The Early Days of Paleogenetics: Connecting Molecules to the Planet
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CHAPTER 1 The early days of paleogenetics: connecting molecules to the planet Steven A. Benner accident, selective pressures, and vestigiality, all 1.1 Introduction constrained by physical and chemical law, differ- Anyone asked to write about the early days feels ent behaviors must be interesting at different elderly. Fortunately, Emile Zuckerkandl’s intro- levels. Biomolecular behaviors that influenced the duction shows that the ideas that led to this ability of a host organism to survive, mate, and volume have been around for some time, at least in reproduce were especially interesting, as these had their basic form, and are rooted in ideas of many been fashioned by natural selection. Behaviors that heroes of modern molecular biology, including did not, were not, because they had not. As a cri- Pauling, Anfinsen, and Zuckerkandl himself. terion for selecting interesting chemical features of In 1980, my laboratory was unaware of a biomolecule to study in detail, an understanding the Pauling–Zuckerkandl paper (Pauling and of the relation between biomolecular structure and Zuckerkandl, 1963; see Chapter 2 in this volume for a behavior and fitness was important. fuller discussion of the implications of this paper) It did not take long at Harvard to realize that when we set out to resurrect ancient proteins from this relation was going to be difficult to under- extinct organisms. My group, then consisting of only stand. There, Martin Kreitman, Robert Dorit, and Krishnan Nambiar and Joseph Stackhouse, was others, including some very dialectical biologists trained to describe the chemical structures and (Levins and Lewontin, 1985), were struggling to behaviors of enzymes. In those days technology was make this connection starting from the side of allowing molecular scientists to extend these biology (Kreitman and Akashi, 1995). Despite this descriptions to atomic resolution, the picosecond interest, it was proving difficult to connect any time scale, and the microscopic rate constant. biomolecular structure or behavior with the sur- But what good were clever experiments to vival of an organism, at least in a way that would determine, for example, which of two hydrogens be compelling to those who chose to deny it was removed by a dehydrogenase (Allemann et al., (Lewontin, 1974; Clarke, 1975; Gillespie, 1984, 1988), or whether the replacement of carbon 1991; Somero, 1995; Powers and Schulte, 1998). In dioxide by a proton on acetoacetate proceeded fact, the discussion was central to the most hotly with retention or inversion of stereochemical con- disputed dispute in molecular evolution, between figuration (Benner et al., 1981)? It occurred to us neutralists and selectionists, where both sides of that we might be doing the biochemical equivalent the dialectic were populated by individuals who of studying a Picasso with an electron microscope. were professionally intent on showing how any Were we not describing biomolecular systems to data interpretable in favor of one side could resolutions far greater than they were designed? equally well support the other. Biomolecules are not designed, however. They are As chemists, we had no part in this fight. the products of natural selection imposed upon However, a review of the contending sides of these random variation in their chemical structures. disputes (Benner and Ellington, 1988) reminded As the result of a combination of historical us of analogous disputes in organic chemistry. 3 4 ANCESTRAL SEQUENCE RECONSTRUCTION These were often Seinfeld arguments about noth- biomolecular behavior, instruction worthy of ing. For example, chemists had for years discussed the growing armamentarium of biophysics and the non-classical carbocation problem (Brown, molecular biology. 1977). This was a disagreement about whether the structures of positively charged organic molecules, 1.2 History as an essential tool to in general, were better modeled by a formula with understand chemistry dotted lines, or by two formulas without dotted lines. Rational observers realized that one model It was clear, however, that Structure Theory in was undoubtedly better for some molecules, chemistry would not support a deep under- whereas the other was better for others. After all, standing of biological molecules. With simple similar issues had been addressed and resolved in molecules, like methane, one does not ask about its many molecular systems. For example, the struc- purpose. This is not true about complex systems, tures of benzene and many boron-containing or living systems, where it is appropriate to ask: compounds both contained dotted lines. Which why does it exist? History can be key to any answer model was best undoubtedly depended on the to why? questions. Any system, natural or human- exact structure of the molecule being discussed. By made, can be understood better if we understand 1980, this dispute had forced chemists to appreci- both its structure and its history. We would not ate a certain truism about molecules: organic understand the QWERTY computer keyboard, the molecules are never productively discussed in Microsoft Windows operating system, or the US terms of a general molecular structure; they must Federal Reserve Bank (for example) if we simply always be considered individually. This truism, of deconstructed each into its parts. An under- course, recognized that the discussion of models standing of the history of each is essential to an for the structure of individual molecules could understanding of the systems themselves. nevertheless be interesting. Structure Theory from chemistry had absolutely To chemists, the neutralist/selectionist dispute no historical component. Methane is how it is was directly analogous. This was essentially a because of its structure. It always has been this disagreement about whether changes in the che- way, and always will be. Where the methane came mical structure of the generic protein would, in from and how it got to us was fully irrelevant to general, change its behavior enough to change its our understanding of this molecule. This raised the contribution to the fitness of the generic organism. next in a series of questions leading to experi- Again, the rational answer was in some cases yes, mental paleogenetics: how were Structure Theory and in other cases no, depending on the exact and natural history to be combined to better structure of the system. Proteins are, after all, understand biomolecules? Fragments of the his- organic molecules, suggesting that they must be tory of life on Earth are found in the geological considered individually. As expected by those strata, of course. But the fossil record is notoriously who understood this truism, the neutralist/selec- incomplete, and would not provide information tionist dispute, in its general form, melted away as about proteins even were it not. Molecular fossils soon as our ability to analyze the behavior of (such as those found in petroleum) can be individual proteins improved (Hey, 1999). informative, but generally not about individual Even in 1980, however, it was clear that con- protein function. Further, any analysis of mole- necting fitness to the behavior of individual bio- cular function must recognize that the behaviors molecules would always remain interesting, for that confer fitness are determined by the system, many reasons. First, that understanding would including other organisms (ecology), the physical certainly help us select behaviors of those biomo- environment (planetary biology), and even the lecules to study in detail. If a behavior was cosmos (astrobiology). This level of complexity important to fitness, it might be highly optimized. defeats most theoretical contexts. Detailed study might therefore instruct us about It was clear, however, that the chemical struc- the interaction between chemical structure and tures of proteins themselves contain historical THE EARLY DAYS OF PALEOGENETICS 5 information. The historical relationships between direct at another. This epithet accuses a profes- proteins related by common ancestry can be sional adversary of building ad hoc explanations inferred by comparing their amino acid sequences, for specific facts (how the zebra got his stripes). a theme that was already well developed by 1980 The events behind a just-so story (an ancestral (Dayhoff et al., 1978). Analysis of protein sequences zebra took a nap under a ladder) cannot be inde- could generate the basic elements of an evolu- pendently verified, and are not mathematically tionary model: a multiple sequence alignment, a modelable. Further, the story could easily be tree, and sequences of ancestral protein sequences replaced by a different story, just as compelling, inferred from these. From these, it might be pos- had the observations been the opposite. It was sible to construct narratives connecting biomole- clear in 1980 that once the insult stuck, papers cular structure to fitness. would be rejected, grant applications would be This process was analogous to processes well turned down, and tenure would be denied. known in the field of historical linguistics Curiously, this issue also had a parallel in (Lehman, 1973), which Robert Breedlove had organic chemistry. Chemists are well known for described to me when I was an undergraduate. their ability to use Structure Theory to explain a set This field infers the features in ancestral languages of facts, only to be told that the facts are opposite, by analyzing the features of their descendent lan- and then to explain the counter-facts using the guages.