It was the Chinese, inevitably, who invented paper – during the Eastern Han period around 200 CE (or AD as I’d put it). Presumably by 201 AD some of the lads at the back of the class had discovered that this new stuff could be folded and launched to land on the desk of the local Confucius, generating much hilarity and presumably a few whacks with a bamboo cane.
Not to be outdone some 21st century scholars have shown that you can do molecular origami with DNA. The idea is fairly simple: take a long strand of DNA (several thousand bases) and persuade it to fold into specific shapes by adding ‘staples’ — short bits of DNA (oligonucleotides). When you mix them together the staples and scaffold strands self-assemble in a single step. It’s pretty amazing but it’s driven by the simple concept of Watson-Crick base pairing (adenine (A) binds to thymine (T): guanine (G) to cytosine (C)).
These things are, of course, almost incomprehensibly small — they are biological molecules remember — each being a few nanometers long. Which means that you can plonk a billion on the head of a pin.
Working on this scale has given rise to the science of nanorobotics — making gadgets on a nanometre scale (10−9 meters or one thousandth of a millionth of a metre) and the gizmos themselves are nanorobots — nanobots to their friends.
Making parcels of DNA must be great fun but it’s not much use until you include the fact that you can stick protein molecules to your DNA carrier. If you choose a protein that has a known target, for example, something on the surface of a cell, you can now mail the parcels to an address within the body simply by injecting them into the circulation.
Molecular origami: Making a DNA parcel with a targeting protein. A bacteriophage is a virus that infects and replicates in bacteria, used here to make single strands of DNA. Short DNA ‘staples’ are designed to fold the scaffold DNA into specific shapes. Adding an aptamer (e.g., a protein that binds to a specific target molecule on a cell (an antigen)) permits targeting of the nanobot. When it sticks to a cell the package opens and the molecular payload is released (from Fu and Yan, 2012).
Open with care
Hao Yan and colleagues from Arizona State University have now taken nanobots a step further by adding a second protein to their targeted vehicle. For their targeting protein they used something that sticks to a protein present on the surface of cells that line the walls of blood vessels when they are proliferating (the target protein’s called nucleolin). Generally these (endothelial) cells aren’t proliferating so they don’t make nucleolin — and the nanobots pass them by. But growing tumours need to make their own blood supply. To do that they stimulate new vessels to sprout into the tumour (called angiogenesis) and this is what Hao Yan’s nanobots target.
As an anti-cancer tactic the nanobots carried a second protein: thrombin. This is a critical part of the process of coagulation by which damaged blood vessels set about repairing themselves. Thrombin’s role is to convert fibrinogen (circulating in blood) to fibrin strands, hence building up a blood clot to plug the hole. In effect the nanobots cause thrombosis, inducing a blood clot to block the supply line to the tumour.
Blood clotting (coagulation). Platelets form a plug strengthened by fibrin produced by the action of thrombin.
Does it work?
These DNA nanorobots showed no adverse effects either in mice or in Bama miniature pigs, which exhibit high similarity to humans in anatomy and physiology.
Fluorescently labeled nanobots did indeed target tumour blood vessels: the DNA wrapping opens when they attach to cells and the thrombin is released …
Fluorescent nanobots targetting tumour blood vessels (Li et al. 2018). The nanorobots have stuck to cells lining blood vessels (endothelial cells: green membrane) by attaching to nucleolin. After 8 hours the nanorobots (red) have been taken up by the cells and can be seen next to the nucleus (blue).
Most critically these little travellers did have effects on tumour growth. The localized thrombosis caused by the released thrombin resulted in significant tumour cell death and marked increase in the survival of treated mice.
Robotic DNA machines are now being referred to as ‘intelligent vehicles’ — a designation I’m not that keen on. Nevertheless, this is a cunning strategy, not least because, although much effort has gone into anti-angiogenic therapies for cancer, they have not been notably successful. Simply administering thrombin would presumably be fatal but, well wrapped up and correctly addressed, it seems to deliver.
Fu, J. and Yan, H. (2012). Controlled drug release by a nanorobot. Nature Biotechnology 30, 407-408.
Suping Li et al. (2018). A DNA nanorobot functions as a cancer therapeutic in response to a molecular trigger in vivo. Nature Biotechnology doi:10.1038/nbt.4071