Notes of a protein crystallographer: quo vadis structural biology?

Correspondence e-mail: xtalp1@aol.com The question has been asked many times, ever since grade school and all through high school and college. It is a question that people in the streets accept as an important theme of the scientific discourse: what are the states of matter? The answer has always been deceptively simple: solid, liquid and gas. Everybody knows that! More scientifically sophisticated responders might add ‘plasma’ as a different configuration of material elements to yield a distinctly different state of matter. To this worn out answer one might reply: where do we include the living systems? Where do we include the myriad of living organisms that populate our air, soil, land and oceans? Explicitly none of these living forms is included in the three classic states of matter. They are neither totally solid nor liquid, nor are they completely gaseous. Traditionally, none of the well recognized states of matter includes the biosphere. By everyone’s admission, living organisms are not solid, liquid or gas. They are a form of matter that includes all the other three accepted categories and then something else. They constitute the ‘living state’ of matter. Those two words connected are part of the title of an intriguing book by Albert Szent-Györgyi, the Hungarian biochemist who won the Nobel Prize in Physiology or Medicine in 1937 for his work on vitamin C. Late in his life, he searched for answers to the cancer puzzle in the intricacies of quantum mechanics (Szent-Györgyi, 1972). Our body is given consistency by a series of solid structures that include bones, a well recognized solid entity that outlasts our own existence. Another key component of our bodies is a reddish solution of a large variety of complex chemicals that we refer to as blood. It carries nutrients to the nooks and crannies of our body and removes the unwanted waste products to maintain a healthy state. We inhale and exhale air, an accepted gaseous mixture of oxygen, nitrogen and other less important components. It is stored in our lungs and distributed to various cavities by a network of blood vessels and capillaries to maintain the metabolic processes required for life itself. Similar conclusions can be drawn from the analysis of other organisms. Physically and chemically these appear to be all the components of the living systems. What else do living organisms have that makes them living? The existence of something else to explain the uniqueness of the living organisms has been part of the scientific discourse since the early ruminations of the human mind on the subject by the Greek school. External forces ranging from ‘spirit’ to ‘soul’ to ‘élan vital’ have been invoked to provide the additional component or element that will transform inanimate matter – admittedly composed of only solid, liquid and gaseous components – to living matter. So what is missing? The plain answer is that nothing is missing, absolutely nothing. But then, what is the difference between a dead cat or a dead cell and a jumping cat or a living cell? Before I provide an answer to the question in terms of the current concepts of physical chemistry, I would like to take a brief historical digression. In my early days of intellectual curiosity regarding molecular biology, I remember reading the writings of Max Delbrück (1906–1981), the German-born biologist who together with Salvador Luria (1912–1991) and Alfred Hershey (1908–1997) were the founding popes of the ‘phage group’. This group has been considered by some as one of the primary seeds for the origins of molecular biology as a field of study. Its members were trying to understand the nature of genes by studying the replication of phages. Delbrück has also been recognized as the unofficial mentor of James D. Watson, who had been introduced to the phage ‘principles’ earlier by Luria. In his early writings, Delbrück expressed the view that when a physicist looks at biology,