Wadanda suka lashe lambar yabo ta Nobel ta 2019 a fannin ilimin halittar jiki ko kuma likitanci, William G. Kaelin, Jr., Gregg L. Semenza da Sir Peter J. Ratcliffe sun riga sun sami lambar yabo ta Lasker na 2016 a cikin Magungunan Asali don aikinsu kan yadda sel suke fahimta da daidaitawa. hypoxia, don haka ba abin mamaki bane. Sun gano kuma sun gano maɓalli mai mahimmanci hypoxia-inducible factor 1 (HIF-1). A yau muna so mu koma ga asalin binciken, wanda shine erythropoietin, ko EPO, kwayoyin mu'ujiza.

Shi ne abu mafi mahimmanci wajen samar da kwayar halittar jan jini

Kwayoyin jajayen jini sune mafi yawan nau'in sel na jini a cikin jini, kuma sune manyan hanyoyin jigilar oxygen da carbon dioxide ta cikin jinin kashin baya. Ana haifar da Erythrocytes a cikin kasusuwan kasusuwa: Kwayoyin hematopoietic na farko sun fara yaduwa kuma sun bambanta zuwa zuriya na kwayoyin jini daban-daban, kuma erythroid progenitors na iya ƙara bambanta da girma zuwa erythrocytes. A karkashin yanayi na al'ada, yawan samar da erythrocyte na ɗan adam yana da ƙasa sosai, amma a ƙarƙashin damuwa irin su zubar jini, hemolysis, da hypoxia, yawan adadin erythrocyte zai iya karuwa har sau takwas. A cikin wannan tsari, erythropoietin EPO yana ɗaya daga cikin mahimman abubuwan.

EPO wani hormone ne wanda aka haɗa musamman a cikin koda. Yanayin sinadaransa furotin ne mai glycosylated sosai. Me yasa a cikin koda? Kimanin lita guda na jini yana gudana ta cikin kodan kowane minti daya, don haka za su iya gano canje-canjen matakan iskar oxygen cikin jini cikin sauri da inganci. Lokacin da iskar oxygen a cikin jini ya ragu, kodan suna amsawa da sauri kuma suna samar da adadi mai yawa na EPO. Ƙarshen yana zagawa ta cikin jini zuwa kasusuwan kasusuwa, inda yake inganta jujjuyawar ƙwayoyin erythroid zuwa jajayen ƙwayoyin jini. Jajayen ƙwayoyin jinin da suka balaga suna fitowa daga kasusuwan kasusuwa zuwa cikin tsarin jini don inganta ƙarfin jiki na ɗaure da iskar oxygen. Lokacin da kodan suka ga karuwar iskar oxygen a cikin jini, suna rage samar da EPO, wanda hakan ke rage adadin jajayen kwayoyin halitta a cikin kasusuwa.

Wannan yana yin daidaitaccen madauki na daidaitawa. Duk da haka, mutanen da ke zaune a tsayin tsayi da kuma wasu marasa lafiya na anemia sau da yawa suna fuskantar yanayin ci gaba da ƙarancin iskar oxygen na jini, wanda ba zai iya kammala zagayawa na sama ba kuma yana motsa koda don ci gaba da ɓoye EPO, ta yadda ƙwayar EPO na jini ya fi na talakawa.

An kwashe kusan shekaru 80 kafin a gano shi

Kamar manyan bincike-bincike da yawa, fahimtar masana kimiyya game da EPO bai kasance cikin tafiya cikin sauƙi ba, tare da tambayoyi da ƙalubale a hanya. Ya ɗauki kusan shekaru 80 daga tunanin EPO zuwa ƙayyadaddun ƙayyadaddun kwayoyin halitta.

A shekara ta 1906, masana kimiyya na Faransa Carnot da Deflandre sun yi wa zomaye na yau da kullun allurar maganin zomayen anemia kuma sun gano cewa adadin jan jini a cikin plasma na zomaye na al'ada ya karu. Sun yi imani cewa wasu abubuwan ban dariya a cikin plasma na iya motsa jiki da daidaita samar da jajayen ƙwayoyin jini. Wannan shine farkon samfurin ra'ayi na EPO. Abin takaici, sakamakon ba a sake maimaita shi ba a cikin shekaru da yawa masu zuwa, musamman saboda ƙidayar sabbin ƙwayoyin jini ba daidai ba ne.

Gwajin parabiosis na Reissmann da Ruhenstroth-Bauer a 1950 sun ba da shaida mai ƙarfi sosai. Ta hanyar tiyata sun haɗa tsarin jijiyoyin jini na berayen masu rai, suna sanya ɗaya a cikin yanayin rashin ƙarfi, ɗayan kuma yana shakar iska. Sakamakon haka, duka berayen sun samar da jajayen ƙwayoyin jini masu yawa. Babu shakka cewa akwai wani hormone a cikin jini wanda ke motsa samar da jajayen kwayoyin halitta, wanda EPO ya samo sunan sa. A gefe guda, EPO yana da matukar damuwa ga hypoxia.

Menene EPO? Sai da wani masanin kimiyar Ba’amurke Goldwasser ya kwashe shekaru 30 kafin ya fayyace matsalar a matakin sinadarai. Idan ma'aikaci yana son yin aiki mai kyau, dole ne ya fara kaifin kayan aikinsa. Ayyukan EPO shine tada sabbin ƙwayoyin jinin jini, ammakidaya na karshen ba daidai bane. Mafi mahimmancin kwayoyin aiki a cikin kwayoyin jinin jini shine haemoglobin mai dauke da heme, wanda ya ƙunshi ion ferrous a tsakiyarsa. Don haka ƙungiyar Goldwasser ta yi wa jariran jajayen ƙwayoyin jini lakabi da isotopes na ƙarfe na rediyoaktif kuma sun haɓaka hanya mai mahimmanci don gano ayyukan EPO. Wannan yana ba da damar keɓancewa da tsarkake ƙarancin ƙima na EPO (nanograms per milliliter) daga samfuran ruwan dabba. Amma keɓewar EPO ya kasance mai matuƙar wahala. Sun canza daga koda zuwa plasma na tumaki na anemia, zuwa fitsarin marasa lafiya da ke da ƙarancin ƙarfe mai tsanani saboda kamuwa da cutar hookworm, kuma a ƙarshe, a cikin 1977, sun tsarkake 8 milligrams na furotin EPO na mutum daga 2,550 na fitsari daga marasa lafiya na Japan masu fama da anemia.

A cikin 1985, an kammala jerin abubuwan gina jiki da kuma cloning na ɗan adam EPO. Halin EPO yana ɓoye polypeptide tare da ragowar amino 193, wanda ya zama sunadarin da ya balaga da ya ƙunshi ragowar amino acid 166 bayan an yanke siginar peptide yayin ɓoyewa, kuma ya ƙunshi shafuka 4 don gyaran glycosylation. A cikin 1998, an bincika tsarin tsarin NMR na EPO da tsarin crystal na EPO da hadadden mai karɓar sa. A wannan lokaci, mutane sun fi fahimtar EPO.

Har ya zuwa yanzu, maganin anemia yawanci yana buƙatar ƙarin jini don sake cika ƙarancin jajayen ƙwayoyin jini. Yayin da mutane ke ƙarin koyo game da EPO, yin allura don ƙarfafa samar da kwayar jinin jini a cikin kasusuwan kasusuwansu ya sa matsalar ta sauƙaƙa. Amma tsarkake EPO kai tsaye daga ruwan jiki, kamar yadda Goldwasser ya yi, yana da wahala kuma yawan amfanin ƙasa ya ragu. Ƙaddamar da furotin na EPO da jerin kwayoyin halitta sun sa ya yiwu a samar da EPO na ɗan adam mai yawa a cikin adadi mai yawa.

Wani kamfani mai suna Applied Molecular Genetics (Amgen) ne ya yi shi. An kafa Amgen a cikin 1980 tare da mambobi bakwai kawai, suna fatan yin magungunan biopharmaceuticals tare da fasahar da ke tasowa na ilimin kwayoyin halitta. Interferon, abubuwan da ke fitar da hormone girma, maganin hanta na hepatitis B, haɓakar haɓakar epidermal suna cikin sunaye masu zafi a cikin jerin abubuwan da suka yi niyya, amma babu ɗayan waɗannan ƙoƙarin da ya yi nasara. Har zuwa 1985, Lin Fukun, masanin kimiyyar kasar Sin daga Taiwan na kasar Sin, ya tono kwayar halittar EPO na dan Adam, sannan ya gane samar da EPO na roba ta hanyar amfani da fasahar sake hadewar DNA.

Recombinant ɗan adam EPO yana da jeri iri ɗaya da furotin EPO na ƙarshe, kuma yana da irin wannan gyaran glycosylation. A zahiri, EPO na ɗan adam mai sake haɗuwa shima yana da aikin EPO na ƙarshe. A cikin watan Yuni 1989, samfurin farko na Amgen, recombinant erythropoietin Epogen, ya amince da FDA ta Amurka don maganin anemia wanda ya haifar da gazawar koda mai tsanani da kuma anemia a maganin cutar HIV. Kasuwancin Epogen ya kai dala miliyan 16 a cikin watanni uku kacal. A cikin shekaru ashirin masu zuwa, Amgen ya mamaye kasuwa don sake haɗa EPO na ɗan adam. Epogen ya kawo Amgen dala biliyan 2.5 a cikin kudaden shiga a cikin 2010 kadai. A shekarar 2018, darajar kasuwar hannayen jari ta Amgen ta kai dala biliyan 128.8, wanda ya sa ya zama kamfani na takwas mafi girma a fannin harhada magunguna a duniya.

Yana da kyau a lura cewa da farko Amgen ya yi aiki tare da Goldwasser don samar da tsarkakakkun sunadaran EPO na ɗan adam don tsarawa, amma Goldwasser da Amgen ba da daɗewa ba sun faɗi saboda bambance-bambancen akida. Goldwasser da Jami'ar Chicago, waɗanda suka yi bincike na asali, ba su taɓa tunanin yin haƙƙin mallaka na hormone da ya gano ba, don haka ba su sami dinari ba don babbar nasarar kasuwanci ta EPO.

Shi -- yaya abin kara kuzari

Lokacin da muke numfashi, oxygen yana shiga cikin mitochondria na sel don fitar da sarkar numfashi kuma ya samar da adadi mai yawa na ATP, babban tushen kuzari a jikinmu. Mutanen da ke fama da rashin lafiya ba su da isassun ƙwayoyin jajayen jini masu lafiya, kuma abin da ya fi yi a kai a kai shi ne rashin samun isasshen iskar oxygen, wanda ke sa su gaji, kamar matsalar numfashi a cikin dogon lokaci. Lokacin da aka yi masa allura tare da EPO na ɗan adam, jikin marasa lafiya na anemia suna samar da ƙarin jajayen ƙwayoyin jini,dauke da iskar oxygen, da kuma samar da mafi yawan makamashin kwayoyin ATP, yadda ya kamata ya kawar da alamun.

Koyaya, wasu ma'aikatan wasanni kuma sun fara tunanin sake haɗa EPO na ɗan adam. Idan ana amfani da hormone recombinant na wucin gadi na nau'in EPO don tada jikin 'yan wasa don samar da ƙarin jajayen ƙwayoyin jini, yana yiwuwa a inganta ikon 'yan wasa don samun iskar oxygen da samar da kwayoyin makamashi, wanda kuma zai iya inganta aikin 'yan wasa a cikin juriya. abubuwan da suka faru kamar su keke, gudu mai nisa da kuma tsallake-tsallake. Wani takarda na 1980 a cikin Journal of Applied Physiology ya nuna cewa abubuwan motsa jiki na jini (erythropoietin, masu ɗaukar iskar oxygen na wucin gadi da ƙarin jini) na iya ƙara jimiri da kashi 34. Idan 'yan wasa sun yi amfani da EPO, za su iya yin gudun kilomita 8 akan injin tuƙa cikin daƙiƙa 44 ƙasa da lokaci fiye da da. A gaskiya ma, hawan keke da marathon sun kasance mafi munin masu laifi don abubuwan motsa jiki na EPO. A lokacin Tour de France na 1998, an kama wani likitan tawagar Spain na ƙungiyar Festina a kan iyakar Faransa tare da kwalabe 400 na EPO na wucin gadi! Sakamakon, ba shakka, shi ne cewa an kori ƙungiyar gaba ɗaya daga cikin yawon shakatawa kuma an dakatar da su.

Kwamitin Olympics na kasa da kasa ya kara EPO a cikin jerin sunayen da aka haramta a wasannin Barcelona na 1992, amma sake tsara gwajin EPO na dan Adam yana da wuyar gaske cewa kafin wasannin 2000 babu wata hanyar da za a iya gane ko 'yan wasa suna amfani da shi. Akwai dalilai da yawa: 1) Abubuwan da ke cikin EPO a cikin ruwan jiki yana da ƙasa sosai, kuma EPO a kowace ml na jini a cikin mutane na al'ada kusan 130-230 nanograms; 2) Amino acid abun da ke ciki na wucin gadi recombinant EPO daidai yake da na ɗan adam endogenous EPO furotin, kawai nau'i na glycosylation ne dan kadan daban-daban; 3) Rabin rayuwar EPO a cikin jini shine sa'o'i 5-6 kawai, kuma ba a iya gano shi gabaɗaya kwanaki 4-7 bayan allura ta ƙarshe; 4) Matsayin EPO na mutum ɗaya ya bambanta sosai, don haka yana da wahala a kafa cikakkiyar ma'aunin ƙididdiga.

Tun daga shekara ta 2000, WADA ta yi amfani da gwajin fitsari a matsayin hanyar tabbatar da kimiyya kawai don ganowar EPO na sake haɗawa kai tsaye. Saboda ƙananan bambance-bambance tsakanin nau'in glycoylated na EPO na wucin gadi na wucin gadi da na EPO na ɗan adam, abubuwan da aka caje na ƙwayoyin ƙwayoyin cuta guda biyu suna da ƙananan ƙananan kuma ana iya bambanta su ta hanyar hanyar electrophoresis da ake kira isoelectric mayar da hankali, wanda shine babban dabarun ga gano kai tsaye na EPO na wucin gadi. Duk da haka, wasu recombinant EPO da aka bayyana ta hanyar sel da aka samu na ɗan adam ba su nuna wani bambanci a cikin glycosylation ba, don haka wasu masana sun ba da shawarar cewa EPO na waje da EPO na endogenous ya kamata a bambanta ta daban-daban abun ciki na isotope carbon.

A gaskiya ma, har yanzu akwai iyakoki a cikin hanyoyin gwaji daban-daban don EPO. Misali, Lance Armstrong, fitaccen dan tseren keke na Amurka, ya yarda cewa ya sha EPO da sauran abubuwan kara kuzari a lokacin nasararsa na Tour de France guda bakwai, amma ba a tabbatar masa da ingancin EPO ba a duk wani gwajin doping a wancan lokacin. Har yanzu dole mu jira mu ga ko "ƙafa ɗaya mafi girma" ko "ƙafa ɗaya mafi girma".

Ta yaya ake samun kyautar Nobel

Kalma ta ƙarshe game da alaƙa tsakanin EPO da Kyautar Nobel ta 2019 a cikin Ilimin Halitta ko Magunguna.

EPO shine mafi yawan al'amuran al'ada na tsinkayen jikin mutum da amsawa ga hypoxia. Saboda haka, Semenza da Ratcliffe, masu kyautar Nobel guda biyu, sun zaɓi EPO a matsayin mafari don nazarin tsarin fahimtar kwayar halitta da daidaitawa zuwa hypoxia. Mataki na farko shine gano abubuwan da ke cikin kwayar halittar EPO wanda zai iya amsawa ga canje-canjen iskar oxygen. Semenza ya gano wani maɓalli 256-tushe mara ƙididdigewa a cikin 3 'ƙarshen ƙarshen kwayar halittar EPO, mai suna ɓangaren amsawar hypoxia. Idan wannan jerin abubuwan ya canza ko share, ikon furotin na EPO don amsa hypoxia yana raguwa sosai. Idan wannan jerin abubuwan an haɗa su zuwa ƙarshen 3 'ƙarshen sauran kwayoyin halitta waɗanda ba su da alaƙa da hypoxia, waɗannan gyare-gyaren ƙwayoyin cuta kuma suna nuna kunnawa kamar EPO.a karkashin yanayin hypoxia.

Ratcliffe da tawagarsa sun gano cewa wannan nau'in amsawar hypoxic ba wai kawai yana cikin koda ko ƙwayoyin hanta da ke da alhakin samar da EPO ba, har ma a cikin sauran nau'in tantanin halitta da yawa waɗanda zasu iya aiki a ƙarƙashin yanayin hypoxic. A wasu kalmomi, wannan amsa ga hypoxia bazai zama takamaiman ga EPO ba, amma a maimakon haka ya zama wani abu mai yaduwa a cikin sel. Wadannan sauran kwayoyin halitta, wadanda ba su da alhakin samar da EPO, dole ne su ƙunshi kwayoyin halitta (kamar abubuwan da aka rubuta da alhakin kunna maganganun kwayoyin halitta) waɗanda ke jin canje-canje a cikin tattarawar iskar oxygen kuma suna ɗaure ga abubuwan amsawa na hypoxic don kunna kwayoyin halitta kamar EPO.