無(wú)血清培養(yǎng)基開(kāi)發(fā)歷史和現(xiàn)狀
發(fā)布時(shí)間：
2022-12-24
作者：
國(guó)內(nèi)細(xì)菌微生物培養(yǎng)基生產(chǎn)企業(yè)
無(wú)血清培養(yǎng)基開(kāi)發(fā)歷史和現(xiàn)狀
動(dòng)物細(xì)胞培養(yǎng)有著極其廣闊的應(yīng)用市場(chǎng)：（一）細(xì)胞可以作為“工廠”來(lái)生產(chǎn)治療性重組蛋白抗體藥物、人用和獸用疫苗等；（二）細(xì)胞本身也可以作為“終產(chǎn)品”：比如免疫細(xì)胞治療和干細(xì)胞培養(yǎng)；（三）細(xì)胞培養(yǎng)也廣泛用于基礎(chǔ)研究領(lǐng)域（包括各種生物活性分析、細(xì)胞內(nèi)和細(xì)胞間信號(hào)傳導(dǎo)機(jī)理的研究等）。作為細(xì)胞生長(zhǎng)的環(huán)境和營(yíng)養(yǎng)來(lái)源，培養(yǎng)基的性能很大程度上決定了細(xì)胞密度和表達(dá)產(chǎn)物的產(chǎn)量及質(zhì)量，因此培養(yǎng)基是工藝開(kāi)發(fā)最重要的環(huán)節(jié)之一。本文將簡(jiǎn)要回顧過(guò)去60年無(wú)血清培養(yǎng)基（Serum-free Medium，SFM）開(kāi)發(fā)歷程，回望幾代科學(xué)家對(duì)于培養(yǎng)基配方開(kāi)發(fā)的不懈努力，進(jìn)而粗淺地聊聊國(guó)際和國(guó)內(nèi)培養(yǎng)基開(kāi)發(fā)的現(xiàn)狀。
雖然動(dòng)物細(xì)胞體外維持培養(yǎng)的研究可以追溯到20世紀(jì)初甚至更早，培養(yǎng)基配方開(kāi)發(fā)劃時(shí)代的里程碑當(dāng)屬Harry Eagle博士分別于1955年和1959年在《科學(xué)》雜志上發(fā)表的兩篇研究文章，1955年Eagle博士發(fā)布細(xì)胞基礎(chǔ)培養(yǎng)基配方，并指出培養(yǎng)基是“一個(gè)包含無(wú)機(jī)鹽、氨基酸、糖、維生素及其它必須營(yíng)養(yǎng)物的等滲透壓且具有pH緩沖能力的混合物”。Eagle在1959年的文章中提出了進(jìn)一步改進(jìn)的配方，并將該配方命名為“Minimal Essential Medium (MEM)”。MEM配方需要在10%以上牛血清濃度下才能支持細(xì)胞生長(zhǎng)，這一配方即使在60年后的今天MEM培養(yǎng)基仍然被用于研究領(lǐng)域和一些疫苗生產(chǎn)工藝?yán)?，Eagle的研究工作無(wú)疑奠定了近代無(wú)血清培養(yǎng)基開(kāi)發(fā)的基礎(chǔ)。有趣的是在Eagle發(fā)明MEM配方同期出現(xiàn)了另一個(gè)里程碑式的成果：1957年科羅拉多大學(xué)醫(yī)學(xué)系教授Dr. Theodore T. Puck從中國(guó)倉(cāng)鼠分離出卵巢細(xì)胞（Chinese Hamster Ovary，CHO）進(jìn)行體外連續(xù)傳代培養(yǎng)。統(tǒng)計(jì)數(shù)據(jù)表明當(dāng)今70%以上的重組蛋白和抗體藥物是通過(guò)CHO細(xì)胞表達(dá)的，目前在臨床中和臨床前研究的新大分子藥物通過(guò)CHO細(xì)胞表達(dá)的占比更高，相信Puck當(dāng)時(shí)肯定沒(méi)有料到半個(gè)世紀(jì)后CHO細(xì)胞會(huì)有如此廣闊的應(yīng)用和深遠(yuǎn)的貢獻(xiàn)。
在上世紀(jì)60年代的培養(yǎng)基配方都需要添加10%甚至更高濃度的血清才能支持細(xì)胞貼壁生長(zhǎng)，無(wú)血清培養(yǎng)基開(kāi)發(fā)可以分為兩個(gè)研究方向推進(jìn)：一條路線是尋找能替代血清支持細(xì)胞在體外擴(kuò)增的營(yíng)養(yǎng)成分。血清含有上千種不同成分，為細(xì)胞體外培養(yǎng)提供廣泛而豐富的營(yíng)養(yǎng)和各種細(xì)胞因子，但動(dòng)物血清的使用存在引進(jìn)外源病毒的風(fēng)險(xiǎn)，因此減少血清濃度甚至完全去除血清對(duì)細(xì)胞培養(yǎng)有著重大的意義；另一條路線則更加重視優(yōu)化配方中營(yíng)養(yǎng)物成分和濃度實(shí)現(xiàn)細(xì)胞的高密度培養(yǎng)，需要指出血清的添加未必能提高細(xì)胞密度，科學(xué)家通過(guò)研究培養(yǎng)基中營(yíng)養(yǎng)成分消耗，發(fā)現(xiàn)提高氨基酸和維生素的濃度可以提高細(xì)胞最高密度。上述兩條路徑又是有交叉的，沿著兩條路徑科學(xué)家們?cè)?0-80年代間研發(fā)出許多不同系列的培養(yǎng)基配方：Dulbecco和Freeman于1959年發(fā)表了改進(jìn)版的MEM配方Dulbecco’s MEM （DMEM）；1984年Iscove又在DMEM基礎(chǔ)上進(jìn)一步改進(jìn)推出了IMEM配方；Moore等人1967年推出RPMI（Roswell Park Medical Institute）系列配方，RPMI在維持無(wú)機(jī)鹽濃度的前提下提高了氨基酸維生素等成分的濃度；1965年和1984年Richard Ham博士發(fā)布了F-10和F-12系列培養(yǎng)基；Charity Waymouth博士1984年研發(fā)了MCDB系列配方。除了眾多學(xué)術(shù)界的研究，在60年代也誕生了三個(gè)老牌培養(yǎng)基公司：GIBCO（Grand Island Biological Company）在紐約州Grand Island成立；JRH Biosciences公司在澳大利亞成立；HyClone在猶他州Logan成立。這些品牌在無(wú)血清培養(yǎng)基研究方面也作出了卓著的貢獻(xiàn)。
培養(yǎng)基配方開(kāi)發(fā)方法有多種，無(wú)法在此一一道來(lái)。其中通過(guò)研究營(yíng)養(yǎng)成分的消耗來(lái)確定添加的量是常用的方法，但受限于分析能力和不確定的血清存在，能夠定量分析的培養(yǎng)基成分不多；培養(yǎng)基混合也是常用的策略，并且通過(guò)和實(shí)驗(yàn)設(shè)計(jì)方法（Design of Experiment, DoE）結(jié)合提高培養(yǎng)基混合實(shí)驗(yàn)的效率。培養(yǎng)基混合優(yōu)化配方最值得一提的是Gordon Sato博士和他的合作者1979年發(fā)表的將DMEM和F-12按照1:1的體積比混合得到的DMEM/F12培養(yǎng)基配方，DMEM/F12綜合了兩個(gè)大相徑庭配方的優(yōu)勢(shì)，提高了細(xì)胞培養(yǎng)的密度。盡管在當(dāng)時(shí)有許多培養(yǎng)基混合配方的嘗試，DMEM/F12混合培養(yǎng)基應(yīng)該是最為成功的，也成為后期許多無(wú)血清培養(yǎng)基配方開(kāi)發(fā)的新起點(diǎn)。
Gordon Sato博士和他之后的科學(xué)家們進(jìn)一步優(yōu)化配方逐漸在替代血清方面取得突破，通過(guò)在基礎(chǔ)培養(yǎng)基里添加蛋白（如胰島素、轉(zhuǎn)鐵蛋白和白蛋白）可以在很大程度上替代血清。而后1982年Hiroki Murakami博士發(fā)現(xiàn)了另外一個(gè)在無(wú)血清條件下促進(jìn)細(xì)胞倍增的主要成分乙醇胺，由此提出了ITES混合物作為無(wú)血清培養(yǎng)基的添加劑（Insulin、Transferrin、Ethanolamine和Selenium），ITES添加可以降低或者免除血清添加并實(shí)現(xiàn)高密度細(xì)胞培養(yǎng)。1991年推出的CHO-S-SFM系列無(wú)血清培養(yǎng)基實(shí)現(xiàn)了CHO細(xì)胞完全無(wú)血清培養(yǎng)。白蛋白的主要功能是作為微量元素的載體，進(jìn)一步研究發(fā)現(xiàn)微量元素等可以替代白蛋白的添加；類胰島素生長(zhǎng)因子IGF-1可以替代胰島素；改進(jìn)鐵離子往細(xì)胞內(nèi)轉(zhuǎn)運(yùn)可以替代轉(zhuǎn)鐵蛋白。90年代中期出現(xiàn)了最早的無(wú)蛋白培養(yǎng)基（Protein-free Medium，PFM），PFM 往往還含有蛋白水解物，通過(guò)用植物來(lái)源的水解物代替動(dòng)物蛋白胨進(jìn)一步降低了動(dòng)物來(lái)源成分的風(fēng)險(xiǎn)。1997年GIBCO推出的CD CHO則是第一個(gè)完全化學(xué)成分確定的培養(yǎng)基（Chemically-defined Medium，CDM），在那個(gè)水解物廣泛采用的時(shí)代，CD CHO是個(gè)培養(yǎng)基開(kāi)發(fā)的里程碑。
90年代靶向重組蛋白藥物的研發(fā)成為推動(dòng)無(wú)血清培養(yǎng)基開(kāi)發(fā)的新動(dòng)力。1987年美國(guó)FDA批準(zhǔn)了首個(gè)通過(guò)動(dòng)物細(xì)胞培養(yǎng)表達(dá)的重組蛋白藥物：即組織纖維蛋白溶酶原激活劑（Tissue Plasminogen Activator, t-PA）上市，自此動(dòng)物細(xì)胞特別是CHO細(xì)胞被越來(lái)越廣泛地應(yīng)用于治療性蛋白抗體的生產(chǎn)。多個(gè)后來(lái)成為“重磅炸彈”級(jí)別的蛋白抗體藥獲批上市對(duì)于培養(yǎng)基配方的開(kāi)發(fā)起了巨大的推動(dòng)作用：比如1997年Rituxan上市；1998年Herceptin、Remicade和Enbrel上市；2002年Humira上市、2004年Avastin上市。這些靶向治療藥物的熱銷推動(dòng)了工業(yè)界開(kāi)發(fā)高密度培養(yǎng)工藝和高品質(zhì)培養(yǎng)基的熱情，2004-2014這10年幾乎每個(gè)跨國(guó)制藥公司都投入大量人力物力開(kāi)發(fā)個(gè)性化化學(xué)成分確定培養(yǎng)基，其中取代水解物成為一個(gè)潮流，而且為了提高通量，微罐反應(yīng)系統(tǒng)也有廣泛的研究和使用。高性能的培養(yǎng)基和工藝推動(dòng)了細(xì)胞培養(yǎng)的水平的大幅提升。上世紀(jì)80-90年代，最高密度只能達(dá)到1-2 百萬(wàn)細(xì)胞每毫升，蛋白表達(dá)水平在幾十毫克每升，相比之下如今CHO細(xì)胞密度可達(dá)到1-3 千萬(wàn)細(xì)胞每毫升，流加培養(yǎng)抗體表達(dá)3-5克每升，也有抗體表達(dá)10克每升以上的案例報(bào)道，現(xiàn)在通過(guò)濃縮流加培養(yǎng)等方法提高細(xì)胞密度，進(jìn)一步提高蛋白抗體表達(dá)。
培養(yǎng)基的開(kāi)發(fā)降低了蛋白藥物生產(chǎn)成本，而且培養(yǎng)基優(yōu)化可以提高抗體藥物的質(zhì)量。隨著諸多重磅炸彈抗體藥物的專利到期臨近，生物類似藥的開(kāi)發(fā)最大的挑戰(zhàn)在于質(zhì)量和原研藥相比的一致性。優(yōu)化培養(yǎng)基可以改善抗體藥質(zhì)量指標(biāo)，包括各種糖型、電荷異構(gòu)體等。這種個(gè)性化的培養(yǎng)基配方開(kāi)發(fā)是近期的熱點(diǎn)領(lǐng)域。
總而言之，過(guò)去半個(gè)世紀(jì)無(wú)血清培養(yǎng)基的開(kāi)發(fā)是一個(gè)迭代優(yōu)化螺旋式上升的過(guò)程，從早期貼壁含血清培養(yǎng)基到現(xiàn)在高性能無(wú)動(dòng)物源完全化學(xué)成分確定培養(yǎng)基的演變是諸多科學(xué)家、培養(yǎng)基公司和藥企共同研發(fā)的成果。
國(guó)際培養(yǎng)基品牌除了前面提到的GIBCO、JRH和HyClone，還有LONZA、BD、Irvine、Merck和其它一些小培養(yǎng)基公司。早期的時(shí)候GIBCO品牌因其高品質(zhì)產(chǎn)品，成為行業(yè)的標(biāo)準(zhǔn)，其他培養(yǎng)基品牌也在近些年奮起直追，推出不少很不錯(cuò)的培養(yǎng)基。隨著2000年后蛋白抗體藥物市場(chǎng)的擴(kuò)大，產(chǎn)業(yè)鏈整合成為潮流，而培養(yǎng)基業(yè)務(wù)具有高利潤(rùn)的特性，培養(yǎng)基公司成為被并購(gòu)的熱門目標(biāo)。
1
第一輪產(chǎn)業(yè)鏈的整合
1999年剛剛NASDAQ上市的測(cè)序和生物試劑公司Invitrogen很有遠(yuǎn)見(jiàn)地在2000年收購(gòu)了當(dāng)時(shí)的Life Technologies（旗下有GIBCO品牌），2009年Invitrogen并購(gòu)Applied Biosystem（ABI）將公司改名為L(zhǎng)ife Technologies；2008年Sigma收購(gòu)了澳大利亞的JRH Biosciences（Ex-Cell系列培養(yǎng)基）；2009年Thermo Fisher收購(gòu)了HyClone品牌（SFM4CHO、CDM4CHO和Cell Boost系列補(bǔ)料）；另外2010年德國(guó)Merck集團(tuán)收購(gòu)Millipore。收購(gòu)培養(yǎng)基公司不僅完善了產(chǎn)品線和技術(shù)解決方案，也為收購(gòu)公司提供了源源不斷的現(xiàn)金流。
2
第二輪產(chǎn)業(yè)鏈的整合
2013年Thermo Fisher收購(gòu)Life Technologies從而獲得GIBCO品牌；之后Thermo Fisher將HyClone品牌培養(yǎng)基業(yè)務(wù)賣給了GE；2014年德國(guó)Merck集團(tuán)收購(gòu)Sigma從而將JRH品牌納入體系，算上2011年收購(gòu)的中國(guó)match培養(yǎng)基公司清大天一，Merck在培養(yǎng)基領(lǐng)域投入的決心相當(dāng)大，2016年Merck公布計(jì)劃在江蘇南通投資建設(shè)大規(guī)模培養(yǎng)基生產(chǎn)廠。
國(guó)內(nèi)培養(yǎng)基長(zhǎng)期依賴進(jìn)口，清大天一是國(guó)內(nèi)較早成立的培養(yǎng)基公司，但業(yè)務(wù)主要集中在動(dòng)物疫苗領(lǐng)域，后被Merck公司收購(gòu)。隨著生物類似藥開(kāi)發(fā)的蓬勃發(fā)展，近幾年國(guó)內(nèi)也涌現(xiàn)出一批有前景的培養(yǎng)基公司，進(jìn)口壟斷的局面或?qū)⒏淖?。在這些培養(yǎng)基公司里上海的最多（奧浦邁、德思特利、沃美、倍諳基、多寧和源培），體現(xiàn)出上海在生物醫(yī)藥研發(fā)的群聚效應(yīng)，不完全統(tǒng)計(jì)還有北京天信和、蘭州建順、深圳壹生科、湛江普奧思等。其中多家公司的創(chuàng)始人和技術(shù)核心都來(lái)自于華東理工大學(xué)生工學(xué)院的背景，也體現(xiàn)出華理生工在產(chǎn)業(yè)內(nèi)的深度。國(guó)內(nèi)培養(yǎng)基公司大多處于發(fā)展早期，應(yīng)當(dāng)努力做好產(chǎn)品開(kāi)發(fā)，加快建設(shè)培養(yǎng)基生產(chǎn)和質(zhì)量體系，增加和生物藥研發(fā)公司的合作，所謂眾人拾柴火焰高，相信在不久的將來(lái)國(guó)內(nèi)也能出現(xiàn)優(yōu)質(zhì)培養(yǎng)基的品牌公司。
肖志華，紐約州立布法羅大學(xué)生物化工博士
The development history and present situation of serum-free medium were briefly discussed
(1) cells can be used as "factories" to produce therapeutic recombinant protein antibody drugs, human and animal vaccines, etc.; (2) cells themselves can also be used as "end products" : for example, immune cell therapy and stem cell culture; (3) cell culture is also widely used in basic research fields (including various bioactivity analysis, intracellular and intercellular signaling mechanisms, etc.). As the environment of cell growth and nutrient sources, media largely determines the performance of cell density and the expression product yield and quality, so the culture medium is one of the most important aspect of technology development. This article will briefly review the past 60 years in Serum free Medium (Serum - free Medium, SFM) development course, looking back to the tireless efforts of generations of scientists for the development of culture Medium formula, and shallow to talk about the present situation of the development of international and domestic Medium.
Although animal cells in vitro culture of research can be traced back to the beginning of the 20th century and even earlier, medium formula development epoch-making milestone when Dr Harry Eagle in 1955 and 1959 respectively in the two articles published in the journal science research articles, released in 1955, Dr Eagle cells basal medium formula, and points out that the medium is "a containing inorganic salt, amino acid, sugar, vitamins and other nutrients must be a mixture of osmotic pressure and pH buffering capacity". Eagle proposed a further improved formula in his 1959 article and named it "Minimal Essential Medium (MEM)". MEM formula under 10% bovine serum concentration is needed to support the cell growth, this formula even after 60 years later still MEM medium is used in the research field and some vaccine production technology, Eagle research work laid the foundation of the modern development of serum free medium. Interesting is invented in Eagle MEM formula at the same time another landmark achievement: in 1957, professor of medicine at the university of Colorado Dr. Theodore t. Puck isolated from Chinese Hamster Ovary cells (Chinese Hamster Ovary, CHO) for continuous subculture in vitro. Statistics show that today more than 70% of the recombinant protein and antibody drug is expressed by CHO cells, currently in clinical and preclinical study of new drug molecules by CHO cells expressing ratio higher, believe that the Puck certainly didn't expect that half a century after the CHO cells have a broad application and profound contribution.
Culture medium formula in the 1960 s all you need to add 10% or higher concentration of serum to support adherent cell growth, serum free medium development can be divided into two research direction: a route is to look for alternative to serum support cells in vitro amplification of nutrients. Serum contains thousands of different ingredients, to provide cell in vitro culture broad and rich in nutrition and all kinds of cytokines, but the use of animal serum carries the risk of introduction of exogenous virus, thus reducing serum concentration or even completely removing serum is of great significance to the cell culture; Another route will pay more attention to optimize the formula of nutrient composition and concentration of cell density cultivation, add do not necessarily need to point out that the serum can improve cell density, medium nutrient consumption, they study found that improve the concentration of amino acids and vitamins can improve the highest density. The above two paths and overlapping, along two paths scientists developed many different between 60-80 - s series medium formula: Dulbecco and Freeman was published in 1959 improved version of MEM MEM Dulbecco 's formula (DMEM); In 1984, Iscove further improved and launched IMEM formula on the basis of DMEM. Moore et al. introduced the Roswell Park Medical Institute formula series in 1967. In 1965 and 1984 Dr Richard Ham published the f-10 and f-12 series of media; Dr. Charity Waymouth developed the MCDB formula series in 1984. In addition to numerous academic studies, three established media companies were born in the 1960s: the Grand Island Biological Company was founded in Grand Island, New York. JRH Biosciences was founded in Australia. HyClone was founded at Logan, Utah. These brands have also made outstanding contributions to serum-free media research.
There are many ways to develop the culture medium formula. Among them, it is a common method to determine the amount of added nutrients by studying the consumption of nutrients, but limited by the analysis ability and the existence of uncertain serum, there are not many medium components that can be quantitatively analyzed. Medium mixing is also a common strategy, and the efficiency of medium mixing Experiment is improved by combining with Design of Experiment (DoE). Medium hybrid optimization formula is the most worth mentioning Gordon and his collaborator, published in 1979, Dr Sato will DMEM and F - 12 according to 1:1 volume than mixed with DMEM/F12 medium formula, DMEM/F12 combines the advantages of two very different formula, the increase of the density of cell culture. DMEM/F12 mixtures were probably the most successful, despite many attempts at the time, and became a new starting point for the development of many serum-free media formulations later.
Dr Gordon Sato and scientists to optimize formula after he has made a breakthrough in alternative serum, by adding the protein in the basal medium (such as insulin, transferrin, and albumin) can replace serum to a great extent. Before 1982, Hiroki Dr Murakami found another in serum-free conditions to promote the main components of the cell multiplication Ethanolamine, thus put forward the technology mixture as the additive of serum free medium (such as Insulin, Transferrin, Ethanolamine, and Selenium), to add and implement technology add can reduce or exempt from serum high-density cell culture. CHO-S-SFM series serum-free culture medium was introduced in 1991. The main function of albumin is to serve as the carrier of trace elements. Insulin-like growth factor igf-1 can replace insulin. Improving iron ion transport to cells can replace transferrin. Appeared in the mid - 90 - one of the earliest Protein free culture Medium (Protein - free Medium, PFM), PFM often contains Protein hydrolysate, by using plant sources hydrolysate instead of animal peptone further reduce the risk of animal origin ingredient. CD CHO, introduced by GIBCO in 1997, was the first Chemically defined Medium (CDM) with a complete chemical composition, a milestone in the development of the Medium at a time when hydrolytes were widely used.
The development of targeted recombinant protein drugs in the 1990s has become a new impetus for the development of serum-free media. In 1987 the FDA approved first by animal cell culture expression of recombinant protein drugs: the fibrin dissolve enzyme originally Activator (Tissue Plasminogen Activator, t - PA), since animal cells especially in CHO cells were more and more widely applied in the production of therapeutic proteins and antibodies. A number of protein-antibody drugs that later became the "blockbuster" class were approved for marketing, which greatly promoted the development of media formulations: for example, in 1997, Rituxan was marketed; In 1998, Herceptin, Remicade and Enbrel were listed. Humira was listed in 2002 and Avastin was listed in 2004. Best-selling drugs that target promoted the industry development of high density cultivation technology and the high quality the enthusiasm of the culture medium, the 10, 2004-2014 in almost every multinational pharmaceutical companies invest a lot of manpower material resources to develop personalized chemical composition to determine the culture medium, which replaced hydrolysate as a trend, and in order to improve the flux, micro tank reaction system also has a wide range of research and use. High performance culture medium and technology have promoted the development of cell culture. 80-90 - s of the last century, the highest density can reach 1-2 million cells per milliliter, protein expression levels in dozens of mg per litre, compared with now CHO cell density can be up to 1-30 million cells per milliliter, flow and develop antibodies express 3-5 grams per liter, also has antibody expression above 10 grams per liter of case reports, through concentrated flow plus now training methods to improve cell density, further improve the protein antibody expression.
The development of culture medium reduces the production cost of protein drugs, and the optimization of culture medium can improve the quality of antibody drugs. As patents for many blockbuster antibody drugs expire, the biggest challenge in the development of biosimilars lies in the consistency of the quality compared with the original drugs. The optimized medium can improve the quality index of antibody drugs, including various sugar types and charge isomers. The development of this personalized medium recipe is a hot field in the near future.
To sum up, in the past half a century development of serum-free culture medium is an iterative optimization spiral process, from the early post wall containing serum culture medium to high performance now no animal source chemical composition to determine the evolution of the medium is completely many scientists, media companies and drug companies to develop.
In addition to GIBCO, JRH and HyClone mentioned above, there are also LONZA, BD, Irvine, Merck and other small media companies. GIBCO became the industry standard in the early days because of its high-quality products, and other media brands have also been catching up in recent years, launching quite a few good ones. With the expansion of the protein antibody drug market after 2000, the integration of the industry chain became a trend, and the media business has the characteristics of high profit, and the media company has become a hot target to be acquired.
1
The first round of industrial chain integration
Has just been listed on NASDAQ in 1999 sequencing and biological reagent company Invitrogen had the foresight to acquired in 2000 when the Life of Technologies (which have GIBCO brand), 2009 Invitrogen m&a Applied Biosystem (ABI) the name of the company to Life Technologies; In 2008 Sigma acquired Australia's JRH Biosciences (ex-cell); In 2009 Thermo Fisher acquired HyClone (SFM4CHO, CDM4CHO and Cell Boost). In 2010 Merck, a German conglomerate, bought Millipore. The acquisition media company not only improved its product line and technical solutions, but also provided a steady stream of cash flow for the acquisition company.
2
The second round of industrial chain integration
In 2013, Thermo Fisher acquired Life Technologies and acquired the GIBCO brand. Thermo Fisher then sold the HyClone brand culture business to GE. Merck, Germany, in 2014 group the Sigma to JRH brand into the system, including 2011 acquisition of Chinese match medium company clearly the tianyi, Merck in the field of medium into the determination of considerable, published in 2016, Merck plans to invest in jiangsu nantong construction factory mass medium.
Domestic media have long been dependent on import. Qingdayi was an early established media company in China, but its business was mainly in the field of animal vaccine, which was later acquired by Merck. With the vigorous development of biological similar drugs, a number of promising media companies have emerged in China in recent years, which may change the situation of import monopoly. In these media company in Shanghai (the most pu Wallace, Germany think trey, walter beauty, times of grand base, much better and the source culture), embody the clustering of Shanghai in the biological medicine research and development, and incomplete statistics and Beijing day, lanzhou built along, one born in shenzhen, zhanjiang, etc. The founders and technical core of many of these companies are all from the background of east China university of science and technology student engineering college, which also reflects the depth of huali student engineering in the industry. Early in the development, mostly domestic medium company should strive to do a good job in product development, production and quality system, to speed up the construction of medium and biological medicine research and development of the company's cooperation, all of the so-called firewood high flame, believe in the near future domestic also can appear high quality medium brand company.
Xiao zhihua, PhD, biochemistry, state university of buffalo, New York