ʻO nā mea lanakila ʻekolu o ka 2019 Nobel Prize in Physiology or Medicine, ʻo William G. Kaelin, Jr., Gregg L. Semenza a me Sir Peter J. Ratcliffe ua lanakila mua lākou i ka 2016 Lasker Prize in Basic Medicine no kā lākou hana e pili ana i ka ʻike a me ka hoʻololi ʻana o nā cell. i ka hypoxia, no laila, ʻaʻole ia he mea kupanaha. Ua ʻike a ʻike lākou i ka mole nui hypoxia-inducible factor 1 (HIF-1). I kēia lā makemake mākou e hoʻi i ke kumu o ke aʻo ʻana, ʻo ia ka erythropoietin, a i ʻole EPO, kahi mole mole.

ʻO ia ka mea nui i ka hana ʻana o ke koko ʻulaʻula

ʻO ke koko ʻulaʻula ka ʻano nui o ke koko i loko o ke koko, a ʻo ia ke kumu nui no ka lawe ʻana i ka oxygen a me ka carbon dioxide ma o ke koko o nā vertebrates. Hoʻokumu ʻia nā Erythrocytes i loko o ka iwi iwi: Hematopoietic stem cell for first proliferate and differentitors in progenitors of various blood cell, and erythroid progenitors hiki ke hoʻokaʻawale hou a oʻo i nā erythrocytes. Ma lalo o nā kūlana maʻamau, he haʻahaʻa loa ka nui o ka hana erythrocyte kanaka, akā ma lalo o ke koʻikoʻi e like me ke koko, hemolysis, a me ka hypoxia, hiki ke hoʻonui ʻia ka nui o ka hana erythrocyte a hiki i ʻewalu manawa. Ma kēia kaʻina hana, ʻo erythropoietin EPO kekahi o nā mea nui loa.

ʻO ka EPO he hormone i hana nui ʻia i loko o ka puʻupaʻa. ʻO kona ʻano kemika he protein glycosylated loa. No ke aha i loko o nā puʻupaʻa? Ma kahi o hoʻokahi lita o ke koko e kahe ana i loko o nā puʻupaʻa i kēlā me kēia minuke, no laila hiki iā lākou ke ʻike wikiwiki a maikaʻi hoʻi i nā loli o ka pae o ka oxygen i loko o ke koko. Ke haʻahaʻa ka pae o ka oxygen i loko o ke koko, pane koke nā puʻupaʻa a hana i ka nui o ka EPO. Kaʻapuni ka hope ma ke kahe koko a hiki i ka iwi iwi, kahi e hoʻoikaika ai i ka hoʻololi ʻana o nā cell progenitor erythroid i loko o ke koko ʻulaʻula. Hoʻokuʻu ʻia nā keʻena koko ʻulaʻula oʻo mai ka iwi iwi i loko o ka ʻōnaehana kaʻa no ka hoʻomaikaʻi ʻana i ka hiki o ke kino ke hoʻopaʻa i ka oxygen. Ke ʻike nā puʻupaʻa i ka piʻi ʻana o ka oxygen i loko o ke koko, hoʻemi lākou i ka hana EPO, ʻo ia ka mea e hoʻemi ai i ka nui o nā keʻena koko ʻulaʻula i loko o ka iwi iwi.

Hana kēia i kahi loop hoʻoponopono kūpono. Eia nō naʻe, ʻike pinepine ka poʻe e noho ana ma kahi kiʻekiʻe a me kekahi mau maʻi anemia i ke ʻano o ka haʻahaʻa haʻahaʻa o ke koko oxygen pae, ʻaʻole hiki ke hoʻopau i ke kahe o luna a hoʻoulu i ka puʻupaʻa e huna mau i ka EPO, i ʻoi aku ka kiʻekiʻe o ke koko EPO ma mua o nā kānaka maʻamau.

Ma kahi o 80 mau makahiki e wehe ai

E like me ka nui o nā ʻike nui, ʻaʻole maʻalahi ka ʻike ʻana o ka poʻe ʻepekema i ka EPO, me nā nīnau a me nā pilikia ma ke ala. Ma kahi o 80 mau makahiki mai ka manaʻo o EPO a hiki i ka hoʻoholo hope ʻana o ka mole kikoʻī.

I ka makahiki 1906, ua hoʻopiʻi nā kānaka ʻepekema Farani ʻo Carnot lāua ʻo Deflandre i nā rabbit maʻamau me ka serum o nā rapeti anemic a ʻike i ka piʻi ʻana o ke koko ʻulaʻula i loko o ka plasma o nā rapeti maʻamau. Ua manaʻo lākou e hiki i kekahi mau mea hoʻohenehene i loko o ka plasma ke hoʻoulu a hoʻoponopono i ka hana ʻana o nā ʻāpana koko ʻulaʻula. ʻO kēia ka prototype manaʻo EPO mua. ʻO ka mea pōʻino, ʻaʻole i hana hou ʻia nā hopena i nā makahiki i hala aku nei, no ka mea, ʻaʻole pololei ka helu o nā ʻulaʻula hou.

ʻO ka hoʻokolohua parabiosis ʻo Reissmann lāua ʻo Ruhenstroth-Bauer i ka makahiki 1950 i hōʻike ikaika loa. Hoʻopili ʻia lākou i nā ʻōnaehana kaʻa o nā ʻiole ola ʻelua, e waiho ana i kekahi i loko o kahi ʻano hypoxic a ʻo kekahi e hanu ana i ka ea maʻamau. ʻO ka hopena, ua hoʻopuka nā ʻiole ʻelua i nā pūnaʻi koko ʻulaʻula nui. ʻAʻohe kānalua he hormone i loko o ke kahe koko e hoʻoulu i ka hana ʻana o nā ʻulaʻula ʻulaʻula, kahi i loaʻa ai ka inoa ʻo EPO. Ma ka ʻaoʻao ʻē aʻe, paʻakikī loa ka EPO i ka hypoxia.

He aha ka molela EPO? Ua lawe i ka ʻepekema ʻAmelika ʻo Goldwasser 30 mau makahiki e wehewehe hope i ka pilikia ma ka pae biochemical. Inā makemake ka mea hana e hana i ka hana maikaʻi, pono e hoʻokala mua i kāna mau mea hana. ʻO ka hana o ka EPO ka mea e hoʻoulu ai i ke koko ʻulaʻula hou, akāʻaʻole pololei ka helu o ka hope. ʻO ka molekele hana koʻikoʻi i loko o ke koko ʻulaʻula ʻo ia ka hemoglobin i loaʻa ka heme, aia kahi ion ferrous ma kona kikowaena. No laila ua kapa inoa ka hui o Goldwasser i ke koko ʻulaʻula hou me nā isotopes hao radioactive a ua hoʻomohala i kahi ala maʻalahi no ka ʻike ʻana i ka hana EPO. ʻO kēia ka mea hiki ke hoʻokaʻawale a hoʻomaʻemaʻe i nā haʻahaʻa haʻahaʻa loa o EPO (nanograms per milliliter) mai nā laʻana wai holoholona. Akā paʻakikī loa ka hoʻokaʻawale ʻana o EPO. Ua hoʻololi lākou mai ke kinikini i ka plasma hipa anemic, i ka mimi o nā mea maʻi me ka hao nui ma muli o ka maʻi hookworm, a hope loa, ma 1977, hoʻomaʻemaʻe 8 milligrams o ke kanaka EPO protein mai 2,550 liters o ka mimi mai nā poʻe maʻi Iapana me ka anemia aplastic.

I ka makahiki 1985, ua hoʻopau ʻia ke kaʻina pūmua a me ka hoʻopaʻa ʻana i nā gene o EPO kanaka. Hoʻopili ka gene EPO i polypeptide me nā koena amino 193, a lilo ia i pūmua oʻo i haku ʻia me 166 koena amino acid ma hope o ka ʻoki ʻia ʻana o ka peptide hōʻailona i ka wā huna, a loaʻa iā 4 mau wahi no ka hoʻololi glycosylation. I ka makahiki 1998, ua kālailai ʻia ka ʻōnaehana hoʻonā NMR o EPO a me ke ʻano aniani o ka EPO a me kāna mea hoʻokipa. I kēia manawa, loaʻa i nā kānaka ka ʻike intuitive loa o EPO.

A hiki i kēia manawa, ʻo ka mālama ʻana i ka anemia e koi pinepine i ka hoʻololi ʻana i ke koko e hoʻopiha i ka hemahema o nā ʻulaʻula. Ke aʻo hou aku ka poʻe e pili ana i ka EPO, ʻo ka hoʻokomo ʻana iā ia e hoʻoulu i ka hana ʻana o ke koko ʻulaʻula i loko o kā lākou iwi iwi ponoʻī ua maʻalahi ka pilikia. Akā ʻo ka hoʻomaʻemaʻe pono ʻana i ka EPO mai nā wai kino, e like me kā Goldwasser i hana ai, paʻakikī a haʻahaʻa nā hua. ʻO ka hoʻoholo ʻana o ka protein EPO a me ke kaʻina gene i hiki ke hana i ka EPO kanaka recombinant i ka nui.

Ua hana ʻia e kahi hui biotechnology i kapa ʻia ʻo Applied Molecular Genetics (Amgen). Ua hoʻokumu ʻia ʻo Amgen ma 1980 me ʻehiku mau lālā, me ka manaʻo e hana i nā biopharmaceuticals me nā ʻenehana hou o ka biology molecular. ʻO Interferon, growth hormone releasing factor, hepatitis B vaccine, epidermal growth factor kekahi o nā inoa wela ma kā lākou papa inoa o nā pahuhopu, akā ʻaʻole i kūleʻa kekahi o kēia mau hoʻāʻo. A hiki i ka makahiki 1985, ʻo Lin Fukun, he kanaka ʻepekema Kina mai Taiwan, Kina, hoʻopaʻa i ka gene o EPO kanaka, a laila ʻike i ka hana ʻana o ka EPO synthetic me ka hoʻohana ʻana i ka ʻenehana recombination DNA.

Loaʻa i ka EPO kanaka recombinant ke kaʻina like me ka protein EPO endogenous, a he like hoʻi ka hoʻololi glycosylation. Ma ke'ano maoli, loa'a ka EPO kanaka recombinant i ka hana o ka EPO endogenous. I Iune 1989, ua ʻae ʻia ka huahana mua a Amgen, recombinant human erythropoietin Epogen, e ka US FDA no ka mālama ʻana i ka maʻi anemia i hoʻokumu ʻia e ka maʻi maʻi maʻi a me ka anemia i ka mālama ʻana i ka maʻi HIV. Ua ʻoi aku ke kūʻai aku ʻo Epogen i $ 16 miliona i loko o ʻekolu mahina. I nā makahiki he ʻelua e hiki mai ana, ua lanakila ʻo Amgen i ka mākeke no ka EPO kanaka hou. Ua lawe mai ʻo Epogen iā Amgen $2.5 biliona ma ka loaʻa kālā ma 2010 wale nō. I ka makahiki 2018, he $128.8 biliona ke kumukūʻai kūʻai o Amgen, ʻo ia ka ʻewalu o ka ʻoihana lāʻau lapaʻau nui loa ma ka honua.

He mea pono e hoʻomaopopo i ka hana mua ʻana o Amgen me Goldwasser e hoʻolako i nā protein EPO kanaka i hoʻomaʻemaʻe ʻia no ka hoʻonohonoho ʻana, akā ua hāʻule koke ʻo Goldwasser lāua ʻo Amgen ma muli o nā ʻokoʻa ideological. ʻO Goldwasser a me kāna Kulanui o Chicago, nāna i hana i ka noiʻi kumu, ʻaʻole i manaʻo e patent i ka hormone āna i ʻike ai, a no laila ʻaʻole i loaʻa i kahi peni no ka kūleʻa pāʻoihana nui o EPO.

ʻO ia -- pehea ia he mea hoʻoulu

Ke hanu mākou, komo ka oxygen i ka mitochondria o nā cell e hoʻokele i ke kaulahao hanu a hana i ka nui o ATP, ke kumu nui o ka ikehu i loko o ko mākou kino. ʻAʻole lawa nā keʻena koko ʻulaʻula olakino i ka poʻe maʻi maʻi, a ʻo ka hopena wikiwiki loa ʻo ia ka lawe ʻole ʻana i ka oxygen, kahi e luhi ai lākou, e like me nā pilikia hanu i ka wā lōʻihi. Ke hoʻokomo ʻia me ka EPO kanaka recombinant, hoʻopuka nā kino o nā maʻi anemia i nā ʻāpana koko ʻulaʻula hou aku.lawe hou aku i ka oxygen, a hoʻonui i ka ikehu mole ATP, e hoʻopau pono i nā hōʻailona.

Eia naʻe, ua hoʻomaka kekahi poʻe hana haʻuki e noʻonoʻo i ka EPO kanaka recombinant. Inā hoʻohana ʻia ka hormone recombinant artificial o ke ʻano EPO e hoʻoulu i ke kino o nā mea pāʻani e hana i nā ʻāpana koko ʻulaʻula hou aʻe, hiki ke hoʻomaikaʻi i ka hiki i nā mea pāʻani ke loaʻa ka oxygen a hana i nā molekele ikehu, hiki ke hoʻomaikaʻi i ka hana o nā mea pāʻani i ka hoʻomanawanui. nā hanana e like me ke kaʻa kaʻa, ka holo lōʻihi a me ka hoʻokele ʻāina. Ua hōʻike ʻia kahi pepa 1980 ma ka Journal of Applied Physiology e hiki i nā mea hoʻoikaika koko (erythropoietin, nā mea lawe oxygen artificial a me nā kahe koko) ke hoʻonui i ka hoʻomanawanui ma 34 pakeneka. Inā hoʻohana ka poʻe haʻuki i ka EPO, hiki iā lākou ke holo i 8 mau kilomika ma ka wili i loko o 44 kekona ka liʻiliʻi o ka manawa ma mua. ʻO ka ʻoiaʻiʻo, ʻo ka paikikala a me nā marathon ka mea hewa loa no nā mea hoʻoikaika EPO. I ka makahiki 1998 Tour de France, ua hopu ʻia kekahi kauka hui Paniolo no ka hui Festina ma ka palena ʻo Farani me 400 mau hue o ka EPO recombinant artificial! ʻO ka hopena, ʻoiaʻiʻo, ua kipaku ʻia ka hui holoʻokoʻa mai ka huakaʻi a pāpā ʻia.

Ua hoʻohui ke Kōmike ʻOlumepika o ka honua i ka EPO i kāna papa inoa i pāpā ʻia ma nā pāʻani Barcelona 1992, akā paʻakikī loa ka hoʻonohonoho hou ʻana i ka hoʻāʻo EPO kanaka ma mua o nā pāʻani 2000 ʻaʻohe ala e ʻike pono ai inā hoʻohana nā mea pāʻani. Aia kekahi mau kumu: 1) He haʻahaʻa loa ka EPO i loko o nā wai kino, a ʻo ka EPO no ka ml o ke koko i nā kānaka maʻamau e pili ana i 130-230 nanograms; 2) ʻO ka hui amino acid o ka EPO recombinant artificial e like like me ka protein endogenous EPO kanaka, ʻokoʻa wale ke ʻano o ka glycosylation; 3) ʻO ka hapalua o ke ola o EPO i loko o ke koko he 5-6 mau hola wale nō, a ʻaʻole hiki ke ʻike ʻia he 4-7 mau lā ma hope o ka hoʻopaʻa ʻana hope; 4) He ʻokoʻa loa ka pae EPO o kēlā me kēia kanaka, no laila paʻakikī ke hoʻokumu ʻana i kahi kūlana quantitative piha.

Mai ka makahiki 2000, ua hoʻohana ʻo WADA i ka hoʻāʻo mimi ma ke ʻano he ʻano hōʻoia ʻepekema wale nō no ka ʻike pololei ʻana i ka EPO recombinant. Ma muli o nā ʻokoʻa liʻiliʻi ma waena o ke ʻano glycoylated o ka EPO recombinant artificial a me ka EPO kanaka, ua liʻiliʻi loa nā waiwai i hoʻopiʻi ʻia o nā molekala ʻelua a hiki ke ʻike ʻia e kahi ʻano electrophoresis i kapa ʻia ʻo isoelectric focusing, ʻo ia ka hoʻolālā nui no ka ʻike pololei i ka EPO recombinant hana. Eia nō naʻe, ʻaʻohe ʻokoʻa o ka glycosylation o kekahi EPO recombinant i hōʻike ʻia e nā cell i loaʻa i ke kanaka.

ʻOiaʻiʻo, aia nō nā palena i nā ʻano hoʻokolohua like ʻole no ka EPO. No ka laʻana, ua ʻae ʻo Lance Armstrong, ka moʻolelo kaʻa paikikala ʻAmelika i ka lawe ʻana i ka EPO a me nā mea hoʻoikaika ʻē aʻe i kāna mau lanakila ʻehiku Tour de France, akā ʻaʻole i hōʻoia maoli ʻia ʻo ia no ka EPO ma kekahi hoʻokolohua doping i kēlā manawa. Pono mākou e kali a ʻike inā "hoʻokahi kapuaʻi ke kiʻekiʻe" a i ʻole "hoʻokahi kapuaʻi ke kiʻekiʻe".

Pehea e hana ai i ka Nobel Prize

ʻO kahi huaʻōlelo hope e pili ana i ka pilina ma waena o EPO a me ka 2019 Nobel Prize in Physiology or Medicine.

ʻO EPO ka hihia maʻamau o ka ʻike a me ka pane ʻana o ke kino o ke kanaka i ka hypoxia. No laila, ua koho ʻo Semenza lāua ʻo Ratcliffe, ʻelua Nobel laureates, i ka EPO i wahi hoʻomaka e aʻo ai i ke ʻano o ka ʻike cell a me ka hoʻololi ʻana i ka hypoxia. ʻO ka hana mua ʻo ka ʻimi ʻana i nā mea o ka gene EPO hiki ke pane i nā loli oxygen. Ua ʻike ʻo Semenza i kahi kī 256-base non-coding sequence ma ka 3 'downstream end of the gene encoding EPO, i kapa ʻia ka mea pane hypoxia. Inā hoʻololi ʻia a holoi ʻia paha kēia kaʻina mea, ua hoʻemi nui ʻia ka hiki o ka protein EPO e pane i ka hypoxia. Inā hoʻohui ʻia kēia ʻano mea i ka hopena o lalo o nā ʻano genes ʻē aʻe i pili ʻole me ka hypoxia, hōʻike pū kēia mau genes i hoʻololi ʻia i ka hoʻāla ʻana e like me EPO.ma lalo o nā kūlana hypoxia.

Ua ʻike ʻo Ratcliffe a me kāna hui ʻaʻole i loaʻa kēia mea pane hypoxic wale nō i loko o nā puʻupaʻa a i ʻole nā ​​​​pūnaewele i kuleana no ka hana ʻana o EPO, akā i nā ʻano cell ʻē aʻe he nui e hiki ke hana ma lalo o nā kūlana hypoxic. I nā huaʻōlelo ʻē aʻe, ʻaʻole kikoʻī kēia pane i ka hypoxia i ka EPO, akā ʻoi aku ka laha nui o nā mea i loko o nā cell. ʻO kēia mau pūnaewele ʻē aʻe, ʻaʻole kuleana no ka hana EPO, pono e loaʻa i nā molekole (e like me nā kumu transcription ke kuleana no ka hoʻohuli ʻana i ka hōʻike gene) e ʻike i nā loli i ka ʻike o ka oxygen a hoʻopaʻa i nā mea pane hypoxic e hoʻohuli i nā genes e like me EPO.