The wonders of DNA

Towards the DNA age

Who would have thought that one day the scientific name of a complex biomolecule would ever become so popular that it is now more frequently used than the word “pizza” in the English language?  Yes, I am talking about DNA, which, according to the word frequency database,  is ranked 2852nd amongst the 5000 most frequently used words in the (American) English language while the word pizza figures at the 3956th position.

I think this is very representative of how the very discovery of DNA and the whole new set of narratives that comes with it have changed Western civilisation to the core: for the best or the worst we now seek DNA-based explanations for anything ranging from personality traits and physical abilities  to love, happiness and careers.  In term of analogy, I tend to think that DNA plays a role analogous to almighty magical substances or alien artefacts that become an integrated part of fictional societies in well written science fiction stories: DNA is a biomolecule with great secrets and powers that we just need to unlock to solve various societal problems.

Computer program and biological program

In this digital age, DNA’s “secrets” and functions have strong similarities with our designed computer programs. In fact, Bill Gates has reportedly written in his book The Road Ahead that “DNA is like a computer program but far, far more advanced than any software ever created”. Now, for anyone who has ever used a computer or a smartphone, it is  clear that a file containing instructions is useless if  one does not have the proper software to read the file. For example, if you download a .pdf file then, unless you have some kind of pdf-reader, you won’t be able to consult its content in a intelligible manner. The same holds for DNA: it contains information encoding for the fundamental biological processes occurring in our cells and beyond but it needs to be read with the proper tools, called proteins, and also protected from alterations due to external factors.

Now, our computer-based programs and DNA’s biological programs are not entirely similar from a physical and conceptual standpoint. In fact, computer-based programs are physically hard-wired in the sense that there is usually no place for randomness in the way (where, when and how) the instructions are to be executed. On the contrary,  DNA and other biomolecules executing DNA’s code are always moving about (thus affecting when and where the execution will take place) in a soup of other “stuff” (possibly affecting how the execution is done too); biological programming is in this sense soft-wired.

This softness of the biological programming  is inevitable in virtue of the fact that the tools executing DNA’s code (proteins) are so small (about a millionth of a millimeter in size) that they end up moving randomly in water by frequently colliding with neighbouring molecules: this is called Brownian motion .  This leads to great complications to comprehend for instance how proteins even find efficiently the piece of code they are meant to read on DNA in the first place.

The advantage however is that, if well organised, the whole execution happens on its own and may well give rise to a great adaptability in the ways with which a biological system spontaneously responds to an external constraint.

In the remainder of this post, I will try to show that one way used by Nature to make DNA’s management, reading and protection efficient is by making use of various “clothings” for DNA, each of which is thought to have various biological functions.

DNA’s wardrobe

What is DNA?

So far I have talked about DNA like in an episode of CSI and have assumed that everybody knew what DNA actually was but I need to delve a bit more in the details for the rest to make sense.

DNA is a ribbon-like molecule whose width is 2 millionth of a millimeter and whose internal structure is that of the famous double-helix represented in the picture above. The DNA code is written with an alphabet of 4 molecules represented by the letters A (for Adenine), T (for Thymine), G (for Guanine) and C (for Cytosine) and visible on the right side of the figure above. The quasi-exclusive complementarity between the bases A and T on the one hand and G and C on another hand is important for efficient DNA packing, transport, protection and enables a straightforward copy/paste mechanism necessary during cellular divisions during which the genetic material has to be duplicated.

Besides how DNA looks like and what it is made of, we also need to worry slightly about some of its chemical properties and how those will have a huge impact on the physical mechanisms by which DNA interacts with its surroundings. DNA stands for Deoxyribonucleic Acid and, as the name suggests, it means it is an acid. In case you have never learned or forgotten what an acid was, let me tell you briefly: for our purpose here, an acid is a molecule that give up one or more protons upon being put in water. Since protons are positively charged, it means that an acid in water becomes negatively charged and is surrounded by positively charged solvated protons and possibly other charged species.  This is one of the aspects of most interests from the physics point of view because the electrostatic interaction between charged species (charges of the same sign repels while charges of opposite sign attract) is the only way by which molecules actually “see” or “feel” each others from afar in solution and this plays a a key role in our wardrobe story.

First outfit: no outfit

Incidentally, like us, DNA can be naked. Naked DNA or bare DNA is the state in which DNA finds itself when it is put in a solvent and stripped of its protons by the surrounding water molecules. In that state, DNA is highly negatively charged and it can be strongly “seen” or “felt” by other molecules and biomolecules if they come close enough to DNA, for instance few tenth of a nanometre from it. The functional role of this bare state is of course not entirely certain but some line of arguments suggests that it could play a role in the random search of proteins for a target coding sequence on DNA or even in the actual physico-chemical recognition mechanism of such a sequence.

Second outfit: the electrostatic invisibility ionic cloak

Due to its very high negative charge, if DNA was only naked in solution, it would attract too much attention from the other molecules in the cell: it would be like a beacon towards which all the positively charged macromolecules would go and gather. Now…this would not necessarilly be an efficient outcome because not all macromoelcules have to operate on DNA and it is also thought that if the proteins tend to be too strongly bound unspecifically on DNA this could slow down considerably the search of a coding sequence by its corresponding protein. Fortunately, as we have seen above, there are not only macromolecules in solution but also ions (charged solvated atoms) that can be up to ten thousand times smaller than a protein.

The positive ions will also be attracted by the beacon that is naked DNA but they will reach it much faster than the other molecules because of their tiny size. Eventually they will form an ionic cloak of positive ions surrounding DNA: this is called the Manning condensation.  Now, the reason why I have decided to call it electrostatic invisibility cloak is because once the Manning condensation has happened, DNA from afar “looks” exactly the same as any other charged chain undergoing the same phenomenon; in other words, this ionic cloak, when worn, makes every charged chain molecule look like any other. Although this is a bit technical, this is fantastically explained in this thesis p. 27. There is an additional aspect to invisibility that has to do with the fact that, in addition to having positive ions “dressing” DNA, the presence of other positive and negative ions floating in solution creates an additional screening effect of what remains of DNA’s visible charge that essentially makes DNA invisible to molecules further than few nanometres. One possible biological role for this invisibility cloak would be to have an actual balance between a DNA that can still attract proteins to read its code while not standing out too much at the same time; thus solving the previously mentioned problems.

 Third outfit: the “zipping” ionic jacket

The ionic cloak is worn by DNA in circumstances where the ions in solution do not have a high positive charge. For instance, there are many sodium ions (Na+) in solution and they will almost surely form a ionic cloak around DNA if let alone. Now, in some circumstances, DNA is confronted to ions with charge +3 or +4 much more charged than Na+; in those cases, DNA will prefer to remove its cloak of simple ions and put on instead a multivalent ion “jacket” where the ions are tightly electrostatically bound to DNA. One could think that simply changing the charge of the ions dressing DNA would not be a life changer but, on the contrary, it does make a huge difference. Of course, Manning condensation a priori still occurs and so does the electrostatic screening by more loosely bound ions but the surprise lies elsewhere: if two DNA molecules wearing such an ionic jacket get close enough to each other, they now attract each other! In case this is not a surprise to you, I remind you that the DNA molecules are of the same charge, even when dressed by ions, and should in principle repell electrostatically in all circumstances. So why do they attract at all? This has been an issue debated in the physics community for easily 20 years now which has various possible answers. Long story short what happens is that the net charge of a molecule is not enough to determine whether its interaction with another molecule will be attractive or repulsive: how are the charges statistically distributed in space appears to be crucial too.

As can be seen in the above figure, although ions are tightly bound to their respective DNA, they also like to be in the gap between the molecules; when they do so they form a sort of electrostatic bridge between the dressed DNA molecules: it is a little bit as if the ions in the gap had become themeselves the beacon towards which DNA molecules want to gather.

This outfit is understood to be crucial for the packaging and transport of DNA in bacteriophages (bacterias’ viruses) or sperm cells whereby the ion-mediated attraction leads to a condensation of DNA on itself, thus forming very compact toroidal shapes (cf. image on the left). Another biological role, more controversial however, imagined for this attractive process between DNAs dressed with strongly charged ions is to help in what is called homologous pairing that plays an important role for genetic diversity during meiosis in sexual organisms, thus including humans.

Fourth outfit: the full protein armor

The strongly charged ions that strongly bind to DNA are not always “small” in size. In eukaryotes, these ions can be in fact large pieces of proteins called histones with few thousands atoms each and strongly positively charged indeed. When in contact with DNA, they self-assemble into a super structure made of 4 such pieces around which DNA wraps about two turns; this is called a nucleosome. Incindentally, it is not really clear whether  DNA is wearing proteins or the other way around! These nucleosomes are then made more stable with additional pieces of proteins and are then thought to form an additional super-super structure called chromatin fiber (see image below).

The aledged roles of what I call here the “full protein armor”outfit are seemingly endless:

• In humans for instance it plays the very important role of making the two metres of DNA each of our cell carries fit into a nucleus that is few thousandth of a millimetre in size. Furthermore, not only does it make DNA incredibly dense but it also does it in a way that makes genetic code accessible to reading proteins.

• More generally, the mechanical properties of the nucleosomes and the chromatin fiber as a whole are thought to be of great importance for both sustaining the mechanical sresses exterted by reading proteins, like the RNA polymerase, and enabling the latter to move on this crowded structure effortlessly, opening a “chromatin road” as it moves along DNA.

• The role played by the histone proteins is truely manyfold because they can also undergo chemical changes while in the fiber, thus enabling a whole range of biological processes to happen. Very generally, these mechanisms are thought to play a key role in gene expression and, in particular, in cell differentiation. As a matter of fact, all our cells contain exactly the same DNA; it is thus a mystery that liver cells do not behave like heart cells for instance. Part of the explanation may be hidden in the actual spatial organisation of DNA within the nucleus, controled as we have seen by the histones.

• There would be no point in calling chromatin a “full protein armor” if it did not have any protective role. It turns out that there is also strong evidence that this very compact state of DNA helps preventing DNA damages due to direct and indirect effects of ionising radations (and UV radiation too) but also from chemical damages thus preserving the integrity, as discussed at the very beginning of the post, of the genetic code.

Conclusion

There are multiple ways to end this post. One of them could be to say that we have just seen another way by whitch DNA is amazing: by having the physical ability to selectively put-on the right type of “ionic clothing” adapted to a particular biological context; and in some way that is true. But thinking a bit more…that would not be fair not to aknowledge those who are in fact always there but somehow never seen, the ions moving around, from very simple ones to highly complex ones without which DNA would simply not function, at least in the biological sense. And in any case what matters in the end is how Nature has enabled all these entities to spontaneously interact with each others in ways that are all too often too smart for us to make sense of them.