顧秀林:盡我所能,翻譯了何美芸博士來信中的大部分。希望讀者有耐心,更希望有人分享我的欣喜:這麽大的進展,要上科學史了。我來發一個尋人啟事:生物學專業的學子,專家,波導:你們在哪裏?你們的專業裏發生天翻地覆的大事了,來關心一個?要不,就快來嘲笑我的翻譯不夠專業吧,指出我在哪裏翻譯的不正確吧!最好請集中火力來猛攻一個我非常認同的觀點:達爾文的隨機突變自然選擇,該進博物館了!一年前如果有人膽敢批評達爾文的進化論,還會被小方以極端輕蔑的口氣斥之為文傻,現在輪到小方自己顯示是個“科傻”的真相了。
科學是永遠進步的,一停就會死。最悲慘的是不是科學要改錯,而是我們的食物被邪惡的轉基因毀了,早在1980年代,決定論的“中心法則”就從根本上被撼動,然而邪惡的轉基因技術還是如毒菌一樣冒出來,被邪惡的孟山都公司瞄準送到我們的飯碗裏。轉基因技術可能安全的理論假設,已經徹底瓦解了,可是轉基因技術這股如泥石流一般的禍水,卻已經彌散在中國大地上——我的祖國被這邪惡糟蹋和毀壞,千呼萬喚,喚不來廟堂糾謬的決斷,祖國的生態安全底線,中國人民免疫力的極限,被邪惡的轉基因食品,左打,右打,打了又打,......要打到何時......這兩個承受力都是有限度的啊
article can be found on the I-SIS website at
http://www.i-sis.org.uk/Evolution_by_Natural_Genetic_Engineering.php
James
Shapiro at University of Chicago Illinois in the United States is among the
pioneers who discovered the new genetics of the ‘fluid genome’ that, by the
early 1980s, had already shaken the scientific establishment to its roots [3]
(see also [2, 4], [5] Living with the Fluid Genome, ISIS publication). All the
basic tenets of conventional genetics that had dominated science and society for
at least half a century were being eroded by exceptions upon exceptions, until
the exceptions outnumbered and overwhelmed the rules.
出版)。統治了科學和社會至少半個世紀的常規(正統)遺傳學說中的所有的原理,一個一個變成了“例外”。直到有一天“例外”占了大多數,主導了整體規則。
1997 paper [1], Shapiro made a powerful case against the neo-Darwinian dogma
that evolution occurs by the natural selection of random mutations.
genomes typically have a modular structure consisting of sets of genes
(operons外顯子)
expressed together. Operons have a characteristic internal structure, with
coding regions for regulator protein(s), structural/enzyme proteins and several
control elements. Every protein coding sequence in turn contains several domains
each with a defined function. Many operons are dispersed throughout the genome,
equipped with different combinations of similar regulatory/control genetic
elements and forming overlapping, often extensive ‘regulons’ (gene expression
networks) finely tuned to different stages of cell growth and development and
changing environmental conditions.
tuned )。
multitudes of protein-effector, protein-protein, protein-nucleic acid, and
nucleic acid- nucleic acid interactions are involved, all highly specific for
every occasion.
surprisingly, genomes have special mechanisms for correcting base sequence
errors during DNA replication. It is extremely hard to imagine how such a genome
could have been assembled or changed piece-meal by the natural selection of
independently occurring random mutations in different genetic elements. On the
other hand, a simple copying (amplification) process followed by cut and splice
different sequence elements together would be easily accomplished. Cells have
all the enzymes and cofactors required for such feats of natural genetic
engineering. In fact, artificial genetic engineering is possible only by using
the enzymes isolated from the bacteria themselves, albeit without the precision
and finesse of natural genetic engineering.
mutations involve features of precise natural genetic engineering Shapiro
discovered ‘adaptive’ mutations in bacteria (recently confirmed, see [6]
Non-Random Directed Mutations Confirmed, SiS 60). He investigated an E. coli
system that depends on generating a fusion lacZ protein, the b-galactosidase
that breaks down lactose to galactose and glucose. The bacterial virus (phage)
Mu was used to construct a strain in which a defective lacZ coding sequence
without its promoter - a control element required for transcription - and
carrying an ochre triplet (a stop codon) at codon 17 - so the transcript cannot
be translated fully - was aligned in tandem with another coding sequence araB
(from the arabinose operon) that has an intact promoter [1].
非隨機生成的突變被確認,SiS
60)。他研究了一種大腸杆菌,它(的生存)依賴於(分泌)lacZ
蛋白和果糖混合物。lacZ
可以把牛乳糖降解為半乳糖。這種細菌的病毒(噬菌體)Mu
被用來建造一個strain,其中有不活躍的、不帶啟動子的lacZ
編碼係列~
啟動子是轉錄所必須的元件,還有一種“三聯體”(ochre
triplet)(一種終止密碼子)
at codon 17,這樣轉錄就不會完整,同時串聯於另一種編碼序列araB
(來自阿拉伯糖操縱子arabinose
operon ),它帶著自己的啟動子。
that way, a precise deletion of intervening sequence is needed to form the
fusion b- galactosidase protein capable of functioning to break down lactose and
enable the cell to growth on a selective medium with lactose as the sole carbon
source.
originally thought that the Mu prophage (phage integrated into the bacterial
genome) would be the passive source of homology (sequence similarity) to enable
the fusion to take place by homologous recombination to loop out the intervening
sequence, and such ‘spontaneous’ break-rejoin events would generate the actual
fusions by removing all blocks to transcription and translation between araB and
a site in lacZ downstream of the ochre triplet codon. But detailed studies
showed that the Mu prophage played an active role in the araB- LacZ fusions
using its transposase enzyme, and the process was precisely regulated by the
cell. Many different proteins and DNA sequences have to come
together in
choreographed succession to form and rearrange the nucleoprotein complexes
necessary for directing the precise cut and splice operations. A large number of
the molecular players have been identified since. In other words, the fusion
events happen as the result of accurate natural genetic engineering carried out
by the E. coli cell.
mobile genetic elements like Mu are found in all organisms, Shapiro thought it
reasonable to hypothesize that the regulatory aspects of the mutational process
exemplified by the araB-LacZ system might apply generally to other
examples
of adaptive mutations (see [6]) and described the numerous cellular functions
involved in different cases. He wrote [1, p.103]: “The depth of regulatory
interactions between cellular signal transduction networks and natural genetic
engineering systems is likely to prove typical rather than
exception.”
夏皮羅據此認為可以提出一個假定,araB-LacZ
代表的突變過程是有調控的(注6),根據不同實例中發現的無數類似的細胞功能,他提出:(注1,103頁):細胞之間的信號轉遞(transduction)網絡這種有調控的互動之深度,可能在說明自然的遺傳工程係統是一種常態,而不是例外。
genetic engineering has large implications for evolution, Shapiro pointed out.
First, large scale
coordinated changes within the genomes of single cells are possible because a
particular natural genetic engineering system can be activated to operate at
multiple sites in the genome. Second, there is opportunity for adaptive feedback
to make genetic changes, thereby greatly accelerating evolutionary change during
episodes of crisis.
From ROM to RW genome
new papers, Shapiro draws an illuminating parallel between the genome and the
computer [7, 8]; at the same time correcting some widely held misconceptions
about the genome.
糾正了一些流傳很廣的謬見。
genome has traditionally been treated as a Read-Only Memory (ROM) subject to
change by copying errors and accidents.” Shapiro writes [7, p. 268]: “I propose
that we need to change that perspective and understand the genome as an
intricately formatted Read-Write (RW) data storage system constantly subject to
cellular modifications and inscriptions.”
第258頁),
我改變視角,把基因組理解為計算機的讀寫數據(RW),常規性地被細胞的操作進行修飾和命名。
ROM view of the genome is encapsulated by Sydney Brenner in his 2012 Alan Turing
Centennial tribute [9]: “Turing’s ideas were carried further in the 1940s by
mathematician and engineer John von Neumann, who conceived of a ‘constructor’
machine capable of assembling another according to a description. A universal
constructor with its own description would build a machine like itself. To
complete the task, the universal constructor needs to copy its description and
insert the copy into the offspring machine. Von Neumann noted that if the
copying machine made errors, these ‘mutations’ would provide inheritable changes
to the progeny.”
von Neumann)推得更遠。紐伊曼構想了一個會按照指令幹組裝活的‘建造者機器’。一個全能的建造者,用自己的圖紙可以組裝出另一個自己。它需要複製自己的圖紙,裝進它的子代機器,讓它去完成組裝任務。馮紐伊曼注意到,如果複製出錯,突變將成為可遺傳的改變,表現在下一代身上。
”
static mechanical view of the genome is a far cry from reality. Even to
reproduce a single protein – originally conceptualised as a single message –
requires elaborate cut and splice operations. The international research
consortium project ENCODE (Encyclopedia of DNA Elements) data have revealed
that
DNA include many ‘non-coding’ segments [10, 11].
term ‘gene’, a theoretical construct that has never been possible to define
rigorously, is now known to be scattered in bits across the genome, overlapping
with bits of multiple genes that have to be spliced together to make a messenger
(m)RNA for translation into protein. The term now used for the bits is ‘coding
sequences’ or exons.
construct)。現在我們知道,在基因組上,“基因”是星星點點地散布其上,一個基因又和很多基因重疊,且必須經過拚接生成信使(m)RNA,然後才能被翻譯生成蛋白質。現在,提到“基因組片段”的通用詞匯是“編碼序列”,或者外顯子。
Turing tape analogy does not take into account the actual physical participation
of the genome in productive and regulatory interactions. The concept of a
Read-Only Turing genome also fails to recognize the essential ‘Write’ capability
of a universal Turing machine, which fits remarkably well with the ability of
cells to make temporary or permanent inscriptions in DNA. (Of course, it is by
no means all down to the genome. A genome outside a cell can do
nothing.
。
The
numerous claims that synthetic biologists have created life in the laboratory
are spurious, as they all depend on putting a synthetic genome into a
pre-existing cell [12] (Synthetic Life? Not By a Long Shot, SiS 47).
47)
it is not so much the cell, but rather the nature of living protoplasm that
keeps eluding our grasp [13, 14] The Rainbow and the Worm, The Physics of
Organisms, and Living Rainbow H2O, ISIS publications.)
H2O活的彩虹,
ISIS 發表)
[1, 7, 8] distinguishes modifications of DNA (rearrangements, deletions,
insertions, mutations) - which he regards as natural genetic engineering proper
- from epigenetic changes involving DNA/histone marks, or via non-coding RNA
species that occur constantly in real time within the life cycle of the cell or
organism. In my view, this distinction is artificial. There is no real
separation between epigenetic and genetic; they form one seamless continuum in
molecular mechanisms that interact with one another directly.
changes)。在這裏,有DNA/組蛋白標記(histone
marks),換句話說,在細胞活機體的生命周期中,非編碼的RNA
species 常規性、實時地發生著改變。在我看來,這樣區分還是留有刀斧痕跡。我不認為遺傳和表觀遺傳可以截然分開。它們的分子機製在細胞裏呈現天衣無縫的連續,二者是直接的互動。
further paper [15], Shapiro himself proposes that during ‘life history events’
such as hybridization and chromosome doubling, viral or bacterial infections,
exposure to environmental toxins, etc., epigenetic changes are often accompanied
by mobilization of transposable elements that change the genome. And non-coding
RNAs (ncRNAs) are involved in mobilizing transposons and in targeting specific
changes in chromatin, the DNA histone protein complex that forms a
chromosome.
(ncRNA)介入其中以激活轉座子。
common connection between epigenetic and genome change is that processed,
alternatively
spliced RNA can be reversed transcribed and inserted into the genome. On the
other hand, certain altered (reformatted) states of /chromatin can be passed on
to subsequent generations; i.e., they are inherited like a
interference RNA can also act independently as genetic material to perpetrate
epigenetic changes across many generations, as part and parcel of the hereditary
legacy of the organism (see [16] RNA Inheritance of Acquired Characters, SiS
63).
genome’, the genome is no longer the constant and unchanging entity previously
assumed. Hence I use the term “natural genetic modification” for the totality of
changes in the genetic information of cells and organisms as they experience
their environments that are all necessary for survival, and some of which are
passed on to the next generation(s) [17].
shall follow Shapiro’s story [7, 8] on actual modifications of DNA base sequence
and the genome structure before dealing with implications on artificial genetic
modification and for society in general. The rest of this series of articles
will elaborate on the epigenetic aspects of natural genetic
modification.