The Age of Imag­ing

by Elio

Not so long ago, it would have seemed im­plau­si­ble that bi­ol­ogy would re­turn to its ori­gins as a vi­sual sci­ence. Some would have con­sid­ered this a re­gres­sion to the days when bi­ol­o­gists were pretty much con­fined to study­ing just what they could see, such as the shapes of or­gan­isms and their tis­sues. Back then, they fo­cused on re­fin­ing what Pliny had ob­served with his bare eyes, what Hooke and Leeuwen­hoek saw un­der the micro­scope. The method­olog­i­cal lines of at­tack were dra­mat­i­cally redirect­ed from the vi­sual by the rev­o­lu­tion­ary dis­cov­er­ies of the sec­ond half of the last cen­tury. Bio­chem­istry, ge­net­ics, mol­e­c­u­lar bi­ol­ogy – none of them re­lied pri­mar­ily on vi­sualizing the struc­ture of ob­jects. For some time, do­ing mor­phol­ogy was sus­pect and, in some quar­ters, even us­ing a mi­cro­scope was equated with do­ing old-fash­ioned sci­ence.

Im­age cour­tesy of Bib­liOdyssey

How bi­ol­ogy has (once again) changed!

Some of the most fun­da­men­tal work done now once again in­volves see­ing shapes and forms. Granted, ge­nomics and its ‑om­i­cal kin­folk can be done with one's eyes closed (but with one's mind open). How­ever, if you look no far­ther, you would miss much of the ex­cite­ment of the day. Nowa­days, mind-blow­ing in­sights come from see­ing with your own eyes.

Bi­o­log­i­cal imag­ing to­day starts with the very small, at the level of mol­e­cules – a field where splen­did ad­vances are be­ing made. A new name, Struc­tural Bi­ol­ogy, was awarded to this sort of study. In my grad­u­ate stu­dent years over half a cen­tury ago, only the rare vi­sion­ary pre­dicted that we would read­ily "see" how an en­zyme works or how macro­mol­e­cules in­ter­act with mol­e­cules large and small! These are grand achieve­ments in­deed. It gets bet­ter: sin­gle mol­e­cule imag­ing meth­ods al­low us to vi­su­al­ize the tiny move­ments made and the forces gen­er­ated by pro­teins or riboso­mes. One can now "see" in real time poly­merases poly­mer­iz­ing and riboso­mes trans­lat­ing.

Mov­ing up a bit in mag­ni­tude, mi­croscopy can also claim amaz­ing de­vel­op­ments. In my days, it was be­lieved that the op­ti­cal mi­croscope had reached its phys­i­cal lim­its and that the elec­tron mi­croscope had se­vere lim­i­ta­tions. Re­cent progress on both these fronts con­tin­ues at a stun­ning pace. Flu­o­res­cence tech­niques, in­clud­ing meth­ods to clean up their sig­nals, per­mit us to see sin­gle mol­e­cules in ac­tion at an ex­cep­tional de­gree of res­o­lu­tion, of­ten in liv­ing cells. And the sig­nals can even be quan­ti­tated. On the hori­zon are other tech­niques un­der de­vel­op­ment that hold promise for even greater res­o­lu­tion.

Newer on the scene is the cou­pling of cry­oto­mog­ra­phy with the elec­tron mi­cro­scope, a tech­nique that per­mits one to vi­su­al­ize the in­te­rior of un­fixed whole cells. In a sense, this lets one crawl in­side a rel­a­tively un­treated cell, take a look around, and see what there is to see. I am re­minded of an old pre­lim exam ques­tion that I had used to tor­ment grad­u­ate stu­dents: If you could get to be small enough to fit in­side a bac­terium, what would you see? We thought this a "cool" ques­tion that par­al­leled the sci­ence fic­tion movie, Fan­tas­tic Voy­age, where a sub­ma­rine with crew is miniatur­ized to 1 μm in length and thus able to travel the blood­stream of its in­ven­tor to de­stroy a blood clot in his brain. How about that! My ques­tion is no longer in the realm of sci­ence fic­tion! Al­though the tech­nique doesn't minia­tur­ize the ex­per­i­menter, the re­sult is the same: one can pre­tend to see what's in­side a bac­terium. The caveat in this state­ment is due to sev­eral fac­tors: the cells have to be quite thin (al­though most prokary­otes in na­ture prob­a­bly qual­ify); not all the struc­tural con­stituents can be re­solved with the same clar­ity; and the high volt­age elec­tron beam used prob­a­bly in­tro­duces dis­tor­tions. Still, crawl­ing in­side a bac­terium is, by any stan­dard, a mag­nif­i­cent achieve­ment. So, what is there to see in­side a "sim­ple" bac­terium? This will be the topic for a fu­ture post­ing.

The Age of Imag­ing is just be­gin­ning. It's hard to pre­dict where it will lead, as the lim­its seem to con­stantly re­cede. Let's go for broke: some­day we should be able to en­joy movies that show what goes on in­side liv­ing cells at the res­o­lu­tion of the elec­tron mi­cro­scope. Maybe even talkies?