The Fatigue Biomarker Story – Part III

Blog written by John Kalns


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This is the third and final part in John Kalns’ story about the discovery of the fatigue biomarker. We ended Part II by discussing peptides, identifying the sequence, and isolating the molecule from saliva. And now for part three…

Picking Up Where We Left Off

[ To validate our findings, we had to synthesize the molecule and compare it to what we thought we had discovered. This is how good science is done, and I am proud of our team’s work. When we finally got the results, we were very surprised…” – end of part two ]

We found that both of our proteins of interest turned out to be unique to the salivary gland itself, not neuropeptides or inflammation signals! By sleuthing through databases, it became absolutely certain that both small proteins were part of a larger protein called Proline Rich Protein (or PRP).

PRP and associated peptides make up about 37% of all the protein found in saliva. They are only produced in the salivary gland, making them the most abundant proteins found in saliva.

What is PRP & What Does It Do?

It’s interesting that nobody seems to know everything that they do. They might be involved in keeping our gums and teeth healthy. More importantly, they don’t resemble anything else, though some scientists have speculated that they have a structure similar to wheat gluten.

Despite all of this, it’s still surprising that there are only a few proteins that don’t fit into any of the other categories; they’re pretty much in their own category. Some mammals (such as primates and select rodents) have the gene to produce PRP, but it’s not clear what they produce – or if it’s produced in abundance. So… why do we make it?

Protein In Our Saliva

To make things even stranger, we produce a lot of PRP – our bodies make and swallow about a gallon of saliva each day. Of that, roughly 100 grams of PRP protein is made and processed in the gastrointestinal tract every single day.

Making protein is a very energy-intensive process. Protein is expensive to make (in terms of energy), and even if you recycle most of it, your body still has to spend a lot of energy doing so. And now, in addition to asking “why do we make it?”, the question becomes: why do we make so much?

Peptides & Proteases

As if our story wasn’t interesting enough… The parent protein PRP is huge – weighing in at about 42,000 molecular weight units. Each of the peptides that comprise the fatigue biomarker are about 700 molecular weight units (or 8 amino acids). The PRP parent is processed by enzymes, called proteases, that specifically cleave – or split – the larger protein into smaller, individual peptides.

Proteases have two features: the ability to recognize, bind to, and fix a protein, and functioning as a “cutting machine”. Some proteases are relatively non-specific and will cut up many types of proteins, while others are very specific. These will target a very precise location on a big protein.

In regards to the fatigue biomarker peptides, it seems likely that the proteases are very specific; they lead to such a dramatic difference in abundance of the two peptides that make up the fatigue biomarker.

More About Fatigue Peptides

Together, these results lead me to conclude that the production of the fatigue peptides is part of a very specific and highly controlled system related to fatigue. In a highly fatigued state, one peptide virtually disappears. What could any of this have to do with fatigue? Well… The data that we have accumulated over several years all points in one direction: energy.

Diving into Sleep Deprivation

Consider this: sleep deprivation and intense physical exertion can both cause fatigue, but more importantly, they can alter the abundance of fatigue peptides. Anecdotal data, “a description of a data point that goes beyond providing the metric(s) being collected” (according to, suggests that the quality of a diet can also alter this composition. 

All of them have one thing in common: a state of uncertainty and high stress that would most likely benefit from more energy. These peptides are eventually swallowed and then processed through the gastrointestinal tract. This makes it seem possible that they do something there – probably something having to do with the gut microbiome.

Guts, Peptides, & Fatigue

We know that the gut microbiome is composed of bacteria and bacteriophages, as well as human immune cells and other cells that line the gastrointestinal tract. There is a growing awareness that the gut microbiome plays an important role in regulating energy recovery from food.

What if the changing levels of the peptides associated with fatigue biomarkers are a sign that we should be recovering as much energy as possible from the food that’s already in our bodies? This seems to fit pretty well with what we know. However, this is only a hypothesis that is yet unproven.

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Primer, D. (2018, September 29). How anecdotal evidence can make or break your insights | by David Primer | Towards Data Science. Medium; Towards Data Science.

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