[Annotated] Cell-free biotech will make for better products

A new type of biological engineering should speed up innovation^[각주:1]

The stuff of life comes wrapped in tiny bags called cells. Inside are DNA molecules^[각주:2] that carry the instructions^[각주:3] for how to run the cell, to make it grow, and to cause it, ultimately, to divide into^[각주:4] two cells, if that is to be its fate. Messages made of a slightly different molecule, RNA, carry these instructions to molecular machines called ribosomes^[각주:5]. A ribosome's job is to read the RNA messages and translate them into^[각주:6] proteins, the workhorse^[각주:7] molecules of cells. Those proteins then supervise^[각주:8] and execute the running, the growing and the dividing. 

It is a system that has worked well over the 4bn years that life has existed on Earth. To some biotechnologists^[각주:9], though, the cell is old hat. They approve of^[각주:10] the machinery of^[각주:11] DNA, RNA, ribosomes and chemicals, ranging from drugs to^[각주:12] the building-blocks of^[각주:13] plastics. But they want to get rid of the bags that contain it, retaining^[각주:14] only the part of the protoplasmic^[각주:15] "gloop^[각주:16]" inside a cell needed to do their bidding^[각주:17].

In this way they hope to control, far more precisely than is possible by conventional^[각주:18] genetic engineering (or even by improved methods of gene modification^[각주:19], such as CRISPR-Cas9, that are now being developed) which genes are translated by the ribosomes - and thus what products are churned out^[각주:20]. Equally important, cell-free biotechnology^[각주:21] of this sort means no biochemical effort is wasted on^[각주:22] running, growing or dividing any actual cells. This initial intention^[각주:23] is to create a quicker way of finding the best genes for making a particular product. In the end, those working in the field aspire to^[각주:24] the idea that cell-free production will equal^[각주:25] mass production^[각주:26]. 

Processing power

A typical recipe for^[각주:27] making cell-free protoplasmic gloop is this. Take four liters of culture^[각주:28] containing E.coli (a gut bacterium favored by^[각주:29] genetic engineers). Split the bacterial^[각주:30] cells open^[각주:31] by forcing them through a tiny valve at pressure, thus shredding^[각주:32] their membranes^[각주:33] and DNA, and liberating^[각주:34] the ribosomes. Incubate^[각주:35] the resulting^[각주:36] mixture at 37ºC for an hour, to activate^[각주:37] enzymes^[각주:38] called exonucleases^[각주:39] that will eat up^[각주:40] the fragmented^[각주:41] DNA. Centrifuge^[각주:42], to separate the scraps of^[각주:43] cell membrane and other detritus^[각주:44] from the gloop that contains ribosomes. Dialyse to remove unwanted^[각주:45] ions^[각주:46]. Then stir^[각주:47] in amino acids^[각주:48] (the building blocks of^[각주:49] proteins), sugar and an energy-carrying molecule called adenosine triphoshate^[각주:50] (ATP) to power the process. Finally, add a pinch of^[각주:51] new DNA to taste, to tell the gloop which proteins it is supposed to produce.

This particular recipe is the one used by Synvirobio of Berkeley, California, a firm founded by Zachary Sun and Richard Murray of the California Institute of Technology and George Church of Harvard University. Other recipes, with different starting organisms^[각주:52], are possible. Yeast works, as does Streptomyces^[각주:53], another bacterium^[각주:54]. Cells from tobacco plants or the ovaries of^[각주:55] Chinese hamsters are also good places to begin. But all such formulae^[각주:56] are variation on the theme of isolating a cell's protein-making machinery^[각주:57] in a free-floating^[각주:58] suspension^[각주:59].

Synvitrobio's engineers have built a robotic system to mix the final stage of their recipe. This robot parcels the purified^[각주:60] protoplasm^[각주:61] into an array of^[각주:62] 384 miniscule^[각주:63] test tubes^[각주:64], each with a volume of a few millionths^[각주:65] of a liter. It then drops some DNA molecules into each tube and the gloop gets to work on the process of turning the information in those molecules into proteins. Currently, the system can handle eight DNA sequences per test tube, meaning 3,072 proteins can be processed in parallel^[각주:66]. The sequences can be up to 10,000 genetic "letters" long - enough to encode^[각주:67] almost any protein you care to mention^[각주:68].

At present^[각주:69], Synvitrobio is using its system to test DNA sequences^[각주:70] (or, rather, the resulting proteins) to see if they might be worth investigating as antibiotic^[각주:71] drugs. Such drugs work by binding to^[각주:72] a biologically important molecule and changing that molecule's characteristics in some way that is detrimental to^[각주:73] the organism of which it is part. To look for this binding, each mini test tube is also supplied with^[각주:74] some of the target molecules, each attached to a "reporter" molecule that emits^[각주:75] a flash of light if binding takes place.

Tubes which flash^[각주:76] brightly indicate that one or more of the DNA sequences therein^[각주:77] are worth a second glance. Synvitrobio's technique is thus able to screen^[각주:78] potential drugs at a rate limited only by the availability of^[각주:79] new DNA sequences. Since synthesizing^[각주:80] new sequences on demand^[각주:81] is now a routine^[각주:82] technology, that means the world's gene libraries^[각주:83] can be plundered for^[각주:84] likely candidates, and the best of these then tweaked^[각주:85] mercilessly^[각주:86] until something good enough for the job turns up. Inserting such sequences into the genomes of organisms is far more time-consuming^[각주:87] than simply dropping them in some gloop.

At the moment, that is the point when Synvitrobio passes the newly discovered molecule on, for a suitable cut of the proceeds^[각주:88], to someone who can turn it out in bulk^[각주:89] by the conventional technique of pasting the relevant gene into^[각주:90] appropriate cells, and breeding these cells in fermentation tanks similar to those used for brewing beer. This is because it is expensive to produce cell-free protoplasm in the volumes required to manufacture antibiotics^[각주:91] for sale^[각주:92]. A few firms are, however, doing so for drugs that can command high prices^[각주:93].

One such is Sutro Biopharma, based near San Francisco, It uses a cell-free system to create antibodies^[각주:94] that inhibits^[각주:95] tumor growth. The firm plans to start trials of STRO-001 in 2018. Cell-free production of the antibodies for that trial is about to begin.

Antibodies are specialized proteins, so once Sutro's system has identified the best candidate for the job, all that is required is to seed the gloop with^[각주:96] the DNA which encodes that candidate. Other firms, though, hope to go further^[각주:97] than this, by devising manufacturing systems^[각주:98] that put together entire metabolic pathways^[각주:99] for the production of chemicals other than proteins. These, as in a natural metabolic pathway, consist of a series of enzymes (another type of specialized protein) that catalyze^[각주:100] a sequence of chemical changes, gradually concerting^[각주:101] one molecule^[각주:102] into another.

Genomatica, an established biotechnology firm based in San Diego, is experimenting with^[각주:103] a cell-free system which produces 1,4-butanediol^[각주:104] in this way from simple sugars. 1,4-butanediol is a small molecule that is used to make polymers^[각주:105] such as Lycra. Generally, it is cheaper to manufacture molecules of this size using chemistry, rather than biology, but 1,4-butanediol is an exception. It is already made for industry with the aid of^[각주:106] genetically modified E. coli. Genomatica's system churns out the enzymes involved in this synthesis^[각주:107], creating an entire cell-free metabolic pathway - and one in which all the sugar is devoted to making the target chemical, rather than a percentage of it being creamed off^[각주:108] to run a cell's other biochemical processes. The firm has not yet put the system to commercial use^[각주:109], but has high hopes for it.

GreenLight Biosciences, a firm in Medford, Massachusetts, proposes to use its own cell-free system, also based on E. coli, to produce industrial quantities of an undigestible^[각주:110] analogue^[각주:111] of ribose^[각주:112], a naturally occurring^[각주:113] sugar, for use in zero-calorie beverages. The company says it has already got its process to the point where it can make thousands of liters of solution of this sugar at a time^[각주:114]. GreenLight is also working on cell-free systems that will generate industrial qualities of specially designed RNA molecules that interfere with^[각주:115] the development of insect larvae^[각주:116], and can thus be used as pesticides. Currently, such RNA costs $5,000 per kilogram to produce. GreenLight thinks that by scaling the process up^[각주:117] it can reduce this to between $50 and $100.

Whether cell-free biotechnology will be able to displace^[각주:118] fermentation by genetically modified organisms as a routine way of making chemicals remains to be seen^[각주:119]. Fermentation is a tried trusted^[각주:120] technique, used by humans since the invention of beer around 12,000 years ago. But the idea of stripping molecular biology^[각주:121] down to^[각주:122] its bare essentials^[각주:123] has an efficiency^[각주:124] about it which suggests that, for some applications^[각주:125] at least, the utility of the biological cell may have run its course^[각주:126]. 

1. speed up ; 속도를 더 내다[높이다] ;; 동의어 speed something up [본문으로]
2. inside are ~ : 도치 구문 [본문으로]
3. carry the instruction ; 지침, 지시, 명령을 수행하다 [본문으로]
4. divide into ; …으로 나누다. [본문으로]
5. ribosome ; [명사] [생화학] 리보솜 ((세포 안의 RNA와 단백질의 복합체; 단백 합성이 이루어짐)) ;; US·UK [ráibəsòum] [본문으로]
6. translate ... into ; 3. ~ (sth) (into sth) (다른 형태로) 바꾸다[옮기다]; 바뀌다 [본문으로]
7. workhorse ; [명사] 열심히 일하는 사람[기계] [본문으로]
8. supervise ; [동사] 감독[지휘/지도]하다 [본문으로]
9. biotechnologist ; [명사] 생물 공학자; 인간 공학자. [본문으로]
10. approve of ; ~을 승인하다, 찬성하다, 인정하다, 검출, 검사하다, 용납하다 [본문으로]
11. machinery ; 3. [U , sing.] ~ (of sth) | ~ (for doing sth) 조직, 시스템, 기구 [본문으로]
12. range from ... to ; 범위가 ~에서 ~에 이르다 [본문으로]
13. building block ; 2. [pl.] building blocks 구성 요소 [본문으로]
14. retain ; 2. (계속) 함유[간직]하다 [본문으로]
15. protoplasmic ; [형용사] 원형질의. [본문으로]
16. gloop ; [U] (美 glop / glɑ:p ; 美 glɑːp /) (비격식) (기분 나쁘게) 질척[찐득]거리는 것 [본문으로]
17. bidding ; 4. (구식 또는 격식) 요청; 명령 [본문으로]
18. conventional ; 2. [주로 명사 앞에 씀] 전통적인, 종래의 [본문으로]
19. gene modification ; 유전자 조작, 변형 [본문으로]
20. churn out ; [동사] 대량 생산하다; 잇달아 내다. ;; 동의어 mass-produce mechanically. [본문으로]
21. biotechnology ; [명사] (전문 용어) 생명 공학 [본문으로]
22. be wasted on ; …에게는 소용없는 일이다 [본문으로]
23. initial intention ; 원래 의도 [본문으로]
24. aspire to ; …을 갈망하다. ;; to have a strong desire to gain or achieve something [본문으로]
25. equal ; 2. [타동사][VN] 맞먹다, 필적하다 [본문으로]
26. mass production ; 대량 생산, 양산 [본문으로]
27. recipe ; 2. ~ for sth (특정 결과를 가져올 듯한) 방안[비결] [본문으로]
28. culture ; 6. CELLS/BACTERIA | [C] (생물 의학) 배양균, 배양 조직 [본문으로]
29. favor ; 2. …에 편들다; 장려하다; 조력하다, 돕다, 지지하다 [본문으로]
30. bacterial ; [형용사] 박테리아[세균]의 [본문으로]
31. split ... open ; 찢어서 벌리다, 열다, 열리다 [본문으로]
32. shred ; [타동사][VN] (-dd-) (갈가리) 자르다[찢다], 채를 썰다 [본문으로]
33. membrane ; 2. (식물의) 세포막 [본문으로]
34. liberate ; [vn] 1. ~ sb/sth (from sb/sth) (국가・사람을 억압・속박으로부터) 해방시키다 [본문으로]
35. incubate ; 2. [타동사][VN] (생물) (세균 등을) 배양하다 [본문으로]
36. resulting ; [형용사] 결과로 초래된 [본문으로]
37. activate ; [타동사][VN] 작동시키다; 활성화시키다 [본문으로]
38. enzyme ; [명사] (생물) 효소 ;; US·UK [|enzaɪm] [본문으로]
39. exonuclease ; (의학) 핵산말단분해효소, 엑소뉴클레아제, 엑소뉴클레에이스[엑소뉴클레아제]. 폴리뉴클레오타이드 쇄(鎖)의 말단으로부터 단일의 모노뉴클레오타이드를 단절하는 핵산분해효소의 하나. ;; US·UK [èksounjúːklieis] [본문으로]
40. eat up ; (~을) 다 먹다 ;; 동의어 eat something up [본문으로]
41. fragmented ; [형용사] 분열된, 조직이 파괴된 [본문으로]
42. centrifuge ; [명사] 원심 분리기 ;; US·UK [|sentrɪfju:dƷ] [본문으로]
43. scrap ; 1. [C] (특히 종이・옷감 등의) 조각 [본문으로]
44. detritus ; [명사] (전문 용어) (생물체 등에 의한 자연발생적인) 쓰레기 [본문으로]
45. unwanted ; [형용사] 원치 않는, 반갑지 않은 [본문으로]
46. ion ; [명사] (물리 또는 화학) 이온 ;; US·UK [|aɪən;英또한|aɪɒn;또한|aɪɑ:n] [본문으로]
47. stir ; 1. MIX | [타동사][VN] ~ sth (into sth) | ~ sth (in) 젓다, (저어 가며) 섞다[넣다] [본문으로]
48. amino acid ; [명사] (화학) 아미노산 [본문으로]
49. building block ; 2. [pl.] building blocks 구성 요소 [본문으로]
50. adenosine triphoshate ; (생화학) 아데노신 3인산 [본문으로]
51. pinch ; 2. SMALL AMOUNT | 자밤(엄지와 검지의 두 손가락 끝으로 한 번 집을 만한 분량) [본문으로]
52. organism ; 1. 유기체, (특히 극도로 작은) 생물(체) ;; 참고 micro-organism [본문으로]
53. streptomyces ; (의학) 스트렙토미세스(속). 스트렙토마이시즈(속)(~(屬)). 스트렙토미세스균. Actinomycetales목(目), Streptomycetaceae과(科)의 미생물의 1속(屬)으로서, 150종(種)으로 분리되며, 보통 토양균이지만 가끔 식물이나 동물에 기생하며, 테트라사이클린(tetracyclines)과 같은 각종 항생제의 산생원으로 주목된다. ;; US·UK [strèptoumáisiːz] ;; 동의어 Streptothrix [본문으로]
54. bacterium ; [명사] (pl. -ri·a[-riə]) BACTERIA의 단수 [본문으로]
55. ovaries ; [명사] (가정학) 난소 [본문으로]
56. formulae ; 3. [C] ~ (for sth/for doing sth) (특정한 일을 이루기 위한) 공식[방식] ;; formula [본문으로]
57. machinery ; . [U , sing.] ~ (of sth) | ~ (for doing sth) 조직, 시스템, 기구 [본문으로]
58. free-floating ; [형용사] 걷잡을 수 없는 [본문으로]
59. suspension ; 2. [U , sing.] 연기, 보류, 유예 [본문으로]
60. purified ; [명사] (약학) 정제한(精製~) [본문으로]
61. protoplasm ; [명사] (생물) 원형질 ;; US [|proʊtəplӕzəm] UK [|prəʊtəplӕzəm] ;; 참고 cytoplasm [본문으로]
62. an array of ; 다수의~, ~의 행렬 [본문으로]
63. miniscule ; [형용사, 명사] 1.극소의 ;; 동의어 MINUSCULE ;; [본문으로]
64. test tube ; [명사] 시험관 [본문으로]
65. millionth ; [ordinal number] 100만 번째 [본문으로]
66. in parallel ; (~와) 동시에, 병렬적으로 [본문으로]
67. encode ; 3. (언어) (외국어로) 표현하다[말을 하다/글을 쓰다] [본문으로]
68. care to mention ; 언급, 말하려고 하다. [본문으로]
69. at present ; 현재는, 지금은, 목하(now) [본문으로]
70. DNA sequence ; [명사] (생명과학) DNA염기순서(~塩基順序) [본문으로]
71. antibiotic ; [명사] (주로 복수로) 항생제, 항생물질 [본문으로]
72. bind to ; …을 하게 만들다. [본문으로]
73. detrimental ; [형용사] ~ (to sb/sth) 해로운 [본문으로]
74. be supplied with ; 공급을 받다 [본문으로]
75. emit ; [타동사][VN] (-tt-) (격식) (빛・열・가스・소리 등을) 내다[내뿜다] [본문으로]
76. flash ; 1. SHINE BRIGHTLY | (잠깐) 비치다[번쩍이다]; 비추다 [본문으로]
77. therein ; [부사] (격식 또는 법률) 그 안에 [본문으로]
78. screen ; [vn] 1. HIDE STH/SB | ~ sth/sb (from sth/sb) 가리다, 차단[보호]하다 [본문으로]
79. availability ; [명사] [U] 유효성, 유용성, 효용; (입수) 가능성 [본문으로]
80. synthesize ; [동사] (전문 용어) (화학 물질을) 합성하다 [본문으로]
81. on demand ; 요구만 있으면 (언제든지) [본문으로]
82. routine ; 2. 일상적인, 보통의 [본문으로]
83. gene library ; [명사] (생명과학) 유전자도서관(遺傳子圖書館) [본문으로]
84. plunder ; [동사] (특히 전시에 어떤 장소를) 약탈[강탈]하다 ;; 참고 pillage [본문으로]
85. tweak ; 2. (기계・시스템 등을 약간) 수정[변경]하다 [본문으로]
86. mercilessly ; [부사] 무자비하게, 무정하게, 잔인하게. [본문으로]
87. time-consuming ; [형용사] (많은) 시간이 걸리는 [본문으로]
88. proceeds ; [pl.] ~ (of/from sth) (물건 판매・행사 등을 하여 받는) 돈[수익금] [본문으로]
89. in bulk ; 포장하지 않고, 산적 화물로 [본문으로]
90. paste ... into ; 1. [타동사][VN + adv. / prep.] 풀로 붙이다 [본문으로]
91. antibiotic ; [명사] (주로 복수로) 항생제, 항생물질 [본문으로]
92. for sale ; (특히 주인이) 팔려고 내놓은 [본문으로]
93. command ; 3. DESERVE AND GET | [타동사][VN] [수동태로는 안 씀.진행형으로는 쓰이지 않음] (응당 받아야 할 것을) 받다 [본문으로]
94. antibody ; [명사] pl. -ies 항체 [본문으로]
95. inhibit ; [동사] 억제[저해]하다 [본문으로]
96. seed ; 3. AREA OF GROUND | [타동사][VN] [주로 수동태로] ~ sth (with sth) 씨앗을 뿌리다 [본문으로]
97. go further ; (말하는 내용에 있어서) 더 나아가다 [본문으로]
98. manufacturing system ; 제조, 생산 시스템 [본문으로]
99. metabolic pathway ; (생리) 대사(代謝) 경로 [본문으로]
100. catalyze ; [타동사] …에 촉매 작용을 미치다, <화학 반응을> 촉진시키다 [본문으로]
101. concert ; [VERB] to settle or adjust by conferring and reaching an agreement concerted their differences [본문으로]
102. molecule ; [명사] (화학) 분자 [본문으로]
103. experiment with ; …을 실험하다. [본문으로]
104. butanediol ; [명사] (약학) 부탄디올 [본문으로]
105. polymer ; [명사] (화학) 중합체, 고분자 [본문으로]
106. with the aid of ; ~의 도움으로 [본문으로]
107. synthesis ; 3. [U] (전문 용어) (인위적으로 화학 물질을 만들어 내는) 합성 [본문으로]
108. cream off ; (자기 이익을 위해 가장 우수한 사람들이나 물건들을) 추려[뽑아] 가다 [본문으로]
109. commercial use ; (법률) 상용(商用) [본문으로]
110. undigestible ; [형용사] 1. (음식이) 소화가 잘 안 되는 ;; 동의어 indigestible [본문으로]
111. analogue ; (격식 또는 전문 용어) 유사체 [본문으로]
112. ribose ; [명사] (생화학) 리보오스 ((주로 RNA에서 얻어지는 오탄당(五炭糖)의 일종)) ;; US·UK [ráibous] [본문으로]
113. occurring ; [형용사] 일어나고 있는, 발생하는 [본문으로]
114. at a time ; 따로따로; 한 번에 [본문으로]
115. interfere with ; 1. ~을 방해하다[~에 지장을 주다] [본문으로]
116. larva ; (pl. lar・vae / 'lAːviː ; 美 'lAːrviː /) 유충, 애벌레 ; US [|lɑ:rvə] UK [|lɑ:və] [본문으로]
117. scale up ; (크기·규모를) 확대하다[늘리다] [본문으로]
118. displace ; [흔히 수동태로] 1. 대신[대체]하다 [본문으로]
119. remain to be seen ; 두고 볼 일이다 [본문으로]
120. tried and trusted [ tested] ; (이미 써 봤기 때문에) 확실히 믿을 수 있는, 믿을 수 있다고 증명된 [본문으로]
121. biology ; 2. 생명 작용[활동] [본문으로]
122. strip down to ; to take off the covers until it is only wearing the items mentioned [본문으로]
123. the bare essentials ; 필수불가결한 것. [본문으로]
124. efficiency ; 1. [U] 효율(성), 능률 ;; 사전에는 불가산이지만 가산으로도 많이 쓰는것을 확인 [본문으로]
125. application ; 2. PRACTICAL USE | [U , C] ~ (of sth) (to sth) 적용, 응용 [본문으로]
126. run [take] its course ; (방해를 받지 않고) 자연스럽게 되어 가다[전개되다] [본문으로]