Discovery 6/26/29

By Richard Bleil

Back in the late ’80’s, as a young chemistry graduate student, I sat in a seminar listening to one of the nation’s premiere biochemists. He was working with an anti-tumor medication, a small organic molecule that bound in the minor groove of DNA to the very specific sequence AAATT (DNA has four nucleic acids, designated G, C, A and T, the sequence of which is the blueprint on how to create proteins that make us who we are, otherwise known as the “genetic code”). The question at hand is how this small organic molecule can actually recognize one specific sequence.

To complicate the question, the molecule can form four special types of bonds called H-bonds. These bonds were expected to be key to this sequence recognition, but it only deepens the mystery. How can four hydrogen bonding regions recognize five base pairs, AAATT?

There seems to be the perception today that “research” means a web search. There’s a good chance that most of what we, as a species, have learned is indeed on the internet, but it is arrogant to assume that we have learned everything that there is. If you did a search for this (certainly back then and probably even today) you will probably find references to his hypothesis. He certainly published enough papers based on his hypothesis. The problem is that his hypothesis is largely based on a very old and discarded idea called the “bifurcated hydrogen bond”, a theory that personally I have trouble believing.

My adviser required every one of his graduate students to come up with a research project on their own and, if not get a publication, at the very least make significant progress on the problem prior to graduation. So, I picked this up as my independent research project, asking one simple question; how does this molecule recognize the nucleic acid sequence?

Research is a long, slow, tedious process including significant library work. I used to buy spiral bound notebooks dedicated to each research project so all of my notes on that project were collected in a single group of notebooks. I had worked on this project for several years, and had already filled three or four of these notebooks. I remember I was working late on the project and decided to get a pop. I walked from the ground floor where our lab was down to the basement where the vending machine was in the stairwell. And there it happened.

Albert Einstein suggested that learning occurs in intuitive leaps. Our knowledge level is stuck on a plateau, and remains there as we work and work and work and work when, suddenly, we have an intuitive leap. An epiphany takes us to the next plateau. I had an epiphany at that moment.

See, the four hydrogens involved in the hydrogen bonds are not recognizing the five nucleic acids, AAATT, but rather, they are recognizing the four spaces between the bases, A (1) A (2) A (3) T (4) T. It is not the attractive intermolecular forces, but rather, the lack of the repulsive forces that are present if you replace one of these nucleic acids with a G or C.

I got so excited. I started jumping and dancing around, and I’m not even sure I got my pop. For that moment, for that one instant, I knew something that nobody else in the world, nobody, knew. Just me. Well, and soon the professor coming down the stairwell.

He saw my excitement, and even though his expertise was not in a related discipline, he asked me what was going on. I explained it to him, and he started jumping around and dancing with me.

This, to me, is the most exciting thing about science research. These leaps, the moments that you and you alone have discovered something completely new, something to contribute to the collective body of human knowledge that nobody else can. You can’t find it on a web search, because nobody but you knows it.

Other fields, no doubt, have the same exciting moments. An artist, wanting to create an image or emotion, can suddenly realize how to convey that feeling after working on it. A programmer can finally figure out a way to write an algorithm unlike anything yet seen. A chef finally figures out that dish that has been solid but seemed to have something missing all along.

These moments come from hard work and personal perseverance. It’s not quick; there is no instant gratification, but the feeling is indescribable. I hope that my readers all can experience this elation at some point in their life; it’s an astounding experience.

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