Il dato è tratto

Il dato è tratto

Da circa 4 anni ho investito le mie scarse abilità residue nella ricerca di una descrizione e di una cura (anche solo parziale e momentanea) della mia patologia. Si tratta di una condizione cronica disabilitante il cui meccanismo patogenetico è ascrivibile a una o più malattie rare, forse sconosciute. Il quadro clinico può ritenersi compatibile con la ME/CFS (Institute of Medicine, 2015).

Nei molti anni di malattia ho faticosamente imparato che l’elemento più importante per tentare di risolvere un caso come il mio è la diagnostica strumentale: un centinaio di visite mediche e di altrettanti tentativi terapeutici empirici non hanno potuto fornire alcun contributo significativo, laddove gli esami hanno sempre prodotto dati concreti.

In questi anni – per la prima volta nella storia – i pazienti hanno accesso diretto a strumenti che permettono di descrivere una porzione importante della propria patologia con uno sforzo minimo: scansione dell’intero patrimonio genetico, metabolomica, e altri pannelli di esami che forniscono simultaneamente alcune migliaia di dati in campo autoimmunitario, di espressione genica, di immunologia, di infettivologia. Si tratta complessivamente di diversi milioni di dati per singolo paziente.

Questo tipo di tecnologia consente teoricamente di descrivere i singoli pazienti rari nell’arco di una manciata di giorni, con solo pochi prelievi, laddove la trafila negli studi medici necessaria per ottenere una analisi con la stessa completezza e definizione richiederebbe probabilmente alcune decine di anni, ammesso che fosse possibile. E sarebbe molto più costosa. Senza contare che alcuni di noi hanno estrema difficoltà anche solo a raggiungere lo studio dei medici.

Le difficoltà che si incontrano nel costruire questo tipo di analisi sono quelle di scegliere il fornitore del servizio, di organizzare la logistica della raccolta e spedizione dei campioni, di analizzare i dati (ma in molti casi l’analisi è informatizzata, e richiede uno sforzo minimo). Ad oggi non esiste un ente che svolga questo lavoro per il paziente, per cui dobbiamo occuparcene noi stessi. Poi c’è il costo degli esami, ma molti di questi esami costano quanto una singola visita da uno specialista, e molto meno di qualunque viaggio della speranza verso centri per cure miracolose. Inoltre alcuni di questi dati (come quelli genetici) restano un patrimonio di conoscenza su noi stessi a cui poter attingere per il resto della propria vita.

Dati raccolti in modo accurato da analisi affidabili possono inoltre essere donati alla ricerca. Ci sono al momento varie possibilità per fare questo, senza sforzi aggiuntivi per il paziente e con potenziali benefici per la comunità.

Tutto ciò premesso, sto cercando pazienti rari (o loro congiunti), che vogliano collaborare con me a organizzare questo tipo di raccolta dati, allo scopo di inquadrare e auspicabilmente risolvere i singoli casi. Io ho già fatto alcuni passi in questa direzione e ho acquisito una modesta ma significativa esperienza, ma mi rendo conto che il compito sarebbe molto più agevole se si lavorasse in gruppo. Sarebbe utile una qualche formazione di tipo tecnico in ambiti come informatica, chimica, ingegneria, fisica, matematica, biologia.

Chi volesse scambiare idee su questo progetto può contattarmi qui:

maccallini.paolo@gmail.com

 

 

 

Annunci

The half-full glass

The half-full glass

This is for the most part the translation in English of an article I wrote in Italian on Whitney Dafoe, several months ago.

Patient zero

The 2016 edition of the Personalized Medicine World Conference (PMWC) (program) was held in San Francisco, about a year ago. During the second day of this meeting, Dr. Andreas Kogelnik, a physician and bioengineer at the Open Medicine Institute, presented some of the data on the energy metabolism of a young man suffering from ME/CFS, as an example of application of newly available metabolomic tests in difficult and still poorly understood conditions. The patient we are talking about is the son of Ronald Davis, a famous geneticist at Stanford University who is currently engaged in an ambitious research program on ME/CFS, at the Open Medicine Foundation. It is Kogelnik himself who reveals in his speech the identity of the man whose metabolic data he is talking about, and on the other hand the unfortunate events of this man were made public by his own family, in order to stimulate scientific research and investments for ME/CFS. The touching story of the progressive decline in intellectual and physical functioning of Whitney (that’s his name), has been told in this video:

A photographer and a photo of his metabolism

Whitney, who is now about 35, is no longer able to move from his bed, to read, and to communicate with his parents. He was previously a popular photographer and has traveled the world. This is his personal website. The latest update (2013) says: “Really sick.  I can’t talk. Can’t type/text enough to communicate. Haven’t had a conversation with someone in 6 months…” Whitney is a peculiar case, both because he has a particularly severe manifestation of ME/CFS (but there are other patients like him), and because his father is a professor of genetics at one of the world’s top universities (Stanford University). And what could a father-scientist do in order to save a son with an incurable condition? He studies, of course! But he does not restrict himself to scour compulsively scientific publications or biology books; he sets up a team of researchers, seeks funds to finance them, and invents new technologies to fight the disease. In the video of the intervention by Andreas Kogelnik, we can see the first outcomes of his efforts. In particular – at minute 8 – we have an eloquent snap-shot of Whitney’s energy metabolism (see figure below).

withney

Joule and glucose

Before examining Whitney’s metabolic data, let’s recall briefly that the process by which our cells extract energy from the chemical bonds of glucose, consists of two phases. The first, glycolysis, occurs in the cytoplasm (outside mitochondria) and allows to obtain two molecules of ATP from each molecule of glucose. The by-product of glycolysis consists of two molecules of pyruvate, for each molecule of glucose processed. But this by-product is the fuel that feeds the second stage, which occurs within the mitochondria. In this second phase, pyruvate is converted into acetyl-CoA (with the synthesis of 3 molecules of ATP for each molecule of pyruvate), and the acetyl-CoA is then sent to the Krebs cycle (also called the citric acid cycle), where 12 more molecules of ATP are produced, per molecule of acetyl-CoA. More precisely, the Krebs cycle produces one molecule of ATP, three of NADH and one FADH2; these last two molecules are sent to the oxidative phosphorylation (mitochondrial membrane) where they are used to synthesize a total of 11 molecules of ATP. The conclusion is that one molecule of glucose allows to produce 2 molecules of ATP in the cytoplasm, and 36 molecules within the mitochondria. (More recently a reinterpretation of the experimental evidence has suggested a slightly different result of 31 molecules of ATP from a molecule of glucose). These are the basics of the energy balance within cells. The issue becomes more complex when one considers that fatty acids and some amino acids are used by mitochondria in order to produce energy.

Half is not enough

What about the snapshot of Whitney’s energy metabolism? When account is taken of the fact that the data were presumably divided by the mean of the reference from healthy volunteers, it appears clear that his generator is running at about half of the average power. In fact, pyruvate (the end product of glycolysis) is about 0.6 of the average value, and all the metabolites of the Krebs cycle are comprised between 0.4 and 0.7. Accordingly, the level of glucose in the blood is slightly increased (Whitney’s pancreas struggles to avoid hyperglycemia, evidently), while the level of the lactate is equally low (lactate is produced from pyruvate). Now, if the cellular energy generator delivers a power (energy released per unit of time) equal to 50% of what the body normally produces, you would expect that those organs with the highest energy requirements, such as brain and muscles, are those which would suffer the most. And this theoretical model, based on real data from Whitney’s thermodynamics, would explain his symptoms. Of course, other interpretations are possible.

Outside the Krebs cycle

But where is the block in Whitney’s cellular energy generator? If glycolysis operates at 50% and if it is the glycolysis which fuels mitochondria, the answer seems simple: the block is in the cytoplasm, i.e. in glycolysis itself, outside the mitochondria. This interpretation of the data is consistent with what shown by Christopher Armstrong and his colleagues of the University of Melbourne, in 2015. The research team was indeed able to highlight a block of glycolysis, analyzing the normal panel of the organic acids in the blood and in the urine of 34 patients with ME/CFS (Armstrong CW et al. 2015). The hypothesis of a block of glycolysis is also compatible with the recent European work on ME patients from Pisa (Italy), in which an over-expression of two fundamental mitochondrial enzymes has been demonstrated (see this post). In fact, if the mitochondria were subjected to shortness of fuel, it would be logical to think that the number of their enzymes would increase, in order to extract every possible joule from the available substrate.

whitney_dafoe_before_and_after_illness

Hypometabolism as an adaptation

Another possible explanation for the overall depression of the energy system (inside and outside mitochondria) is the one provided by Robert Naviaux, in his recent publication on metabolism of ME/CFS patients. According to his vision, mitochondria are partially turned off, as a response to a persistent or past environmental threat (mainly infections or toxic substances); this response is an evolutionarily conserved mechanism, whose role is to protect the body from the threat, a bit like fever is a defense system that promotes the immune response against a virus or a bacterium. If this was true, the mitochondria block should be managed in concert with the glycolysis block, otherwise you would have the accumulation of toxic substances, such as lactate. So this hypothesis fits well with the experimental data on Whitney. It is interesting to note that recently a similar mechanism has been described as a possible basis for bacterial persistence: exposed to antibiotics, bacteria turn off their energy metabolism and thus survive to these chemicals which, for the most part, target enzymes of their metabolic machinery (Shan Y et al. 2017). This makes a lot of sense, since more than 1.45 billions years ago mitochondria were in fact bacteria (R). So Whitney’s hypometabolic state could in fact represent an evolution of bacterial persistence.

Conclusions

Whitney’s metabolism reveals an overall halving of the power delivered by the power generators of his cells. Apparently the defect is in the initial part of glucose metabolism, outside the mitochondria, and of course it is reflected on mitochondrial metabolism, which is depressed. However other interpretations of these data are possible, such as the one proposed by Naviaux and colleagues, of an overall depression of the energy system as an evolutionarily conserved response to external threats (real or perceived). In addition, although a reduction in energy of 50% would seem to explain the symptoms, you can not say that this reduction is the cause of the disease, rather than one of its many consequences.