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20.5: Asal Usul Kehidupan Kimia di Dunia RNA - Biologi

20.5: Asal Usul Kehidupan Kimia di Dunia RNA - Biologi



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Dalam skenario kolam pasang surut, dengan nuansa 'paling cocok' dengan asal-usul kehidupan di lingkungan yang berkurang, energi untuk pembentukan polimer dari monomer organik berasal dari lingkungan bumi yang terlalu panas. Dalam skenario itu, kami mempertimbangkan kemungkinan bahwa rantai nukleotida mungkin telah disintesis, dan bahkan direplikasi untuk membentuk populasi asam nukleat. Tetapi jika lingkungan prebiotik tidak mereduksi, dari mana energi akan datang untuk membuat polimer apa pun, apalagi polimer yang dapat mereplikasi dirinya sendiri? Jika Anda menebak bahwa energi disediakan oleh gradien proton antara sel proto asam yang terbungkus biofilm dan lautan basa…, Anda akan benar! Dalam hal ini, maka polimer akan disintesis di ruang tertutup, dan bukan di kolam pasang surut hanya untuk tersebar dan diencerkan di lautan yang lebih luas. Dan kemudian, bagaimana kimia replikatif, informasional dan katalitik muncul dari monomer dan polimer organik ini? Polipeptida akan terbentuk, tetapi mereka tidak memiliki dasar kimia atau struktural yang melekat untuk replikasi diri. Tidak seperti polipeptida, kita melihat dalam menggambarkan skenario kolam pasang surut yang dilakukan polinukleotida (asam nukleat)! Faktanya, bukti semakin banyak untuk mendukung hipotesis yang semakin diterima bahwa kehidupan berasal dari a dunia RNA:

  • RNA hari ini termasuk ribozim yang mengkatalisis replikasi mereka sendiri (misalnya, intron self-splicing).
  • Beberapa RNA adalah bagian dari ribonukleoprotein dengan setidaknya aktivitas ko-katalitik (ingat ribosom, spliceosom dan partikel pengenalan sinyal sekretori).
  • Retrovirus (misalnya, HIV) menyimpan informasi genetik mereka di genom RNA yang mungkin merupakan bagian integral dari munculnya kehidupan seluler.

Ribozim, struktur ribonukleoprotein, dan retrovirus mungkin merupakan warisan dari dunia RNA prebiotik. Bahkan, dalam 'in vitro studi evolusi', ribozim polimerase yang mereplikasi diri dalam tabung reaksi menjadi lebih efisien dalam mereplikasi berbagai RNA yang semakin lama dan semakin kompleks dari waktu ke waktu. Untuk lebih lanjut tentang autokatalis ini, klik Evolusi Ribozim Buatan yang Mendukung Dunia RNA Awal.

Ada hipotetis Skenario dunia RNA untuk asal usul replikasi, polimer katalitik, dan bahkan bahan kimia organik nyata autokatalis yang dapat mengkatalisis sintesisnya sendiri. Jadi, mana yang mungkin lebih dulu? Sebuah RNA yang menggandakan diri atau molekul lain yang menggandakan diri, bahkan molekul organik yang dapat menggandakan diri? Diperdebatkan, evolusi kimia dari RNA autocatalytic adalah peregangan, tapi setidaknya satu molekul organik, Akecil-Adenosin Tasam-Ester (AATE), adalah replikasi diri saat ini autokatalis. Mungkinkah molekul organik seperti AATE telah menjadi pendahuluan prebiotik ke dunia RNA? Struktur dan replikasi AATE dijelaskan di bawah ini.

Reaksi replikasi berlangsung dalam langkah-langkah berikut:

  • Ester aminoadenosine triacid mengikat molekul lain dari aminoadenosine.
  • Kedua aminoadenosin, sekarang dalam orientasi yang berlawanan, dapat menarik dan mengikat ester kedua.
  • Setelah penataan ulang ikatan, molekul terpisah menjadi dua molekul AATE.

Reaksi ini bersifat katalitik karena stereokimia dari molekul yang bereaksi menciptakan afinitas molekul ester aminoadenosin pertama untuk molekul aminoadenosin bebas tambahan, dan kemudian untuk ester bebas kedua. Struktur yang terbentuk memungkinkan (yaitu, mengkatalisis) hubungan aminoadenosine kedua dan ester diikuti dengan pemisahan kedua molekul AATE. Perubahan halus dan berurutan dalam konformasi molekul menghasilkan perubahan afinitas molekul satu sama lain. Dalam reaksi replikatif, konsentrasi AATE, ester bebas dan aminoadenosin bebas akan mendorong reaksi. Mungkinkah molekul mirip AATE telah menjadi nenek moyang dari replikasi polimer yang diautokatalisis? Bisakah replikasi molekul mirip AATE prebiotik telah mengarah ke dunia RNA? Bisakah RNA primitif distabilkan dengan mengikat peptida prebiotik pendek, menjadi pelopor ribozim? Kemungkinan molekul mirip AATE prebiotik sangat menarik karena 'triasid' termasuk basa nukleotida, purin adenosin! Di sisi lain, kemungkinan prebiotik mereplikasi kompleks RNA-peptida menyiratkan asal usul kehidupan di Dunia RNA-Protein (bukan eksklusif RNA-dunia)! Apakah kehidupan dimulai di dunia RNA atau dunia protein RNA, replikasi yang dikatalisis tentu saja merupakan sifat lain dari kehidupan.


Asal usul kehidupan di sumber air panas

Mata air panas yang membantu bahan organik berubah menjadi kehidupan.

50 tahun yang lalu, sebuah meteorit mendarat di Victoria membawa banyak bahan penyusun kehidupan, termasuk asam amino, nukleobasa, dan lipid. Molekul organik ini terbentuk ketika senyawa dalam debu bintang, yang terkumpul di meteorit, bereaksi di bawah suhu rendah dan sinar UV saat melewati ruang angkasa.

Banyak ahli astrobiologi berpikir asal usul kehidupan di Bumi dimulai ketika meteorit yang membawa bahan organik serupa jatuh ke planet ini sekitar empat miliar tahun yang lalu.

Pertanyaan besarnya adalah bagaimana bahan organik ini bersama dengan apa yang sudah ada di Bumi – yang disebut ‘sup’ prebiotik – berubah menjadi kehidupan.

“Kami pikir mata air panas di permukaan bumi memiliki jawabannya,” kata Luke Steller dari Pusat Astrobiologi Australia UNSW. “Suhu yang tinggi dan paparan ke atmosfer memungkinkan proses unik yang tidak ditawarkan oleh lingkungan bawah laut.

“Siklus dehidrasi (melalui penguapan) dan rehidrasi (dengan percikan dari geyser atau kolam) di sumber air panas memungkinkan gelembung lipid kecil yang disebut 'vesikel' terbentuk di sekitar molekul.

“Vesikel yang mengandung materi genetik yang tepat bisa jadi merupakan ‘sel proto’ – nenek moyang sel hidup modern.”

Steller saat ini berkolaborasi dengan Dr Anna Wang, dari Sekolah Kimia UNSW, untuk melacak kapan – dan bagaimana – kimia menjadi biologi.

Akhir tahun lalu, Steller dan Wang melakukan perjalanan ke Rotorua di Selandia Baru dengan ABC Catalyst untuk menciptakan kembali formasi sel proto ini di lingkungan sumber air panas yang sesungguhnya.

“Hampir semua jenis reaksi kimia bisa terjadi di sumber air panas,” kata Wang.

“Jika Anda menggabungkannya dengan materi luar angkasa yang membombardir planet ini empat miliar tahun lalu, mereka menjadi tempat yang paling menarik secara kimiawi di Bumi.”

Dimulai dengan gelembung

Vesikel, juga dikenal sebagai membran lipid, memainkan peran penting dalam melindungi molekul genetik dalam sel kita dan, berpotensi, nenek moyang semua sel.

"Sebuah gelembung di sekitar beberapa molekul adalah langkah pertama menuju organisme individu," kata Steller. “Entitas ini, sebuah sel proto, dapat bersaing dengan sel proto lain dan mulai menjalani evolusi Darwin.

“Tanpa penghalang, tidak ada yang memisahkan materi genetik dari hal lain – itu akan menjadi encer dan bagian dari sup yang homogen.”

Mata air panas di Selandia Baru membawa Anna Wang dan Luke Steller selangkah lebih dekat ke proses geologis kompleks yang mungkin menjadi asal mula kehidupan di Bumi. Kredit: Katalis ABC.

Para peneliti terinspirasi oleh upaya David Deamer dan Bruce Damer dari University of California Santa Cruz, untuk menguji pembentukan vesikel di laboratorium dunia nyata.

Steller dan Wang menyiapkan botol lipid (asam lemak) seperti yang ditemukan di meteorit dan RNA – asam nukleat yang penting bagi kehidupan. RNA diteorikan telah ada di awal Bumi.

Dikombinasikan dengan mata air panas (mengandung mineral terlarut dan garam), campuran ini adalah contoh sup prebiotik yang mungkin menghasilkan sel pertama yang bereplikasi.

“Ketika kami pertama kali mencampur sup prebiotik dengan air panas dan menenggelamkan botol ke dalam mata air panas, suhu tinggi mengeringkan bahan-bahannya,” kata Steller. "Proses pengeringan lipid dan RNA ini bersama-sama 'menjebak' RNA terkonsentrasi di antara lapisan lipid."

Ketika sup direhidrasi – sebuah proses yang terjadi secara alami di sumber air panas dengan memercik – para peneliti melihat vesikel yang mengandung bentuk RNA pekat.

“Dengan memiliki siklus basah-kering ini, semua molekul organik penting yang mengambang di sekitar akan dijejalkan di dalam satu tempat kecil. Ini dapat membantu molekul berinteraksi dan bereaksi secara kimia.

“Karena terkotak-kotak, vesikel-vesikel ini tiba-tiba memiliki ‘identitas’ mereka sendiri dan dapat mulai bersaing, meningkat dalam kompleksitas dan berkembang menuju sesuatu yang seperti kehidupan.”

Laboratorium yang berantakan

“Early Earth adalah tempat yang berantakan,” kata Steller. “Ada banyak mineral dan kimia air yang berbeda, dan tanah liat menggelegak di sekitar kolam mata air panas.

Pemandian air panas di Rotorua, Selandia Baru adalah tempat yang sempurna untuk mempelajari asal usul kehidupan. Kredit: Katalis ABC.

"Ada banyak percikan, kilat, dan berbagai cairan serta gas yang bergejolak, mendidih, dan bercampur."

Bepergian ke Rotorua menawarkan kesempatan bagi para peneliti untuk melakukan eksperimen 'bukti tanah' dan menunjukkan bahwa konsep yang ditunjukkan di lab cukup kuat untuk tetap berlaku di lingkungan yang lebih berantakan.

“Melakukan eksperimen prebiotik dalam tabung reaksi kaca bersih tidak benar-benar mewakili apa yang terjadi di Bumi awal,” kata Steller.

“Meskipun kita tidak dapat kembali ke masa lalu, kita memiliki bukti geologis bahwa mata air panas ada di awal Bumi. Dalam beberapa hal, mengunjungi sumber air panas terasa seperti kembali ke sumbernya.”

Blok bangunan kehidupan

Wang terpesona oleh langkah perakitan mandiri pertama untuk kehidupan di Bumi: di mana bahan kimia dapat bersatu dan bertransisi menjadi biologi.

“Dalam studi asal usul kehidupan, kami mengajukan pertanyaan seperti: 'Fisika apa yang diperlukan untuk perakitan sendiri?', 'Apa konteks geologis yang dapat membantu semua proses tersebut?', dan 'Bantuan apa yang kami dapatkan dari luar angkasa? yang bisa membantu mengkatalisasi kehidupan ini?'

“Semua faktor ini datang bersama sekali – dan itu sangat sukses sehingga mampu bertahan selama miliaran tahun dan berkembang menjadi semua kehidupan yang kita lihat hari ini.

“Ada chemistry bersama untuk tanaman, virus, bakteri, dan kita. Memahami bagaimana semua itu terjadi dapat membantu kami membangun mikroreaktor yang lebih baik untuk membuat barang biologis, atau untuk mengidentifikasi target obat potensial untuk penyakit.”

Steller adalah bagian dari tim yang lebih luas di UNSW yang membantu NASA dalam memahami bagaimana kehidupan mungkin telah dilestarikan di planet lain di tata surya kita.

“Asal usul kehidupan adalah bagian dari narasi umat manusia,” katanya.

“Mempelajari lebih banyak tentang itu tidak hanya bermanfaat bagi sains, tetapi juga membantu kita mengembangkan pemahaman kita tentang siapa diri kita dan tempat kita di alam semesta.”

Artikel ini pertama kali diterbitkan di Science Channel Australia, platform berita asli The Royal Institution of Australia.

Ruang Berita UNSW

Berita terbaru dan terbaik dari University of New South Wales.

Baca fakta sains, bukan fiksi.

Tidak pernah ada waktu yang lebih penting untuk menjelaskan fakta, menghargai pengetahuan berbasis bukti, dan menampilkan terobosan ilmiah, teknologi, dan rekayasa terbaru. Cosmos diterbitkan oleh The Royal Institution of Australia, sebuah badan amal yang didedikasikan untuk menghubungkan orang-orang dengan dunia sains. Kontribusi keuangan, betapapun besar atau kecilnya, membantu kami menyediakan akses ke informasi sains tepercaya pada saat dunia sangat membutuhkannya. Harap dukung kami dengan memberikan donasi atau membeli langganan hari ini.

Berikan donasi

Abstrak

Konsep Dunia RNA menyatakan bahwa ada periode waktu dalam sejarah Bumi primitif - sekitar 4 miliar tahun yang lalu - ketika zat hidup utama adalah RNA atau sesuatu yang serupa secara kimiawi. Dalam 50 tahun terakhir, ide ini telah berubah dari spekulasi menjadi ide yang berlaku. Dalam Tinjauan ini, kami merangkum logika kunci di balik Dunia RNA dan menjelaskan beberapa kemajuan terbaru yang paling penting yang telah dibuat untuk mendukung dan memperluas logika ini. Kami juga membahas cara kerja sama molekuler yang melibatkan RNA akan memfasilitasi kemunculan dan evolusi awal kehidupan. Masa depan penelitian RNA World seharusnya sangat dinamis.


Diterbitkan oleh Royal Society di bawah ketentuan Lisensi Atribusi Creative Commons http://creativecommons.org/licenses/by/4.0/, yang mengizinkan penggunaan tidak terbatas, asalkan penulis dan sumber asli dicantumkan.

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Kasus sulit tentang asal usul kehidupan hanya-RNA

Hipotesis dunia RNA mungkin merupakan model yang paling banyak dipelajari untuk kemunculan kehidupan di Bumi. Meskipun banyak bukti yang mendukung gagasan bahwa RNA mampu memulai replikasi diri autocatalytic dan dengan demikian memulai munculnya kehidupan, kelemahan yang tampaknya tidak dapat diatasi dalam teori juga telah disorot. Masalah-masalah ini dapat diatasi dengan pendekatan eksperimental baru, termasuk lingkungan di luar keseimbangan, dan eksplorasi ko-evolusi awal RNA dan biomolekul kunci lainnya seperti peptida dan DNA, yang mungkin diperlukan untuk mengurangi kekurangan RNA- hanya sistem.

Dugaan bahwa kehidupan di Bumi berevolusi dari 'Dunia RNA' tetap menjadi salah satu hipotesis paling populer untuk abiogenesis, bahkan 60 tahun setelah Alex Rich pertama kali mengajukan gagasan itu [1]. Untuk beberapa, bukti berdasarkan fosil molekuler di mana-mana dan keanggunan gagasan bahwa RNA pernah memiliki peran ganda sebagai pembawa informasi dan katalis prebiotik memberikan dukungan yang luar biasa untuk teori tersebut. Namun demikian, keraguan tetap ada seputar evolusi kimia dunia RNA, yang skenario klasiknya didasarkan pada urutan temporal pembentukan nukleotida, polimerisasi/replikasi bebas enzim, rekombinasi, enkapsulasi dalam vesikel lipid (atau kompartemen lain), evolusi ribozim dan akhirnya inovasi kode genetik dan terjemahannya (Gambar 1) [2,3]. Kritik umum adalah bahwa RNA terlalu kompleks untuk muncul de novo dalam lingkungan prebiotik, bahwa katalisis adalah sifat RNA yang relatif jarang dan membutuhkan untaian panjang yang tidak masuk akal, bahwa repertoar katalitik RNA terlalu terbatas dan sulit untuk membayangkan skenario di mana prekursor dan bahan baku terjadi pada konsentrasi yang cukup untuk memungkinkan replikasi dan evolusi [4].

Representasi skema dari hipotesis dunia RNA klasik.

Awalnya, sintesis dan polimerisasi acak nukleotida menghasilkan kumpulan oligomer asam nukleat, di mana replikasi non-enzimatik yang diarahkan template dapat terjadi. Reaksi rekombinasi menghasilkan generasi oligomer yang lebih panjang. Baik oligomer panjang dan pendek dapat melipat menjadi struktur dengan kompleksitas yang berbeda-beda, menghasilkan munculnya ribozim fungsional. Ketika kompleksitas meningkat, RNA replikase pertama muncul, dan enkapsulasi menghasilkan sel proto dengan identitas genetik berbeda yang mampu berevolusi. Pada kenyataannya, kemungkinan banyak proses terjadi secara paralel, bukan secara bertahap, dan enkapsulasi mungkin terjadi pada tahap apa pun.

Awalnya, sintesis dan polimerisasi acak nukleotida menghasilkan kumpulan oligomer asam nukleat, di mana replikasi non-enzimatik yang diarahkan template dapat terjadi. Reaksi rekombinasi menghasilkan generasi oligomer yang lebih panjang. Baik oligomer panjang maupun pendek dapat melipat menjadi struktur dengan kompleksitas yang berbeda-beda, menghasilkan munculnya ribozim fungsional. Ketika kompleksitas meningkat, RNA replikase pertama muncul, dan enkapsulasi menghasilkan sel proto dengan identitas genetik berbeda yang mampu berevolusi. Pada kenyataannya, kemungkinan banyak proses terjadi secara paralel, bukan secara bertahap, dan enkapsulasi mungkin terjadi pada tahap apa pun.

Terobosan dalam kimia prebiotik menunjukkan bagaimana blok bangunan penting RNA (dan biomolekul lainnya) mungkin telah terbentuk di bawah skenario primordial yang berbeda mengatasi banyak kekhawatiran tentang masuk akal RNA atau munculnya asam nukleat terkait di dunia prebiotik [5-9]. Similarly, demonstrations of enzyme-free polymerisation and copying of nucleic acids from activated building blocks [10–13] and the innate potential of random RNA strands to recombine and ligate show that the emergence of longer RNA strands capable of catalysis is, in principle, feasible [14–16]. NS in vitro selection of ribozymes has over the years revealed the impressive catalytic repertoire of nucleic acids, despite their conformal and sequence-based limitations compared with proteins [17]. RNA is particularly adept at manipulations of its own phosphate backbone — precisely the chemistry needed to catalyse self-replication.

Despite these rebuttals, it has not yet been possible to demonstrate robust and continuous RNA self-replication from a realistic feedstock (i.e. activated mono- or short mixed-sequence oligonucleotides). Major obstacles for RNA copying such as efficiency, regiospecificity and fidelity and are discussed elsewhere [18,19] but are mostly true for both non-enzymatic and enzymatic scenarios. The ever-looming strand dissociation problem is of particular concern (Figure 2). The high melting temperature (TM) of long RNA duplexes, such as those that arise from template-directed replication, results in the formation of dead-end duplex complexes in the absence of highly evolved helicases. When complementary RNA strands are separated, for example, by heat denaturation, reannealing occurs orders of magnitudes faster than known copying reactions [18].

A schematic illustrating nucleic acid replication and the strand separation problem.

Template copying, both enzymatic and non-enzymatic, is well established. However, the melting temperature (TM) of the resulting nucleic acid duplex is typically high, and as such, strand dissociation unfavourable and replication cycles are strongly inhibited. Possible solutions include lowering duplex TM by introducing backbone heterogeneity or non-equilibrium conditions such as fluctuations in temperature (T), concentration (C), ionic strength/divalent ion concentration (Saya), pH or viscosity (η).

Template copying, both enzymatic and non-enzymatic, is well established. However, the melting temperature (TM) of the resulting nucleic acid duplex is typically high, and as such, strand dissociation unfavourable and replication cycles are strongly inhibited. Possible solutions include lowering duplex TM by introducing backbone heterogeneity or non-equilibrium conditions such as fluctuations in temperature (T), concentration (C), ionic strength/divalent ion concentration (Saya), pH or viscosity (η).

In the case of ribozymes, only ‘simple’ ligation or recombination-based RNA replication from defined oligonucleotides has been demonstrated [20–23]. Such systems have only a limited ability to transmit heritable information and so are not capable of open-ended evolution — the ability to indefinitely increase in complexity like living systems [24]. Open-ended evolution requires that a replicase must at least be able to efficiently copy generic sequences longer than that required to encode its own function. This topic has been reviewed in detail elsewhere [24,25].

The search for an RNA replicase ribozyme, a cornerstone of the RNA world hypothesis, is largely founded on improvements of the scaffold of the R18 RNA polymerase ribozyme, which itself is an optimised version of the complex class I ligase ribozyme [26]. The discovery of the class 1 ligase, which is capable of ligating RNA with higher efficiency and better turnover than most ribozymes, was perhaps a lucky coincidence (or misfortune, if better ribozymes were missed), and can optimistically be expected to occur on average every 1 in 2000 selection experiments [27]. Considering this, it is truly astonishing how far this single ribozyme family has been developed. Initially capable of copying only very simple templates [27], variants of the polymerase are now able to copy complex templates [28,29], including the synthesis of an entire catalytic domain of a polymerase itself from trinucleotides [30], achieved through copying and subsequent ligation of fragments albeit with multiple human interventions. The much anticipated ‘riboPCR’, the amplification of RNA sequences in a ribozyme-catalysed polymerase chain-like reaction, has so far only been successful for very short primer dimers, which can be melted rapidly at relatively low temperatures, therefore minimising temperature-induced RNA hydrolysis [29]. The apparent limitations of riboPCR with respect to amplification of long strands complicate self-replication scenarios, although schemes evoking the asymmetric replication of short RNAs (where ‘antisense’ strands are produced in excess over coding ‘sense’ strands) followed by ligation or recombination into an active replicase could still provide an elegant solution to the problem [31,32].

RNA is capable of this process but more time is needed to identify either conditions or replicators of sufficient complexity that are able to solve the various problems associated with protein-free RNA replication.

RNA in isolation (including ribozymes) is simply not sufficient to catalyse its own replication, and substantial help from either other molecules or the environment is essential.

RNA replication was never really central during early molecular evolution but rather the late result of a (crudely) replicating non-enzymatic metabolism [33–37] or an early ‘polypeptide first’ world [38–40]. We will not discuss the merits of these scenarios here, but believe it is crucial to test and challenge the predictions made by these alternative models experimentally.

To identify suitable conditions for such an in-laboratory origin, a ‘flexible’ approach is probably the best choice in light of the large number of possible geochemical conditions that have been proposed to host the emergence of life [46]. In other words, it is most sensible to perform key experiments under relaxed but plausible experimental boundary conditions instead of trying to implement strict restraints based on educated guesses about a specific prebiotic environment. Once a set of experimental conditions that can sustain certain crucial reactions such as RNA synthesis, building block activation and self-replication have been identified, it will help to pinpoint plausible geochemical scenarios automatically. There are several examples of such problem-oriented approaches, e.g. tackling the strand inhibition problem during the replication of long RNAs using viscous solvents and temperature oscillations [47], overcoming low substrate concentrations and the fragility of RNA by working under frozen conditions [48,49] or implementation of scenarios enabling multistep, uninterrupted synthesis of key building blocks of nucleotide synthesis [50] or nucleotides themselves [16]. In addition, combining typical model RNA world reactions with non-equilibrium settings based upon thermal gradients shows great promise [51]. For example, gas bubbles in combination with thermal gradients cause dissolved materials to cycle between dry and wet states and enable the key steps of precursor/oligonucleotide accumulation and RNA phosphorylation, while drastically increasing ribozyme activity and facilitating RNA encapsulation into vesicle aggregates [52]. Oscillating salt concentrations in such environments cause local melting of nucleic acid duplexes up to 20°C lower than the TM, which could provide an environmental route to overcoming the strand dissociation problem [53]. It remains to be seen if such environments can eventually support coupled cycles of RNA activation, replication and encapsulation under continuous conditions.

Similar combined efforts will also be necessary if RNA alone is insufficient to drive continuous self-replication and evolution. In this case, it may be necessary to diversify the pool of feedstock molecules by taking into account the chemical and conformational heterogeneities found in many experimental scenarios. For example, nucleic acid polymers with non-inheritable backbone heterogeneities (e.g. 2′–5′ versus 3′–5′ backbone heterogeneity for RNA [54] or mixed nucleotide backbones formed from RNA, DNA or other nucleic acid types [55]) have fascinating properties. In particular, some chimeric backbones decrease duplex stabilities, which could help to mitigate the strand dissociation problem [56]. Such a ‘mixed’ scenario seems plausible in view of the prebiotic clutter [57]. Recent synthesis strategies coming from different laboratories have found strong evidence that RNA and DNA could have arisen from the same set of precursor molecules [9,58], and ribozymes that can read and write both nucleotide backbone chemistries have already been found [59]. Even though heterogeneous nucleic acids pose a general problem for hereditability of genetic information, such chimaeras could have played an important role as non-genetic catalysts similar to modern proteins. Exploring such heterogeneous scenarios poses major experimental challenges, as many of the standard tools used to study RNA, particularly reverse transcription and (deep) sequencing, are harder or impossible with mixed backbone chemistries. Nevertheless, it remains important to investigate these scenarios and, if necessary, develop new molecular biological tools that can cope with non-homogeneous nucleic acid backbones [60].

Plausible help for RNA might also come from primitive polypeptides (thoroughly discussed elsewhere [61]) Nearly, all ribozymes found in extant biology are associated with proteins that help them to carry out their function under intracellular conditions. These ribonucleoprotein complexes are thought to be remnants of an ancient biology where polypeptides could have supported folding and substrate binding of catalytic RNAs [62,63]. Before the advent of translation, these peptide cofactors would have been very simple or even comprised of a pool of random peptides with sequence biases [64]. As such, they would probably not have been initially capable of precise functionalities requiring a well-defined active site (although there might have been some notable exceptions [65]). Even such simple peptides could have been crucial for RNA protection during non-enzymatic replication [18] and during ribozyme-catalysed RNA copying [66]. It is tempting to speculate that peptides might have also granted ancient ‘ribonucleopeptide RNA replicases’ improved non-specific affinity to their substrates (i.e. a primer-template duplex), which is required for processivity but difficult to achieve with the polyanionic phosphate backbone of RNA alone. An advantage of this hypothesis is that an early co-evolution of RNA and peptides makes the transition to protein-dominated biology seem more plausible. Moreover, an early cooperation between RNA and peptides might also provide an elegant route to the formation of the first protocells before the advent of membrane-bound compartments [67]. As with nucleic acid heterogeneity, the inclusion of peptides represents an enormous analytical and experimental challenge, which will only be addressed by close collaboration between multiple disciplines within the origin of life field.

There remains the hope for origin of life scenarios where RNA plays a major role as an information carrier and catalyst. New experimental approaches using out-of-equilibrium settings could finally result in genuine RNA-based self-replicating systems capable of open-ended evolution. More complex scenarios involving RNA, DNA, peptides, simpler polynucleotides, chimeric intermediates or other yet unknown helper molecules may also be required, which will complicate the analytical understanding of the model systems and may ultimately render the term ‘RNA world’ in its traditional sense obsolete.


3. HASIL

Our experimental results indicate that enhanced RNA cleavage occurs due to the presence of metals (i.e., metal-catalyzed hydrolysis) in nearly all pH conditions (Figure 4, Table 1). However, at pH 3.2, increasing metal concentration decreases the rate of degradation (Figure 4). Catalysis at pH 3.2 is best mitigated by Mg 2+ at 50 mM (kobs(h -1 ) = 1.28 x 10 –2 ) followed by Fe 2+ at 50 mM (kobs(h -1 ) = 2.47 x 10 –2 ) then Mn 2+ at 50 mM (kobs(h -1 ) = 2.57 x 10 –2 ) relative to the negative control (kobs(h -1 ) = 8.06 x 10 –2 ) (Figure 4, Table 1). Between pH 5.4 and 8, RNA incubations containing Mg 2+ are generally more stable than those containing Fe 2+ or Mn 2+ (Figure 4, Table 1). This preference is most apparent in saturation curves fitted to a one-site binding model which indicates a stability optimum at pH 5.4 where the maximum rate of RNA cleavage in the presence of Mg 2+ (Bmaksimal(h -1 ) = 0.95 x 10 –2 ) is notably lower than for Fe 2+ (Bmaksimal(h -1 ) = 7.1 x 10 –2 ) (Figure 5, Table 2). Trends for Mn 2+ solutions are quantitatively similar to Fe 2+ between pH 3.2 and 8 (Figure 4, Table 1). At pH 9, we record the most rapid metal-catalyzed hydrolysis rates in our experiments. One-site binding models show that Fe 2+ (Bmaksimal(h -1 ) = 47.4 x 10 –2 ) is more stable than Mg 2+ (Bmaksimal(h -1 ) = 96.1 x 10 –2 ) although we observed Fe 2+ (and Mn 2+ ) precipitate from solution (Figure 5, Table 2). Results for the basalt analog solutions tend toward less overall metal-catalyzed hydrolysis in Mg 2+ -rich solutions (e.g., forsteritic) over Fe 2+ -rich solutions (e.g., fayalitic) (Figure 6).

Logam pH 3.2 pH 5.4 pH 6.7 pH 8 pH 9
kobs (h −1 ) (10 –2 ) SEM (10 –3 ) T1/2 (H) kobs (h −1 ) (10 –2 ) SEM (10 –3 ) T1/2 (H) kobs (h −1 ) (10 –2 ) SEM (10 –3 ) T1/2 (H) kobs (h −1 ) (10 –2 ) SEM (10 –3 ) T1/2 (H) kobs (h −1 ) (10 –2 ) SEM (10 –3 ) T1/2 (H)
[Fe 2+ ]
50 mM 2.47 1.40 28 5.07 1.70 14 24.1 14.5 3 30.0 6.10 2 28.9 13.2 2
25 mM 3.41 0.70 20 4.26 0.50 16 16.5 1.30 4 27.7 12.6 3 13.3 2.65 5
10 mM 4.49 3.05 15 2.58 1.85 27 4.40 3.65 16 14.1 13.8 5 12.1 5.50 6
5 mM 4.24 2.55 16 1.44 0.95 48 2.26 2.75 31 6.76 11.3 10 7.48 1.20 9
2.5 mM 4.17 1.10 17 0.54 0.25 130 0.74 3.80 94 0.65 0.25 107 5.40 7.00 13
[Mg 2+ ]
50 mM 1.28 0.50 54 0.75 0.70 92 7.42 3.75 9 6.76 0.30 10 62.3 11.3 1
25 mM 1.97 0.65 35 0.92 0.05 76 5.61 1.45 12 4.41 3.00 16 44.9 25.1 2
10 mM 2.43 2.05 29 0.73 0.10 95 3.31 1.30 21 2.16 0.70 32 29.0 31.2 2
5 mM 2.77 0.40 25 0.63 0.40 110 2.46 1.45 28 1.85 6.10 37 13.4 13.9 5
2.5 mM 3.40 2.15 20 0.20 0.10 347 1.44 3.20 48 1.06 4.10 65 5.32 0.60 13
[Mn 2+ ]
50 mM 2.57 0.05 27 5.22 0.35 13 28.6 25.5 2 82.7 20.7 1 87.5 29.9 1
25 mM 2.03 1.70 34 5.68 0.80 12 12.2 24.1 6 58.9 9.05 1 127 62.1 1
10 mM 4.24 2.00 16 2.64 2.90 26 6.29 18.0 11 25.4 3.10 3 104 27.9 1
5 mM 4.22 2.28 16 2.07 3.10 33 2.95 6.95 24 14.1 11.0 5 92.2 4.65 1
2.5 mM 7.03 3.10 10 0.53 1.10 131 0.72 0.25 97 4.20 3.00 17 6.04 12.9 11
Basalt Analogs [Mg 2+ :Fe 2+ ]
80:20 2.05 0.65 34 0.78 0.20 89 2.35 1.50 29 8.20 3.70 8 19.9 30.3 3
50:50 2.68 0.35 26 2.29 3.95 30 11.1 1.75 6 20.4 6.05 3 22.8 25.4 3
20:80 2.20 3.30 32 2.70 2.40 26 20.3 3.85 3 17.7 9.30 4 19.7 11.2 4
Negative Control
0 mM 8.06 4.85 9 0.16 0.70 433 0.20 0.15 355 1.82 1.30 38 0.81 1.10 86
Logam pH Bmaksimal (h −1 ) (10 –2 ) SEM (10 –3 ) KD SEM
[Fe 2+ ] 5.4 7.14 4.46 18.8 2.74
6.7 90.9 469 134 89.7
8 47.3 73.3 24.1 8.03
9 47.4 147 38.7 22.1
[Mg 2+ ] 5.4 0.95 0.99 3.97 1.59
6.7 9.86 6.47 17.7 2.77
8 11.7 21.1 37.8 12.7
9 96.1 86.2 27.3 5.06


20.5: Origins of Life Chemistries in an RNA World - Biology

The RNA world hypothesis simplifies the complex biopolymer networks underlining the informational and metabolic needs of living systems to a single biopolymer scaffold. This simplification requires abiotic reaction cascades for the construction of RNA, and this chemistry remains the subject of active research. Here, we explore a complementary approach involving the design of dynamic peptide networks capable of amplifying encoded chemical information and setting the stage for mutualistic associations with RNA. Peptide conformational networks are known to be capable of evolution in disease states and of co-opting metal ions, aromatic heterocycles and lipids to extend their emergent behaviours. The coexistence and association of dynamic peptide and RNA networks appear to have driven the emergence of higher-order informational systems in biology that are not available to either scaffold independently, and such mutualistic interdependence poses critical questions regarding the search for life across our Solar System and beyond.

This article is part of the themed issue 'Reconceptualizing the origins of life'.


My Grandfather's Ax

Scientists have long considered alternative chemistries for RNA, synthesizing molecules with alien components that have even found their way into biotechnology applications. Nicholas Hud, a chemist at the Georgia Institute of Technology, takes a broader approach — perhaps every component was different and each changed over time. To explain, Hud employs an ancient Greek paradox called “my grandfather’s ax”: If your father replaced the handle and you replaced the blade, the result would be an entirely new ax. “Everyone accepts that DNA comes from RNA and DNA is harder to make than RNA,” Hud said. “So if you’re willing to accept that DNA evolved from RNA, then why not that RNA is product of evolution of proto-RNA?”

An alternative hypothesis is that RNA as we know it has undergone substantial chemical and biological evolution. “The origins of life and the origin of the genetic code are no longer synonymous,” said Antonio Lazcano, a biologist at the National Autonomous University of Mexico in Mexico City and former president of the International Society for the Study of the Origin of Life who was not involved in Hud’s study. “You can have a significant part of the genetic code that will be the outcome of biological evolution and a largely undescribed stage of chemical evolution.”

Scientists have been examining molecules with alternative bases or sugars almost since RNA was proposed as the first biological molecule in the 1960s. But this approach creates an overwhelming set of possible permutations, as each of the three components — sugar, phosphate and base — has numerous potential replacements. “The chemical space becomes enormous,” Hud said. “It’s a really big task to find out what came first.”

Hud’s team started with the bases, looking for candidates that could form something like the traditional base pairs of RNA and DNA, in which certain bases seek each other out like lost lovers in RNA, adenine binds only with uracil and guanine with cytosine. It’s this pairing that enables the molecules’ unique capacity to store information. Each molecule acts as a template for the next generation, creating a sort of mirror image of its predecessor.

But Hud also wanted base pairs that, unlike traditional bases, could spontaneously assemble into long polymers. “If you have a complex mixture of thousands of molecules, the chemistry relies on what reacts the fastest,” Hud said. “The molecules need to organize themselves.”

Rather than limit themselves to the four bases used in RNA, the members of Hud’s team considered a library of roughly 100 structurally similar molecules, including only those that were predicted to have existed on prebiotic Earth or in meteorites, which may have carried with them essential components of life. “We’re foolish if we don't think about this: either why nature picked these four or what nature did before picking these four,” Freeland said.


RNA-DNA World Circumvents RNA World Sticking Point

Even those who doubt the RNA World hypothesis may be hard-pressed to argue against it. Consider the predicament faced by a team of scientists at Scripps Research. They suspected that RNA was a poor candidate for life chemistry’s original self-replicating molecule. RNA, they believed, was simply too sticky. That is, they thought that complementary RNA strands in the primordial ooze would have had a hard time separating because strand-separating enzymes would not have existed yet.

And yet these same scientists had found that an organic compound called diamidophosphate (DAP)—a compound that could have been present in the ooze—could have played a crucial role in modifying ribonucleosides and stringing them together into the first RNA strands. This finding didn’t necessarily favor the RNA World hypothesis. In fact, it was, potentially, compatible with the RNA-DNA World hypothesis, which the Scripps Research team found plausible. But the Scripps Research team hadn’t shown that DAP could do for DNA what it did for RNA.

This deficiency, if it may be called that, has been rectified. In the chemistry journal Angewandte Chemie, the Scripps Research scientists reported that DAP, together with 2‐aminoimidazole, can (amido)phosphorylate and oligomerize deoxynucleosides to form DNA, and do so under conditions similar to those of ribonucleosides.

The details appeared in a paper titled “Prebiotic Phosphorylation and Concomitant Oligomerization of Deoxynucleosides to form DNA.” The paper’s authors say that their new finding is the latest in a series of recent discoveries pointing to the possibility that DNA and its close chemical cousin RNA arose together as products of similar chemical reactions, and that the first self-replicating molecules—the first life forms on Earth—were mixes of the two.

“Recent demonstrations of RNA‐DNA chimeras enabling RNA and DNA replication, coupled with prebiotic co‐synthesis of deoxyribo‐ and ribo‐nucleotides, have resurrected the hypothesis of co‐emergence of RNA and DNA,” the article’s authors wrote. “Combined with previous observations of DAP mediated chemistries and the constructive role of RDNA chimeras, the results reported here help set the stage for systematic investigation of a systems chemistry approach of RNA‐DNA coevolution.”

“The pyrimidine 5’‐O‐amidophosphates are formed in good (≈60%) yields,” the authors detailed. “Intriguingly, the presence of pyrimidine nucleos(t)ides increased the yields of purine‐deoxynucleotides (≈20%). Concomitantly, oligomerization (≈18–31%) is observed with predominantly 3′,5′‐phosphodiester DNA linkages, and some (<5%) pyrophosphates.”

Although the new work may lead to new practical applications in chemistry and biology, its main significance is that it addresses the age-old question of how life on Earth first arose. In particular, it paves the way for more extensive studies of how self-replicating DNA-RNA mixes could have evolved and spread on the primordial Earth and ultimately seeded the more mature biology of modern organisms.

“This finding is an important step toward the development of a detailed chemical model of how the first life forms originated on Earth,” said Ramanarayanan Krishnamurthy, PhD, the article’s senior author and an associate professor of chemistry at Scripps Research.

The finding also nudges the field of origin-of-life chemistry away from the hypothesis that has dominated it in recent decades: The RNA World hypothesis posits that the first replicators were RNA-based, and that DNA arose only later as a product of RNA life forms.

A strand of RNA can attract other individual RNA building blocks, which stick to it to form a sort of mirror-image strand—each building block in the new strand binding to its complementary building block on the original, “template” strand. If the new strand can detach from the template strand, and, by the same process, start templating other new strands, then it has achieved the feat of self-replication that underlies life.

But while RNA strands may be good at templating complementary strands, they are not so good at separating from these strands. Modern organisms make enzymes that can force twinned strands of RNA—or DNA—to go their separate ways, thus enabling replication, but it is unclear how this could have been done in a world where enzymes didn’t yet exist.

Krishnamurthy and colleagues have shown in recent studies that “chimeric” molecular strands that are part DNA and part RNA may have been able to get around this problem, because they can template complementary strands in a less-sticky way that permits them to separate relatively easily.

The chemists also have shown in widely cited papers in the past few years that the simple ribonucleoside and deoxynucleoside building blocks, of RNA and DNA respectively, could have arisen under very similar chemical conditions on the early Earth.

This line of thinking is encouraged by the current study, which suggests that primordial DAP could have been as helpful to DNA as it is to RNA.

“We found, to our surprise, that using DAP to react with deoxynucleosides works better when the deoxynucleosides are not all the same but are instead mixes of different DNA ‘letters’ such as A and T, or G and C, like real DNA,” said Eddy Jiménez, PhD, the study’s first author and a postdoctoral research associate in the Krishnamurthy lab.

“Now that we understand better how a primordial chemistry could have made the first RNAs and DNAs, we can start using it on mixes of ribonucleoside and deoxynucleoside building blocks to see what chimeric molecules are formed—and whether they can self-replicate and evolve,” Krishnamurthy asserted.

He added that the work may also have broad practical applications. The artificial synthesis of DNA and RNA—for example in the PCR technique that underlies COVID-19 tests—amounts to a vast global business but depends on enzymes that are relatively fragile and thus have many limitations. Robust, enzyme-free chemical methods for making DNA and RNA may end up being more attractive in many contexts, Krishnamurthy suggested.


'When chemistry became biology': looking for the origins of life in hot springs

Hot springs may have been the ‘spark’ that helped organic matter turn into life – these UNSW Sydney scientists have put this hypothesis to the test in New Zealand.

Hot springs in New Zealand took Dr Anna Wang and Mr Luke Steller a step closer to the complex geological processes that happened on early Earth. Image: ABC Catalyst.

50 years ago, a meteorite landed in Victoria carrying many of the building blocks for life, including amino acids, nucleobases and lipids. These organic molecules formed when compounds in stardust, which had collected on the meteorite, reacted under low temperatures and UV light as it passed through space.

Many astrobiologists think life on Earth could have been kickstarted when meteorites carrying similar organic matter fell to the planet around four billion years ago.

The big question is how this organic matter along with what was already on Earth – called prebiotic ‘soup’ – turned into life.

“We think hot springs on the Earth’s surface hold the answer,” says Mr Luke Steller, PhD candidate at UNSW’s Australian Centre for Astrobiology. “Their elevated temperature and exposure to the atmosphere allow for a unique process that underwater environments don’t offer.

“The cycle of dehydration (by evaporation) and rehydration (by splashing from geysers or pools) in hot springs allows small lipid bubbles called ‘vesicles’ to form around molecules.

“Vesicles containing the right genetic material could have conceivably been ‘protocells’ – the ancestors of modern living cells.”

Mr Steller is currently collaborating with Dr Anna Wang, Scientia Fellow in the School of Chemistry, to trace when – and how – chemistry became biology.

Late last year, Mr Steller and Dr Wang travelled to Rotorua in New Zealand with ABC Catalyst to recreate this protocell formation in a real hot spring environment. The Catalyst episode, ‘Asteroid Hunters’, airs tonight.

“Almost any sort of chemical reaction could happen in a hot spring,” says Dr Wang.

“If you combine that with the extra-terrestrial material bombarding the planet four billion years ago, they become the most chemically-exciting places on Earth.”

It starts with a bubble

Mr Luke Steller recreating protocell formation in the hot springs in Rotorua, New Zealand. Image: ABC Catalyst.

Vesicles, also known as lipid membranes, play a vital role in protecting the genetic molecules in our cells and, potentially, the ancestors to all cells.

“A bubble around some molecules is the first step towards an individual organism,” says Mr Steller. “This entity, a protocell, could be capable of competing with other protocells and start undergoing Darwinian evolution.

“Without a barrier, there is nothing to separate the genetic material from anything else – it would be dilute and part of a homogeneous soup.”

The researchers were inspired by the efforts of Prof David Deamer and Dr Bruce Damer from the University of California, Santa Cruz, to test vesicle formation in a real-world lab.

Mr Steller and Dr Wang prepared vials of lipids (fatty acids) like those found in meteorites and RNA – a nucleic acid essential for life. RNA is theorised to have been present in early Earth.

Combined with hot spring water (containing dissolved minerals and salts), this mixture is an example of a prebiotic soup that might have led to the first replicating cell.

“When we first mixed the prebiotic soup with the hot spring water and submerged the vials into a hot spring, the high temperatures dried out the ingredients,” says Mr Steller. “This process of drying down the lipids and RNA together ‘trapped’ the concentrated RNA between the lipid layers.”

When the soup was rehydrated – a process that occurs naturally in hot springs by splashing – the researchers saw vesicles containing concentrated RNA form.

“By having these wet-dry cycles, all the important organic molecules floating around gets crammed inside one little place. This can help the molecules interact and chemically react.

“Being compartmentalised, these vesicles suddenly have their own ‘identities’ and can start competing, increasing in complexity and evolving towards something life-like.”

Hot springs in Rotorua, New Zealand. Image: ABC Catalyst.

A messy laboratory

Hot springs take astrobiologists a step closer to the complex geological processes that happened on early Earth.

“Early Earth was a messy place,” says Mr Steller. “There were many different minerals and water chemistries present, and clays bubbling around in hot spring pools.

“There was a lot of splashing, lightning and different fluids and gases all getting churned up, boiled and mixed around.”

Travelling to Rotorua offered an opportunity for the researchers to ‘ground-proof’ experiments and show that concepts demonstrated in the lab are robust enough to stay true in messier environments.

“Conducting prebiotic experiments in clean glass test tubes doesn’t really represent what happened on early Earth,” says Mr Steller.

“While we can’t go back in time, we have geological evidence that hot springs were present on early Earth. In some ways, visiting hot springs feels like going back to the source.”

The building blocks of life

Dr Wang is fascinated by the first self-assembly step to life on Earth: where chemicals were able to come together and transition into biology.

She recently received a prestigious $1.7m international life science grant to create self-propagating synthetic cells.

“In origin of life studies, we ask questions like: ‘What physics were necessary for self-assembly?’, ‘What was the geological context that could have helped all those processes?’, and ‘What help did we get from outer space that could have helped catalyse this life?’

“All of these factors came together once – and it was so successful that it was able to persist through billions of years and evolve into all of life that we see today.

“There is shared chemistry to plants, viruses, bacteria, and us. Understanding how it all came about could help us build better microreactors for manufacturing biological goods, or to identify potential drug targets for disease.”

Mr Steller is part of a wider team at UNSW assisting NASA in understanding how life may have been preserved on other planets in our solar system.

“The origin of life is part of humanity's narrative,” he says.

“Learning more about it isn’t only beneficial for science, it’s helping us develop our understanding of who we are and our place in the universe.”


Tonton videonya: Back to the Moon Lecture 1: This Time to Stay? (Agustus 2022).