Bio­lo­gic­al tran­sist­or enables com­put­ing with­in liv­ing cells, study says

And now a team of Stan­ford Uni­ver­sity bioen­gin­eers has taken com­put­ing bey­ond mech­an­ics and elec­tron­ics into the liv­ing realm of bio­logy. In a paper pub­lished March 28 in Sci­ence, the team details a bio­lo­gic­al tran­sist­or made from genet­ic mater­i­al — DNA and RNA — in place of gears or elec­trons. The team calls its bio­lo­gic­al tran­sist­or the ​“tran­scriptor.” ​“Tran­scriptors are the key com­pon­ent behind amp­li­fy­ing genet­ic logic — akin to the tran­sist­or and elec­tron­ics,” said Jerome Bon­net, PhD, a postdoc­tor­al schol­ar in bioen­gin­eer­ing and the paper’s lead author. The cre­ation of the tran­scriptor allows engin­eers to com­pute inside liv­ing cells to record, for instance, when cells have been exposed to cer­tain extern­al stim­uli or envir­on­ment­al factors, or even to turn on and off cell repro­duc­tion as needed. ​“Bio­lo­gic­al com­puters can be used to study and repro­gram liv­ing sys­tems, mon­it­or envir­on­ments and improve cel­lu­lar thera­peut­ics,” said Drew Endy, PhD, assist­ant pro­fess­or of bioen­gin­eer­ing and the paper’s seni­or author.

The bio­lo­gic­al computer

In elec­tron­ics, a tran­sist­or con­trols the flow of elec­trons along a cir­cuit. Sim­il­arly, in bio­lo­gics, a tran­scriptor con­trols the flow of a spe­cif­ic pro­tein, RNA poly­merase, as it travels along a strand of DNA. ​“We have repur­posed a group of nat­ur­al pro­teins, called integ­rases, to real­ize digit­al con­trol over the flow of RNA poly­merase along DNA, which in turn allowed us to engin­eer amp­li­fy­ing genet­ic logic,” said Endy. Using tran­scriptors, the team has cre­ated what are known in elec­tric­al engin­eer­ing as logic gates that can derive true-false answers to vir­tu­ally any bio­chem­ic­al ques­tion that might be posed with­in a cell. They refer to their tran­scriptor-based logic gates as ​“Boolean Integ­rase Logic,” or ​“BIL gates” for short. Tran­scriptor-based gates alone do not con­sti­tute a com­puter, but they are the third and final com­pon­ent of a bio­lo­gic­al com­puter that could oper­ate with­in indi­vidu­al liv­ing cells. Des­pite their out­ward dif­fer­ences, all mod­ern com­puters, from ENI­AC to Apple, share three basic func­tions: stor­ing, trans­mit­ting and per­form­ing logic­al oper­a­tions on inform­a­tion. Last year, Endy and his team made news in deliv­er­ing the oth­er two core com­pon­ents of a fully func­tion­al genet­ic com­puter. The first was a type of rewrit­able digit­al data stor­age with­in DNA. They also developed a mech­an­ism for trans­mit­ting genet­ic inform­a­tion from cell to cell, a sort of bio­lo­gic­al Inter­net. It all adds up to cre­at­ing a com­puter inside a liv­ing cell.

Boole’s gold

Digit­al logic is often referred to as ​“Boolean logic,” after George Boole, the math­em­atician who pro­posed the sys­tem in 1854. Today, Boolean logic typ­ic­ally takes the form of 1s and 0s with­in a com­puter. Answer true, gate open; answer false, gate closed. Open. Closed. On. Off. 1. 0. It’s that basic. But it turns out that with just these simple tools and ways of think­ing you can accom­plish quite a lot. ​“AND” and ​“OR” are just two of the most basic Boolean logic gates. An ​“AND” gate, for instance, is ​“true” when both of its inputs are true — when ​“a” and ​“b” are true. An ​“OR” gate, on the oth­er hand, is true when either or both of its inputs are true. In a bio­lo­gic­al set­ting, the pos­sib­il­it­ies for logic are as lim­it­less as in elec­tron­ics, Bon­net explained. ​“You could test wheth­er a giv­en cell had been exposed to any num­ber of extern­al stim­uli — the pres­ence of gluc­ose and caf­feine, for instance. BIL gates would allow you to make that determ­in­a­tion and to store that inform­a­tion so you could eas­ily identi­fy those which had been exposed and which had not,” he said. By the same token, you could tell the cell to start or stop repro­du­cing if cer­tain factors were present. And, by coup­ling BIL gates with the team’s bio­lo­gic­al Inter­net, it is pos­sible to com­mu­nic­ate genet­ic inform­a­tion from cell to cell to orches­trate the beha­vi­or of a group of cells. ​“The poten­tial applic­a­tions are lim­ited only by the ima­gin­a­tion of the research­er,” said co-author Mon­ica Ort­iz, a PhD can­did­ate in bioen­gin­eer­ing who demon­strated autonom­ous cell-to-cell com­mu­nic­a­tion of DNA encod­ing vari­ous BIL gates.

Build­ing a transcriptor

To cre­ate tran­scriptors and logic gates, the team used care­fully cal­ib­rated com­bin­a­tions of enzymes — the integ­rases men­tioned earli­er — that con­trol the flow of RNA poly­merase along strands of DNA. If this were elec­tron­ics, DNA is the wire and RNA poly­merase is the elec­tron. ​“The choice of enzymes is import­ant,” Bon­net said. ​“We have been care­ful to select enzymes that func­tion in bac­teria, fungi, plants and anim­als, so that bio-com­puters can be engin­eered with­in a vari­ety of organ­isms.” On the tech­nic­al side, the tran­scriptor achieves a key sim­il­ar­ity between the bio­lo­gic­al tran­sist­or and its semi­con­duct­ing cous­in: sig­nal amp­li­fic­a­tion. With tran­scriptors, a very small change in the expres­sion of an integ­rase can cre­ate a very large change in the expres­sion of any two oth­er genes. To under­stand the import­ance of amp­li­fic­a­tion, con­sider that the tran­sist­or was first con­ceived as a way to replace expens­ive, inef­fi­cient and unre­li­able vacu­um tubes in the amp­li­fic­a­tion of tele­phone sig­nals for transcon­tin­ent­al phone calls. Elec­tric­al sig­nals trav­el­ing along wires get weak­er the farther they travel, but if you put an amp­li­fi­er every so often along the way, you can relay the sig­nal across a great dis­tance. The same would hold in bio­lo­gic­al sys­tems as sig­nals get trans­mit­ted among a group of cells. ​“It is a concept sim­il­ar to tran­sist­or radi­os,” said Pak­poom Sub­soon­torn, a PhD can­did­ate in bioen­gin­eer­ing and co-author of the study who developed the­or­et­ic­al mod­els to pre­dict the beha­vi­or of BIL gates. ​“Rel­at­ively weak radio waves trav­el­ing through the air can get amp­li­fied into sound.”

Pub­lic-domain biotechnology

To bring the age of the bio­lo­gic­al com­puter to a much speedi­er real­ity, Endy and his team have con­trib­uted all of BIL gates to the pub­lic domain so that oth­ers can imme­di­ately har­ness and improve upon the tools. ​“Most of bio­tech­no­logy has not yet been ima­gined, let alone made true. By freely shar­ing import­ant basic tools every­one can work bet­ter togeth­er,” Bon­net said. The research was fun­ded by the Nation­al Sci­ence Found­a­tion and the Town­shend Lamarre Found­a­tion. Inform­a­tion about Stanford’s Depart­ment of Bioen­gin­eer­ing, which also sup­por­ted the work, is avail­able at bioen​gin​eer​ing​.stan​ford​.edu. The depart­ment is jointly oper­ated by the School of Engin­eer­ing and the School of Medi­cine. Source: Stan­ford School of Medi­cine (BY ANDREW MYERS)