Mady Hornig: How do you solve a problem like CFS?

March 1, 2013

Simon McGrath explains how Mady Hornig is applying tools used to understand other complex illnesses in an effort to unlock the secrets of ME/CFS.

Mady HornigIn a recent article I looked at the huge studies Professor Mady Hornig has underway looking for pathogens or signs of immune abnormalities in ME/CFS. While these are immensely impressive, I thought they were eclipsed by the main theme of her presentation: her jaw-dropping work in other illnesses. It took me a few attempts to fully grasp some of the more complex material, but I was left in a state of stunned admiration. And that doesn’t happen very often, as anyone who’s seen my posts will know. The prospect of her transferring some of these cutting-edge approaches to ME/CFS is mouth-watering.

Mady Hornig is Director of Translational Research at the Center for Infection and Immunity (CII), Columbia University, and her goal is to understand illnesses where brain and immunity are believed to take centre stage. This is an ideal fit for ME/CFS, given that most researchers suspect that the brain and/or immunity play a central role in the illness.

Why some illnesses are so hard to pin down

What was so fascinating for me about Professor Hornig’s talk was the sheer breadth of approaches used to tackle many different illnesses, all of which are, like ME/CFS, challenging to study. The progress made in these other illnesses gave me real hope that similar breakthroughs are possible in ME/CFS too.

Perhaps the best place to start is simply with the question: why are some diseases so hard to crack? In an ideal world, a pathogen occurs in every case of the disease, but never in healthy individuals. But real life is often not that simple, even where a pathogen is responsible for a disease. For example, 90% of people infected with the tuberculosis bacteria don’t develop “TB”, and it’s not entirely clear why not. Rubella virus can cause birth defects if the woman is infected in the first third of her pregnancy, but not if she’s infected later.

Three Strikes and you’re Ill

3strikes-potMady Hornig has a “Three Strikes” hypothesis to explain may of these situations. She believes three things are all needed for some diseases to take hold: (i) specific gene variants, (ii) an environmental trigger and (iii) the right timing. A good example of the Three Strikes hypothesis is where pot-smoking in teenagers is associated with psychosis in adults – but only for those with a particular version of a gene. Pot is the environmental trigger, starting to smoke pot in teen years is the key timing (those who didn’t take pot until adulthood don’t have the risk) and the association only applies to those born with a certain version of a gene, COMT v158, where neurotransmitter regulation is impaired.

It’s easy to see how such a convoluted route to disease can be hard to unravel. If the trigger was a particular infection – or even infection in general – at a particular time, how can you find the link to something that happens many years later? This kind of ‘hit and run’ scenario has been proposed in ME/CFS, where it’s a particular problem because most ME/CFS cases aren’t diagnosed until several years after onset.

There’s some evidence for ‘hit and run’ in other conditions, where the damage isn’t seen for decades. Infection in pregnant women can be associated with illnesses – including heart disease and depression – in their children up to 50 years later. For instance, with Major Depression, Hornig and colleagues used blood samples taken from pregnant mothers years earlier, and found that cytokines – indicating a maternal infection during pregnancy – were associated with abnormal brain responsse in their depressed daughters 40 years later.

Case study : PANDAS

no, not that type of panda

no, not that sort of panda

I think this work is brilliant. It’s about PANDAS, which are believed to be autoimmune disorders, triggered by bacteria, that lead to neuropsychiatric symptoms – and they occur almost exclusively in children. PANDAS are characterised by OCD, anxiety and even tics, where the symptoms come on very suddenly after a streptococcus infection (usually strep throat or Scarlet Fever). The underlying biology seemed to be that strep bacteria trigger ‘autoantibodies’, antibodies that attack strep but also happen to attack human cells, particularly in the basal ganglia in the brain. It’s not clear how the antibodies cross the blood-brain barrier, but that’s likely to be an important factor in explaining why most strep infections don’t cause PANDAS.

From children to mice

Hornig’s team used a mouse model to study the illness in more detail. They infected mice with the same bacteria that cause strep throat and found obsessive-compulsive behaviour similar to that seen in humans (for mice it includes repeated back-flipping). Crucially, they were able to show that mice produced antibodies against strep in the blood, but that these antibodies also bound to brain proteins. What’s more, they found deposits in the brains of PANDAS mice, and the presence of these deposits was linked to PANDAS symptoms. Maybe some pictures will help:

clipart from Clickr.com
Clipart from Clickr.com

Next, they did something very clever. They were able to reproduce the PANDAS syndrome – back-flips and all – in healthy mice that had been injected with serum from PANDAS mice – no Strep involved. (Serum is the part of the blood that contains antibodies). Critically, they found deposits in the brains of these previously-healthy mice, indicating that antibodies from the serum had attacked the brain of the healthy mice, leading to the PANDAS symptoms. To make sure it was really the antibodies in the serum doing the damage, they selectively removed antibodies from the serum – and it could no longer induce PANDAS in healthy mice. (more detail)pandas-abs

From mice back to children

Then they were able to identify the proteins in mouse brains that were being targeted by the autoantibodies linked with PANDAS. The proteins included two that are produced in response to stress (one is snappily called HSP-70). The team now returned to the children with PANDAS and looked at those children’s sera – and found the children’s sera (and antibodies) bound to the same protein, HSP-70, that was attacked in mice.

So Mady Hornig and her colleagues, including Ian Lipkin, started off with a human illness triggered by strep bacteria, then looked at that illness in detail in a mouse model, showing the key role of autoantibodies in the disease. And they found a likely target protein in the mouse brain for these antibodies. Finally, they completed the cycle by showing that children with PANDAS have sera that attacks the human version of the protein involved in mice. That is neat.

Following the evidence: ‘deDiscovery’ opens up new frontiers

“We need our bugs”

Hornig stressed that ruling out unfounded proposed associations with illness is just as important as making new discoveries, so that researchers can move on. For ME/CFS, XMRV is the classic case. Mady Hornig also worked on the proposed link between measles virus and autism, and showed there was no association between measles virus in the gut and children with autism and gut problems. However, she did find that these children had alarmingly low levels of proteins needed to take up nutrients properly. The children also had an unusual mixture of gut bacteria, and many had significant levels of a bacteria known as Sutterella, which is rare in healthy people. So a study that began searching for a link between measles and autism ended up highlighting problems with the gut function and bacteria, a new avenue for research.

Sleep and cognition problems: gut bacteria link in ME/CFS?

Mady Hornig says: “we need our bugs”, stressing the importance of understanding the role of the gut in many different types of phenomena, including cognitive symptoms and sleep. It turns out that gut bacteria play a crucial role in ensuring good quality sleep. Normally, as we digest a meal in the evening, chemicals produced by gut bacteria enter the blood and help us both get to sleep and stay asleep.  Who knows, perhaps there is a causal link between with the frequent gut problems reported in ME/CFS and the widespread sleep problems experienced.

Every illness is different and will require different approaches to solve. But I was impressed by the broad range of techniques, and sheer imagination used in tackling these other illnesses. Mady Hornig wrapped up her talk by saying “We are really committed to using all the tools that are available to us to try to find an answer” to ME/CFS. If Mady Hornig brings to ME/CFS research the imagination, innovation and expertise she’s shown with other illnesses, then I think the chance of substantial progress is very high.

 

Simon McGrath has a biochemistry degree from Oxford University. He later worked for Oxfam, a UK charity. After having ME/CFS for nearly 20 years, he takes a very keen interest in the latest research.

 

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27 comments

{ 27 comments… read them below or add one }

Sasha March 4, 2013 at 2:33 pm

Thanks, Simon – another great article. We're lucky to have you explaining this stuff to us so clearly!

SOC March 4, 2013 at 2:40 pm

Excellent article, Simon! We are very fortunate to have brilliant researchers like Dr Hornig working on ME/CFS.

Simon March 4, 2013 at 2:55 pm
Sasha

Thanks, Simon – another great article. We're lucky to have you explaining this stuff to us so clearly!

SOC

Excellent article, Simon! We are very fortunate to have brilliant researchers like Dr Hornig working on ME/CFS.

Thanks! And I agree we are really lucky to have people like Mady Hornig on the case, I think it's going to make a big difference. She's also seems genuinely concerned about patients, and willing to engage with them too. She was very good about answering quite a few detailed questions, and she will be speaking at this year's Invest in ME Conferernce in May – about her pathogen study.

snowathlete March 4, 2013 at 6:50 pm

"They infected mice with the same bacteria that cause strep throat and found obsessive-compulsive behaviour similar to that seen in humans (for mice it includes repeated back-flipping)."

I thought that was just me. Maybe that's why I'm so tired?
View attachment 4573

Thanks for the article Simon, I thought it was great, and really exciting how Mady Hornig works.

Allyson March 4, 2013 at 8:07 pm

Thanks indeed SImon, i saw on the news in the last few days a new treatment for HIV – a pill they give patients for 2 weeks which causes the (?latent) virsus to emerge so they can they hit it.

Sorry do not recall more details sucha s name of drug or place ,…though i suspect it was in Australia. I saw it ont he evening news ulletin so likely the ABC.

Simon March 5, 2013 at 1:48 am
snowathlete

"They infected mice with the same bacteria that cause strep throat and found obsessive-compulsive behaviour similar to that seen in humans (for mice it includes repeated back-flipping)."

I thought that was just me. Maybe that's why I'm so tired?
View attachment 4573

Thanks for the article Simon, I thought it was great, and really exciting how Mady Hornig works.

That animation is absolutely brilliant! Great work.

Actually, Mady Hornig had a video clip of the mouse back flipping in her presentation but due to a technical glitch it wouldn't play :(

Allyson

Thanks indeed SImon, i saw on the news in the last few days a new treatment for HIV – a pill they give patients for 2 weeks which causes the (?latent) virsus to emerge so they can they hit it

I saw that too, amazing stuff. Latency is a big reason they thought HIV could never be cured: as a retrovirus it integrates into your normal DNA – if its replicating drugs can block the replication and along with immune system can kill those cells too. If its latent and just sitting there in a dormant state it's completely safe, and can then reactivate later. Study was presented at the Retrovirus conference in Atlanta by an Oz professor, but hasn't been peer-reviewed or published yet.

Marco March 5, 2013 at 4:31 am

Thanks Simon
I have to admit that I'm mightily impressed with Mady Hornig's approach.

Overstressed March 5, 2013 at 6:34 am

Thanks Simon, great article! This is off-topic, but do you know if she's married ? ;)
Personally I think, if she would find a pathogen, I think she would be able to solve many neurological conditions.

Best regards,
OS.

Simon March 5, 2013 at 7:50 am

Mady Hornig quote
Mady Hornig has been it touch to say how pleased she was to have her work featured here, and also said this, which I quote with permission:

This work is long overdue for a dreadful and neglected illness. I am so looking forward to the day when our ideas and diligence can deliver something beyond hopes and promises.

Mady Hornig

I was very touched by that.

Sorry, OS, can't help!

Sasha March 5, 2013 at 8:12 am
Simon

Mady Hornig quote
Mady Hornig has been it touch to say how pleased she was to have her work featured here, and also said this, which I quote with permission:

That's great – as a patient, I'm really delighted to hear that from a researcher.

jimells March 5, 2013 at 10:32 am

Simon, do you have any idea how long the PANDAS research took? As in, was it months, years, or decades?

Thanks for another great article. I look forward to reading more of your work.

Simon March 5, 2013 at 11:50 am
jimells

Simon, do you have any idea how long the PANDAS research took? As in, was it months, years, or decades?

Thanks for another great article. I look forward to reading more of your work.

Thanks:) I think PANDAS work has gone on for decades, but I think Hornig's PANDAS work on mice was over a couple of years, but not really sure.

Esther12 March 5, 2013 at 4:51 pm

Thanks a lot Simon.

It made learning fun! It was really nice to read something informative that wasn't a challenge to get through. Looking forward to future articles.

Simon March 5, 2013 at 5:12 pm
Esther12

Thanks a lot Simon.
It made learning fun! It was really nice to read something informative that wasn't a challenge to get through. Looking forward to future articles.

Thanks – glad you enjoyed it. You should have seen the original talk: brilliant, but almost in Greek if you're a non-scientist. Will try to reduce everything to cartoon mice and pot-smoking where possible.

Esther12 March 5, 2013 at 6:43 pm
Simon

Thanks – glad you enjoyed it. You should have seen the original talk: brilliant, but almost in Greek if you're a non-scientist. Will try to reduce everything to cartoon mice and pot-smoking where possible.

I'm grateful for the Beano version. Thanks a lot for working out how to translate her talk for the rest of us.

beaker March 6, 2013 at 9:14 pm

Thanks for the article. It's nice to know we have someone like that on our team !

Simon March 9, 2013 at 2:50 pm

Another Three Strikes example?

Waverunner has posted an interesting study looking at how genes can interact with maternal infection with a virus to increase the risk of Schizophrenia – a bit like the gene/pot-smoking/teen-start example Mady covered in her talk:.
Virus and Genes Involved in Causation of Schizophrenia

original paper here: http://www.nature.com/mp/journal/vaop/ncurrent/full/mp20132a.html

Waverunner March 9, 2013 at 3:12 pm

Simon: Thanks. Hornig seems to be a great scientist. In a few years, we all should be able to have whole genome sequencing done at a reasonable price. This will be a point, where a wave of new information will flood the medical field. Scientists like Hornig hopefully will benefit from this.

CallieAndToby March 14, 2013 at 8:25 am

It can happen in teenagers and young adults also (the pandas or pans).

CallieAndToby March 14, 2013 at 8:31 am

It can happen in teenagers and young adults also (the pandas or pans).

Simon March 15, 2013 at 1:09 pm
CallieAndToby

It can happen in teenagers and young adults also (the pandas or pans).

Thanks for pointing that out. Mady Hornig did mention it, but I'm afraid it's one of the things I left on the cutting room floor.

MEMum April 2, 2013 at 8:22 am

Hi Simon
Great article. Has Mady Hornig found anyone with ME/CFS with anti basal ganglia antibodies (ABGAs)? Our daughter has had ongoing strep infection (high ASO titres), also a couple of active viruses. Her main symptoms are chronic exhaustion, due to sleep delay/non-refreshing sleep and memory/learning problems. She has been diagnosed with ME, and found in November to have ABGAs to the pyruvate kinase receptor. She is 18 and does not have any of the typically reported PANDAS symptoms. Any thoughts?
I also have a Biochemistry (and Physiology) degree from many decades ago,which helps me follow some of the research.

Simon April 2, 2013 at 4:14 pm
MEMum

Hi Simon
Great article. Has Mady Hornig found anyone with ME/CFS with anti basal ganglia antibodies (ABGAs)? Our daughter has had ongoing strep infection (high ASO titres), also a couple of active viruses. Her main symptoms are chronic exhaustion, due to sleep delay/non-refreshing sleep and memory/learning problems. She has been diagnosed with ME, and found in November to have ABGAs to the pyruvate kinase receptor. She is 18 and does not have any of the typically reported PANDAS symptoms. Any thoughts?
I also have a Biochemistry (and Physiology) degree from many decades ago,which helps me follow some of the research.

Thanks. And I'm sorry to hear about your daughter.

Mady Hornig didn't mention anything about ABGAs re ME/CFS: the PANDAS section was completely separate from the ME/CFS stuff, really as an example of how other hard-to-study illnesses have been tackled, rather than suggesting identical mechanisms were at play.

The planned work on ME/CFS protein host profiles might show up signs of autoimmunity – I'm afraid I don't know enough about the area to know if they could do that. Also, the targeted proteomics mass spectroscopy in the same stdy might itself show up ABGAs/ASO antibodies – apparently it depends on what proteins are in the reference database. If ABGAs and ASOs are present in ME/CFS patients, and are in the reference protein databases, then they could show up.

However, I would say that Mady Hornig is big on autoimmune disorders so will be alive to the possibilities. If nothing shows up when the new studies report later this year it might be worth contacting her to raise the issue.

Simon May 28, 2013 at 9:12 am

When I mentioned this blog to my nieces, Rebecca and Emma, they insisted on looking up back-flipping mice on youtube, and this is what they found:

Bob June 22, 2013 at 6:48 pm

This blog gets a brief mention from Jørgen Jelstad here:
http://debortgjemte.com/2013/06/19/vindu-mot-hjernen/

Simon July 17, 2013 at 3:14 am

I came across this PNAS article by Ian Lipkin where he talks about the '3 strikes' theory of genes, environment and timing and mentions the importance of prospective cohorts:

Perhaps the most difficult challenge will be that of obtaining and integrating population and exposure data before the onset of disease so that we can examine the effects of host and environmental factors over the lifespan. Efforts are underway to do this through establishment of prospective birth cohorts comprising populations of 100,000 or more children and their parents. Such cohorts, joined with improvements in pathogen surveillance and discovery, toxicology, genetics, proteomics, and systems biology, will allow us to view the world of microbial pathogenesis in three dimensions—(genes) × (environment) × (timing)—yielding insights not only into acute diseases but also into chronic ones.

What's particularly interesting about this is that the Chronic Fatigue Initiative are tapping in to a long-term prospective study run by Harvard, that includes biological samples and is likely to have sample from before the time any individuals with CFS got sick. So if people got infected a year before going down with CFS, there is a chance the study will have samples in that period.

Firestormm July 17, 2013 at 7:55 am

Simon you have your digits in so many pies :) Thanks :thumbsup:

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