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1、合成生物學(xué)(Synthetic biology) (概念、原理、應(yīng)用),馬飛,人工染色體(技術(shù)),BAC(細(xì)菌人工染色體)：Bacteria 以細(xì)菌作為對象，將DNA片段與質(zhì)粒重組后轉(zhuǎn)入細(xì)菌中繁殖 YAC(酵母人工染色體)：Yeast 以酵母作為對象 PAC(噬菌體人工染色體)：Phagemid 以噬菌體作為對象 TAC(可轉(zhuǎn)化的細(xì)菌人工染色體) MAC(哺乳類人工染色體) ,合成生物學(xué)應(yīng)運(yùn)而生,Synthetic Biology,What is Synthetic Biology?,Taking an engineering approach to design and applying i

2、t to Biology 使用工程策略設(shè)計(jì)并應(yīng)用于生物學(xué),What is Synthetic Biology? 1. Biology 2. Chemistry 3. Engineering 4. Re-Writing,Biologists Chemists Engineers “Re-Writers”,“The code is 3.6 billion years old. Its time for a re-write.” -Tom Knight,Biology “Test models by building them”,合成生物學(xué),指人們將“基因”連接成網(wǎng)絡(luò)，讓細(xì)胞來完成設(shè)計(jì)人員設(shè)想的各種

3、任務(wù)。 例如把網(wǎng)絡(luò)同簡單的細(xì)胞相結(jié)合，可提高生物傳感性，幫助檢查人員確定地雷或生物武器的位置。 再如向網(wǎng)絡(luò)加入人體細(xì)胞，可以制成用于器官移植的完整器官。,人工合成脊髓灰白質(zhì)炎病毒cDNA,美國紐約大學(xué)Wimmer 實(shí)驗(yàn)室于2002年報(bào)道了化學(xué)合成 脊髓灰白質(zhì)炎病毒cDNA，并用RNA聚合酶將它轉(zhuǎn) 成有感染活力的病毒RNA。 開辟了利用已知基因組序列，不需要天然模板，從化合物單體合成感染性病毒的先河。,Wimmer從裝配平均長度為69 bp的寡核苷酸入手，結(jié)合了化學(xué)合成與無細(xì)胞體系的從頭合成，用了3 年時(shí)間完成了這個(gè)劃時(shí)代的工作。,Venter 實(shí)驗(yàn)室發(fā)展了合成基因組, X-174 噬菌體基因是

4、單鏈環(huán)狀 DNA，是歷史上第一個(gè)被純化的DNA 分子，也是第一個(gè)被測序的DNA分子。 X- 174 噬菌體對動(dòng)植物無害，是合適的合成研究對象。 美國Venter 實(shí)驗(yàn)室發(fā)展了合成基因組的工作， 該實(shí)驗(yàn)室只用兩周就合成了 X-174 噬菌體基因 (5,386bp) 。 Venter實(shí)驗(yàn)室的技術(shù)改進(jìn)主要有： (1)用凝膠來提純寡核苷酸以減少污染； (2) 嚴(yán)格控制退火連接溫度來防止與不正確的序列發(fā)生連 接； (3)采用聚合酶循環(huán)裝置來裝配連結(jié)產(chǎn)物。,合成生物學(xué)國際會(huì)議,2004 年6 月在美國麻省理工學(xué)院舉行了第一屆 合成生物學(xué)國際會(huì)議。 會(huì)上除討論了科學(xué)與技術(shù)問 題外，還討論了合成生物學(xué)當(dāng)前與將

5、來的生物學(xué)風(fēng)險(xiǎn)，有關(guān)倫理學(xué)問題，以及知識(shí)產(chǎn)權(quán)問題。 隨著這個(gè)領(lǐng)域的發(fā)展，對于合成生物學(xué)的安全性的考慮愈來愈多。 現(xiàn)在不僅通過合成生成病毒，而且已經(jīng)可以合成細(xì)菌。,合成生物學(xué)開辟了設(shè)計(jì)生命的前景,一方面有可能合成模仿生命物質(zhì)特點(diǎn)的人工化學(xué)系統(tǒng)；另一方面也可能重新設(shè)計(jì)微生物 如Keasling 實(shí)驗(yàn)室向大腸桿菌中導(dǎo)入青蒿與酵母的基因，使大腸桿菌能在調(diào)節(jié)下合成青蒿素，從而顯示了有效而價(jià)廉的治療瘧疾的前景 合成生物學(xué)今后將能生成自然界不存在的新的微生物。,應(yīng)用示例,Schultz 實(shí)驗(yàn)室研究向大腸桿菌蛋白質(zhì)生物合成裝置中添入新組份，使之能通過基因生成非天然的氨基酸，結(jié)果取得了成功。但是要在真核細(xì)胞做到

6、這一點(diǎn)還有難度。 2003年，Schultz 實(shí)驗(yàn)室報(bào)道了一種向酵母加 入非天然氨基酸密碼子的方法，成功地向蛋白質(zhì)中導(dǎo)入了5 種氨基酸。 目前，能摻入到蛋白質(zhì)的非天然氨基酸已有80多種。 今后將可以直接向蛋白質(zhì)導(dǎo)入順磁標(biāo)記、金屬結(jié)合、光敏異構(gòu)化等的氨基酸，促進(jìn)蛋白質(zhì)結(jié)構(gòu)與功能的研究。,應(yīng)用示例,Brenner 提出向細(xì)胞DNA中摻入天然不存在的堿基來發(fā)展人工遺傳系統(tǒng), 支持人工生命形式。 合成生物學(xué)也將對生命起源，其他生命形式的研究作出貢獻(xiàn)。,控制生命,目前，研究人員正在試圖控制細(xì)胞的行為，研制不同的基因線路即特別設(shè)計(jì)的、相互影響的基因。 波士頓大學(xué)生物醫(yī)學(xué)工程師科林斯已研制出一種“套環(huán)開關(guān)”

7、，所選擇的細(xì)胞功能可隨意開關(guān)。 加州大學(xué)生物學(xué)和物理學(xué)教授埃羅維茨等人研究出另外一種線路： 當(dāng)某種特殊蛋白質(zhì)含量發(fā)生變化時(shí)，細(xì)胞能在發(fā)光狀態(tài)和非發(fā)光狀態(tài)之間轉(zhuǎn)換，起到有機(jī)振蕩器的作用，打開了利用生物分子進(jìn)行計(jì)算的大門。,維斯和加州理工學(xué)院化學(xué)工程師阿諾爾一起，采用“定向進(jìn)化”的方法，精細(xì)調(diào)整研制線路，將基因網(wǎng)絡(luò)插入細(xì)胞內(nèi)，有選擇性地促進(jìn)細(xì)胞生長。,發(fā)展方向,維斯目前正在研究另外一群稱為“規(guī)則系統(tǒng)”的基因，他希望細(xì)菌能估計(jì)刺激物的距離，并根據(jù)距離的改變做出反應(yīng)。 該項(xiàng)研究可用來探測地雷位置(TNT：生物傳感器)。,維斯另一項(xiàng)大膽的計(jì)劃是為成年干細(xì)胞編程 促進(jìn)某些干細(xì)胞分裂成骨細(xì)胞、肌肉細(xì)胞或軟骨

8、細(xì)胞等，讓細(xì)胞去修補(bǔ)受損的心臟或生產(chǎn)出合成膝關(guān)節(jié)。 盡管該工作尚處初級(jí)階段，但卻是生物學(xué)調(diào)控領(lǐng)域中重要的進(jìn)展。,J. Craig Venter：基因組替換,成功利用基因組取代技術(shù)，將一種細(xì)菌改變?yōu)榱硪环N與之親緣關(guān)系較為緊密的另一細(xì)菌。這種由J. Craig Venter 進(jìn)行的 “移植(transplantation)”技術(shù)，有望將合成基因組插入細(xì)胞，用于生產(chǎn)合成生命。 用Mycoplasma mycoides的基因組取代與之關(guān)系密切的 Mycoplasma capricolum的基因組 C. Lartigue et al. “Genome transplantation in bacteri

9、a: Changing one species to another“ Science, June 28, 2007.,人類歷史上第一個(gè)人造染色體合成成功,美科學(xué)家稱“人造生命”技術(shù)已被掌握 最具爭議的美國著名科學(xué)家克雷格文特爾宣布，他的研究小組已經(jīng)合成出人類歷史上首個(gè)人造染色體，并有可能創(chuàng)造出首個(gè)永久性生命形式，以此作為應(yīng)對疾病和全球變暖的潛在手段。 該研究部分由美國能源部出資，希望藉此研制出新型環(huán)保燃料。由文特爾召集，諾貝爾醫(yī)學(xué)獎(jiǎng)獲得者漢密爾頓史密斯領(lǐng)導(dǎo)的研究小組在這方面已經(jīng)進(jìn)行了5年研究。 文特爾已用化學(xué)藥品在實(shí)驗(yàn)室中研制出一種合成染色體。,文特爾研究小組研制出的這種新型染色體即實(shí)驗(yàn)室合

10、成支原體(Mycoplasma laboratorium)，是一種經(jīng)過簡化拼接的生殖支原體(Mycoplasma genitalium)DNA序列，他們將這種合成支原體移植到活細(xì)胞中，使之在細(xì)胞中起主控作用，變換成一種新的染色體。 按照實(shí)驗(yàn)計(jì)劃，最終這個(gè)染色體將控制這個(gè)細(xì)胞并變成一個(gè)新的生命形式。 這種新單細(xì)胞生物體被命名為“合成器”，受381個(gè)基因控制，包含56萬個(gè)堿基對。這些基因是維持細(xì)菌生命所必備的，使它能夠攝食和繁殖。由于新的生物體是在現(xiàn)存生物體上搭建，其繁殖和新陳代謝仍然依賴原來生物體的胞內(nèi)機(jī)制。 從這一角度看，它并非完全意義上的新型生命形式。但這種給特定基因賦予特定任務(wù)的觀點(diǎn)已被眾

11、多生物學(xué)家廣泛接受。,“這是人類自然科學(xué)史上一次重大進(jìn)步，顯示人類正在從閱讀基因密碼走向有能力重新編寫密碼，這將賦予科學(xué)家新的能力，從事以前從未做過的研究。” 他希望這項(xiàng)突破有助于發(fā)展新能源，應(yīng)對氣候變化造成的負(fù)面影響。如創(chuàng)造出具有特殊功能的新微生物，可被用作替代石油和煤炭的綠色燃料，或用來幫助清除危險(xiǎn)化學(xué)物質(zhì)或輻射等；還可用來合成能吸收過多二氧化碳的細(xì)菌，為解決氣候變暖貢獻(xiàn)力量。,然而制造永久生命形式的前景極具爭議性，有可能激起道德、倫理等方面的激烈辯論。 加拿大生物倫理學(xué)組織ETC團(tuán)體主任帕特穆尼說，文特爾制造出了“一個(gè)基架，在此基架上人們幾乎可以制造出任何東西”，“它可以用于研究新型藥物

12、，也可以用于對人類產(chǎn)生巨大威脅的生物武器”。,2009：Venter：Science,把蕈狀支原體的基因組加以改造，使它能夠終移植到山羊支原體內(nèi)，形成了一個(gè)新的蕈狀支原體細(xì)胞。 這也是今年這篇科研論文的雛形，在國外的科學(xué)媒體上曾經(jīng)引發(fā)熱烈的討論。,2010年的重要大事：“人造生命”誕生,John Craig Venter攪亂了(生命)科學(xué)界,用化學(xué)合成的基因組構(gòu)建一個(gè)細(xì)菌細(xì)胞,Venter的實(shí)驗(yàn) http:/www.science- 支原體是已知的可以自由生活的最小生物,也是最小的原核細(xì)胞。 是一種原核微生物, 內(nèi)部結(jié)構(gòu)很簡單，基因組僅有一百多萬堿基對，遠(yuǎn)小于真核生物基因組十億級(jí)的堿基數(shù)量，這

13、也是Venter選擇操作它的原因。 Venter早在1995年就對生殖支原體測序，并致力于研究維持自由生命的最小基因組。 在2008年，Venter的團(tuán)隊(duì)合成了長達(dá)59萬堿基對的生殖支原體基因組。 此后，他們選擇生長速度更快的蕈狀支原體來做實(shí)驗(yàn)。 如果僅僅從技術(shù)上來說，Venter做了一個(gè)無懈可擊的實(shí)驗(yàn)，“人造生命”思路和流程都做得無懈可擊。,三個(gè)步驟：合成、組裝和移植,合成 ： 蕈狀支原體的基因組是一條大片段的DNA分子，序列是A、T、G、C四種脫氧核糖核苷酸的排列組合。 通過實(shí)驗(yàn)確定維持其生命周期的最小基因組，并加上4個(gè)“水印基因”作為標(biāo)記。 用計(jì)算機(jī)精確計(jì)算需要合成DNA分子序列，并用化

14、學(xué)方法合成A、T、G、C堿基，并使其按所要求序列延伸。 這是它被稱為“人造生命”或者“化學(xué)合成”的關(guān)鍵。 Venter用化學(xué)方法合成了一千多個(gè)約1kb的DNA片段，作為這次組裝的基本材料。,組裝： 因?yàn)楹铣缮飳W(xué)技術(shù)上的局限，不能直接合成上萬堿基對的DNA大分子，所以Venter等人巧妙地借助啤酒酵母和大腸桿菌的幫助，把1Kb的DNA分子有序準(zhǔn)確的連成超過1000kb的片段。 移植： Venter等把這個(gè)合成基因組移植到不含限制性酶切系統(tǒng)的山羊支原體中，基因組能使用后者的酶系統(tǒng)進(jìn)行自我復(fù)制，經(jīng)過多代繁殖后，長成的菌落已經(jīng)純粹由蕈狀支原體組成。,Venter：“創(chuàng)造了一個(gè)計(jì)算機(jī)為父母的生命”,J

15、CVI：將8個(gè)由60個(gè)核苷酸組成的DNA片段， 首次人工合成實(shí)驗(yàn)老鼠的線粒體基因組,使用8個(gè)只含有60個(gè)核苷酸的DNA片段，讓它們同酶和化學(xué)試劑的混合物相結(jié)合，在50下孵化1小時(shí)，5天內(nèi)合成出了實(shí)驗(yàn)鼠的線粒體基因組，得到的基因組能夠糾正具有線粒體缺陷的細(xì)胞內(nèi)的異常。,用途：生物能源、生物除污,Venter下一步的計(jì)劃就是合成某種海藻基因組，這種新型海藻可以通過光合作用把空氣中的二氧化碳轉(zhuǎn)化成汽油或者柴油等清潔能源，從而有效解決目前的氣候變化和能源危機(jī)。 疫苗、藥物、生物能源、生物除污等,What is Synthetic Biology?,從原理角度來看,Synthetic Biology,U

16、ndergraduates in Synthetic Bio.,international Genetically Engineered Machines,http:/parts.mit.edu/registry/index.php/Main_Page,Lego Assembly for DNA Parts,http:/parts.mit.edu/registry/index.php/Assembly:Standard_assembly,Self-organized Pattern Formation,What can you make in SB?,Arsenic Detector,膿毒癥,

17、砷,Modifying life,Biotechnology Techniques that use living organisms or parts of organisms to produce a variety of products (from medicines to industrial enzymes) Genetic Engineering Introduction of genetic changes (add, modify, delete) into an organism to achieve some goal Synthetic Biology Create n

18、ovel biological functions and tools by modifying or integrating well-characterized biological components (i.e. genes, promoters) into higher order genetic networks,Synthetic Biology History,1970 First gene synthesized from scratch (alanine tRNA) 1978 Nobel prize awarded to Werner Arber, Daniel Natha

19、ns and Hamilton Smith for the discovery of restriction enzymes 1978 (Boyer at UCSF) A synthetic version of the human insulin gene was constructed and inserted into the bacterium E. coli. 1980 Kary Mullis invents PCR 1991 Affymetrix chip-based oligonucleotide synthesis 2003 First iGEM competition, cr

20、eation of standardized parts libraries at MIT,Biotechnology 1.0 Research Workflow,1. Concept,2. Collect DNA fragments (PCR, isolation, vendors, etc),6. Transform,7. Test,3. Bench work,5. Verify DNA,4. Sequence,DNA synthesis costs are dropping,For example the bacteria Mycoplasma genitalium has the sm

21、allest genome out of all living cells: 517 genes over 580 kb. Minimal costs of oligo creation (not including error-checking): Mid 1990s: $1/bp = $580,000 Circa 2000: $0.35/bp = $203,000 2006: $0.11/bp = $63,800 Ambitious prediction of not-too-distant future (Church et al, 2004): $0.00005/bp = $29,Sy

22、nthesis lengths are increasing,Commercial DNA Synthesis Companies,Data Source: Rob Carlson, U of W, Seattle,Bioneer South Korea,Cinnagen Tehran, Iran,Takara Biosciences Dalian, China,Inqaba Biotec Pretoria, South Africa,Fermentas Vilnius, Lithuania,Bio S&T, Alpha DNA, Biocorp Montreal, Canada,GENEAR

23、T Regensberg, Germany,MWG Bangalore, India,Zelinsky Institute Moscow, Russia,ScinoPharm Shan-hua, Taiwan,Genosphere Paris, France,Biolegio Malden, Netherlands,Ambion Austin, Texas,Biosearch Novato, California,Bio-Synthesis Lewisville, Texas,Chemgenes Wilmington, Mass.,BioSpring Frankfurt am Main, Ge

24、rmany,Biosource Camarillo, CA,Dharmacon Lafaette, Co.,CyberGene AB Novum, Sweden,Cortec DNA Kingston, Ontario, CA,Eurogentec Belgium, U.K.,DNA Technology Aarhus, Denmark,Genemed Synthesis S. San Francisco, CA,DNA 2.0 Menlo Park, CA,Metabion Munich, Germany,Microsynth Balgach, Switzerland,Japan Bio S

25、ervices Japan,Blue Heron Biotechnology Bothell, WA,Geneworks Adelaide, Australia,Imperial Bio-Medic Chandigarh, India,Bioserve Biotechnologies Hyderabad, India,Genelink Hawthorne, NY.,DNA Synthesis (Caruthers method),Error Rate: 1% 0.9950 = 0.60 300 seconds per step,Microarray oligonucleotide synthe

26、sis,The power of parallelism,Chip-based versus linear synthesis,Oligonucleotides synthesized,Single-stranded fragments of 50-90 nucleotides 3-overlapping next fragment by 17 nucleotides (Tm calculated 52-56),Steps 1 to 5 involve multiple rounds of PCR (heating to 95, cooling to 56, and PCR at 72). N

27、umber of rounds depends on number of fragments. Carried out by PCR machine.,Final step of amplification of complete gene driven by use of excess of terminal single-stranded fragments,PCR-based oligo ligation,In theory, the scale of synthesis is unlimited,Biotechnology 2.0 Research Workflow,1. Concep

28、t,2. Design / debug/ test,4. Design oligos,6. Transform,7. Test,5. Synthesize DNA,3. Run code,What are the implications of DNA synthesis capacity + freedom of information?,The problem: “Dual Use” Research,Dual use research includes life sciences research: With legitimate scientific purpose That may

29、be misused to pose a biologic threat to public health and/or national security.,How easy is it to get this technology?,What can we do?,Number of Individuals,Individuals Intent,honorable,dishonorable,Bin Laden Genetics, Inc.,Disgruntled Researcher,Garage Bio-Hacker,Basic Researcher,Risk spectrum,Basi

30、c logic circuits,Borrowing from electrical engineering,Protein Expression Basics,RNA polymerase binds to promoter RNAP transcribes gene into messenger RNA Ribosome translates messenger RNA into protein,Z,Z Promoter,Z Gene,Protein,Transcription,RNA Polymerase,DNA,Translation,Messenger RNA,Regulation

31、Through Repression and Induction,Repressor proteins can bind to the promoter and block the RNA polymerase from performing transcription The DNA site near the promoter recognized by the repressor is called an operator The target gene can code for another repression protein enabling regulatory cascade

32、s,Z Promoter & Operator,Z Gene,R Gene,R,R,R Promoter,Transcription Translation,DNA Binding,RNA Polymerase,Logic Circuits,Proteins are the wires/signals Promoters + decay implement the gates Any finite-state digital circuit can be built For example, X or Y Z,X,Y,R1,Z,R1,R1,X,Y,Z,=,gene,gene,gene,Tran

33、scription-Based Inverter,Protein concentrations are analogous to electrical current BUT proteins do not function in an isolated system and need to be unique,0,1,1,0,R,R,Z,Simple Inverter Model,R,Operator,Z Gene,Z,R,Cooperativity,Cooperative DNA binding is where the binding of one protein increases t

34、he likelihood of a second protein binding Cooperativity adds more non-linearity to the system Increases switching sensitivity Improves robustness to noise,Z Promoter & Operator,Z Gene,R Gene,R,R,R Promoter,Transcription Translation,Cooperative DNA Binding,RNA Polymerase,R,Cooperative Inverter Model,

35、R,R,Operator,Z Gene,Z,R,BioCircuit Computer-Aided Design,SPICE,BioSPICE,steady state,dynamics,BioSPICE: a prototype biocircuit CAD tool simulates protein and chemical concentrations intracellular circuits, intercellular communication single cells, small cell aggregates,Genetic Circuit Elements,input

36、 mRNA,ribosome,promoter,output mRNA,ribosome,operator,translation,transcription,RNAp,RBS,RBS,A BioSPICE Inverter Simulation,input,output,repressor,promoter,They work in vivo Flip-flop (Gardner & Collins, 2000) Ring oscillator (Elowitz & Leibler, 2000) However, cells are very complex environments Cur

37、rent modeling techniques poorly predict behavior,“Proof of Concept” Circuits,time (x100 sec),A,C,B,B,_ S,_ R,A,_ R,B,_ S,A,time (x100 sec),time (x100 sec),RS-Latch (“flip-flop”),Ring oscillator,Cellular Logic Summary,Current systems are limited to less than a dozen gates Three inverter ring oscillat

38、or (Elowitz, 2000) RS latch (Gardner, 2000) Inter-cell communication (Weiss, 2001) A natural repressor-based logic technology presents serious scalability issues Scavenging natural repressor proteins is time consuming Matching natural repressor proteins to work together is difficult,Cellular Logic S

39、ummary,Sophisticated synthetic biological systems require a scalable cellular logic technology with good cooperativity Zinc-finger proteins can be engineered to create many unique proteins relatively easily Zinc-finger proteins can be fused with dimerization domains to increase cooperativity A cellu

40、lar logic technology of only zinc-finger proteins should hopefully be easier to characterize,Single Zinc-Finger Structure,DNA Three Base Recognition Region,Zinc Atom,Alpha Helix,Two Beta Sheets,Poly-Finger ZFPs,A.C. Jamieson, J.C. Miller, and C.O. Pabo. Drug discovery with engineered zinc-finger pro

41、teins. Nature Reviews Drug Discovery, May 2003,Complex systems,Q: But if we dont fully understand all the rules of biology, how can we create anything more than basic systems? A: We can press our limits by modularizing and simplifying as much as possible.,Standardization of Components Predictable pe

42、rformance Off-the-shelf Mechanical Engineering (1800s) & the manufacturing revolution (e.g. Henry Ford) Abstraction Insulate relevant characteristics from overwhelming detail Simple components that can be used in combination From Physics to Electrical Engineering (1900s) Decoupling Design & Fabricat

43、ion Rules insulating design process from details of fabrication Enable parts, device, and system designers to work together VLSI electronics (1970s),Enabling Synthetic Biology,Characterization,Catalog input-output characteristics of existing and new parts/devices,Standardization,Physical connections

44、 Functional connections Performance,SB works via three layers of abstraction,Devices,Parts,Systems,Abstraction in biology,Devices,Parts,Systems,Barriers,- Technological - Legal - Ethical,Synthetic Biology: Intellectual Property,Relationship of synthetic biology to intellectual property law has been

45、largely unexplored. The relevant research space already contains broad patents on foundational technology. Synthetic biology commons? Tools of open source property rights coupled with viral licensing,Synthetic Biology: Intellectual Property,What is patentable and/or copyrightable? Broad biological f

46、unctions Specific sequences Specific uses Sources of uncertainty in synthetic biology as related to IPR definitions What are effects of alternate definitions of what is patentable and copyrightable on: Development of field? Efficiency? Justice?,Synthetic Biology: Intellectual Property,Patents on fun

47、damental ideas in synthetic biology Example: A patent on the idea of a biological part: a piece of DNA with specific function that can be combined with another part in a predefined fashion. Such a patent would be impossible to circumvent. It represents a fundamental concept that underpins synthetic

48、biology. See Stanford patent on System and method for simulating operation of biochemical systems. United States Patent 5914891,Synthetic Biology: Intellectual Property,Patents on fundamental biological functions Example: A patent on a genetically-encoded inverter Such a patent would be almost impos

49、sible to circumvent because it represents a basic biological function that is of use in a range of synthetic biological systems. See US Dept of Health patent on Molecular computing elements, gates and flip-flops. United States Patent 6774222 See Boston University patent on Multi-state genetic oscill

50、ator. United States Patent 6737269 See Boston University patent on Bistable genetic toggle switch. United States Patent 6841376 See Boston University parent on Adjustable threshold switch. United States Patent 6828140,Synthetic Biology: Intellectual Property,Patents on classes of biological molecule

51、s with a particular function Example: A patent on the use of zinc finger proteins to bind a specific sequence of DNA. Such a patent is not impossible to circumvent because there are other proteins that bind DNA and that could be engineered to bind new sequences. See MIT patent on Poly zinc finger pr

52、oteins with improved linkers. United States Patent 6903185 See Scripps Research Institute patent on Zinc finger binding domains for GNN. United States Patent 6610512 See Sangamo Biosciences, Inc. patent on Regulation of endogenous gene expression in cells using zinc finger proteins. United States Pa

53、tent 6607882,Synthetic Biology: Intellectual Property,Patent on a particular biological molecule. Example: A patent on the sequence of a particular protein that senses light and transmits a signal into the cell. Such a patent would likely be fairly easy to circumvent because there are probably a few

54、 amino acids that could be changed in the protein such that it would it would still be functional yet not have the exact same sequence as specified in the patent. There are exceptions to this rule: Some proteins that have been so optimized for a specific function that any mutation in the sequence ca

55、n lead to less functionality (e.g., the peptide drug Ziconitide).,http:/parts.mit.edu,Open commons of biological functions,Open-access biology?,When a technology is proprietary, both the ability and interest in examining & troubleshooting problems is restricted to those with the IP Might open-access

56、 biology generate a higher quality product? Or would it stifle innovation through a lack of interest?,Programmed Organisms (編程性物種) Super-efficient agriculture via altered nutrient uptake (nitrogen fixing plants, etc) Controlled crop maturing (count days) Chemically controlled pets Biological robots

57、Beneficial bacterial infections programmed to augment immunity, provide needed vitamins, etc. Cells that circulate in the body as an extension of immune system,Synthetic Biology Applications,Smart Materials (聰明材料) Living self-repairing materials (自我修復(fù)) New devices and assembly technologies Nanofabri

58、cation of micro and macro materials Energy production and storage (能量產(chǎn)生與儲(chǔ)存) New biological pathways,Synthetic Biology Applications,Medical Molecular medical devices Reversal of aging (返老還童) Disease fighting (抗病) Implantable living battery for medical device out of electric eel cells. Humans that pho

59、tosynthesize (人類光合成),Synthetic Biology Applications,Sensors (傳感器) Smart sensors Use cells to read, process, output information Detect arbitrary substances Self-reproducing chemical/radioactivity sensors Detect biotoxins and encapsulate. flash when it does. Responsive materials (e.g., oil lubricants

60、by design/need) Tools to measure concentration of protein in cell Ecosystem debugger (read/write) Intelligent Biosensors (智能型傳感器),Synthetic Biology Applications,Terraforming,Creating life on other worlds 仿地成形（尤指在科幻小說中，在外星球創(chuàng)建仿地球的生存環(huán)境，以使人類能夠生存）,Newly discovered archaea,Extremophiles: Thermophiles to P

61、sychrophiles,Life as a hyperthermophile (high temperature) Problem: At high T, membranes become too fluid and permeable. Adaptation: Change the lipids to be more waxy Problem: at T 70 C, DNA & RNA starts to degrade Adaptation: Increase the salt solution within the cell to protect them. Adaptation: G

62、enomic bias towards the more stable G-C base pairs Problem: Proteins dont fold as well at high T Adaptation: Evolve more stably-folding proteins (e.g., tighter hydrophobic cores) Life as a psychrophile (low temperature) Problem: At low T, membranes become too stiff. Adaptation: Change the lipids to

63、be more greasy. Problem: Water freezes, and ice crystals break cells Adaptation: Use “antifreeze” molecules to inhibit crystal growth Problem: Not enough energy to overcome chemical barriers Adaptation: Evolve more active enzymes,Life as an extremophile,Oxyphiles organisms that love oxygen(需氧) Probl

64、em: Oxygen reactions produce reactive species like oxygen free radicals, Adaptation: Develop anti-oxidants (e.g., some vitamins and flavinoids) Halophiles organisms that live in high-salt environments(高鹽) Problem: Reverse osmotic pressure desiccates cells Adaptation: Produce something inside cell (u

65、su. glycine, sometimes potassium) whose osmotic pressure balances that of salt outside cell. Acidophiles/Alkalophiles organisms that love acidic/basic conditions(酸堿) Problem: Proteins can be degraded by changes in pH (e.g., ceviche) Adaptation: Use molecular pumps to keep the interior pH close to neutral. Xerophiles organisms that live in extremely dry environments(干燥) Problem: water evaporates. Adaptation: Protect surface (desert varnish) Adaptation: Increase interi

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