Consider this question: if you wanted to build a virus de novo, what would be first on your parts-list? I don't mean this to sound like a bio-defense fellowship application, but instead I mean to ask, how much do we know, mechanically, about common viruses?
I'll start with what I think is the most important piece: a DNA (or RNA) packaging motor. The reason I think this is so critical is because the virus, at its simplest, is a structurally sound and chemically stable genome. Somehow after replication a virus must package into its daughter an entire copy of its genome. So how does the nucleic acid get in there?
Image courtesy Nature, Jiang Lab
If we wanted to build a virus, we obviously would need some sort of biological motor. One that can latch on somewhere, recognize viral (and not cellular!) DNA, then shove it into the empty viral shell. What specifications should we consider for this motor? Since this packaging motor needs some sort of energy input, I think it would be wise to use the host cell's ATP store. After all, it's just sitting around, right? What about once this virus particle find the next target cell; it will want to inject its DNA into that cell. Unfortunately for us, there isn't going to be much ATP lying around outside cells (not even in blood).
Luckily, nature has already solved this dilemma, and we can find out how if we ask the right questions. It turns out that you can monitor actual viral DNA packaging motors using optical tweezers, and gain some insights about how the virus operates. And this is something that the Bustamante lab here at Berkeley does very well. We've managed to measure the forces exerted by a single packaging motor of phi29, a bacteriophage (read "virus for bacteria").
The authors of this paper found that even a single motor can generate enormous forces when packaging DNA (well, enormous by biological standards). Using ATP alone, it can exert forces up to 50 pN (that's 50×10-12 Newtons), which is astonishing for its size. By comparison, each molecule of myosin, the force-generating protein in your muscles, can generate a force of only 5 pN. Which means that the packaging motors in the bacteriophage are about 10 times stronger than an equivalent number of your myosin motors.
The authors did a quick back-of-the-envelope calculation that suggested the DNA inside the virus must be at a pressure equivalent to 60 atmospheres. The raison d'etre of the motor became clear—when the new virus finds a host cell, it must pop open like a champagne bottle and allow its DNA to shoot into the new target cell. The virus relies on this mechanism to infect a new cell precisely because there is no ATP (and therefore no energy source) available outside the target cell. Ingenious!
It turns out this calculation provided a prediction that was testable. It suggested that DNA inside virii should be so dense that it ought to have almost crystalline order, something DNA normally resists very much. And a recent paper from Nature provides confirmation of this prediction through cyro-electron microscopy. It appears that the DNA is so well ordered that electron microscopy imaging can make out the pattern inside the virus. Seed Magazine has a fascinating, and less technical, breakdown of this work on their site.
There is much insight to be gained by considering biological objects as mechanical devices. In my opinion, cell biology and biophysics is diverging into two complementary paths: (1) understanding the physical basis of biological activity, and (2) understanding how redudant, overlapping signalling pathways give rise to robust decision-making networks. Of course synthetic biology sometimes attempts to bridge this gap, by creating biology that performs some novel task.
Comments are open. Your thoughts?
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