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       À̱չΠ±³¼ö        2015.03.16 17:27        14985
´Ù¿î·Îµå : Áö´ÉÇü ¹ÙÀÌ¿À ½Ã½ºÅÛ¿¡ ÀÇÇÑ °íÇ°Áú Ç×ü ÀǾàÇ° »ý»ê¼º ±Ø´ëÈ­_À̱չΠ±³¼ö2.pdf(483 Kb)
 

Áö´ÉÇü ¹ÙÀÌ¿À ½Ã½ºÅÛ¿¡ ÀÇÇÑ °íÇ°Áú Ç×ü ÀǾàÇ° »ý»ê¼º ±Ø´ëÈ­

 

Çѱ¹°úÇбâ¼ú¿ø À̱չΠ±³¼ö

 

1. °³¿ä  
  CHO (Chinese Hamster Ovary) ¼¼Æ÷ÁÖ´Â Ä¡·á¿ë Ç×ü ÀǾàÇ°ÀÇ »ý»êÀ» À§ÇÏ¿© »ê¾÷ÀûÀ¸·Î °¡Àå ¸¹ÀÌ »ç¿ëµÇ´Â ¼¼Æ÷ÁÖÀÇ Çϳª·Î, ÇöÀç ÆǸŵǴ 1/3ÀÌ»óÀÇ Ä¡·á¿ë ´Ü¹éÁúÀÌ CHO ¼¼Æ÷¸¦ ÅëÇØ »ý»êµÇ°í ÀÖ´Ù (Ç¥1). ÇöÀç±îÁö CHO ¼¼Æ÷¸¦ ÀÌ¿ëÇÑ Ä¡·á¿ë ´Ü¹éÁúÀÇ »ý»êÀº ¸Å³â 20-30%ÀÇ ¼ºÀåÀ» °ÅµìÇÏ¿© ½ÃÀå ±Ô¸ð°¡ Áö¼ÓÀûÀ¸·Î È®´ëµÇ°í ÀÖÀ¸¸ç Á¦Ç° °¡°Ýµµ ºñ½Î±â ¶§¹®¿¡ °íºÎ°¡°¡Ä¡¸¦ âÃâÇÒ ¼ö ÀÖ´Ù. Ç×ü ÀǾàÇ°À» ºñ·ÔÇÑ Ä¡·á¿ë ´Ü¹éÁúÀº °í¿ë·® Åõ¿©°¡ ºÒ°¡ÇÇÇϱ⠶§¹®¿¡ ÀûÁ¤¼öÁØÀÇ »ý»ê¼ºÀ» È®º¸ÇÏ¿© Á¦Á¶¿ø°¡¸¦ ³·Ãß´Â °ÍÀÌ ½ÃÀå °æÀï·Â È®º¸¸¦ ÅëÇÑ Á¦Ç°È­ ¼º°øÀÇ °ü°ÇÀ̸ç, ´Ü¼øÈ÷ »ý»ê¼ºÀ» ³ôÀÌ´Â °Í»Ó¸¸ ¾Æ´Ï¶ó È¿·ÂÀÌ ÀÖ´Â Ç×ü¸¦ ¼Õ»ó ¾øÀÌ ±ÕÀÏÇÏ°Ô »ý»êÇÏ´Â °Íµµ ¸Å¿ì Áß¿äÇÏ´Ù.

 

Ç¥1. Top selling biologic drugs (Huggett and Lahteenmaki, 2012)


  ÇöÀç±îÁö °í»ý»ê¼º ¶Ç´Â °íÇ°Áú Ç×ü¸¦ ¹ßÇöÇÏ´Â CHO ¼¼Æ÷ÁÖ¸¦ ±¸ÃàÇϱâ À§Çؼ­´Â Ÿ°Ù »ý»êÀ¯ÀüÀÚ¸¦ À¯ÀüÀÚ ¾È¿¡ ¹«ÀÛÀ§·Î »ðÀÔÇÏ¿© °ú¹ßÇö ½ÃŲ ÈÄ ´Ù¾çÇÑ Å¬·ÐµéÀ» ¼±º°ÇÏ´Â °úÁ¤ÀÌ °¡Àå ¸¹ÀÌ ¾²¿© ¿ÔÀ¸¸ç, ÀÌ ¶§ °¢ Èĺ¸ Ŭ·ÐµéÀÇ À¯ÀüÀÚ ÁõÆø ¹× ¹è¾çȯ°æ ÃÖÀûÈ­°úÁ¤ÀÌ ÇÊ¿äÇÏ´Ù. ÇÏÁö¸¸ ÀÌ °úÁ¤Àº ºñ¿ë, ³ëµ¿·Â, ¹× ½Ã°£ÀÇ ¼Ò¿ä°¡ Å©°í, °¢°¢ Ŭ·ÐµéÀÇ Æ¯¼ºÀÌ ¿¹Ãø°¡´ÉÇÏÁö ¾Ê±â ¶§¹®¿¡ ¸Å °úÁ¤¸¶´Ù °¢ »ý»ê ¼¼Æ÷ÁÖ¿¡ ÀûÇÕÇÑ ÇÁ·Î¼¼½º¸¦ °³¹ßÇÏ¿©¾ß ÇÑ´Ù. µû¶ó¼­ ÃÖ±Ù¿¡´Â ÃÖ¼ÒÀÇ ºñ¿ë°ú ³ëµ¿·Â ¹× ½Ã°£À» ¼ÒºñÇϸ鼭 Ç×»ó ¿¹Ãø °¡´ÉÇÑ °í »ý»ê¼º CHO ¼¼Æ÷ÁÖ¸¦ °³¹ß ÇÒ ¼ö ÀÖ´Â Ç÷§Æû ±â¼úÀÇ È®º¸¿¡ ´ëÇÑ °ü½ÉÀÌ Ä¿Áö°í ÀÖ´Ù.

 

  ÇöÀç transcriptome, translatome, proteom µîÀ» °üÂûÇÏ´Â -omics ½Ã½ºÅÛ»ý¹°ÇÐÀ» ÀÌ¿ëÇÑ Å¸°Ù¹ß±¼°ú ¼¼Æ÷ÀÇ À¯ÀüÀÚ¸¦ Á÷Á¢ Á¶ÀÛÇÏ´Â targeted engineeringÀÇ µµÀÔÀÌ »ó´çÈ÷ ÁøÇàµÇ°í ÀÖ´Ù. À̵éÀ» ÅëÇØ CHO ¼¼Æ÷ÁÖÀÇ ³ôÀº »ý»ê¼ºÀ» µµ¸ðÇÏ°í »ý»êµÇ´Â Ä¡·á¿ë Ç×üÀÇ Ç°ÁúÀ» Çâ»ó½ÃÅ°´Â °ÍÀº ¹«ÀÛÀ§ÀûÀÎ ¿£Áö´Ï¾î¸µ°ú ºñ±³ÇßÀ» ¶§ ¿¹Ãø °¡´ÉÇÑ °á°ú¸¦ ¾òÀ» ¼ö ÀÖ¾î ½Ç·Î Áö´ÉÇü ¹ÙÀÌ¿À ½Ã½ºÅÛÀ̶ó°í ÇÒ ¼ö ÀÖ°Ú´Ù (±×¸²1).

±×¸²1. ½Ã½ºÅÛ »ý¹°ÇÐÀ» ÀÌ¿ëÇÑ CHO ¼¼Æ÷ÁÖÀÇ ¿£Áö´Ï¾î¸µ (Kildegaard et al., 2013)

 

2. -Omics¸¦ ÀÌ¿ëÇÑ Å¸°Ù ¹ß±¼

  ÃÖ±Ù Àü ¼¼°èÀÇ ´Ù¾çÇÑ ¿¬±¸ ±â°ü¿¡¼­ CHO genomeÀ» ¹àÈ÷±â À§ÇÑ ¸¹Àº ¿¬±¸°¡ ÁøÇàµÇ¾úÀ¸¸ç, genome Á¤º¸¸¦ ÀÌ¿ëÇÑ ´Ù¾çÇÑ ºÐ¼® ¹æ¹ý ¹× ÀÀ¿ë ±â¼úÀÌ °³¹ßµÇ°í ÀÖ´Ù. ´ëÇ¥ÀûÀÎ ¼º°ú·Î´Â ¹Ì±¹ÀÇ GT-life sciences°¡ Áß±¹ÀÇ BGI-Shenzhen°ú ÇÕÀÛÇÏ¿© CHO-K1 ¼¼Æ÷ÁÖÀÇ genome sequence¸¦ ¹àÇô³»¾ú´Ù (Xu et al., 2011). ¹àÇôÁø CHO genome °ü·Ã ÀÚ·á´Â ¿Â¶óÀÎ»ó¿¡ database¸¦ ±¸ÃàÇÏ¿© ´©±¸³ª ¹«·á·Î ÀÚÀ¯·Ó°Ô ±× ¼Ò½º¸¦ ÀÌ¿ëÇÒ ¼ö ÀÖ°Ô ÇÏ¿´°í ÀÌ Á¤º¸¸¦ ±â¹ÝÀ¸·Î CHO ¼¼Æ÷ÁÖ¸¦ ÀÌ¿ëÇÑ »ý¹° ÀǾàÇ° »ý»ê¼º Çâ»óÀ» À§ÇÑ ´Ù¾çÇÑ ¿¬±¸°¡ ÁøÇàµÉ °ÍÀ¸·Î Àü¸ÁµÈ´Ù (Hammond et al., 2012). ¶ÇÇÑ CHO ¼¼Æ÷ÁÖÀÇ ±â¿øÀÎ Female Chinese hamster (Cricetulus griseus)ÀÇ genomeÀ» sequenceÇÏ¿© ±×·ÎºÎÅÍ À¯·¡ÇÑ ´Ù¾çÇÑ CHO ¼¼Æ÷ÁÖµéÀÇ Â÷ÀÌÁ¡µîÀ» ±Ô¸íÇÏ¿© °¢ ¼¼Æ÷ÁÖµéÀÇ ÀÌÇØ¿Í ÀÌ¿ë¿¡ µµ¿òÀÌ µÉ ¼ö ÀÖ°Ô ÇÏ¿´´Ù (±×¸²2) (Lewis et al., 2013).

 

±×¸²2. CHO ¼¼Æ÷Áֵ鰣ÀÇ mutation landscape (Lewis et al., 2013)


  ½Ã½ºÅÛ »ý¹°ÇÐÀ» ¹ÙÅÁÀ¸·Î ÇÑ ¿À¹Í½º(omics) Á¤º¸ ÅëÇÕ ºÐ¼® ±â¼úÀº ¼÷ÁÖ ¼¼Æ÷ÁÖÀÇ »ý»ê¼º, ¼¼Æ÷ »ýÁ¸À², »ý»êÇ°ÀÇ Ç°Áú °­È­¸¦ À§ÇÑ Å¸°ÙÀÇ Å½»öÀ» °í¿ë·®À¸·Î ó¸®(high-throughput) °¡´ÉÇÏ°Ô ¸¸µé¾ú´Âµ¥, ±× ±â¼úÀº transcriptome, translatome, proteome µî À¯ÀüÀÚ ¹ßÇöÀÇ ´Ù¾çÇÑ ´Ü°è¿¡ Àû¿ëµÇ°í ÀÖ´Ù. Àû¿ë ¿¹¸¦ »ìÆ캸¸é, ´Ü¹éÁú °í¹ßÇö Á¶°ÇÀÎ Àú¿Â ¹è¾ç ½Ã¿Í butyrate ó¸® ½Ã CHO ¼¼Æ÷³»¿¡¼­ transcriptome°ú proteomics°¡ ¾î¶»°Ô º¯ÇÏ´ÂÁö »ìÆ캸¾Æ¼­ »ý»ê¼ºÀÌ ³ôÀº ¼¼Æ÷ÁÖ ¾È¿¡¼­ ¾î¶°ÇÑ À¯ÀüÀÚ°¡ ¸¹ÀÌ ¹ßÇöµÇ´ÂÁö¸¦ È®ÀÎÇÑ °æ¿ìµµ ÀÖ°í ¼¼Æ÷»ç¸ê¹æÁöÀ¯ÀüÀÚÀÎ Bcl-xLÀ» ¹ßÇö½ÃŲ °í¹ßÇö ¼¼Æ÷ÁÖ¿Í ´ëÁ¶±ºÀÎ Àú¹ßÇö ¼¼Æ÷ÁÖ¸¦ ºñ±³ÇÏ¿© proteomeÀ» È®ÀÎ ÇÑ °æ¿ìµµ ÀÖ´Ù (Carlage et al., 2009; Kantardjieff et al., 2010). ¶ÇÇÑ nCounter NanoStringÀ» ÀÌ¿ëÇÏ¿© ¼¼Æ÷³» mRNAºÐ¼®À» ÅëÇØ ¼¼Æ÷»ç¸êÀÌ ÀϾ´Â ½ºÆ®·¹½º ȯ°æ¿¡¼­ °í¹ßÇö µÇ´Â À¯ÀüÀÚµéÀ» ¹ß±¼°ú Á¦Ç° Ç°ÁúÀ» ÀúÇØÇϴ ȯ°æ¿¡¼­ °í¹ßÇö µÇ´Â À¯ÀüÀÚ¸¦ ¹ß±¼ÇÏ´Â ¿¬±¸µéµµ ¼öÇàµÇ¾ú´Ù (Lee et al., 2014; Ha et al., 2015). transcriptome°ú proteome°£ÀÇ Â÷À̸¦ ¿¬°áÇϱâ À§Çؼ­´Â ¼¼Æ÷³»ÀÇ Àü»çÈ¿À²À» ¹àÈ÷´Â translatomeÀÇ ¿¬±¸°¡ ÁøÇàµÇ¾î Ÿ°Ù À¯ÀüÀÚ ¼±Á¤À» ÇÑÃþ ´õ È¿À²ÀûÀÌ°Ô ¸¸µé ¼ö ÀÖ°Ô µÇ¾ú´Ù (Courtes et al., 2013). ÀÌ·¸°Ô ´Ù¾çÇÑ ºÐ¼®À» ÅëÇؼ­ »õ·Ó°Ô ¹ß°ßµÈ ¿©·¯ Ÿ°Ù À¯ÀüÀÚ´Â ½ÇÁ¦ ¿£Áö´Ï¾î¸µ¿¡ Àû¿ëÇßÀ» ¶§ ¾ó¸¶³ª È¿°ú°¡ ÀÖÀ»Áö ±×¸®°í ¾ó¸¶³ª ºü¸£°Ô ±× screeningÀÌ °¡´ÉÇÒ Áö°¡ Áß¿äÇÑ Æ÷ÀÎÆ®°¡ µÉ °ÍÀÌ´Ù.


3. Targeted engineeringÀÇ µµÀÔ

  CHO ¼¼Æ÷ÁÖÀÇ genomeÀÌ ¹àÇôÁö¸é¼­ ´õ¿í È°¹ßÇÑ ¹ßÀüÀÌ µ¸º¸ÀÌ´Â ºÐ¾ß´Â targeted engineeringÀÌ´Ù. Targeted engineeringÀÇ °æ¿ì ¿øÇÏ´Â À¯ÀüÀÚÀÇ ¿°±â¼­¿­¸¸ ÀÖÀ¸¸é ±× À¯ÀüÀÚ¸¦ ƯÀÌÀûÀ¸·Î knockout ÇÒ ¼öµµ ÀÖ°í genome »óÀÇ ¿øÇÏ´Â ºÎºÐ¿¡ ¿ÜºÎÀ¯ÀüÀÚ¸¦ ƯÀÌÀûÀ¸·Î »ðÀÔ(knock in) ÇÒ ¼öµµ ÀÖ´Ù. ƯÈ÷ knockoutÀÇ °æ¿ì ÀÌÀü¿¡´Â RNA interference ±â¼úÀ» ÀÌ¿ëÇÑ down regulation¸¸ °¡´ÉÇß´ø ¹Ý¸é ÀÌÁ¨ genome»óÀÇ À¯ÀüÀÚ¸¦ mutation½ÃÄѼ­ ±â´ÉÀ» ¿ÏÀüÈ÷ Â÷´ÜÇÔÀ¸·Î¼­ Á» ´õ ¿µ±¸ÀûÀÌ°í È®½ÇÇÏ°Ô Æ¯Á¤ À¯ÀüÀÚ¸¦ ¾ø¾Ö ±× È¿°ú¸¦ º¼ ¼ö ÀÖ´Ù. ÀÌ·¯ÇÑ ¹æ¹ýÀº meganuclease, zinc finger nuclease (ZFN), transcriptional activator like effector nuclease (TALEN) µîÀÇ ¼ø¼­·Î ¹ß´ÞÇؿԴµ¥, ÃÖ±Ù¿¡´Â ´õ¿í È¿À²ÀÌ ÁÁÀº CRISPR/Cas9 ±â¼úÀ» ÀÌ¿ëÇÑ engineeringÀÌ ¸¹ÀÌ ÁøÇàµÇ°í ÀÖ´Ù (±×¸²3). CHO ¼¼Æ÷ÀÇ °æ¿ì ZFN°¡ Ãʹݱ⿡ knockoutÀ» ¸ñÀûÀ¸·Î ¸¹ÀÌ ¾²¿´À¸¸ç GS, DHFR, FUT8, Bax, Bak À¯ÀüÀÚ µîÀÌ knockout µÇ¾î¼­ È¿°ú¸¦ º¸¾Ò´Ù (Cost et al., 2010; Liu et al., 2010; Malphettes et al., 2010; Santiago et al., 2008). À¯ÀüÀÚ »ðÀÔÀÇ °æ¿ì¿¡´Â ¾ÆÁ÷ CHO ¼¼Æ÷¿¡ ½ÃµµÇÑ ¿¹°¡ ¾ø´Âµ¥, Àΰ£¼¼Æ÷ÁÖ¿¡¼­´Â ¾î´À Á¤µµ ½Ãµµ°¡ µÇ°í Àֱ⠶§¹®¿¡ CHO ¼¼Æ÷ÁÖ¿¡µµ Á¶¸¸°£ µµÀÔÀÌ °¡´ÉÇÒ °ÍÀ¸·Î ¿¹»óµÈ´Ù.

±×¸²3. (a) ZFN, (b) TALEN, (c) CRISPRÀÇ ºñ±³
(Puchta and Fauser, 2014) 


  ´Ù¾çÇÑ targeted engineering ±â¼ú Áß¿¡¼­µµ CRISPR/Cas9 ±â¼úÀº º¸´Ù °£ÆíÇÏ°í ºñ¿ëÀÌ ³·¾Æ¼­ ÃÖ½ÅÀÇ ¿¬±¸¿¡ ¸¹ÀÌ »ç¿ëµÇ°í Àִµ¥, µ§¸¶Å©ÀÇ The Novo Nordisk Foundation Center for Biosustainability¿¡¼­´Â CHO-K1 genome³»¿¡ À§Ä¡ÇÏ´Â single guide RNAs (sgRNAs)¸¦ °Ë»öÇÏ°í È®ÀÎÇÒ ¼ö ÀÖ´Â CRISPY¶ó´Â web±â¹ÝÀÇ bioinformatics ÅøÀ» °³¹ßÇÏ¿´´Ù. ÀÌ ÅøÀº ÃÑ 27,553°³ÀÇ À¯ÀüÀÚ¿¡ ´ÞÇÏ´Â 1,970,449°³ÀÇ Å¸°Ù ¿°±â¼­¿­À» °¡Áö°í ÀÖÀ¸¸ç genome »óÀÇ off-target sitesµµ Ç¥±âÇÏ¿© CRISPR/Cas9 ±â¼úÀÇ »ç¿ëÀ» Á» ´õ ¿ëÀÌÇÏ°Ô ¸¸µé¾îÁÖ¾ú´Ù (Ronda et al., 2014).


4. °íÂû

  ¹àÇôÁø CHO genome°ú ¿À¹Í½º ±â¼úÀ» ÀÌ¿ëÇÑ ½Ã½ºÅÛ »ý¹°ÇÐÀÇ »ç¿ëÀº ¹«ÀÛÀ§ÀûÀÎ ¿£Áö´Ï¾î¸µº¸´Ù ¼¼Æ÷ÀÇ º»ÁúÀÎ À¯Àüü¿¡ Á» ´õ Á÷Á¢ÀûÀ¸·Î ´Ù°¡°¡±â ¶§¹®¿¡ º¸´Ù ¿¹Ãø °¡´ÉÇÑ ¿£Áö´Ï¾î¸µÀ» ÇÒ ¼ö ÀÖ´Ù´Â °Í¿¡ Å« Àǹ̰¡ ÀÖ´Ù. ¾ÆÁ÷±îÁö´Â ¿©·¯ ¿¬±¸ÆÀµéÀÌ ¸ðµÎ »ç¿ëÀÌ °¡´ÉÇÑ baseline reference¸¦ Çü¼ºÇÏ´Â ´Ü°è¿¡ ±×Ä¡Áö¸¸ ÀÌÈÄ¿¡´Â ´Ü¹éÁúÀÇ ¹ßÇö°ú ±× Ç°Áú¿¡ ¿µÇâÀ» ³¢Ä¡´Â À¯ÀüÀÚµéÀ» list up ÇÏ°í À̸¦ Àû¿ëÇÏ´Â °ÍÀÌ Áß¿äÇØÁú °ÍÀÌ´Ù. ±×·¯³ª À¯ÀüÀÚÀÇ Àü»çÁ¤µµ (transcriptome)¿Í ´Ü¹éÁúÀÇ ¹ßÇöÁ¤µµ (proteome)¸¦ ºñ±³Çغ¸¸é Ç×»ó ±× Á¤µµ°¡ ºñ·ÊÇÏÁö ¾Ê¾Æ ±× »çÀÌ¿¡ ¹àÇôÁöÁö ¾ÊÀº ¹«¾ð°¡°¡ ÀÖÀ» °ÍÀ¸·Î ¿¹»óµÇ¸ç, ¾î¶°ÇÑ À¯ÀüÀÚÇü(genotype)°ú Ç¥ÇöÇü(phenotype)À» º¯°æ½ÃÄ×À» ¶§ ±×°ÍÀÌ ¼¼Æ÷°¡ »ý»êÇÏ´Â Ç×üÀÇ Ç°Áú¿¡ ¾î¶°ÇÑ ¿µÇâÀ» ³¢Ä¡´Â Áöµµ È®½ÇÇÑ ÀÌÇØ°¡ ¼º¸³µÇÁö ¾Ê¾Ò´Ù. ÀÌ·¯ÇÑ °ÍµéÀº ¾ÆÁ÷±îÁö Á÷Á¢ÀûÀÎ ¿£Áö´Ï¾î¸µÀ» ÅëÇØ È®ÀÎÇϴ°ÍÀÌ ÃÖ¼±Àε¥, ´ÙÇàÀ̵µ targeted engineering°ú À̸¦ À§ÇÑ web±â¹Ý µ¥ÀÌŸº£À̽º¸¦ ÀÌ¿ëÇÏ¿© Á» ´õ ºü¸£°í ¼Õ½¬¿î knockout ¿£Áö´Ï¾î¸µÀÌ °¡´ÉÇÏ°Ô µÇ¾ú°í ÀÌ´Â ÇöÀç CHO ¼¼Æ÷ÁÖ¸¦ ¿¬±¸ÇÏ´Â ¸¹Àº ±×·ì¿¡¼­ ½ÇÇàÇÏ°í ÀÖ´Â ¿¬±¸À̱⵵ ÇÏ´Ù. ÇöÀç È°¹ßÈ÷ ÁøÇàµÇ°í ÀÖ´Â knockout ±â¼ú ¿Ü¿¡ knock in ±â¼úµµ CHO ¼¼Æ÷ÁÖ¿¡¼­ Àû¿ëÀÌ °ð °¡´ÉÇÏ°Ô µÉ °ÍÀε¥ ÀÌ´Â ÁÖ·Î genome»ó¿¡¼­ ¿ÜºÎ À¯ÀüÀÚ¸¦ °í¹ßÇö ÇÒ ¼ö ÀÖ´Â ÀÚ¸®¸¦ ã´Âµ¥ ¿¬±¸ÀÇ ÃÊÁ¡ÀÌ ¸ÂÃçÁö°Ô µÉ °ÍÀ̸ç, CHO ¼¼Æ÷ÁÖ¿¡ Á¸ÀçÇÏÁö ¾Ê´Â À¯ÀüÀÚ¸¦ ¹ßÇö½ÃÄѼ­ »ý»êµÇ´Â Ç×üÀÇ Ç°ÁúÀ» ³ôÀ̴µ¥µµ Àû¿ëµÉ ¼ö ÀÖÀ» °ÍÀÌ´Ù.


Âü°í¹®Çå

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2. Cost, G.J., Freyvert, Y., Vafiadis, A., Santiago, Y., Miller, J.C., Rebar, E., Collingwood, T.N., Snowden, A., and Gregory, P.D. (2010). BAK and BAX deletion using zinc-finger nucleases yields apoptosis-resistant CHO cells. Biotechnology and bioengineering 105, 330-340.
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