I Know What I Like

 

I guess most of us at some time or other will have stood gazing at a painting for a while before muttering ‘Wow, that’s awesome’ or words to that effect if we’re not into the modern argot. Some combination of subject, style and colour has turned our crank and left us thinking we wouldn’t mind having that on our kitchen wall.

Given the thousands of years of man’s daubing and the zillions of forms that have appeared from pre-historic cave paintings through Eastern painting, the Italian Renaissance, Impressionism, Dadaism and the rest to Pop Art, it’s amazing that everyone isn’t a fanatic for one sort or another. The sane might say the field’s given itself a bad name by passing off tins of baked beans, stuff thrown at a canvas and unmade beds as ‘art’ but, even so, it seems odd that it remains a minority obsession.

Can science help?

Science is wonderful, as we all know, but the notion that it might arouse the collective artistic lust seems fanciful. Nevertheless, unnoticed by practically everyone, our vast smorgasbord of smears has been surreptitiously joined over the last 30 years by a new form: an ever-expanding avalanche of pics created by biologists trying to pin down how animals work at the molecular level. The crucial technical development has been the application of fluorescence in the life sciences: flags that glow when you shine light on them and can be stuck on to molecules to track what goes on in cells and tissues. The pioneer of this field was Roger Tsien who died, aged 64, in 2016.

Because this has totally transformed cell biology we’ve run into lots of brilliant examples in these pages — recently in Shifting the Genetic Furniture, in Caveat Emptor and John Sulston: Biologist, Geneticist and Guardian of our Heritage and in the use of red and green tags for picking out individual types of proteins that mark mini-cells within cells in Lorenzo’s Oil for Nervous Breakdowns.

To mark the New Year this piece looks at science from a different angle by focussing not on the scientific story but on the beauty that has become a by-product of this pursuit of knowledge.

Step this way: entrance free

So let’s take a stroll through our science gallery and gaze at just a few, randomly selected works of art.

  1. Cells grown in culture:

This was one of the first experiments in my laboratory using fluorescently labelled antibodies, carried out by a student, Emily Hayes, so long ago that she now has a Ph.D., a husband and two children. The cells are endothelial cells (that line blood vessels). Blue: nuclei; green: F-actin; red: Von Willebrand factor, a protein marker for endothelium.

 

  1. Two very recent images taken by my colleague Roderik Kortlever of a senescent mouse fibroblast and of mouse breast tissue:

 

 

 

 

 

 

3. Waves of calcium in firing neurons:

One of my fondest memories is helping to do the first experiment that measured the level of calcium within a cell, carried out with my colleague the late Roger Tsien and two other friends. I only grew the cells: Roger had designed and made the molecule, quin2. We didn’t know it at the time but Roger’s wonder molecule was the first of many intracellular ‘reporters.’ Roger shared the 2008 Nobel Prize in Chemistry for his discovery and development of the green fluorescent protein with organic chemist Osamu Shimomura and neurobiologist Martin Chalfie.

This wonderful video of a descendant of quin2 in nerve cells was made in Dr. Sakaguchi’s lab at Iowa State University.

 

4. Calcium wave flooding a fertilized egg: Taro Kaneuchi and colleagues at the Tokyo Metropolitan University:

Click for a time-lapse movie of an egg cell that has been artificially stimulated to show the kind of calcium change that happens at fertilization. In this time-lapse movie the calcium level reaches a maximum signal intensity after about 30 min before gradually decreasing to the basal level.

 

5. The restless cell (1):

This movie shows how protein filaments in cells can continuously break down and reform – called treadmilling. Visualised in HeLa cells using a green fluorescent protein that sticks to microtubules (tubular polymers made up of the protein tubulin) by HAMAMATSU PHOTONICS.

 

6. The restless cell (2):

This movie shows how mitochondria (organelles within the cell) are continuously changing shape and moving within the cell’s interior (cytosol). Red marks the mitochondria; green DNA within the nucleus. HAMAMATSU PHOTONICS.

 

7. Cell division:

Pig kidney cells undergoing mitosis. Red marks DNA (nucleus); green is tubulin: HAMAMATSU PHOTONICS.

 

8. DNA portrait of Sir John Sulston by Marc Quinn commissioned by the National Portrait Gallery:This image looks a bit drab in the present context but in some ways it’s the most dramatic of all. John Sulston shared the 2002 Nobel Prize in Physiology or Medicine with Sydney Brenner and Robert Horvitz for working out the cell lineage of the roundworm Caenorhabditis elegans (i.e. how it develops from a single, fertilized egg to an adult). He went on to sequence the entire DNA of C. elegans. Published in 1998, it was the first complete genome sequence of an animal — an important proof-of-principle for the Human Genome Project that followed and for which Sulston directed the British contribution at the Sanger Centre in Cambridgeshire, England. The project was completed in 2003.

The portrait shows colonies of bacteria in a jelly that, together, carry all Sulston’s DNA. This represents DNA cloning in which DNA fragments, taken up by bacteria after insertion into a circular piece of DNA (a plasmid), are multiplied to give many identical copies for sequencing.

 

9. “Brainbow” mice by Tamily Weissman at Harvard University:

The science behind this astonishing image builds on the work of Roger Tsien. Mice are genetically engineered to carry three different fluorescent proteins corresponding to the primary colours red, yellow and blue. Within each cell recombination occurs randomly, giving rise to different colours. The principle of mixing primary colours is the same as used in colour televisions.  In this view individual neurons in the brain (specifically a layer of the hippocampus) project their dendrites into the outer layer. Other magnificent pictures can be seen in the Cell Picture Show.

It’s certainly science – but is it art?

A few years ago the Fitzwilliam Museum in Cambridge staged Vermeer’s Women, an exhibition of key works by Johannes Vermeer and over thirty other masterpieces from the Dutch ‘Golden Age’. I tried the experiment of standing in the middle of each room and picking out the one painting that, from a distance, most caught my amateur eye. Funny thing was: not one turned out to be by the eponymous star of the show! Wondrous though Vermeer’s paintings were, the ones that really took my fancy were by Pieter de Hooch, Samuel van Hoogstraten and Nicolaes Maes, guys I’d never heard of.

Which made the point that you don’t need to be a big cheese to make a splash and that in the new Dutch Republic of the 17th century, the most prosperous nation in Europe, there was enough money to keep a small army of splodgers in palettes and paint. Skillful and incredibly patient though these chaps were, they simply used the tools available to paint what they saw in the world before them — as for the most part have artists down the ages.

But hang on! Isn’t that what we’ve just been on about? Scientists applying enormous skill and patience in using the tools they’ve developed to visualize life — to image what Nature lays before them. So the only difference between the considerable army of biological scientists around the world making a new art form and the Old Masters is that the newcomers are unveiling life — as opposed to the immortalizing a rather dopy-looking aristocrat learning to play the virginal or some-such.

Controversial?

Not really. Let’s leave the last word to Roger Tsien. In our final picture there are eight bacterial colonies each expressing a different colour of fluorescent protein arranged to grow as a San Diego beach scene in a Petri dish. It became the logo of Roger’s laboratory.

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Getting your DNA in a twist

I have a good friend who has just emerged triumphant from a run-in with bowel cancer – she’s in complete remission! Almost as wonderful is the fact that colliding with cancer has converted her from a genuine non-scientist to one who devours biology like fish and chip suppers. Spotting a recent volley of media items about four-stranded ‘quadruple helix’ DNA in human cells, she was on Twitter in a flash: “Does this mean that people with cancer have lots more quadruplex DNA than normal?” As she knows I can’t stand the Tweet cult she was probably amazed to get a reply: short answer: “No.”

But as ever in science, there’s a long(er) response. So, if you’re interested in the gyrations and gymnastics of which your genetic code is capable, read on …

The DNA double helix

The DNA double helix

Beautiful DNA

As you know, DNA comes as a double helix – a 2-chain spiral of small units (called nucleotides) that stick together (the units contain bases, so they’re ‘base-paired’). The oft-reproduced double helix image is beautiful because it’s a repetitive structure and you can easily see how it can be ‘unzipped’ so that each half can be used as a template to make a copy and regions can be ‘read’ to make RNA and proteins – though it was really designed to enable biologists to make endless unzipping jokes about genes and jeans.

The two DNA molecules of the helix stick together because of a balance between three forces: (1) weak electronic attraction between some atoms in the bases (called hydrogen bonds), (2) a sort of glueyness between the bases because their chemical structure means they don’t like water much and they’d rather snuggle up together, and (3) a repulsion between the chains because of the repeated phosphate groups all the way along the backbone (these carry an electric charge and likes repel, as we know).

Ugly DNA

But with all these attractions and repulsions you might think there would be lots of ways nucleic acids could get tangled up with each other – and there is. So the common form of double helix (the beautiful shape) is B-DNA but there’s also A-DNA, C-DNA and Z-DNA. If you just change the conditions a bit (pinch of salt or whatever) you can tweak the interactions so bits of the bases that don’t interact in B-DNA will do so to give a slightly different shape (usually a bit distorted – ugly). As you can see from the structure, Z-DNA is more Homer Simpson than Watson and Crick.

B- and Z-DNA

B- and Z-DNA

B-DNA and Z-DNA

We can’t reproduce the environment of DNA in the nucleus so we don’t really have a clue but the betting is that short bits of DNA jink in and out of these odd structural formations – just as part of the continuous flexing of the molecules. There’s also a couple of other things that can happen that have been known for a long time – again just dependent on the precise conditions in which a piece of DNA finds itself.

Sexy modelling

The first is a variant on the hydrogen bonds that form between bases. One way to think of this is to imagine two circles of five people, each ring holding hands and facing outwards. Each person is an atom in the bases of DNA. Let’s think of base pairing as the two nearest in the circles getting close enough to kiss. That’s one hydrogen bond. But, of course, the two other pairs on either side will now be quite close: if one of them also manages to kiss (tongues may be used) now we have two hydrogen bonds – which is what holds the bases A and T together. But suppose that the pair on the other side (who must also be quite close with all this adjacent necking going on) decide they really fancy joining in and are so excited that they twist the circle out of shape to do so. That this can happen has been known for years (it’s called Hoogsteen base pairing after the voyeur what spotted it) and when it does it can distort the helix enough for a third DNA strand to wrap round the original two – so you get triple-stranded DNA.

A sexual need

Similarly, if you tweak the conditions you can get four strands of DNA to come together and indeed we’ve known for yonks that happens naturally during recombination (that’s when genetic material gets swapped between Mum and Dad chromosomes – the reason for sex). When that happens you can think of four DNA strands forming a cross, each quadrant contains DNA from one strand of a chromosome, base-paired to that in the next quadrant – which is how bits get swapped around.

Non-sexual hugging?

So there’s nothing new about odd DNA shapes but what has made the news is that for the first time, rather than looking at what can be made to happen in a test tube, Shankar Balasubramanian and his pals have looked in whole cells. To do this they made an antibody that sticks only to ‘quadruple helix’ DNA structures – G-quadruplexes. The upshot is that they detected quadruplexes scattered throughout chromosomes and they see more in cells that are rapidly dividing than in ones that are just sitting there (they looked in some cancer cells in culture that do divide quite rapidly – but bear in mind that in tumours cells aren’t diving all that fast). So the inference is that they might form as part of DNA replication and, if you can target them by their antibody, maybe you could do something similar with a drug that would stop cells dividing. And if you could target that to cancer cells you could stop them in their tracks.

And the catch …

Simple. But there are some problems. It’s possible the antibody helps the quadruplexes to form – so it could even be a cunning artifact. But if we assume it isn’t – then we come face to face with a really big problem. There are zillions of ways you can kill cancer cells. The difficulty is that there isn’t one that selects cancer cells from normals. It may be possible (though it’s not evident how) to target quadruplexes and block cell division – but there are lots of cells that we need to divide rapidly just to keep us going – and, if quadruplexes are real, presumably they have ’em. So non-specific killing is probably not a good idea. Twas ever thus.

References

Biffi, G., Tannahill, D., McCafferty, J. and Balasubramanian, S. (2013). Quantitative visualization of DNA G-quadruplex structures in human cells. Nature Chemistry published online: 20 January 2013 | doi: 10.1038/nchem.1548

http://www.cam.ac.uk/research/news/four-stranded-quadruple-helix-dna-structure-proven-to-exist-in-human-cells/