Mitochondrial and Energy Metabolism Dysfunction in ME/CFS — Myhill, Booth and McLaren-Howard Papers

[Hip]

If my naive understanding is right, within a cell an ATP molecule releases one of its 3 phosphate groups, when energy demands require it, a phosphate group being the energy form that cells can immediately utilise.

It is not the phosphate group itself that contains energy; the energy is actually contained in the chemical bond that attaches the phosphate group to the adenosine group.

You can think of a chemical bond as a compressed metal spring that joins and locks the phosphate and adenosine groups together. Because the spring is compressed, the spring contains energy, and when you break the chemical bond by removing a phosphate group, that energy in the compressed spring is released, and can do useful work.

Think of it like the compressed spring you have inside a cocked air rifle: because the air rifle spring is compressed, there is energy contained and stored in the rifle, which will be released when you later pull the trigger.

Conversely, when you re-attach a phosphate back onto the adenosine, it needs a supply of energy to do that, because you have to first compress the spring in order to attach the phosphate.

This re-attaching of a phosphate is like using the strength of your arms to cock the air rifle, where you are compressing the air rifle's spring.

And this is what happens in the mitochondria: when an ADP molecule returns to the mitochondria for recycling, the energy that the mitochondria generate is used to compress the spring in the bond which re-attaches a phosphate group to ADP to produce ATP. In that way, you store the energy in the ATP molecule's bonds, which like the cocked spring in an air rifle, is ready to be released whenever needed.

I am just wondering if this is more like a flywheel energy storage mechanism, which some green vehicles utilise. The flywheel stores a lot of kinetic energy, and so holds energy that is (almost) instantly available when needed. The flywheel slows as the vehicle absorbs useful energy from it, and then the fuel source is used to top up the flywheel's kinetic energy store.

Energy is found in one of two forms: kinetic energy (the energy of motion) and potential energy (a static situation where the energy is stored and ready to be liberated).

The energy in a flywheel is kinetic energy, because the flywheel is in motion.

The energy stored in a compressed spring (and a chemical bond) is potential energy, so in this aspect, the flywheel recycling analogy is not so appropriate for describing ATP/ADP; although the flywheel analogy does of course capture the idea of energy storage and recycling.

The potential energy stored in ATP is better thought of as a compressed, cocked spring, ready to release its energy.

So the ATP molecule, with once of its phosphate groups removed for useful work, has now become an ADP molecule, which by itself is cannot make available its phosphate groups as useful "energy packets" for the cell's consumption.

The ADP molecule (with 2 phosphate groups) can release one of its phosphate groups to provide further energy if there is a high energy demand. When this occurs, the ADP then becomes AMP (with 1 phosphate group).

To break down ADP into AMP in order to liberate energy, cells use the adenylate kinase reaction, in which two molecules of ADP combine to make one of ATP (which is then used for energy) and one of AMP.

However, unless there is an energy shortage emergency, my understanding is that the body does not normally further break down ADP to AMP in this way, because it is hard for the body to later recycle AMP back to ADP, and then ultimately back to ATP.

Because it is hard to recycle the AMP molecule back to ADP, the AMP just tends to get thrown away, which not only wasteful, but can also lead to a bit of a disaster, because then you are left with an acute shortage of these ADP molecules. It is this acute shortage of ATP/ADP molecules that leads to PEM, in the theory proposed by Myhill, Booth and McLaren-Howard.

By contrast, it is easy for cells to recycle to ADP back to ATP (provided the mitochondria are working properly). So under normal circumstances, I believe the body sticks with this, and does not break down ADP any further to extract more energy.

The reason it is proposed that ME/CFS patients do sometimes break down ADP further into AMP is because ME/CFS patients do not have enough energy supplied by their mitochondria (and/or because there is an impediment in the ADP to ATP recycling machinery), due to mitochondrial dysfunction, and so ME/CFS patients can very quickly enter into an energy shortage emergency, when they start to do any physical exercise which puts high demand on the energy supplies.

So during this energy shortage emergency that occurs in exercise, that's when the cells in the body start to break down ADP into AMP, just to extract every last ounce of energy, as energy is in such short supply (because the mitochondria are not able to supply enough energy to meet the high energy demands that physical exercise places on the body).

As mentioned, to break down ADP into AMP in order to liberate energy, cells use the adenylate kinase reaction, in which two molecules of ADP combine to make one ATP and one AMP.

This converting of 2 molecules of ADP into ATP plus AMP provides more energy, and gets you through the energy shortage emergency occurring during exercise; but then a short time later there is a major price to pay: because you have thrown away a lot of your ADP molecules by converting them to AMP, so now you have another problem — the problem of having not enough ADP and ATP molecules to transport the energy generated in the mitochondria into the cell.

So that then sends you into second energy metabolism emergency, this time not caused by a shortage of mitochondrial energy production, but by a shortage of the ATP/ADP molecules that are necessary to transport the energy generated in the mitochondria into the cell. It is this second energy emergency situation that creates the state of PEM, according to the theory and hypothesis proposed by Myhill, Booth and McLaren-Howard.

 

[nandixon]

What is it in ME/CFS that prevents aerobic glycolysis from taking place? Might there be a problem with the pyruvate transporters (mitochondrial pyruvate carrier, MPC), or is it just that the mitochondria are running very inefficiently, so they cannot effectively burn the pyruvate?

Some recent work by Fluge & Mella may suggest a problem relating to the pyruvate dehydrogenase complex. (See this post: http://forums.phoenixrising.me/inde...r-chronic-fatigue-syndrome.47856/#post-785089)

 

[Barry53]

It is not the phosphate group itself that contains energy; the energy is actually contained in the chemical bond that attaches the phosphate group to the adenosine group.

Etc ...

Many thanks for taking the time to explain this @Hip, much appreciated.

I think a key point your post helps reinforce for me, is that the adenosine groups are the energy carriers, as per the petrol tankers (sorry, gasoline trucks ) in your example. If lots of them break down for some reason (meaning fewer of them, and/or they go much slower) then, even though the energy might be available at source, it is no use whatsoever without the means to transport it to where it is needed.

And this is what happens in the mitochondria: when an ADP molecule returns to the mitochondria for recycling, the energy that the mitochondria generate is used to compress the spring in the bond which re-attaches a phosphate group to ADP to produce ATP. In that way, you store the energy in the ATP molecule's bonds, which is ready to be released whenever needed.

Is the upshot of this, that for every 3 ADP molecules, they end up being recycled to become 2 ATP molecules?

Your excellent help has sparked off a few more questions I am afraid:-

1) Does any one cell effectively "own" a given number of ATP/ADP molecules (or their equivalent in phosphate groups?), a bit akin to having its own carrier fleet? I am trying to get a feel for whether the ATP/ADPs come in with the fresh fuel, or whether they primarily exist as part of an energy transportation mechanism localised within the cell.

2) If I am on the right track with '1', are these same carriers also responsible for transporting "fresh", unrecycled energy through the cell to the point of use? i.e. The energy resulting from fuel/oxygen combining? And what sort of quantities per cell are we talking about?

3) If (the 'ifs' keep getting bigger) I am on the right track with '1' and '2', does this then mean that if the ATP/ADP count is severely reduced, then the cell's ability to transport fresh incoming energy becomes severely impaired, not just its ability to recycle energy within the cell itself?

Once again, many thanks.

 

[Hip]

I think a key point your post helps reinforce for me, is that the adenosine groups are the energy carriers, as per the petrol tankers (sorry, gasoline trucks ) in your example. If lots of them break down for some reason (meaning fewer of them, and/or they go much slower) then, even though the energy might be available at source, it is no use whatsoever without the means to transport it to where it is needed.

Petrol tankers is fine by me — I am also in the UK. I just used the US phrase "gasoline trucks" because more people will understand that, including those in the UK.

Yes, ATP (a fully loaded gasoline truck) carries the energy generated in the mitochondria (in our analogy, the mitochondria is the oil refinery that makes the gasoline) to where the energy is needed in the cell.

In my understanding, a major shortage of trucks is thought to occur after exertion, during the PEM period; but otherwise, ME/CFS patients will generally have enough trucks to deliver the energy (except possibly the Group B patients).

Strenuous exercise destroys many trucks by the process previously explained (the adenylate kinase reaction), and that's why after exercise there is shortage of trucks to deliver the energy to the cell, and that's the theory of why you get PEM. The body then manufactures some brand new trucks in its truck factory (de novo synthesis of ATP), so after a few days, things go back to normal, as you will have then rebuilt your truck fleet. One you've rebuilt your truck fleet, the PEM is over.

However, note that even when ME/CFS patients are not performing exercise and are not in PEM, there are still energy shortage problems, but those problem appear to occur in the oil refinery itself (the mitochondria) and in some related energy metabolism areas, rather than in the fleet of gasoline trucks.

Is the upshot of this, that for every 3 ADP molecules, they end up being recycled to become 2 ATP molecules?

No, every single ADP molecule returning to the mitochondria for recycling will be kitted out with an extra phosphate, so they are all turned into ATP. If you have 10 ADP molecules returning to the mitochondria for recyling, you get 10 ATP molecules once they are recycled.

1) Does any one cell effectively "own" a given number of ATP/ADP molecules (or their equivalent in phosphate groups?), a bit akin to having its own carrier fleet? I am trying to get a feel for whether the ATP/ADPs come in with the fresh fuel, or whether they primarily exist as part of an energy transportation mechanism localised within the cell.

Yes, that is more or less right, as I understand it. Once the cell has manufactured its ATP molecules, they are like a fleet of trucks used by that cell which ferry energy from the mitochondria into the cell, and then return back to the mitochondria to repeat the job. They repeat this job around 500 to 750 times a day (ref: here). So they are pretty busy trucks.

In terms of the number of mitochondria you have per cell, this is around 1000 to 2000 individual mitochondria.

In terms of how many ATP molecules there are in each cell, by my calculation it is around 1.2 billion molecules of ATP per cell (since there are around 2 × 10^-15 moles of ATP per cell — ref here).


However, not all energy used by the cell is supplied by mitochondria. In addition to the mitochondria, there is another supplier of energy, which is called glycolysis, and glycolysis takes place within the cytosol of the cell, not in the mitochondria. Like the mitochondria, glycolysis also operates by recycling ATP from ADP.

If necessary, glycolysis can supply ATP energy independently of the mitochondria (though it operates better and more efficiently when it works in conjunction with the mitochondria). When it works independently, it is called anaerobic glycolysis; when it works in conjunction with the mitochondria, it is called aerobic glycolysis.

The problem when glycolysis works independently (anaerobic glycolysis) is that you get a lactic acid build up. You don't get this issue if glycolysis in conjunction with the mitochondria. But because the mitochondria appear to be dysfunctional in ME/CFS, possibly this may force glycolysis to work independently of the mitochondria, which then may explain why ME/CFS patients have problems with lactic acid build up.


There is also a third energy supplier in the cell: the creatine phosphate system of recycling ATP from ADP, and this also works independently to mitochondria; but I don't think this is of much relevance to ME/CFS, as this system is only designed to provide very short bursts of energy output (it runs out of energy after around 12 seconds of use).

2) If I am on the right track with '1', are these same carriers also responsible for transporting "fresh", unrecycled energy through the cell to the point of use? i.e. The energy resulting from fuel/oxygen combining?

Oxygen, sugar/carbohydrates and fat from our diet and from breathing are the raw fuel materials that mitochondria and glycolysis use to generate energy. They then package up the energy into ATP molecules.

3) If (the 'ifs' keep getting bigger) I am on the right track with '1' and '2', does this then mean that if the ATP/ADP count is severely reduced, then the cell's ability to transport fresh incoming energy becomes severely impaired, not just its ability to recycle energy within the cell itself?

The cell's ability to transport the energy newly generated in the mitochondria and in glycolysis from the raw fuel materials (oxygen, sugar/carbohydrates and fat) is indeed impaired if there is a shortage of ATP/ADP molecules.

You get a shortage of ATP/ADP molecules if you try to make energy from the adenylate kinase reaction (in which two ADP molecules are converted into ATP plus AMP), because in this process, you permanently lose an ADP molecule.

As I understand it, this is shortage of ATP/ADP molecules is something that occurs during PEM, and is the cause of PEM (according to the Myhill, Booth and McLaren-Howard hypothesis; but note this hypothesis has not yet been proven).

I believe the shortage of ATP/ADP molecules may also occur a lot more in the Group B ME/CFS patients, as these patients may be relying on the adenylate kinase reaction to supply energy, and thus the Group B patients will tend to lose ADP molecules all the time.


But this shortage of ATP/ADP molecules that is thought to occur in ME/CFS is a downstream problem, resulting from 5 prior mitochondrial and energy metabolism dysfunctions that Myhill, Booth and McLaren-Howard found in ME/CFS patients.

These 5 dysfunctions are the ones the "ATP Profiles" test examines and measures, and all 5 are listed and detailed in the first post of this thread.

 

[Hip]

Some recent work by Fluge & Mella may suggest a problem relating to the pyruvate dehydrogenase complex. (See this post: http://forums.phoenixrising.me/inde...r-chronic-fatigue-syndrome.47856/#post-785089)

Very interesting.

I came across a drug called dichloroacetate (DCA) which apparently stimulates the pyruvate dehydrogenase complex. Here it says:

Dichloroacetate indirectly activates the pyruvate dehydrogenase complex by inhibiting the pyruvate dehydrogenase kinases by the same mechanism as pyruvate.

DCA has not been licensed by the FDA, but is used as a speculative cancer treatment, and can be bought online.


I wonder if DCA might help couple glycolysis to the mitochondria, so that the more efficient aerobic glycolysis can take place, rather than the less efficient anaerobic glycolysis (which also causes the problem of lactic acid build up).

EDIT: looks like someone on this forum has already tried dichloroacetate for ME/CFS, with some positive results. See this thread.

 

[Barry53]

Petrol tankers is fine by me — I am also in the UK ... etc

Many thanks once again @Hip. Still working my way through your post. It really is very helpful.

 

[ash0787]

" the AMP is changed into IMP (Inosine monophosphate) plus ammonia, and the IMP is further degraded to Inosine, and then to Hypoxanthine, then to Xanthine and finally eliminated as Uric acid. "

I suppose that explains the question I had as to why you cant just test for AMP in the urine to prove this theory

 

[Barry53]

@Hip: Cannot claim to understand everything you posted, but in truth for my needs I do not have to - not for the moment anyway. But I do have a better handle on what is going on now ... I think.

My main confusion was with what is actually is being recycled. I think what we are saying here, it is basically the energy carriers that are recycling. The fact that when an ADP "returns to depot" with 2 phosphate groups, to pick one up before emerging as an ATP, is I deduce, simply down to the fact that biologically that is the most efficient way of doing it; always having either 2 or 3 "energy parcels" on board, always picking one up and dropping one off, providing the recycling rate is not exceeded. But if the carrier fleet goes dysfunctional, then the ones with only 2 on, end up having a second phosphate group unceremoniously removed, which (this is a pure guess) may be more costly to the cell anyway because that is not what our biology is optimised for. And moreover, any carrier with only 1 left, is basically a truck that the cell now has to scrap, because our biology has no way to way of recharging it again.

Fascinating stuff.

As a slight but interesting aside, my son was saying he thinks one theory suggests that back in the (very!) early days of life on Earth, cells and mitochondria may have been separate life forms, and that they evolved a symbiotic relationship, eventually evolving into their modern form. Do not know if it is true, but I somehow like the notion that it might be.

 

[Barry53]

" the AMP is changed into IMP (Inosine monophosphate) plus ammonia, and the IMP is further degraded to Inosine, and then to Hypoxanthine, then to Xanthine and finally eliminated as Uric acid. "

I suppose that explains the question I had as to why you cant just test for AMP in the urine to prove this theory

I had wondered that too. Thanks to @Hip, and also to your post here, I now have a tiny bit more insight here .

 

[ash0787]

Also I had a thought based on something I read earlier, if we think that the metabolism is unable to process sugar normally in the typical aerobic manner and instead is using certain amino acids for glycolytic energy production,
could an experiment not be done where you starve the person and then feed a radioactively marked sugar
then make them do something which makes them use a lot of energy, then see how much of the sugar remains in the body vs a control ?

 

[Deepwater]

As a slight but interesting aside, my son was saying he thinks one theory suggests that back in the (very!) early days of life on Earth, cells and mitochondria may have been separate life forms, and that they evolved a symbiotic relationship, eventually evolving into their modern form. Do not know if it is true, but I somehow like the notion that it might be.

I've actually read that, but I don't know if it is accepted science or not, viz I came across the following quotation in another book entirely:
"They were once independent organisms. About two billion years ago they in effect moved into primitive cells, establishing a symbiotic relationship, and thereafter evolved with their hosts into complex creatures such as ourselves The bargain struck was that mitochondria … get a home and the cells in which they reside get an energy supply." [1] [1] A.J. Klotzko, A Clone of Your Own? Oxford 2004, p. 20.

 

[dyfalbarhau]

It is a generally accepted idea as far as I'm aware - there are also suggestions that specialised cell organelles in plants entered via the same or a similar process, and it isn't a particularly controversial idea. I remember during my undergraduate degree in biology it was presented essentially as "this is probably basically what happened".

 

[Hip]

It looks like at the IACFS/ME 2016 Conference, Dr Neil McGregor said he found high levels of hypoxanthine in the blood of ME/CFS patients during post-exertional malaise (see Cort's article).

This may tie up with the Myhill, Booth and McLaren-Howard theory of PEM, in which PEM is theorized to be caused by ADP molecules being broken down into AMP (via the adenylate kinase reaction), and then in the muscles, AMP is further metabolized according to the following pathway:

AMP is changed into inosine monophosphate plus ammonia, the inosine monophosphate is then degraded to inosine, and then to hypoxanthine, then to xanthine, and finally eliminated in the urine as uric acid (see @Norman E. Booth's earlier post here).

So McGregor is finding high levels of hypoxanthine in PEM, which is I think what is predicted in the Myhill, Booth and McLaren-Howard theory of PEM.

 

[markiz2001]

From the MEA website, under current research..
4) Comparison of results from a commercial and NHS blood test to assess mitochondrial function

This study will be comparing the results of a commercial blood test for mitochondrial function that has been developed by Dr Sarah Myhill and colleagues with the results from an international and widely accepted test of mitochondrial function which has a long and successful track record in clinical diagnosis and research of muscle disease particularly in the UK.

The aim is to determine the efficacy of each set of tests in relation to ME/CFS. In the exciting case that a synergy between the two diagnostic approaches exists, it is hoped that this preliminary study will promote an investigation into a more inclusive and highly resolved analytical technique for metabolic testing of people with ME/CFS.

Lead researcher: Dr Sarah Jayne Boulton

what "widely accepted" test is there for mitochondrial function? where can you get a test?

 

[Barry53]

what "widely accepted" test is there for mitochondrial function? where can you get a test?

Do we know when these studies will be publishing their results?

 

[Mary]

Hi @Hip - here are my Myhill test results, I'd like to see if you could figure out where I would fit on the Mitochondrial Energy Score graph - thank you so much!

 

[Hip]

Mary's ATP Profiles Test Results

@Mary, looking at your ATP Profiles test results above, the five decimal figures hand written by Dr Myhill on the far right side of the page are the efficiency values for the five processes of energy metabolism function that are measured by the "ATP Profiles" test. These five process I have labelled from (1) to (5) in the first post of this thread.

(I have colored with red and orange circles the figures that Dr Myhill used to calculate these efficiency values, and I have shown the calculation in red text).

These five processes of energy metabolism when working normally will each have a value of around 1. If a process is completely and totally blocked and is not working at all, it will have a value of 0. And any value in between 0 and 1 shows partial functioning of that process.

So in your case, you can see on your test results page that the two processes of energy metabolism that are particularly weak are the ADP to ATP Conversion Efficiency (otherwise known as Oxidative Phosphorylation), where you have an efficiency value of 0.64; and ADP-ATP Translocator "IN" (otherwise known as Translocator Protein In), where you have an efficiency value of 0.25.

Because your Oxidative Phosphorylation is blocked (ie, has a low value of 0.64), this puts you into what Myhill et al call the Group B Patients. They believe Group B patients try to compensate for the shortfall in energy and ATP most likely by using the adenylate kinase reaction to make ATP. And they think Group B patients in particular may benefit from D-ribose supplementation. See this post for more info about these groups.

In the first post of this thread, you might like to read the sections entitled:

(3) Oxidative Phosphorylation = efficiency of oxidative phosphorylation
(5) Translocator Protein In = efficiency of ATP transport into the cell

which will tell you more about these two processes of energy metabolism that are weak in your case.

Note that Myhill et al use the term "translocator protein" to refer to the adenine nucleotide translocator (ANT).



The Mitochondrial Energy Score (MES) is a single figure indicating the overall efficiency of your whole energy metabolism (by taking all five processes into account), and is simply calculated by multiplying the five individual efficiency figures together. So taking your five efficiency figures, found scribbled on the right hand side of your "ATP Profiles" test results page, and multiplying them together we get:

MES for Mary = 0.86 × 0.95 × 0.64 × 0.83 × 0.25 = 0.11

So 0.11 is your final Mitochondrial Energy Score (MES), which is pretty low. Dr Myhill as also hand written this 0.11 figure on your test results page.

Below I have drawn a horizontal purple line which corresponds to your Mitochondrial Energy Score of 0.11 on the figure 4a graph from the Myhill et al 2009 paper. Healthy people (the black dots on the top right of the graph) have MES values of 1 and above. A MES value of 1 corresponds to the horizontal dotted red line on the graph. So your result, the purple line, is quite a long way below that dotted red line.

Have a look at the "CFS Ability" scale on the graph below, which runs from 0 to 10 on the horizontal axis of the graph (these values of 0 to 10 correspond to the severity of ME/CFS as measured on the Bell CFS Disability Scale for each patient). You see on the graph that ME/CFS patients who have a similar MES scores to you typically have a Bell CFS Disability score of around 2 or 3 (these are very severe and severe and patients).

So I am guessing that at the time you had this test done, your illness severity, as measured on the Bell CFS Disability Scale, would have been around 2 or 3 or thereabouts (in fact the Bell scale runs from 0 to 100, so your illness severity would have been around 20 or 30 on the Bell scale). Is that right? Were you around 20 or 30 on the Bell scale at the time you had this test done?

Mitochondrial Energy Score (Derived From the "ATP Profiles" Blood Test),
Plotted Against the Disease Severity Level for Each ME/CFS Patient.

Above originates from figure 4a in Myhill, Booth and McLaren-Howard's 2009 Paper.
​

The "15/100" figure that Dr Myhill wrote at the bottom of your ATP Profiles test results I believe refers to where you are calculated to be on the Bell CFS Disability Scale, given the MES value of 0.11 that you have. (See the bottom of this later post for more info)

 

[Mary]

@Hip - thank you so much! I never could have figured all that out. I am one of the people who benefits from d-ribose, I've been taking it for almost 10 years. And I would guess my Bell disability score is between 20 and 30 - I am confined to the house a majority of the time, I can't perform strenuous activity, I would say my activity is 30% at most of what it should be, though I am not confined to bed most of the day (except when crashed). I spend a lot of time sitting in a chair reading. So 20 to 30 is pretty accurate.

Tomorrow when I have more energy I will read more about oxidative phosphorylation and translocator protein in, and will go over your post in more depth.

Thank you again - I appreciate this so much!

eta: My energy is a little better than when I had the Myhill testing done, due to adding in thiamine and BCAAs and methylfolate - though my stamina or endurance really has not increased; I just feel better more often, but seem to crash just as easily. (dang!)

 

[Hip]

@Hip - thank you so much!

A pleasure, Mary.

I am one of the people who benefits from d-ribose, I've been taking it for almost 10 years.

In my understanding of Myhill, Booth and McLaren-Howard's studies, D-ribose is going to be particularly important and helpful in any PEM period, so perhaps some extra dosing of this supplement during PEM might help get you through PEM more quickly.

Also, note that Q10 is important for oxidative phosphorylation, which is one of your weak areas, so possibly supplementing with Q10 may help. You may have seen in the PEM Busters post how some forum members are using pretty high doses of Q10 (around 800 mg or more) during PEM to successfully mitigate and even eliminate PEM.



One other thing: looking at your Mitochondrial Translocator Protein Study test, which tries to identify what chemicals or biological compounds may be blocking your mitochondrial translocator protein, they found that lanolin, and also a dye precursor (possibly from a hair dye) was attached to your translocator protein. They also found a suspected immune complex, which I am guessing might arise from some autoimmunity.

So lanolin and some sort of dye precursor (as well as the immune complex) may be having a detrimental and blocking effect in your mitochondria.

Lanolin is of course found in many cosmetics: face cream moisturizers, lipstick and so forth.

Your Translocator Protein In is significantly blocked, having an efficiency value of only 0.25, and I think the theory is that the chemicals found attached to the translocator protein in this test may be responsible for blocking it.

 

[Barry53]

So Mary's MES score is just 11% of a normally healthy person's score.