October 2013

Listing unsolved problems

When the great mathematical scientist George Dantzig was a first-year graduate student at the University of California, Berkeley, in the 1940s, he missed a lecture one day and went late to copy the homework problems that the professor had put up on the board at the end of class. He thought the two problems that day were harder than previous ones, but he pushed on and within a few weeks turned in his solutions. Six weeks later, the professor showed up at Dantzig’s apartment, wanting him to read the introduction of a paper he had written so that he could get the manuscript describing Dantzig’s solution to one of the problems submitted for publication. Dantzig was confused. It turned out that the lecture that Dantzig had missed had been on important unsolved problems in statistics. After completing his coursework, he went to talk to the professor about a dissertation topic. The professor indicated that the two solutions to the previously unsolved problems were more than adequate. Dantzig polished his solutions a bit and got his degree.
As I noted last month, my coauthors and I are in the process of revising our textbook, “Biochemistry.” In addition to taking stock of fields that have made tremendous progress since the previous edition, I also try to enumerate some of the most interesting open questions in biochemistry, at least for myself and sometimes for inclusion in the book. These questions can be fundamental or applied, narrow or broad. Having such lists written down can be interesting as a tool for assessing progress over the years. How much progress has there been on the questions from the previous edition? Are there entirely new questions that could not even have been articulated earlier? Let me list three of the questions that have been intriguing me at this point.
The first is one of the great questions in all of human history: What is the origin of life? Over time, attempts to address this question through studies of the abiotic synthesis of amino acids and nucleic-acid precursors, enzyme-free replication of nucleic acids, and the spontaneous formation and reproduction of membrane-bound, cell-like structures have revealed insights and provided constraints limiting possible origins, but many questions remain. Of course, a wide range of evidence indicates that all known life shares a common ancestor, and this sometimes is interpreted to mean that life originated only once. However, it is possible that the origination of structures with many of the properties of living things, while undoubtedly a rare event, could have occurred more than once, but that life from other origins left no known traces and could not compete with our branch once it was established. In any case, further studies of the origin of life certainly will yield new insights into chemistry and biochemistry and — who knows — may lead to publications of which we are all likely to remember both the results and where we were when we first heard about them.
The second question involves the relevance of the differences between the dilute and relatively simple buffer solutions that biochemists are fond of studying and more accurate representations of the crowded and partially organized environments inside cells. Under what circumstances does extrapolating from results from simple solutions yield significantly incorrect conclusions about the biochemistry inside cells? For some enzyme systems, particularly those with unstable or highly diffusible intermediates, substrate channeling, where the products of one active site are channeled directly into another active site without being released into solution, has been demonstrated. However, demonstration of such channeling can be quite challenging, and it has not been investigated for most systems. For many signal-transduction systems, complexes of proteins are assembled through specific yet transient and relatively loose interactions. These complexes both store information about signals and function in signal amplification and other types of modulation. Simple biochemical models that assume rapid diffusion and mixing almost certainly are wrong in most cases, but the circumstances under which the deviations between these models and reality are significant remain to be explored fully, and more sophisticated models need to be developed and tested.
My third question is this: What is the molecular basis of memory? Studies from neuroscience have revealed that the storage of memory is intimately connected to the number and strengths of synapses (connections) between neurons. A number of key molecules have been identified, including the neurotransmitter serotonin, the second messenger cyclic AMP (cAMP), cAMP-dependent protein kinase and the transcription factor CREB (cAMP response element binding protein). Nonetheless, a clear articulation of how memories are stored and recalled remains elusive. A very recent paper has implicated another molecule, in this case, a histone-binding protein, to the age-related loss of memory acuity. Are memories stored in the form of specific chromatin structures that, in turn, control synaptic strengths? It may be that our understanding of the molecular basis of memory will continue to evolve, but new discoveries may result in more dramatic new insights. Continued progress may result in intellectually satisfying understanding but also may generate new translational opportunities. As I continue to age, I am sure that if simple treatments were available that would restore my memory to the effortless recall of my youth I would be near the front of the line.
Relatively early in my tenure as director of the National Institute of General Medical Sciences, I organized an effort for the NIGMS staff to develop a set of top-10 lists of important unsolved problems. You may be comforted to know that this concept was met with a substantial amount of resistance, as staff members were concerned that these "government bureaucrat"-generated lists were going to be used in a heavy-handed manner to drive the agenda for NIGMS-supported science, an affront to the strong appreciation of the value of investigator-initiated approaches that so permeates the institute. Nonetheless, I think we found it to be a stimulating exercise that promoted understanding of the perspectives of different individuals and groups within the institute. In that same spirit, I would propose that interested members of the American Society for Biochemistry and Molecular Biology and others contribute their ideas. Please send your question along with a few sentences about why you think it is interesting or important to jberg@pitt.edu or post it as a comment to this column. With a robust response, the results may be useful in helping the society move forward and in making our case regarding the importance of biochemistry and molecular biology to the public and to Congress.

Photo of Jeremy BergJeremy Berg (jberg@pitt.edu) is the associate senior vice-chancellor for science strategy and planning in the health sciences and a professor in the computational and systems biology department at the University of Pittsburgh.

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