"We're digging too deeply not to get meaningful results" (paraphrase of) Ron Davis Click to expand...

The OMF's New Mitochondria Study

Metabolomics

Mass Spectrometers

As a mass spectrometrist who has migrated into the realm of clinical chemistry, I frequently tell my clinical chemistry colleagues that mass spectrometrists want to take over the world. Alan Rockwood, Ph.D Click to expand...

The UK Goes MEGA

Pilot Study Approach - The pilot study approach has been used with great success by The Solve ME/CFS Initiative (SCMI) and now the Simmaron Research Foundation. This approaches provides smaller amounts of money to gather the data needed to get large federal grants. This more open approach to ME/CFS has helped to paved the way for many studies including the repeat exercise studies, the Light's gene expression studies, Isabel Barao's immune gene study, Gordon Broderick's modeling studies, McGowan's epigenetic's study and others. (The SMCI has just announced it will fund a new grant package aimed at producing more pilot studies; more on that later.)

The Big Study Approach - The big study approach used by the Chronic Fatigue Initiative provides the money to do full-scale research projects. This approach resulted in the groundbreaking Lipkin/Hornig blood study, the Lipkin pathogen study and the Hansen mitochondrial study.

The Mega Study Approach - seeks to capitalize on progress in developing ever more effective data mining techniques to do large studies to get at the molecular roots of ME/CFS. This expensive, all in one approach requires bringing many investigators together to tackle ME/CFS. Thus far it's being employed by the Open Medicine Foundation and the MEGA alliance in the UK.

Mega Studies Catching On

The Grand Challenge

Good things keep happening in the chronic fatigue syndrome (ME/CFS) world and not all of them are on the federal level. Private efforts emphasizing collaboration and working together are continuing to produce surprising results and make waves. The Open Medicine Foundation (OMF) is a good example of that. In just the last month it's packed on another $1,000,000 in private donations and that means a new study is underway.The size of OMF's success may be surprising, but the fact that it is a success isn't really. Put together a visionary program with top research talent the money is hopefully going to flow, and it has; $5 million dollars of it since 2012 with the vast majority of it coming recently.[fright][/fright]This time $400,000 of it is flowing to the newest member of the team, mitochondrial expert Dr. Robert Naviaux. Dr. Naviaux's 100 person study will be looking in the smallest molecules in the body for the molecular roots of ME/CFS.The really, really nice thing about the study is what came before it. This is not an exploratory study; that study - an 80 patient study using patients from Dr. Gordon's and Dr. Cheney's practices - has been done. Using a process called metabolomics that study (unpublished) found evidence of a unique chemical signature in ME/CFS patient's blood; a signature Dr. Naviaux hopes could provide a diagnostic biomarker, and spur the development of new "rational therapies" to treat ME/CFS.Metabolomics is one of the newer 'omics" (genomics, proteomics) which advances in molecular characterization and data mining are thrusting to the fore in medical research. Metabolomics measures the metabolites or small molecules a cell produces as it does its work. Generally defined as any molecule less than 1 kDa in size, these metabolites provide a snapshot of what’s happening in a cell.Dr. Naviaux explains metabolism in terms of happens when our genetic heritage interacts with our environment. He uses the by-products or metabolites our cells produce to provide a new lens through which to “see” and understand the "inner world of the cell". He calls metabolomics “eavesdropping" on the collective conversations of the cells in the body".This is not just a mitochondrial or metabolomics study by the way. It's part of Ron Davis's grand plan to understand ME/CFS. Davis will extend the study by mating the genetic information he's gathering with the metabolomics data Naviaux is gathering.The first metabolomics database was created eleven years ago just down the road from Dr. Naviaux at Scripps University in San Diego. In January 2007, the first draft of the human metabolome was completed at the Human Metabolome Project (HMP) at the University of Alberta, Canada.The big gun metabolomics brings to the research field is the mass spectrometer. It's proponents believe that mass spectrometer's (MS's) ability to discriminate between different molecules and different forms of proteins, will open up a golden age in biomarker discovery. MS's can detect small modifications of proteins or the presence of very small molecules that other techniques cannot.Current clinical assays are generally too crude to pick the small alterations of proteins and other cells that can play a role in disease. Many tests, for instance, to lump together different forms of protein that may produce different biological effects.The high cost of mass spectrometers, however, has limited their spread, thus far, as a diagnostic tool in the medical field. MS spectrometers need to demonstrate that they can provide clinically relevant information that other kinds of assays cannot in order for commercial labs to justify a substantial investment in machines and training. That's a work in progress.[fleft][/fleft]The search forbiomarkers has been fruitful, though. The altered metabolism of cancer cells (in process called the "Warburg effect"), for instance, allows researchers to closely track the extent of cancer with PET scans. A mass spectrometer discovery of a small molecule metabolite called (R)-2-hydroxyglutate which appears to signal the transformation of healthy cells into cancers could ultimately lead to earlier diagnoses of cancer. MS's are being used in many medical fields including cancer, pathogens, diabetes and other chronic illnesses.Using the mass spectrometers in his lab Dr. Naviaux can measure over 500 small molecules representing over 60 biological pathways in a single sample of blood. In his first study of 80 patients he found evidence of small molecule/molecules in ME/CFS patients that he believes could a) provide a diagnostic biomarker and b) provide an opportunity for a new treatment approach.Naviaux's essay on the Open Medicine Foundation site suggests that the metabolite may be a signal produced by the mitochondria to communicate to the nucleus that the cell is in danger. This danger response, Dr. Naviaux believes, stops the cells from communicating with other cells in order to protect themselves. The result is a kind of system shutdown that would make sense in the context of chronic fatigue syndrome (ME/CFS).The other really nice thing about the Naviaux study is that it's already underway. This study looks like it will be completed as quickly as possible.[fright][/fright]The United States is not the only country that's thinking big. The U.K. is going MEGA: it’s aim - to produce the biggest ME/CFS study ever.Three approaches to solving chronic fatigue syndrome in the nonprofit/private realm seem to have prevailed. All have been successful.The first attempt at a kind of mega-study approach probably was the Pharmacogenomics study put together by Suzanne Vernon at the CDC in the early 2000's. This early attempt brought together a diverse set of researchers to use advanced computational analyses to make sense of a wide array of clinical, genetic, laboratory and gene expression data.The next major mega-study type attempt was probably the Open Medicine Foundation's call for a sweeping approach to ME/CFS in 2012 which eventually coalesced into Ron Davis's End ME/CFS Project of which the Severely Ill Big Data project is a part. The Severely Ill contains a limited number of patients but involves one of the deepest dives into the molecular foundations of chronic fatigue syndrome yet seen. (The OMF just announced that the data collection phase of the study is done; it was wrapped up remarkably quickly).The NIH's intramural study involving everything from metabolic chambers to stem cells to ME/CFS mice to exercise studies to pathogen testing to autonomic nervous system, etc. constitutes probably the third mega-study ever undertaken in this disease.Now comes "The Grand Challenge"Now the UK is embarking on its own look at everything we possibly can, multi-dimensional, multi-researcher study aptly titled " the Grand Challenge ". No more small, underpowered studies who results can be brushed off by the powers that be from this group. The goal of The Grand Challenge is to produce a massive, impeccably designed study whose results cannot be ignored. If it's successful, and there's no reason it shouldn't be if it gets the funding it need, it should indeed be a game-changer.[fleft][/fleft]It's projected to involve all the "omics" (genomics, proteomics, metabolomics) as well as immune, pathogen and other testing. An important goal of this massive project would be to ferret out the subsets we all believe are there.A recent workshop brought together leaders in various fields - many of whom have not been associated with ME/CFS before - to lay the foundations for the project. At the conclusion, the alliance behind the project, the ME/CFS Epidemiology and Genomics Alliance (MEGA), stated it will seek funding for it this year and hope to begin the project next year.Part of the project includes a genomics study of at least 10,000 adult and 2,000 child patients. In an MEAction piece ME/CFS patient and blogger Simon McGrath underscored what a unusual undertaking this is:“We’re talking about huge cohorts and there’s nothing like this anywhere in the world. Plus a lot of new researchers are coming to play. A whole load of talent from other areas is taking a keen interest in ME/CFS for the first time, ready to apply some smart technology — widely used in other, less-neglected illnesses — to our illness. Finally, it looks like we will see biomedical research in the UK on a big enough scale, and with enough new technology, to make deep inroads into understanding this illness — or illnesses.”A key member of the Alliance, Bristol University epidemiologist and genomics specialist George Davey Smith - whose resume extends to some 600 plus citations (and who loves to take on big projects like this) - stated that the study could yield a new era in ME/CFS research.With it’s focus on using the "omics" (genomics, proteomics, metabolomics) to understand ME/CFS, the Grand Challenge bears a resemblance to the Open Medicine Foundation/Ron Davis End ME/CFS Project. Hopefully the Grand Challenge and the End ME/CFS project will meet up at some point.The UK spent $8 million on the Pace study and got nothing but underwhelming results and a huge controversy on its hands. Now it has the opportunity to fund some real science. Let’s hope it steps up.