历史是未来的指路明灯,从一个科学家的研究历史可以很细致的知道癌症研究的一些历史过程。
Bishop JM是1989年因为发现细胞癌基因(原癌基因)而获得诺贝尔奖。先简约看看他的研究历史。或许对某个学生将来进入自己的研究领域有启发意义。
Varmus HE和Bishop JM开始的时候与Vogt PK一起研究肿瘤病毒,那个时候肿瘤病毒学说盛行,美国开始了寻找癌症病毒的计划,因为很多人深信某些病毒可能是癌症的根源。Varmus HE和Bishop JM也不例外。他们研究鸡的肉瘤病毒如何导致肿瘤发生,该实验需要DNA杂交实验,检测逆转录病毒的反转录后DNA插入位点等。见文献:
Varmus HE, Bishop JM, Vogt PK.
Appearance of virus-specific DNA in mammalian cells following transformation by Rous sarcoma virus.
J Mol Biol. 1973 Mar 15;74(4):613-26.
Stehelin D, Varmus HE, Bishop JM.
Detection of nucleotide sequences associated with transformation by avian sarcoma viruses.
Bibl Haematol. 1975 Oct;(43):539-41.
1976 年值得纪念,因为用没有被鸡肉瘤病毒感染的鸡的组织做对照时,发现本来设计出来用来检测逆转录病毒的反转录后DNA插入情况的,意外发现没有被鸡肉瘤病毒感染的鸡的组织也总是被检测到存在类似鸡肉瘤病毒的反转录后类似的DNA序列,原癌基因被意外发现了,因此,研究不要总是寻找与别人一样,相反,不一样才可能是重要发现。见文献:
Stehelin D, Varmus HE, Bishop JM, Vogt PK.
DNA related to the transforming geneMoon of avian sarcoma viruses is present in normal avian DNA.
Nature. 1976 Mar 11;260(5547):170-3.
随后又在RNA水平证实正常动物细胞也存在类似鸡肉瘤病毒的RNA.进一步证实原癌基因存在的真实性。见文献:
Spector DH, Baker B, Varmus HE, Bishop JM.
Characteristics of cellular RNA related to the transforming gene of avian sarcoma viruses.
Cell. 1978 Feb;13(2):381-6.
Spector DH, Smith K, Padgett T, McCombe P, Roulland-Dussoix D, Moscovici C, Varmus HE, Bishop JM.
Uninfected avian cells contain RNA related to the transforming gene of avian sarcoma viruses.
Cell. 1978 Feb;13(2):371-9.
随着发现很多动物体内都存在类似鸡肉瘤病毒的DNA序列,而低等生物很少存在,Bishop JM等人提出病毒的转化基因来自正常动物细胞的假说,并给出确凿的证据。见文献:
Spector DH, Varmus HE, Bishop JM.
Nucleotide sequences related to the transforming gene of avian sarcoma virus are present in DNA of uninfected vertebrates.
Proc Natl Acad Sci U S A. 1978 Sep;75(9):4102-6.
Bishop JM, Baker B, Fujita D, McCombe P, Sheiness D, Smith K, Spector DH, Stehelin D, Varmus HE.
Genesis of a virus-transforming gene.
Natl Cancer Inst Monogr. 1978 May;(48):219-23.
接着,在蛋白水平证实鸡肉瘤病毒转化基因编码的蛋白类似正常鸡细胞内的一种蛋白。目的很明确,试图说明什么?癌基因学说?见文献:
Levinson AD, Oppermann H, Levintow L, Varmus HE, Bishop JM.
Evidence that the transforming gene of avian sarcoma virus encodes a protein kinase associated with a phosphoprotein.
Cell. 1978 Oct;15(2):561-72.
Oppermann H, Levinson AD, Varmus HE, Levintow L, Bishop JM.
Uninfected vertebrate cells contain a protein that is closely related to the product of the avian sarcoma virus transforming gene (src).
Proc Natl Acad Sci U S A. 1979 Apr;76(4):1804-8.
癌基因学说开始拉开了序幕:
Bishop JM.
Enemies within: the genesis of retrovirus oncogenes.
Cell. 1981 Jan;23(1):5-6.
开始研究细胞癌基因及其产物的特征和功能,而这种研究总离不开与病毒的转化基因和其产物的特征和功能的比较:
Parker RC, Varmus HE, Bishop JM.
Cellular homologue (c-src) of the transforming gene of Rous sarcoma virus: isolation, mapping, and transcriptional analysis of c-src and flanking regions.
Proc Natl Acad Sci U S A. 1981 Sep;78(9):5842-6.
Smart JE, Oppermann H, Czernilofsky AP, Purchio AF, Erikson RL, Bishop JM.
Characterization of sites for tyrosine phosphorylation in the transforming protein of Rous sarcoma virus (pp60v-src) and its normal cellular homologue (pp60c-src).
Proc Natl Acad Sci U S A. 1981 Oct;78(10):6013-7.
遗传学方法发现了恶性神经内分泌肿瘤细胞中细胞癌基因c-myc发生扩增,c-Ki-ras也发现类似。随后开始了肿瘤基因和其产物的研究热潮:
Alitalo K, Schwab M, Lin CC, Varmus HE, Bishop JM.
Homogeneously staining chromosomal regions contain amplified copies of an abundantly expressed cellular oncogene (c-myc) in malignant neuroendocrine cells from a human colon carcinoma.
Proc Natl Acad Sci U S A. 1983 Mar;80Devil:1707-11.
Schwab M, Alitalo K, Varmus HE, Bishop JM, George D.
A cellular oncogene (c-Ki-ras) is amplified, overexpressed, and located within karyotypic abnormalities in mouse adrenocortical tumour cells.
Nature. 1983 Jun 9-15;303(5917):497-501.
Bishop JM.
Cancer genes come of age.
Cell. 1983 Apr;32(4):1018-20.
Schwab M, Alitalo K, Klempnauer KH, Varmus HE, Bishop JM, Gilbert F, Brodeur G, Goldstein M, Trent J.
Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour.
Nature. 1983 Sep 15-21;305(5931):245-8.
Alitalo K, Winqvist R, Lin CC, de la Chapelle A, Schwab M, Bishop JM.
Aberrant expression of an amplified c-myb oncogene in two cell lines from a colon carcinoma.
Proc Natl Acad Sci U S A. 1984 Jul;81(14):4534-8.
Brodeur GM, Seeger RC, Schwab M, Varmus HE, Bishop JM.
Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage.
Science. 1984 Jun 8;224(4653):1121-4.
Schwab M, Ellison J, Busch M, Rosenau W, Varmus HE, Bishop JM.
Enhanced expression of the human gene N-myc consequent to amplification of DNA may contribute to malignant progression of neuroblastoma.
Proc Natl Acad Sci U S A. 1984 Aug;81(15):4940-4.
Schwab M, Ramsay G, Alitalo K, Varmus HE, Bishop JM, Martinsson T, Levan G, Levan A.
Amplification and enhanced expression of the c-myc oncogene in mouse SEWA tumour cells.
Nature. 1985 May 23-29;315(6017):345-7.
Schwab M, Varmus HE, Bishop JM.
Human N-myc gene contributes to neoplastic transformation of mammalian cells in culture.
Nature. 1985 Jul 11-17;316(6024):160-2.
Small MB, Hay N, Schwab M, Bishop JM.
Neoplastic transformation by the human gene N-myc.
Mol Cell Biol. 1987 May;7(5):1638-45.
Liu E, Hjelle B, Morgan R, Hecht F, Bishop JM.
Mutations of the Kirsten-ras proto-oncogene in human preleukaemia.
Nature. 1987 Nov 12-18;330(6144):186-8.
90年代之后,Bishop继续沿着自己以前的发现研究,没有大的改变,主要研究癌基因的转化功能,与癌基因作用的蛋白,癌基因之间的协同,癌基因对癌症细胞的表型维持和逆转等。见文献:
http://www.ncbi.nlm.nih.gov/entr ... splay&DB=pubmed
肿瘤分子生物学和遗传学权威weinberg ra 的研究历史可能对我们研究癌基因和抑癌基因具有莫大帮助.
上个世纪70年代末,weinberg ra 的研究生涯是从病毒与癌变关系入手的,那时他主要研究逆转录病毒如何转录,翻译,整合入动物细胞,可能那时因为逆转录酶的发现激活了该研究领域,并且这种病毒当时有人认为其整合入动物细胞可以引起基因突变,从而与癌变建立某种联系。文献参见:
Weinberg RA, Warnaar SO, Winocour E. Isolation and characterization of simian virus 40 ribonucleic acid. J Virol. 1972 Aug;10(2):193-201.
Weinberg RA. Nuclear RNA metabolism. Annu Rev Biochem. 1973;42:329-54.
Rothenberg E, Smotkin D, Baltimore D, Weinberg RA. In vitro synthesis of infectious DNA of murine leukaemia virus. Nature. 1977 Sep 8;269(5624):122-6.
Andersson P, Goldfarb MP, Weinberg RA. A defined subgenomic fragment of in vitro synthesized Moloney sarcoma virus DNA can induce cell transformation upon transfection.Cell. 1979 Jan;16(1):63-75.
可能是从病毒转化实验得到启示,癌细胞的表型受少数基因决定,因为病毒基因中具有转化能力的基因只是很小的一个片断, Weinberg RA等大胆推测化学诱导的癌细胞中也可能具有类似的基因片断,因此开始了其癌症研究生涯中具有决定意义的实验,该简单的实验折射出无限的思索和寻踪:
Shih C, Shilo BZ, Goldfarb MP, Dannenberg A, Weinberg RA. Passage of phenotypes of chemically transformed cells via transfection of DNA and chromatin.
Proc Natl Acad Sci U S A. 1979 Nov;76(11):5714-8.
1981年,Weinberg RA实验室如法炮制,在不同的肿瘤中发现可能存在不同的癌基因,奠定了其至今坚持癌基因学说的实验基础:
Shih C, Padhy LC, Murray M, Weinberg RA. Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts.Nature. 1981 Mar 19;290(5803):261-4.
Shilo BZ, Weinberg RA. Unique transforming gene in carcinogen-transformed mouse cells.Nature. 1981 Feb 12;289(5798):607-9.
1982 年,他的实验室分离出那个癌基因,奇迹是竟然这个基因序列类似肉瘤病毒的癌基因RAS的序列,一个巧合,30000多个基因,为什么偏偏是这个基因巧合?随后发现这个细胞癌基因与原癌基因差别只是一个氨基酸序列,于是提出癌基因激活的一种方式:点突变,这样突变与癌变的关系似乎建立了起来。
Parada LF, Tabin CJ, Shih C, Weinberg RA. Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene. Nature. 1982 Jun 10;297(5866):474-8.
Shih C, Weinberg RA. Isolation of a transforming sequence from a human bladder carcinoma cell line.Cell. 1982 May;29(1):161-9.
Tabin CJ, Bradley SM, Bargmann CI, Weinberg RA, Papageorge AG, Scolnick EM, Dhar R, Lowy DR, Chang EH. Mechanism of activation of a human oncogene.Nature. 1982 Nov 11;300(5888):143-9.
接着,由于RAS只能转化非整倍体的NIH-3T3细胞而不能转化原代培样的成纤维细胞,于是经过分析和实验,他的实验室证明两个癌基因可以转化原代培养的大鼠的成纤维细胞,并提出了分子水平的多步癌变学说:
Land H, Parada LF, Weinberg RA. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes.Nature. 1983 Aug 18-24;304(5927):596-602.
Land H, Parada LF, Weinberg RA. Cellular oncogenes and multistep carcinogenesis.
Science. 1983 Nov 18;222(4625):771-8.
那时发现突变的P53是癌基因,可以与RAS协同转化细胞:
Parada LF, Land H, Weinberg RA, Wolf D, Rotter V. Cooperation between gene encoding p53 tumour antigen and ras in cellular transformation.
Nature. 1984 Dec 13-19;312(5995):649-51.
1985年,依照类似的思想:癌症的各种表型由少数遗传因素(激活的基因决定),开始了研究癌细胞转移的基因的搜寻实验:
Bernstein SC, Weinberg RA. Expression of the metastatic phenotype in cells transfected with human metastatic tumor DNA.Proc Natl Acad Sci U S A. 1985 Mar;82Devil:1726-30. Erratum in: Proc Natl Acad Sci U S A 1988 Aug;85(15):5581.
另一方面从反面证明癌的表型维持由少数癌基因决定,同时发现细胞癌基因突变方式多样:
Drebin JA, Link VC, Stern DF, Weinberg RA, Greene MI. Down-modulation of an oncogene protein product and reversion of the transformed phenotype by monoclonal antibodies.Cell. 1985 Jul;41(3):697-706.
Chipperfield RG, Jones SS, Lo KM, Weinberg RA.
Activation of Ha-ras p21 by substitution, deletion, and insertion mutations.
Mol Cell Biol. 1985 Aug;5Musical Note:1809-13.
在理论方面,Weinberg RA.按照癌基因之间的协同关系,对癌基因进行了分类:
Weinberg RA. The action of oncogenes in the cytoplasm and nucleus.
Science. 1985 Nov 15;230(4727):770-6.
1986年,他们对不同癌基因的蛋白产物进行了分析,另外开始了癌基因的信号通路的研究,因为他们发现不同的癌基因之间协同和反映不同:
McCoy MS, Weinberg RA. A human Ki-ras oncogene encodes two transforming p21 proteins.Mol Cell Biol. 1986 Apr;6(4):1326-8.
Stern DF, Roberts AB, Roche NS, Sporn MB, Weinberg RA. Differential responsiveness of myc- and ras-transfected cells to growth factors: selective stimulation of myc-transfected cells by epidermal growth factor.Mol Cell Biol. 1986 Mar;6(3):870-7.
Bargmann CI, Hung MC, Weinberg RA. The neu oncogene encodes an epidermal growth factor receptor-related protein.Nature. 1986 Jan 16-22;319(6050):226-30.
发现不同的癌基因对应不同的癌的表型:
Land H, Chen AC, Morgenstern JP, Parada LF, Weinberg RA. Behavior of myc and ras oncogenes in transformation of rat embryo fibroblasts.
Mol Cell Biol. 1986 Jun;6Devil:1917-25.
同年,他们找到了第一个抑癌基因:RB
Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, Dryja TP. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma.
Nature. 1986 Oct 16-22;323(6089):643-6.
1989年推出被引用上千次的文献:
Weinberg RA. Oncogenes, antioncogenes, and the molecular bases of multistep carcinogenesis.
Cancer Res. 1989 Jul 15;49(14):3713-21.
1989年之后,直到1999年,10年之间Weinberg RA一直致力于癌基因相互作用的基因,癌基因的激活方式,癌基因发生的频率,癌基因与抑癌基因的关系,抑癌基因的作用方式,抑癌基因发生的频率,与癌症的相关性,这些基因如何导致癌症等等,
1999年值得纪念,因为首次证明了有限的基因可以转化人类细胞:
Hahn WC, Counter CM, Lundberg AS, Beijersbergen RL, Brooks MW, Weinberg RA. Creation of human tumour cells with defined genetic elements.
Nature. 1999 Jul 29;400(6743):464-8.
随后,对人类不同组织的细胞进行了转化实验:
Elenbaas B, Spirio L, Koerner F, Fleming MD, Zimonjic DB, Donaher JL, Popescu NC, Hahn WC, Weinberg RA. Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells.
Genes Dev. 2001 Jan 1;15(1):50-65.
关于这些被转化的细胞核型是否非整倍体化,存在争议,但是Weinberg捍卫自己的学说和结果:
Zimonjic D, Brooks MW, Popescu N, Weinberg RA, Hahn WC.
Derivation of human tumor cells in vitro without widespread genomic instability.
Cancer Res. 2001 Dec 15;61(24):8838-44.
2002年发表了制造人类癌细胞的文献总结:
Hahn WC, Weinberg RA.
Rules for making human tumor cells.
N Engl J Med. 2002 Nov 14;347(20):1593-603. Review. No abstract available. Erratum in: N Engl J Med. 2003 Feb 13;348(7):674.
2004年证明不同物种,不同组织的细胞发生转化需要改变不同的信号通路
Rangarajan A, Hong SJ, Gifford A, Weinberg RA.
Species- and cell type-specific requirements for cellular transformation.
Cancer Cell. 2004 Aug;6(2):171-83.
现在,Weinberg RA的研究方向似乎向肿瘤转移的分子生物学方向进步,不知道癌基因学说在他的努力下还有什么激动人心的事情发生,目前似乎已经达到顶峰,然而,Weinberg RA的思想顶峰过早预测可能会失败。
Peter Duesberg是癌症研究领域的一个特殊人物,原因在于其独特的思维方式。这位具有传奇色彩的教授,有很多头衔,科普宣传他是当代的唐吉科德,而科学界有人认为他是癌症研究领域的哥白尼,不管怎样,只有真的了解他的研究历史,才可能真的能够理解他。Peter Duesberg最早进入癌症研究领域也是从研究逆转录病毒开始:
Duesberg PH.
Physical properties of Rous Sarcoma Virus RNA.
Proc Natl Acad Sci U S A. 1968 Aug;60(4):1511-8.
Duesberg PH.
On the structure of RNA tumor viruses.
Curr Top Microbiol Immunol. 1970;51:78-104.
下面两篇文章是DUESBERG早期参与发现病毒癌基因的证据:
Duesberg PH, Vogt PK.
Differences between the ribonucleic acids of transforming and nontransforming avian tumor viruses.
Proc Natl Acad Sci U S A. 1970 Dec;67(4):1673-80.
Lai MM, Duesberg PH, Horst J, Vogt PK.
Avian tumor virus RNA: a comparison of three sarcoma viruses and their transformation-defective derivatives by oligonucleotide fingerprinting and DNA-RNA hybridization.
Proc Natl Acad Sci U S A. 1973 Aug;70Musical Note:2266-70.
可能只是注意逆转录肿瘤病毒的结构,所以他最早发现逆转录病毒癌基因,但是却没有机会发现细胞癌基因了。
Kawai S, Duesberg PH, Hanafusa H.
Transformation-defective mutants of Rous sarcoma virus with src gene deletions of varying length.
J Virol. 1977 Dec;24(3):910-4.
Duesberg PH, Vogt PK.
Avian acute leukemia viruses MC29 and MH2 share specific RNA sequences: evidence for a second class of transforming genes.
Proc Natl Acad Sci U S A. 1979 Apr;76(4):1633-7
Bister K, Duesberg PH.
Structure and specific sequences of avian erythroblastosis virus RNA: evidence for multiple classes of transforming genes among avian tumor viruses.
Proc Natl Acad Sci U S A. 1979 Oct;76(10):5023-7.
Duesberg PH.
Transforming genes of retroviruses.
Cold Spring Harb Symp Quant Biol. 1980;44 Pt 1,:13-29. Review.
由于在病毒癌基因方面的权威性,通过多重分析比较病毒癌基因和细胞原癌基因之间的结构、功能、产物等等之后,Duesberg PH在1983年开始质疑细胞癌基因的存在,也开始了他反癌基因潮流研究的开始:
Duesberg PH.
Retroviral transforming genes in normal cells?
Nature. 1983 Jul 21-27;304(5923):219-26. Review.
1985年依然质疑癌基因学说:
Science. 1985 May 10;228(4700):669-77. Links
Activated proto-onc genes: sufficient or necessary for cancer?Duesberg PH.
Proto-onc genes are normal cellular genes that are related to the transforming (onc) genes of retroviruses. Because of this relationship these genes are now widely believed to be potential cancer genes. In some tumors, proto-onc genes are mutated or expressed more than in normal cells. Under these conditions, proto-onc genes are hypothesized to be active cancer genes in one of two possible ways: The one gene-one cancer hypothesis suggests that one activated proto-onc gene is sufficient to cause cancer. The multigene-one cancer hypothesis suggests that an activated proto-onc gene is a necessary but not a sufficient cause of cancer. However, mutated or transcriptionally activated proto-onc genes are not consistently associated with the tumors in which they are occasionally found and do not transform primary cells. Further, no set of an activated proto-onc gene and a complementary cancer gene with transforming function has yet been isolated from a tumor. Thus, there is still no proof that activated proto-onc genes are sufficient or even necessary to cause cancer.
1987年依然反对癌基因学说,逐渐向非整倍体假说靠拢:
Duesberg PH.
Cancer genes: rare recombinants instead of activated oncogenes (a review).
Proc Natl Acad Sci U S A. 1987 Apr;84Musical Note:2117-24.
The 20 known transforming (onc) genes of retroviruses are defined by sequences that are transduced from cellular genes termed protooncogenes or cellular oncogenes. Based on these sequences, viral onc genes have been postulated to be transduced cellular cancer genes, and proto-onc genes have been postulated to be latent cancer genes that can be activated from within the cell to cause virus-negative tumors. The hypothesis is popular because it promises direct access to cellular cancer genes. However, the existence of latent cancer genes presents a paradox, since such genes are clearly undesirable. The hypothesis predicts that viral onc genes and proto-onc genes are isogenic; that expression of proto-onc genes induces tumors; that activated proto-onc genes transform diploid cells upon transfection, like viral onc genes; and that diploid tumors exist. As yet, none of these predictions is confirmed. Instead: Structural comparisons between viral onc genes, essential retroviral genes, and proto-onc genes show that all viral onc genes are indeed new genes, rather than transduced cellular cancer genes. They are recombinants put together from truncated viral and truncated proto-onc genes. Proto-onc genes are frequently expressed in normal cells. To date, not one activated proto-onc gene has been isolated that transforms diploid cells. Above all, no diploid tumors with activated proto-onc genes have been found. Moreover, the probability of spontaneous transformation in vivo is at least 10(9) times lower than predicted from the mechanisms thought to activate proto-onc genes. Therefore, the hypothesis that proto-onc genes are latent cellular oncogenes appears to be an overinterpretation of sequence homology to structural and functional homology with viral onc genes. Here it is proposed that only rare truncations and illegitimate recombinations that alter the germ-line configuration of cellular genes generate viral and possibly cellular cancer genes. The clonal chromosome abnormalities that are consistently found in tumor cells are microscopic evidence for rearrangements that may generate cancer genes. The clonality indicates that the tumors are initiated with, and possibly by, these abnormalities, as predicted by Boveri in 1914.
然而,1987年,他似乎或者现在已经成为事实20年了,他质疑癌基因学说的同时,也否认艾滋病是传染病,更不承认艾滋病的元凶是HIV.为此,引起SCIENCE杂志对其进行了4个对月的调查,结果我不清楚,大家看看,仁者见仁
Duesberg P.
HIV is not the cause of AIDS.
Science. 1988 Jul 29;241(4865):514, 517.
Duesberg PH.
Human immunodeficiency virus and acquired immunodeficiency syndrome: correlation but not causation.
Proc Natl Acad Sci U S A. 1989 Feb;86(3):755-64. Review.
Duesberg P.
Duesberg's PNAS paper.
Science. 1989 Mar 3;243(4895):1125.
Duesberg P.
Defective viruses and AIDS.
Nature. 1989 Aug 17;340(6234):515.
Duesberg PH.
"The Duesberg phenomenon": Duesberg and other voices.
Science. 1995 Jan 20;267(5196):313-4;
他反对癌基因学说的关键是基因表达量的问题,也就是他认为细胞原癌基因要致癌必须获得类似病毒启动子的强力转录力量:
Wu Y, Zhou H, Duesberg P.
Unmutated proto-src coding region is tumorigenic if expressed from the promoter of Rous sarcoma virus: implications for the gene-mutation hypothesis of cancer.
Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6393-7.
Duesberg PH.
Oncogenes and cancer.
Science. 1995 Mar 10;267(5203):1407-8.
Hua VY, Wang WK, Duesberg PH.
Dominant transformation by mutated human ras genes in vitro requires more than 100 times higher expression than is observed in cancers.
Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9614-9.
由于对癌基因学说的坚决反对,他的研究经费被切断,但是1997年,他在私人捐赠下,和他的学生证实提出癌变的非整倍体假说:
Li R, Yerganian G, Duesberg P, Kraemer A, Willer A, Rausch C, Hehlmann R.
Aneuploidy correlated 100% with chemical transformation of Chinese hamster cells.
Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14506-11.
1999年,Weinberg实验室宣布有限的癌基因可以转化人类细胞时,他检测了这些细胞,说这些细胞时非整体核型,依然支持非整倍体假说,为此,肿瘤研究领域争论再次掀起:
Li R, Sonik A, Stindl R, Rasnick D, Duesberg P.
Aneuploidy vs. gene mutation hypothesis of cancer: recent study claims mutation but is found to support aneuploidy.
Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3236-41.
现在,可以看看这位教授几十年的研究结果了,癌变的非整倍体假说:
Duesberg P, Rasnick D.
Aneuploidy, the somatic mutation that makes cancer a species of its own.
Cell Motil Cytoskeleton. 2000 Oct;47(2):81-107. Review.
Duesberg P, Li R.
Multistep carcinogenesis: a chain reaction of aneuploidizations.
Cell Cycle. 2003 May-Jun;2(3):202-10. Review.
Duesberg P, Li R, Fabarius A, Hehlmann R.
Aneuploidy and cancer: from correlation to causation.
Contrib Microbiol. 2006;13:16-44. Review.
问题产生和解决的源头
从古至今,人类一直不能摆脱的问题很多,但是最重要的问题莫过于是非问题(或对错问题,或主观与客观一致的问题)。因为几乎我们面临的所有问题通过追根溯源办法都可能最总归于该问题。多年的挫折经验积累,人类发现惟有理解事物的真相才可能根本解决该问题.
西方很早就提出了追求真理的口号。中国古代一直流行道德第一,才能第二,该观念现在依然受到推崇.然而,人类面临的第一问题是:是非问题,而不是道德问题。
是非问题决定生死,决定生活质量,而道德问题只是是非问题解决后才衍生的问题,说到底,是人类内部生存竞争基础上的一种协议.没有竞争不会有道德的产生,没有竞争,道德没有必要产生。况且,是非问题不解决,道德也只是盲目的道德,甚至是愚蠢的道德。因此,坚持追求真理第一位,不但非常重要,并且明知有效。
坚持道德第一,本质上是一种自我封锁和愚民政策。因为,道德第一常常使很多人在是非问题面前屈服于所谓的道德,而迷失方向,进而,一切问题随之而生。
坚持是非问题第一,道德才成为是非问题,这样道德不再是顽固的枷锁,而成为时刻有可能被改变问题。也只有道德时刻与是非保持一致才可能具有进步的价值,否则,就是桎梏或者成为玩笑。现在中国社会产生的很多奇怪现象的本质就是道德和是非问题分离结果。
人类有嘲笑和讽刺各种道德的各种理由和本钱,但是没有人有嘲笑和讽刺真理的理由和本钱。
说到底,人类的第一重要问题是是非问题而不是道德问题,这个问题的颠倒是东西方竞争差距产生的根本原因。
古老的东方进步优于西方源于那时人类的思维进步整体上还处于经验时期,东方在经验积累上优于西方。然而,对于真理的追求和鼓励使西方人早于东方人进入理性时代:认识世界本来面目的真理时代,这时东方就落后了。虽然后来中国人很多人认为中国的落后是科技的落后,而科技的落后是社会制度的落后,但是事实上是我们在认识问题的方法上整体落后了,在认识结果上表现为科技和社会制度的落后。
不论科技问题还是社会问题都首先是真理问题,但是至今,我很少听到追求真理的呼声.除了20-70年代,***提出过这样的口号,但是似乎没有将这个问题深深种植于我们民族的基因之中,因为现在这样的口号不再了,甚至很多无知的人认为这样的口号过时了.实际上,这个问题依然是我们面临的头等大问题,看看我们学术的水平和社会问题,不论科学还是社会学,都值得担忧。
最近,政府提出建设创新型国家的口号,然而,创新的核心问题依然是真理是非问题.但政府为什么用创新来代替真理?
提出追求真理比提出创新更能够目标明确,因为真理是创新的核心本质,离开本质谈论现象是本末倒置。
人类的学问介因问题而生,不论科学、宗教、文学、艺术还是哲学等等。
不同的问题和解决问题的方式决定了学问的性质和发展方向。
对于问题,人类需要依赖工具来解决,工具基本可以分为两类:思想工具和物质工具。一些问题只能借助思想工具来解决,比如人生的本质和意义。一些问题需要思想工具和物质工具的结合来解决,主要是科学问题。
对于同一个问题有不同的看法是因为人类具有不同的思想方式。哲学是一种思想方式,也可被理解为一种思维工具,放弃哲学就意味着放弃思想工具,意味着思想残废。
依赖不同的思维方式产生了不同的哲学和宗教。依赖不同的思维方式和物质工具产生了不同的具体学科。
人类文化的核心是:思维工具和物质工具。
物质工具是人类在认识事物特质基础上,对物质特性的利用,而事物的特性是事物与其他事物之间的特殊关系。
问题的本质是事物的关系:历史关系,横向关系,层次关系。
认识事物需要设定坐标,建立概念,然后分析不同概念的关系。思维混乱的根源在于基本概念的不明确。错误起源于概念与事物的对应关系.建立新概念是明确新事物与已知事物之间关系。
实验认识事物需要得到纯化的物质(对应绝对概念),只有纯化的物质之间的关系才是真正的关系。早期的物理学和化学诞生就是这样,可想,没有他们不可能有现在的生物化学和分子生物学,因为我们首先无法获得纯化的物质,更不要说研究他们之间的关系了。
新工具诞生于纯化物质。
分离纯化物质目前有两种方法:利用物质的特性,从大量原料中分离;利用物质特性,大量合成,比如化学和分子克隆。分离纯化目前依然是现代工业的基石。
确立因果关系需要明确几种关系,这种关系称为Koch’s规则,当初Robert Koch (1843-1910)用这样的逻辑来推测微生物与疾病的关系,拓展开来也似乎可以用于其他因果关系的识别。有4个原则:1)微生物必须存在于所有的患者体内,2)这种微生物必须能够从患者体内分离(并体外培养),3)分离的微生物必须能够在适当动物体内引起该疾病,4)从实验引起患病的动物体内能够分离到该微生物。
癌症病因探询也应当遵循Koch’s规则,如果什么因素是癌症的直接原因,那么:1)所有的癌细胞都具有该物质,2)这种物质可以从癌症细胞中分离出来,3)这种物质可以在动物体内引起类似的癌症,4)从被动物机体诱导的癌症细胞中可以分离到该物质。
一种物质如果是癌症的原因,那么应当遵循下面原则:1)所有的癌症细胞中都必须有该物质(必要条件),2)一定的该物质必然能够引起癌症,阻断该物质后,癌症消失(充分条件)。