Archive for June, 2015

Quantum Leap in Viral Detection Could Impact ME/CFS and Fibromyalgia

June 7, 2015

“I firmly believe that new technology drives science and generally has a much larger impact than individual basic science discoveries.” Stephen Elledge

Breakthrough findings in an individual disorder are special, but developing new technology that expands our ability to understand many diseases is something else entirely. It provides the potential to make a difference on a truly vast scale. Those types of breakthroughs are coming with increasing frequency.

research lab tests

Technological advances in medicine are appearing at a stunning rate.

  • Last month Mark Davis and his huge immune machine determined that exposures to herpesviruses, in particular, vastly altered the states of our immune system.
  • Just last week researchers uncovered a lymphatic network in the brain that provides a new window on neuro-immune disorders.
  • This week the journal Science published a breakthrough study that has major implications for understanding the role pathogens play in illness.

Each one could shed light on diseases like chronic fatigue syndrome and fibromaylgia

The astonishing thing for us in the ME/CFS community is that two of the three researchers mentioned are also working on ME/CFS.

Pathogen Detection on Steroids

“Now that we can look at all viruses, it’s a complete game-changer.”

Steven Elledge, a Harvard researcher, is one of them. He pioneered a technique that quickly and thoroughly determines both the antibodies present in the blood and the strength of that response. Antibodies are produced by B-cells in response to pathogens. Because they continue to be produced for decades after an infection antibodies provide a library of past infective events. Until now, though, the search for antibodies has been a plodding, arduous one.

Viruscan test

Elledge’s new test presents a quantum leap in screening for pathogens.

Pre-Elledge –  researchers and doctors determined whether antibodies to a pathogen are present one antibody at a time. Post-Elledge – they’ll be able to look for all known antibodies to all 216 viruses known to infect humans a person – in a single blood sample – for about $25. This isn’t just a major leap in efficiency – it’s a quantum leap.

It doesn’t get much better than creating breakthrough results cheaply. Ian Lipkin called the feat “a technological tour de force and stated “This is a powerful new research tool.”

The Study

Comprehensive serological profiling of human populations using a synthetic human virome George J. Xu, Tomasz Kula, Qikai Xu, Mamie Z. Li,  Suzanne D. Vernon, Thumbi Ndung’u, Kiat Ruxrungtham,  Jorge Sanchez, Christian Brander, Raymond T. Chung,  Kevin C. O’Connor, Bruce Walker,  H. Benjamin Larman,  and Stephen J. Elledge Science 5 June 2015: aaa0698 [DOI:10.1126/science.aaa0698]

The new technology was used to screen for antibody reactions to more than 1,000 strains of 206 viruses in over 500 people across the globe. It found that the average person had been exposed to about ten viruses but that some had been exposed to as many as 25.

Not surprisingly, Epstein-Barr virus (EBV) lead the list. Almost 90% of the people tested had been exposed to this ubiquitous virus. Herpesviruses, rhinoviruses, adenoviruses, influenza viruses, respiratory syncytial virus, and enteroviruses were most commonly found viruses. Not surprisingly, the older you get, the more viruses you’ve been exposed to.

The test is not perfect – it misses some very low-level antibodies and may not pick up antibodies in people with depleted immune systems (such as some ME/CFS patients). Antibody responses that decline over time also make it more difficult to find antibodies to very early infections.  While the test was completely accurate for people exposed to HIV or hepatitis C, it uncovered evidence of chicken-pox exposure in only about 25-30% of those who’d had it.

Elledge said, however, that improvements to the test will enable it to pick up those antibodies.

He’s not stopping at viral antibodies. He’s working on similar tests to assess autoantibodies and antibodies to bacteria and fungi.

The Chronic Fatigue Syndrome (ME/CFS) Connection

“That’s what happens when you invent technology — you can’t imagine what people will do with it. They’re so clever.” Steven Elledge

Autoimmune disorders such as multiple sclerosis – long believed to have a pathogen connection – and cancer were the first diseases mentioned in connection with this technology. The test is so cheap, though – a mere $25 –  there’s no reason it can’t be run in many diseases – including those for which pathogens are not suspected. A virology professor at University of Nottingham, Dr. Will Irving, noted it could be valuable in any disease of “unknown etiology “.

“Indeed in any other disease of unknown aetiology – identifying specific virome reactivity could give a major clue as to a causative agent.” Dr. Will Irving

viruses

Antibodies to over 200 viruses scanned – in a drop of blood

Irving noted the test may be helpful in determining the cause of primary biliary cirrhosis (PBC), for instance. PBC is a liver disease that produces extreme fatigue, autonomic dysfunction and a symptom profile very much like ME/CFS. It’s one of the fatiguing disorders Dr. Julia Newton has been studying alongside ME/CFS.  Irving suggested the new test could help determine if PBC is triggered by viruses.

The recent antibody findings in postural tachycardia syndrome – and the infectious triggers commonly found in that disorder – make it another obvious choice. Fibromyalgia – which is often triggered by a virus – is another possibility.

As to ME/CFS – Elledge is already studying it. He’s one of the new researchers, Suzanne Vernon, a co-author of the new study, enticed into the ME/CFS field as Research Director of the Solve ME/CFS Initiative. Vernon got Elledge to study ME/CFS simply for the cost of shipping samples to him. (ME/CFS patients were in the Science study.)

The Solve ME/CFS Initiative announced Elledge was trolling ME/CFS patients blood for antibodies using his new technique last year. ME/CFS is obviously on the Harvard team’s minds. Tomasz Kula, a co-author of the study, highlighted chronic fatigue (syndrome) as a prime candidate for this technology.

Earlier Elledge talked about the ME/CFS research he’s been doing with the Solve ME/CFS Biobank samples

“We have developed a technology that reveals all the viruses targeted by the antibodies in a blood sample. We plan to use this technology to examine the blood from people with and without CFS in order to find viruses that are associated with CFS. We hope this study will identify a pathogen as a likely causative agent of the disease in order to focus future study.

We also have a related technology that reveals all the targets of autoantibodies in a blood sample.  We also plan to apply this technology to the sample blood samples to look for evidence of immune dysfunction in people with CFS.

In a recent Facebook post Suzanne Vernon talked about ME/CFS and the Science study.

“It was so fun to work with this remarkable team on this really cool approach to test for more than 200 viruses (and more than 1,000 virus strains!) in a drop of blood. Blood from ME/CFS patients was included along with blood samples from around the world. George Xu, Steve Elledge and I will continue to dive into the data to see if there are virus patterns unique to ME/CFS.”

In response to a query whether the technology would allow research to discern ME/CFS clusters based on enteroviral, herpesvirus, or mixed patterns of infection, Suzanne replied “Exactly”.

Stephen Elledge

 

“I have always wanted to make an impact on the world, to have my life on earth count for something,” he said. “By contributing to basic research, I hope my work can accelerate discoveries to improve the lives and health of people.” Steven Elledge

Stephen Elledge Ph.D., a geneticist, runs the almost 30-person Elledge Lab at Harvard Medical School. He’s co-authored almost 300 papers over the past thirty years.  He was drawn to biology and genetics early by the promise the work had to transform biology. ”

“The potential for transforming biology was very clear, even stunning. And I decided I wanted to be a part of that.” Steven Elledge

In 2012 he (and another ME/CFS researcher, Dr. Michael Houghton) were awarded the Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Science.

Not Ready for Prime Time – Yet

The test has not been commercialized yet.  The study, published in one of the most prestigious science journals in the world, has gotten enormous publicity which will surely help develop the technology into a commercial product.

Cutting Edge Work From Within the ME/CFS Community

From Unutmaz to Elledge to Mark and Ron Davis the ME/CFS community is getting access to top researchers and their cutting-edge technology. It’s also in some cases getting access to technology  being developed specifically to understand this disorder.

Gordon Broderick’s modeling efforts at the Institute for Neuro-immune Medicine, Ron Davis’s development of ways to analyze the HLA regions of our genome, and the methods Julia Newton developed to analyze muscle cell activity were all developed in-house to better understand ME/CFS.

“Medical Game-Changer” To Shed New Light on Neuroimmune Diseases

“The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.”

In what’s being touted as a “medical game-changer” researchers at the University of Virginia have uncovered a new way the brain interacts with the immune system.

The researchers were looking for ways immune cells recirculate within the meninges – the protective membranes that envelop the brain – when they stumbled upon an amazing finding in this day and age – a major new anatomical feature of the brain.

Structural and functional features of central nervous system lymphatic vessels. Antoine LouveauIgor SmirnovTimothy J. KeyesJacob D. EcclesSherin J. Rouhani, J. David PeskeNoel C. DereckiDavid CastleJames W. MandellKevin S. Lee, Tajie H. Harris, Jonathan Kipnis. Naturedoi:10.1038/nature14432

lymph system brain

The lymph system and the brain: before and after: from Univ of Virginia

First, they found high concentrations of immune cells around the dural sinuses – veins that drain blood and cerebral spinal fluid from the brain and empty into the jugular vein. A closer look revealed that high numbers of  T-cells were aligned linearly along endothelial cell structures along the sinuses.  That finding piqued their interest: endothelial cells line the two major transportation venues in the body – the blood vessels and the lymphatic system. Could they have stumbled on an undiscovered pathway between the body and the brain?

Further testing revealed the structures were part of a undiscovered section of lymphatic  system in the brain.  That was a shocker. The anatomy of the brain, they thought, had been fully mapped years ago.

“I really did not believe there are structures in the body that we are not aware of. I thought the body was mapped,” said Dr. Jonathan Kipnis, who runs the University of Virginia lab where the discovery was made. “I thought that these discoveries ended somewhere around the middle of the last century. But apparently they have not.”

Then again, the lymph system has historically been a bit of an odd man out.  First described by Hippocrates in 400 BC, it was rediscovered as the “milky veins in the gut of a well fed dog” in the 17th century but then was virtually ignored until 1937 when Howard Florey showed that lymph nodes become enlarged in inflammation.

Getting the Garbage Out

The finding helps to solve a longstanding mystery.  The brain is a busy place. That almost by definition means its going to produce a lot of byproducts.  But where did they go? Absent knowledge of any means of getting rid of toxins, the prevailing hypothesis for many years was that the brain broke down the toxins to their essential elements and then reused them.  That hardly passed the smell test but it wasn’t until 2012 that one part of the brains waste removal system – the glymphatic system – was identified.

Now we know that a traditional – and presumably much more efficient – lymphatic system also exists in the brain. (If I got it right, the authors believe the glymphatic fluids probably drain into the new lymphatic system.)

The location of this part of the lymphatic system – situated alongside a major blood vessel – was difficult to see.  Unless it was dissected in just right manner it was invisible.

The lymphatic network  found that runs from the eyes to over the olfactory lobe to the sinuses.

Filtration System

The lymphatic system transports immune cells to lymph nodes – central immune staging areas  packed with immune cells. Lymph nodes are also responsible for filtering out foreign particles and cancer cells. Disturb the lymphatic system and you can get a bollixed up immune response and a toxin laden system.

Two different types of lymphatic vessels exist: vessels with valves that collect fluid and vessels without valves which fluid passes through. The lymphatic vessels found in this study are valveless- they’re designed to let the lymph fluid pass right though the meninges into the neural sinuses and into the lymph nodes.

High Potential

The filtration part of the lymph system appears to be getting the most play right now.

garbage truck

How’s your filtration system doing?

The potential this system – or rather the potential a dysfunction of this system – could have on disease is large.  In fact one of the researchers went so far as to say that it was hard to imagine a neuro-immune disorder that was not impacted by this pathway.

“We believe that for every neurological disease that has an immune component to it, these vessels may play a major role. Hard to imagine that these vessels would not be involved in a [neurological] disease with an immune component.”

He hadn’t been drinking too much bubbly. Maiken Nedergaard, director of the University of Rochester Center for Translational Neuromedicine agreed saying that “Essentially all neurodegenerative diseases are associated with the accumulation of cellular waste products. Understanding and ultimately discovering how to modulate the brain’s system for removing toxic waste could point to new ways to treat these diseases.”

Picture central nervous system inflammation. Free radicals are punching holes in membranes. Cells are dying. Pathogens are wreaking havoc.  The  “garbage” that all this activity produces in the form of dead and damaged cells and pathogens needs to be flushed out of the system before more damage results.

The classic example of a bollixed up CNS lymphatic system causing disease could be Alzheimer’s with it’s accumulations of amyloid proteins. One researcher studying Alzheimer’s said

“Understanding how the brain copes with waste is critical. In every organ, waste clearance is as basic an issue as how nutrients are delivered. In the brain, it’s an especially interesting subject, because in essentially all neurodegenerative diseases, including Alzheimer’s disease, protein waste accumulates and eventually suffocates and kills the neuronal network of the brain.”

ME/CFS?

Chronic fatigue syndrome could fit in that picture. The high brain lactate levels and low glutathione levels Shungu found in ME/CFS patient brains suggest high rates of anaerobic energy production and its accompanying toxic by-products could be present.  The recent Japanese study suggested inflammation was present. Low blood flows to the brain could easily be producing high levels of “garbage”.   (Stroke is another condition the new findings could illuminate.)

breakthrough

The finding will provide new insights into neuro-immune disorders

Studies indicate that most of the glymphatic flushing that occurs in the brain occurs during sleep – a problematic time for many people with ME/CFS and fibromyalgia. Then there’s Dr. Perrin who swears that his lymphatic drainage techniques help people with chronic fatigue syndrome.  He believes the cognitive and other problems found in ME/CFS are due to too much sludge in the system.

It’s not clear how researchers will use this new knowledge but  it is clear that tools are present that can exploit this new finding and provide better understanding of neuro-immune disorders – perhaps at some point even ME/CFS.