheaper medicines • Better healthcare • Cheaper healthcare • Less (rather than more) healthcare

disparity

G551D is the third most common mutation, affecting ~4% of patients. For patients homozygous for ∆508, Vertex has another drug, VX-809, which acts by increasing the transport of CFTR protein to the cell surface. A phase 2 clinical trial of combined VX-809 and VX-770 treatment in ∆508 patients is in progress.

Vx-770 potentiates CFTR function by promoting decoupling between the gating cycle and ATP hydrolysis cycle. Jih KY. et al. PNAS. 2013; 110: 4404-9

Vx-770; Ivacaftor

A CFTR potentiator in patients with cystic fibrosis and the G551D mutation (most prevalent gating mutation)

Ramsey BW, et al. N Engl J Med. 2011; 3658: 1663-72

Complex disease will be stratified into a series of pathway specific disorders creating opportunities for

both companion diagnostics and targeted prevention and treatments.

But also a new Taxonomy of disease will be created based upon knowledge of causative pathways and

networks rather than signs and symptoms.

Creation of a New Taxonomy first requires an “Information Commons” in which data on large populations of patients become broadly available for research

use and a “Knowledge Network” that adds value to these data by highlighting their inter-connectedness and integrating them with evolving knowledge of

fundamental biological processes

Toward Precision Medicine. US Nat Acad Sci 2011

Reclassification of human disease by identifiable causal pathways

The MRC/NIHR National Phenome Centre, Imperial College, London

Patient reported

Clinical

Functional

Cellular

Molecular

Integrating knowledge for Systems Medicine Auffray, Adcock, Chung, Djukanovic, Pison, Sterk. Chest 2010;137:1410-16

The “Grand Challenge” is how to combine the different data types for interrogation

Metabolomics

DNA and RNA sequencing

Imaging

Functional imaging

Microbiome

Lifestyle database

Family history

The ‘holy trinity of biology’ where biology drives technology - drives computational/mathematical tools.

• This requires a cross-disciplinary environment where scientists of many different disciplines learn to speak the languages of the other scientists and learn to work together in teams.

• When this is practiced effectively enormous amounts of biological information can be generated rapidly.

Personalised or P4 Medicine: Predictive Preventive

Personalised Participatory

Cross-Disciplinary culture

Team Science

Biological Information

Wellness Quantified Disease Demystified

The Living Systems Revolution: a New Paradigm in Science and Medicine

We are all living systems, sharing the same properties common to all living systems: intelligent, dynamic, open, complex, nonlinear, individual, purposive, equilibrium-seeking, identity-driven, diverse, inter-connected, inter-dependent and continually interacting.

This process occurs through a constant ‘buzz’ of information transfer, from one information field to another.

Applying these insights to medicine offers stunning revelations that transform clinical practice like never before. This is Living Systems Medicine.

The network diagram shown here represents a map of protein-protein interactions after single receptor stimulation

Fungal cell Mammalian cell: kidney cell

Capturing ME/CFS in a Word Cloud or Wordle: a patient’s perspective (2009)

• CFS/ME is a manfestation of a disordered complex system in which different components in different patients are failing. • The key will be to identify what those components are so that effective diagnostics and treatments can be given tailored to the individual patient.

Why is now a good time: the opportunity MRC initiative shows that by bringing new scientists into the field high quality

science can achieve grant success – increase in confidence of scientific community.

The emergence of large collections of patients and biobanks for research. New methods now available to stratify CFS/ME using statistical methods

combined with application of ‘omics technologies (genomics, proteomics, metabolomics etc).

The use of other diseases to explore subphenotypes of CFS/ME e.g. fatigue in Sjögrens syndrome, primary biliary cirrhosis, IFN therapy for hepatitis.

Formation of critical mass of scientists e.g. Centre for Musculoskeletal Aging (Liverpool, Sheffield and Newcastle), Institute for Aging (Newcastle).

Success of Collaborative model for increasing research capacity successful in lung disease.

CFS/ME Charities enthusiastic to work together for patient benefit.

CFS/ME fits the new medical paradigm of stratified (personalised or P4 - predictive, preventive, personalised and participatory) medicine in being CFS/ME a highly complex disorder and driven by different underlying causative pathways leading to different disease subtypes. Recognising this complexity mandates a different approach to uncovering novel cellular and molecular mechanisms (or endotypes). Understanding these endotypes will lead to new treatments.

A different approach is needed

1) There is great new strength in working together at this time in medical science.

2) A joined-up approach will require different professionals working in teams (multi-disciplinarity) e.g. consortia, networks.

3) Attention needs to be paid to prioritising topics for research focus and fund-raising.

4) Attention directed to new and early career researchers and engaging a wide range of new fields (mathematics, environmental science etc).

Will this new approach work?

Understanding the mechanisms of CFS/ME – a call for proposals

Research proposals should focus on one or more of six priority areas identified by experts in the fields (see below). A key aim of this call is to encourage new and innovative partnerships between researchers already working on CFS/ME and

those in associated areas. The call is focused on the following research areas: • Autonomic dysfunction • Cognitive symptoms • Fatigue • Immune dysregulation (e.g. through viral infection) • Pain • Sleep disorders • Additionally, the call encourages capacity building in CFS/ME research and the

entry of new researchers into the field

Applications should seek to understand these mechanisms through the study of cross-disease symptomology, and pathways,

in the clinic and/or laboratory.

The UK Respiratory Research Collaborative 2005

Industry

NIHR/NHS Wellcome Trust

US NIH EU/FP7

MRC Respiratory Awards* committed per year (2004-2008)

£0

£2

£4

£6

£8

£10

£12

£14

2004 2005 2006 2007 2008

VA

LUE

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AW

AR

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IN

MIL

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N

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0

5

10

15

20

25

NU

MB

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F A

WA

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Value of Research Grants in GBP Value of Fellowships in GBPNumber of Research Grants Number of Fellowships

* Figures refer to awards committed, not spend – based on analysis from September 2009

Chronic Fatigue Syndrome

Research Foundation

Chronic Fatigue Syndrome

Research Foundation Launch Wellcome Collection on April 22nd 2013

The CMRC Executive Board met for the first time in September. Achieving this level of collaboration is a major and exciting development and could lead to significant impact in increased funding for M.E./CFS and stimulating partnership

with researchers from other research areas.

CMRC Charter: Aim “ Promote the highest quality of basic and applied evidenced based and peer reviewed

research in to CFS/ME”

Chronic Fatigue Syndrome

Research Foundation

The Charter: Objectives Develop, inform and update a national strategy Promote the need for research Facility all high quality research Encourage multidisciplinary research Facilitate investment in research infrastructure Raise the profile Promote good career structure Foster collaborations Promote conditions NHS research Increase financial support Raise awareness of achievements Share information

Chronic Fatigue Syndrome

Research Foundation

CMRC Workstreams

• Funding – Specific calls, work with funders – Infrastructure, collaborations

• Awareness/publicity – Publish research, work with charities

• Increasing capacity – Masters courses, PhD studentships, work with

universities • Organisation

– Membership, website, funding, meetings, annual conference

Chronic Fatigue Syndrome

Research Foundation

Chronic Fatigue Syndrome

Research Foundation

Membership and associate Membership

• UK-based: medical practitioners, health care professionals, researchers & charities involved in CFS/ME research

• Must – Deliver (members) or support (Associate) research – Work collaboratively and professionally – Not harass or abuse researchers

Chronic Fatigue Syndrome

Research Foundation

Chronic Fatigue Syndrome

Research Foundation

1st CMRC Conference, Bristol, September 2014

Chronic Fatigue Syndrome

Research Foundation

Coming

Together Build

Capacity

Engage Strengthen The influence of the whole is greater than

the sum of the individual parts