A dichotomy of research…..

by Jim Caryl


I AM a juggler by profession, but it is not balls that I juggle; instead, I juggle variables.

I currently work on basic technologies research. This does not mean to say that my research is basic, rather it means that the technologies that we are trying to develop are at a fundamental, or grass-roots, level. As such, some might call such research ground-breaking; though I hasten to add that this term is more considered in it’s metaphorical context. If any of you have ever had to dig in a new garden, or have led the way in deep snow on a mountain, then you’ll have some idea of what breaking new ground is all about. It is hard, unrelenting and there is no lateral movement, you either move forward into new ground, or you back-step until you get to base camp and set off in a new direction.

I am working on a biochemical reaction (a reaction involving biomolecules such as proteins and DNA) that has been shown to work in solution, in a tube. Other people have shown this, and I have shown it. However, interesting as this reaction is, we want to go further with it and have it work on a solid gold surface. Why? Well, ultimately we would like to be able to control the reaction by using an electric field, to turn it on or off, or better still control the precise level of its activity.

Having a biological system that works at the flick of a switch seems like a pretty cool idea, right? You’re sitting in a small, dusty village in central Africa or central South America. You’ve taken a load of blood and saliva samples that you intend to test for certain antibodies, or for the presence of current bacterial or viral diseases. It’s hot, there is no power and it took you a week of travel to get there. You are worried that your samples will degrade before you can get into a position to test them, and if you are especially well funded, you will have brought a whole portable lab with you, at great cost, and at great loss if it breaks on route.

What if, instead of the above hassle, you take out the small box you brought with you, in which there are several foil-wrapped packets containing plastic cassettes about the size of your thumb, but considerably flatter. What if you could inject the blood or saliva sample in at one end of the cassette, wait a minute and at the other end one of several LEDs light up. The combination of LEDs will tell you what the cassette has detected. Inside the cassette are small flow-channels that each contain different biomolecules that have all been painstakingly developed to function in this capacity. Simple, potentially very cheap, a laboratory on a chip.

Furthermore, you flick a switch on the cassette, which makes the juice from the small battery alternate from just powering the LEDs to instead put an electric field through the flow-cells; you can now conduct a second set of reactions using biomolecules that had been inactive until that point. TWO labs on a chip! Lab on a chip technology already exists, but there is much further for it to go, and this requires basic technologies research.

Ideally we would have a chip that could perform logic functions, so rather than it just detecting molecule A and it saying “hey man, you’ve got some molecule A here”, or likewise with molecule B; perhaps if molecule A and molecule B are both present, then this indicates something more serious, which is indicated by the presence of molecule C. Rather than you wasting time, and another chip, going back and testing the blood sample again for molecule C, the chip can detect both A AND B in combination, and in doing so will have activated another internal component that is able to then detect C. However, if the chip detects only B, NOT A, then this could indicate something else, so it triggers something that can detect this something else, perhaps molecule D. See? A logical chip.

Well, returning from the realms of near-future science fiction, in order to achieve any of the above in my basic technologies research, there are several variables we (meaning I) need to juggle, and this is where the fun pain starts:

  • Most biochemical reactions have certain requirements, one of which is for the molecules to be able to jumble and tumble, bend and change, which they can do when floating around in solution. However, when binding biomolecules onto a solid surface you are, to a lesser or greater extent, limiting their ability to move; no movement = poor reaction.
  • Binding biomolecules onto a surface also has another problem, you only have two-dimensions of molecules, and there is only so much surface available. I’m sure you can all appreciate, area is often less than volume, so consequently, we’re not dealing with very many molecules! So figuring out whether the reaction has taken place is limited by our (meaning my) ability to detect it. Advanced detection techniques exist that allow you to detect the most minute of reaction products, but all such techniques have their flaws and represent several weeks worth of optimisation in themselves.
  • Once you have your key biomolecule on the surface, you need to throw in the other molecules that are the reactants. If you want to make a cake, and you have your oven (analogous to our surface-bound biomolecule) primed and ready to go, you’ll need to mix the ingredients of you cake. However, what if your eggs have gone off? They only last so-long after all, flour isn’t really a problem, if stored correctly, but eggs, oh dear. Well, this is the other problem we (meaning I) have; one of the component molecules I need is quite unstable, so once I’ve created it it doesn’t last very long, so I always need to check to make sure it still works (i.e. more time for experiments needed).
  • Assuming that all the above steps go according to plan, the final hurdle is “the machine“. The machine is what allows me to add things onto my gold surface, a little bit at a time. It can tell me that the bits that I’ve added have bound to each other, but it can’t tell me that the reaction has worked; I’ve already mentioned about needing a separate detection technique. The machine follows instructions, often rather too literally, and we have to monitor it carefully to make sure it is actually doing and performing as we (meaning I) expect it to. Occasionally it breaks, which usually means its out of operation for several weeks before we can get it fixed. The irony is that ultimately we will be able to detect that the reaction has happened on a surface, but we’re in the process of inventing it!

All of the above “balls” have to be in play for a successful experiment to be performed, and there are any number of things that can go wrong at each step to foul things up. Once we (meaning I) think one step is completely sorted, another (which was previously sorted) will then stop working, ad infinitum. The amusing thing is, all of the above is just to get us to the point where we can try controlling the reaction with an electric field.

For a more complete analogy of the perils and pitfalls of academic research, click here.