Krishnamurthy Lab

Science and Life: Selection and Evolution

(Why things are the way they are and not otherwise)

 Ram Krishnamurthy

I am a chemist who has a deep interest in the origins of life both from a scientific and philosophical aspect. I guess that was a natural result of the way I was brought-up in the coastal city of Chennai, India. I grew up in a typical Hindu orthodox family; my father was lawyer and my mother was a homemaker; both of them endowed with a strong sense of family values. We were living in a surrounding that was steeped in religious atmosphere admixed with a healthy dose of questioning that is typical of Hindu culture: what is the ultimate basis for what we see around us? What is the unchanging reality that gives rise to world around us that is ever changing? This mixture of abstract and philosophical approach was preparing me for what was to come later in my life.

My interest in science was kindled by a fascination with the structure of molecules as it related to how they function. Why does this molecule/chemical smell this way or why does it have a color that changes when I change this part of the molecule?

Why are things the way they are and not otherwise?

This question became part of my thought process whenever I observed something.  This questioning process received a scientific-boost when I began watching the TV series “Cosmos” by Carl Sagan that was just being televised. The journey into the cosmos in Sagan’s “imaginary space ship” was simply mesmerizing. I was riveted by the episode in which Sagan explains how the face of a Samurai warrior of the Heike clan came to be inscribed on the crab shell found in the waters of the Inland sea in Japan! That a “selection” process, natural or otherwise, could determine the outcome of why things are the way they are in Nature began to appeal to me. The question remained whether this same “selection” process could explain why Nature had settled on certain special molecules of life and life-processes. More on that later!

My continuing fascination with molecules led me to the science of making them – through chemistry. I pursued my bachelors (university of Madras), and masters (IIT, Bombay) and moved on to my Ph.D. in chemistry (The Ohio State University, Columbus). It was there that I chanced upon my “Yoda” who would lead me on the path to the question of “whether selection could operate at the molecular level?” In 1990, I listened to a talk by the great chemist Professor Albert Eschenmoser. His lecture beautifully outlined how chemical research – using the toolbox of chemistry – could be used to understand why nature chose RNA as the molecule that is at the center of many biochemical and life processes. I suddenly sensed that my life-long passion of questioning “why things are the way they are and not otherwise” could be translated to the level of molecules and, perhaps, even answer questions relating to origins of life! I immediately wrote to Professor Eschenmoser expressing my admiration of his work and requesting a chance to work with him. I did not hear from him for many months; it was unnerving. Will I be offered a chance? If not what will I do next? When I had almost given up hope, almost 6 months later, a letter arrived from Zurich informing me that I had been offered a post-doctoral position at his lab in the Swiss Federal Institute of Technology (ETH). I was excited beyond words and ran with that letter breathlessly to my Ph.D. advisor who enthusiastically encouraged me to accept this offer at what he called “the Harvard of Europe”. In 1992 June I left for Zurich ….

Working with Eschenmoser at the ETH was a like a chemist’s version of heaven. Eschenmoser was like a father figure; he was strict in his logic, wise in his interpretations and humanitarian in dealing with his co-workers. My work at ETH was quite successful; exciting discoveries, and understanding their implications, were exhilarating. At the request of Eschenmoser I extended my stay by 6 more months before I took up a position at the Scripps Institution of Oceanography in La Jolla, in Dec 1994, where I worked on understanding the role of minerals in controlling the chemical outcomes of certain simple chemical reactions pertaining to the formation of sugar molecules, particularly the type of sugar (ribose), which is the “R” in the RNA. In July 1996, I was recruited to The Scripps Research Institute (TSRI) by Eschenmoser to start a lab, jointly with him, continuing the quest to understand the structure of DNA/RNA from an origins-of-life perspective. This collaborative effort uncovered many variations of DNA/RNA that were able to function like RNA (Watson-Crick base pairing properties). The more variations we studied to show how there could have been other potential alternative candidates for Nature to chose from, the more it dawned on me as to “how unique” RNA was! RNA seemed to be optimal for what it does – store information, transfer information, mediate the information transfer between DNA and proteins and host of other activities that are continually being discovered. But this led to another question: “optimum with respect to what?”

By 2009 Professor Eschenmoser had retired and I continued the journey at TSRI to understand the “optimal-nature” of RNA from a structure-function perspective. How are the parts of this big molecule, RNA/DNA, contributing to its ‘optimal’ function? Why did nature settle on these specific four alphabets A, U (T), G and C in RNA (in DNA)? What was the role of the five-membered sugar ring in RNA and DNA? It was already known that the negative charge on the phosphate coupled with its stability and solubility in water was important for the function of RNA and DNA. The role of the ribose-sugar (five-membered ring) and the four alphabets (A, U(T), G and C) were still not settled in my mind. As I was mulling about the subject matter for a review article I had been invited to write, my mind dwelled on certain puzzling results from our previous work (with Eschenmoser) on other substitutes to the four letters (A, U(T), G, C) of RNA/DNA, and the answer to “why these four alphabets” suddenly dawned on me. This was the “eureka” moment, but without the bathtub! I could picture these four alphabets dancing in a sea of water behaving like oil droplets; they would stick together once the right partners “found” each other. It turns out that these four alphabets in RNA/DNA seem to be the best at coming together and forming duplex structures with the Watson-Crick specificity of base-pairing in an aqueous environment at neutral pH. The ring structure of the sugar in RNA/DNA turned out to be (again by comparison with other cyclic and acyclic sugars) the optimal in enabling and maintaining the Watson-Crick specificity of these four alphabets under aqueous conditions, again at neutral pH. What began to emerge was a pattern where Nature first selects molecules/systems based on certain physical and chemical parameters and, once a selection has been made, evolves those molecules/systems further by fine-tuning them to be optimal for a given environment.

What began as a fascination with structure-function relationship led to many “why and why not” questions. Pursing this pathway slowly led to the realization that the iterative process of selection and evolution – with an aim for optimal function (“survival”) for a given environment – seems to be at the heart of why things are the way they are and not otherwise, both in the microcosm and macrocosm. In other words, at the beginning the environment controlled what could be selected and what can evolve. But once a system evolved to a level that it could sustain itself, it acquired the capability to survive by changing itself and/or its environment. Such a process, strikingly, parallels what biology has achieved with life, wherein an organism is able to adapt to survive the changing environment. In this context, it is tempting to compare the process of how life started and got established on earth, by chemical selection and an evolutionary process – with how we as humans are born into a given environment and evolve to find our optimal surroundings that define ourselves, and our happiness. In both cases there is a “transformation” from what is controlling to what becomes the controller. Perhaps, there are a few lessons to be learnt for our own living as we try to understand how molecules came together to give rise to what we call “life”.

For all the advances that have happened in the origins of life field, we are still far away from a complete understanding of the details of how life came to be, many billions of years ago. But at the same time the very desire to know keeps me up at night wondering …. “if the whole process had to start again from the beginning will we end up where we are (again)?” If yes “why” and if not, “why not”! And interestingly, but not surprisingly, the very same questions also exist in our own lives and tug at our hearts and minds!