Nobel 2019 – Oxigenul câștigă marele premiu

William G. Kaelin, Jr. (WK), Johns Hopkins University, Baltimore &Dana-Farber Cancer Institute, Boston
Sir Peter J. Ratcliffe, (PR), Oxford University; Director, Clinical Research, Francis Crick Institute, London&Director for Target Discovery Institute, Oxford
William G. Kaelin, Jr. (WK), Sir Peter J. Ratcliffe, (PR), Gregg L. Semenza (GS), Johns Hopkins University – Director, Vascular Research Program

Aceștia sunt cei trei medici-cer-cetători ale căror descoperiri privind modul în care celulele simt și se adaptează la oxigenul disponibil au fost răsplătite anul acesta cu Premiul pentru fiziologie sau medicină, după ce mai câștigaseră (2016), tot în tandem, și altă importantă dis-tincție: Albert Lasker Basic Medi-cal Research Award.

Marea aventură a vieții lor de cercetători, atitudinea lor și nu în ultimul rând răspunsurile lor la întrebările reporterului nobel-prize.org, ne oferă o lecție super-bă, pe care ar trebui măcar să o citim, dacă nu să o și învățăm, cu gândul la cât și cum Contează Sănătatea…

Ce semnificație au aceste des-coperiri?
Nivelul oxigenului (O2) are, cum bine știm, mari fluctuații, iar celulele trebuie să-și adapteze metabolismul la toate schimbările și… să o facă rapid. Celulele noastre nu-l pot stoca iar dacă sunt probleme cu „transpor-tatorul”, celulele roșii, ele vor muri, afectând în final creierul și ducând la moartea întregului organism. Lucrul extraordinar este că există un senzor și un mecanism special care „simt” hipoxia (scăderea nivelului) și „comandă” creșterea numărului de celule roșii. Senzorul acesta se află în rinichi, care secretă eritropoietină (EPO – un hormon codificat de o genă situată pe cromozomul 7) în mo-mentul în care alimentarea cu O2 are probleme. Mecanismul este migrarea rapidă a EPO spre măduva osoasă, stimulând producția de eritrocite – celulele roșii. (De altfel, în cazuri de chimioterapie sau insuficiență renală se administrează EPO!)
Ceea ce a clarificat tandemul celor trei Laureați a fost modul în care celulele renale activează gena EPO, ca răs-puns al deficienței de O2 și apoi o decuplează când alimentarea este suficientă. Acum, încă de la început fusese clar că trebuia să existe un factor care să activeze EPO: o proteină care să se cupleze la un fragment de ADN în vecinătatea unei gene cu rol de potențiator (enhancer). Cel care a identificat acest potențiator a fost GS, care i-a dat și numele: hypoxia inducible factor – HIF. Când celulele nu mai au O2 suficient, HIF intră în nucleul lor și activează gena EPO. În același timp, PR și WK au identificat și o altă proteină, VHL, responsabilă cu distrugerea HIF când nivelul de O2 este ridicat, și astfel, cei trei Lau-reați au ajuns să pună în evidență un comutator molecular care să răspundă la nivelurile de O2. („The elegant switch”, cum l-a numit Comitetul Nobel!), și astfel au rezolvat acest atât de importantă „puzzle”. Spun important inclusiv pentru că ei au găsit că HIF activează și alte 200 de gene…

Utilitatea?
Descoperirea în organisme a unor căi sensibile la O2 are mare importanță în tratarea unor boli cât se poate de diverse. Este o cunoaștere nouă, permițând industriei farmaceutice să dezvolte medicamente care, după caz, să poată activa sau suprima mecanismul de detectare a O2, dar și ajuta în tratarea unor pacienți cu maladii cardiace, cancer pulmonar sau care pur și simplu au probleme de hipoxie.

WK: „Știți, eu cred puternic în cercetarea bazată pe curiozitate sau pe ipoteze. Știu că este un mod complementar altor moduri de a produce cunoaștere dar cred că în final ceea ce m-a condus pe mine la știință și pe mulți alți cercetători este că nouă ne plac aceste puzzle interesante … Și pentru că eu, ca și ceilalți laureați, avem pregătire de medici, noi înțe-legem foarte bine importanța oxige-nului în atât de multe maladii omenești… Astfel, acum că înțelegem calea, se deschid o mulțime de opor-tunități pentru intervenția farma-cologică în boli cum ar fi cancerul, dar și în atacuri de cord sau AVC… Dar, privind înapoi, a fost vorba de un puzzle foarte interesant pe care am încercat să-l rezolvăm.”

GS: „Am început prin a studia problema foarte specifică și oarecum limitată a reglării modului de produc-ție a celulelor roșii … Și de aici s-au dezvoltat atât de multe domenii ale fiziologiei și medicinii… Este uluitor.”

PR: „Da, cred în curaj și cred că este un aspect important că noi producem cunoaștere – asta fac eu ca cercetător finanțat din fonduri publice. Cu-noașterea are o singură calitate care efectiv se poate defini: este o cunoaștere bună, este adevărată, este corectă. La final, ideea este că o anumită cunoaștere poate fi mai valoroasă decât alta, probabil că și acest lucru e adevărat, dar este extrem de dificil de a face evaluări în perspectivă, și acesta este un exem-plu în care pornim într-o călătorie fără o înțelegere clară a valorii acelei cunoașteri și cred că valoarea ei a crescut. Cum va arăta efectiv viitorul, este o altă întrebare, dar este important ca cercetătorii să aibă curajul și să li să permită să ajungă să obțină cunoaștere de dragul cunoașterii, adică inde-pendent de valoarea percepută în momentul creației. Iar istoria științei ne spune mereu și mereu că valoarea acelei cunoașteri poate crește cu impactul asupra cerce-tărilor altor oameni, împrejurărilor, a tot felul de probleme aleatorii și imprevizibile puse în mișcare.”

Dincolo de dezvoltarea tratamen-telor pentru anemie, AVC-uri, cancer și alte situații în care nivelul O2 pare să fie critic, același mecanism, sau unul ase-mănător, este cel căruia îi datorăm viața pe Pământ așa cum o trăim azi, o viață în care organismele au trebuit să se adapteze la nivelul O2 din mediul lor.

Cum spune Andrew Murray, U. Cam-bridge: “Chiar atunci, la început, avem un fel de tranziție funda-mentală în interiorul vieții, când oxigenul nu a mai fost toxic ci a devenit o parte vitală a fiziologiei noastre… (Și) Desigur, vine și provo-carea recentă de a răspunde fluc-tuațiilor în alimentarea cu oxigen, iar cercetările (laureate cu Nobel) acest lucru l-au arătat.”

Prof. Dr. Andrei Dorobanșu, fizician

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