Structural biologists are revealing the astounding complexity of the molecular machinery of life. But why is it so hard to get any real sense of our molecular nature?
I’d like to show you your inner molecule but, to be perfectly honest, I don’t think you’re interested. Which is rather frustrating for scientists like myself who have spent a career in structural biology working out what the molecules of human life look like. You know – proteins, nucleic acids, carbohydrates, lipids. The stuff we’re all made of.
It may seem odd to complain about a lack of interest in our molecular nature because people seem to be endlessly fascinated – if not obsessed – by DNA, one of the most famous biological molecules of all time. We have little trouble understanding its importance, as the stuff of our genes, in shaping our identity and experience. It links us through evolution to every other living thing on earth and is an essential part of the story of who we are. Our individual stories can take unpleasant turns when our genes malfunction as a result of mutations that cause hereditary diseases or cancers. And lately the manipulation of DNA has been driving the fascinating, if controversial, business of genetically modifying the animals and plants on our farms; even changes to human DNA are now up for discussion as the recent debates around mitochondrial transfer and genome editing have shown.
But with DNA the focus is on the idea of genetics as an explanatory framework, rather than on the molecule itself. You can tell that’s the case because as soon as someone mentions gene products, the myriad protein molecules encoded by genes, suddenly there’s a switch-off. These minuscule molecular machines perform a bewildering range of tasks inside and outside the living cell – including synthesising pretty much all the other interesting molecules in our bodies – but even so the conversation stalls. We just don’t talk about proteins. For most people there’s no sense of connection, despite the fact that to have a sense of anything involves the protein ion channels and neurotransmitter receptors in our brains relaying the electrical and chemical signals that constitute thought. Why are we not more interested in the molecules we’re made of?
I guess I shouldn’t complain. It’s hard to love a protein molecule. It’s hard even to get to know one. They’re so small that you’re not ever likely to clap eyes on one unless you have access to a laboratory. It seems unfair that these vital micro-machines should be so incognito.
If I asked you right now to think of a protein, any protein, what picture would come into your mind? I don’t wish to be judgemental but I’m guessing you may well have drawn a blank. Everyone knows what DNA looks like with its oh-so-elegant double helix. But what about myoglobin, the first protein to have its structure worked out in three-dimensions – just a few years after DNA grabbed the limelight? Not such a celebrity.
Part of the problem is bad PR. John Kendrew’s work to solve the structure of myoglobin, a handy oxygen store found in muscle cells, was in fact a more impressive scientific feat that figuring out DNA (no mean achievement in itself). But the end product lacked pizzaz. It was no looker, to be sure. You can see for yourself in London’s Science Museum where the original atomic model painstakingly constructed by Kendrew in 1960 is on show as part of the Churchill’s Scientists exhibition. It’s well worth a visit if you would like to meet one of your inner molecules. The myoglobin model in the display is from sperm whale but the version in your body basically looks identical. (That’s one of the clever and unappreciated things about structural biology: it reveals similarities at the molecular level that testify to the evolutionary unity of all living things, at a level even deeper than correspondences between DNA sequences.)
Kendrew’s myoglobin model buried in a forest of rods
On show at the museum: Kendrew’s myoglobin model buried in a forest of rods Photograph: Stephen Curry/Personal Collection
It may not be pretty but there is a certain majesty to Kendrew’s model. It’s big – about a metre and a half on a side – and fantastically detailed. Every atom is on display. However, it’s not exactly easy to take in because the wireframe model has to be supported on a dense forest of wooden rods and these rather dominate proceedings. You have to peer closely to discern the wire connections between atoms and to get an idea of how the molecule takes shape. From every angle the view is obscured and fragmented. It’s difficult to appreciate that there is a superb piece of natural engineering lurking within.
But it’s not just the rods that are the problem. The thousands of protein structures that tumble out of labs every year can now be displayed in an instant in your web browser. You can go to the Protein Data Bank (PDB) where they are stored and have a look. The PDB has been working hard in recent years to make these structures accessible to the non-specialist but I wonder how many drop by?
I suspect it’s hard to drum up visitor traffic because most people don’t feel enough of a connection with their molecular selves to have a reason to go exploring. It’s not just the looks – a significant part of the problem is the complexity. To really appreciate a large biological molecule you have to know something about what it does and that often involves a fair bit of chemistry. In every case, the back story is full of arcane detail. The fancy computer graphics these days might soften some of the complex edges, and make the molecule appear friendlier, more appealing, but that’s not enough if you can’t get a handle on how the protein fits into the scheme of things.
Computer-generated representations of protein and RNA in a molecular embrace (an aminoacyl tRNA synthetase) Facebook Twitter Pinterest
Computer-generated representations of protein (grey) and RNA (orange and yellow) in a molecular embrace (an aminoacyl tRNA synthetase) Photograph: Stephen Curry/Personal Collection
The situation is made even worse by the fact that molecules are often worked on and presented to the world one at a time. Because of that isolation it can be difficult to get the sense of the thing, never mind absorb the idea that the protein you are looking at is a part of you.
That’s why I am such a fan of the work of David Goodsell, an associate Professor of Molecular Biology at the Scripps Research Institute in California. In addition to his day job as a scientist, he has faced down the complexity and isolation intrinsic to the scientific analysis of bimolecular structure by creating beautiful paintings of cellular interiors. These images put the molecules of life into a rich and meaningful context. There is some artistic licence in his work to be sure, but it is informed by the latest science – the scales, shapes and numbers of the molecular participants of these living landscapes are based on the best available information. If you would like to see inside yourself in magnificent molecular detail I highly recommend his illustrated book, The Machinery of Life, which I’ve written about before.
The molecular world comes even more alive in the animations of Drew Berry, a biomedical animator at the Walter and Eliza Hall Institute for Medical Research in Melbourne. Berry has brought a truly cinematic vision to the portrayal of biological molecules. He has taken us the closest we have yet come to seeing what really happens at the molecular level within the cells of our bodies – the processes that keep us ticking, such as the replication of DNA needed before every cell divides, or the translation of the gene sequences into the proteins that structure our cells and keep the biochemistry of life in motion. Here he is giving a TEDx talk at Sydney in 2011, showing off some of his best work. Please take a look – the animation starts at 2:48.
Drew Berry explains his art and his science at TEDx Sydney, 2011
Berry’s animations are fantastic. Like Goodsell he is committed to bringing as much rigour and scientific detail as possible to his depictions of the machinations of life. (In an accompanying post, he explains the philosophy and process of his work). There’s an impressive exactitude here, combined with a passion to show us what we are like at a granular level far beyond the ken of our senses.
The power of these animations in revealing our molecular selves is undeniable. And yet… there is an inescapable artifice that raises yet another barrier between us and our molecular components. The proteins and DNA within us cannot be seen even with the best light microscopes since they are far smaller than the wavelength of light. Scientists therefore have to resort to a bizarre toolkit of indirect methods such as X-ray crystallography, nuclear magnetic resonance or cryo-electron microscopy to provide the data that allow three-dimensional molecular models to be reconstructed in the computer. Nothing is ever seen directly though we can be confident that these techniques yield atomic coordinates accurate enough to specify how the molecules are constructed. For his movies Berry has the choice of how best to render the resulting structures – with individual atoms as spheres, or perhaps just displaying the molecular surfaces – and to colour them to enhance distinctions between different molecular parts and players (in reality, most proteins are rather colourless). These decisions are entirely reasonable and help us to see what is going on but the fact remains that none of the representations used shows what the molecules really look like because no-one has ever seen one.
None of which is to diminish Berry’s work. You can tell from his TEDx talk that he is serious about this stuff. As a structural biologist I appreciate more than most the lengths he has gone to to get things right. But even though I am immersed daily in this world, there’s one final problem with making a connection to our inner molecules that I’ve discovered in watching Berry’s careful, artful animations. However many times I tell myself that all the jiggling machinery depicted his films is at work every second of every day inside every cell of my body, somehow it still doesn’t seem quite real to me. The same is true of Goodsell’s elaborate scientific paintings. The complexity on show is mind-boggling, but immediately raises a disturbing question: how on earth does the whole shebang keep going for the decades of a human life without grinding to a halt?
Is it is too much for the mind to accept its dependence on so many thousands of molecular encounters – encounters that seem blind and mechanical? The jostling actions of mere molecules sits uncomfortably with my sense of myself as a rational agent and perhaps that is ultimately what disrupts any deep-rooted sense of the molecular self. It doesn’t matter that I know that all these molecular interactions are vital for life, that I know they have been shaped and guided by the unseen hand of evolutionary selection over billions of years, or that I’m quite comfortable with my evolutionary connections to the history of life on Earth. None of this helps me to make forge a relationship with my inner molecules that I can feel.
There is some serious cognitive dissonance going on here that is personally and professionally disturbing. Despite all my years in structural biology, it appears that knowing is not enough.
Watch the video. URL: https://youtu.be/WFCvkkDSfIU