The best laid plans of mice and men

I sent a copy of the previous post (reprinted below) about an idea to diagnose and treat chronic fatigue syndrome to Dr. Norman Sharpless, the author of the Cell review on cellular senescence.  He thought the idea was “great”; and, even better, he ran the lab which did the test I wanted to try.  I also sent a copy to a patient group.  “Solve ME/CFS Initiative”, and they want to use the post on their website.

Sharpless noted that the problem with ideas like this is accumulating patients, something the patient group could probably provide.  So all went well until 8 days ago when Dr. Sharpless was named to be the head of the National Cancer Institute, with its 4.5 billion dollar  budget by President Trump.  Being a full prof at the University of North Carolina Medical School, he would have been the ideal individual to run the study (or find someone to do it), but he now has far bigger fish to fry.

After I wrote to congratulate him, he wrote back reiterating that the idea was good, but he said he had to sever all connections with the lab he founded due to conflict of interest considerations.  He did give me the name of someone to contact there, which is where the matter stands presently.

Since the idea is based on the correlation between the amount of fatigue after chemotherapy with the level of a white cell protein (p16^INK4a), he would have had no problem accumulating chemotherapy patients as head of NCI, but again the spectre of conflict of interest rears its ugly head.  Repeating the chemotherapy study to make sure the results are in fact real is the first order of business.

So there you have a research idea, endorsed by the new head of the NCI.  I am a retired neurologist, who no longer has a license to practice medicine (but who doesn’t need a license to think).

If you’re an academic out there, looking for something to do, write up a grant proposal.  The current treatments do help people live with chronic fatigue syndrome, but they are in no sense treatments of the underlying problem.

Here is the original post

How to (possibly) diagnose and treat chronic fatigue syndrome (myalgic encephalomyelitis)

As a neurologist I saw a lot of people who were chronically tired and fatigued, because neurologists deal with muscle weakness and diseases like myasthenia gravis which are associated with fatigue.  Once I ruled out neuromuscular disease as a cause, I had nothing to offer then (nor did medicine).  Some were undoubtedly neurotic, but there was little question in my mind that some of them had something wrong that medicine just hadn’t figured out.  Not it hasn’t been trying.

Infections of almost any sort are associated with fatigue, probably because components of the inflammatory response cause it.  Anyone who’s gone through mononucleosis knows this.    The long search for an infectious cause of chronic fatigue syndrome (CFS) has had its ups and downs — particularly downs — see https://luysii.wordpress.com/2011/03/25/evil-scientists-create-virus-causing-chronic-fatigue-syndrome-in-lab/

At worst many people with these symptoms are written off as crazy; at best, depressed  and given antidepressants.  The fact that many of those given antidepressants feel better is far from conclusive, since most patients with chronic illnesses are somewhat depressed.

Even if we didn’t have a treatment, just having a test which separated sufferers from normal people would at least be of some psychological help, by telling them that they weren’t nuts.

Two recent papers may actually have the answer. Although neither paper dealt with chronic fatigue syndrome directly, and I can find no studies in the literature linking what I’m about to describe to CFS they at least imply that there could be a diagnostic test for CFS, and a possible treatment as well.

Because I expect that many people with minimal biological background will be reading this, I’ll start by describing the basic biology of cellular senescence and death

Background:  Most cells in our bodies are destined to die long before we do. Neurons are the longest lasting (essentially as long as we do).  The lining of the intestines is renewed weekly.  No circulating blood cell lasts more than half a year.

Cells die in a variety of ways.  Some are killed (by infections, heat, toxins).  This is called necrosis. Others voluntarily commit suicide (this is called apoptosis).   Sometimes a cell under stress undergoes cellular senescence, a state in which it doesn’t die, but doesn’t reproduce either.  Such cells have a variety of biochemical characteristics — they are resistant to apoptosis, they express molecules which prevent them from proliferating and most importantly, they secrete proinflammatory molecules (this is called the Senescence Associated Secretory Phenotype — SASP).

At first the very existence of the senescent state was questioned, but exist it does.  What is it good for?  Theories abound, one being that mutation is one cause of stress, and stopping mutated cells from proliferating prevents cancer. However, senescent cells are found during fetal life; and they are almost certainly important in wound healing.  They are known to accumulate the older you get and some think they cause aging.

Many stresses induce cellular senescence.  The one of interest to us is chemotherapy for cancer, something obviously good as a cancer cell turned senescent has stopped proliferating.   If you know anyone who has undergone chemotherapy, you know that fatigue is almost invariable.

One biochemical characteristic of the senescent cell is increased levels of a protein called p16^INK4a, which helps stop cellular proliferation.  While p16^INK4a can easily be measured in tissue biopsies, tissue biopsies are inherently not easy. Fortunately it can also be measured in circulating blood cells.

The following study — Cancer Discov. vol. 7 pp. 165 – 176 ’17 looked at 89 women with breast cancer undergoing chemotherapy. They correlated the amount of fatigue experienced with the levels of p16^INK4a in a type of circulating white blood cell (T lymphocyte).  There was a 44% incidence of fatigue in the highest quartile of  p16^INK4a levels, vs. a 5% incidence of fatigue in the lowest. The cited paper didn’t mention CFS nor did the highly technical but excellent review on which much of the above is based [ Cell vol. 169 pp. 1000 -1011 ’17 ]

But it is definitely time to measure p16^INK4a levels in patients with chronic fatigue and compare them to people without it.  This may be the definitive diagnostic test, if people with CFS show higher levels of p16^INK4a.

If this turns out to be the case, then there is a logical therapy for chronic fatigue syndrome.  As mentioned above, senescent cells are resistant to apoptosis (voluntary suicide).  What stops these cells from suicide? Naturally occurring cellular suicide inhibitors (with names like BCL2, BCL-XL, BCL-W) do so .  Drugs called sensolytics already exist to target the inhibitors causing senescent cells to commit suicide.

So if excessive senescent cells are the cause of CFS, then killing them should make things better. Sensolytics do exist but there are problems; one couldn’t be used because of side effects.  Others do exist (one such is Venetoclax) and have been approved by the FDA for leukemia — but it isn’t as potent .

So there is a potentially both a diagnostic test and a treatment for CFS.

The initial experiment should be fairly easy for research to do — just corral some CSF patients and controls and run a test for p16^INK4a levels in their blood cells. Also easy on the patients as only a blood draw is involved.

This, in itself, would be great, but there is far more to think about.

If CFS patients have too many senescent cells, getting rid of them — although (hopefully) symptomatically beneficial — will not get rid of what caused the senescent cells to accumulate in the first place. In addition, getting rid of all of them at once would probably cause huge problems causing something similar to the tumor lysis syndrome – https://en.wikipedia.org/wiki/Tumor_lysis_syndrome.

But these are problems CFS patients and

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