By Rob Mitchum

Alan Turing is best known as the father of the modern computer, a skillful World War II codebreaker, and a pioneer in the study of artificial intelligence. But in the last years before Turing’s death at age 41, he  aimed his genius at a different target: the then-stalled field of developmental biology. By the middle of the 20th century, many scientists had tried and failed to explain how a complex organism could form itself from a simple embryo originally made up of identical cells. One 19th century biologist, Hans Driesch, grew so frustrated with the problem that he gave up and wrote a text on vitalism, the doctrine that life cannot be explained by science alone.

In a 1952 paper called “The Chemical Basis of Morphogenesis,” Turing rushed headlong into this challenge, building a mathematical model of how patterned cells can be formed from non-patterned beginnings. It was Turing’s only published work on the topic; he died two years later. But in those 35 pages, he predicted elements of developmental biology that wouldn’t be discovered for 30 more years, coined a term that is central to the field today, and accidentally sparked a new sub-field of mathematical study for a bonus. In a recent Nature retrospective commemorating Turing’s 100th birthday, University of Chicago scientist John Reinitz wrote, “What Turing should receive credit for is opening the door to a new view of developmental biology…He was well ahead of his time.”

Reinitz’s own research is deeply indebted to Turing’s landmark paper. A professor with appointments in Statistics, Ecology & Evolution, and Molecular Genetics & Cell Biology, Reinitz’s laboratory studies how gene expression controls the development of the fruit fly Drosophila melanogaster. As part of those efforts, the laboratory has built several computational models of gene transcription and fly development, one of which is a specific example of a class of equations in Turing’s paper, Reinitz said in an interview about his essay.

Beyond that direct lineage, Reinitz admires the paper (”The article is just a pile of interesting ideas.”) and teaches it in his courses. But it wasn’t fully appreciated in the field of developmental biology until decades after its publication, when the role of DNA and the molecules that Turing preemptively named “morphogens” became more widely known in biology.

“When I was in grad school, this paper was circulating, and it was considered to be a sort of interesting but crazy paper,” Reinitz said. “It didn’t have anything about genes, and when I first saw it, it was really before any of these morphogens had actually been found. So it didn’t seem to have any direct bearing on actual experimental science.”

The core of the paper is a computational model — one of the first ever published, Reinitz said — that mathematically proved one could create complex patterns from a symmetrically organized cell. Early in development, the “pluripotent” cells of the embryo are each capable of developing into a wide range of cell types, from blood to skin to muscle to hair. Indeed, if an embryo is split in two early enough, it can form two entire organisms…as is the case with identical twins.

Classic linear mathematics can’t explain how one generic cell can produce so many unique descendants. So Turing’s model employed a “mathematical trick,” using the interplay of two diffusing factors (Turing’s “morphogens”) to produce the temporary instability necessary for a pattern to form. That these morphogens had never been observed in scientific experiments at the time he published was beside the point; Turing simply wanted to show that pattern-making could be done with a minimum of elements.

“I think that one of the things that’s seriously misunderstood about the paper is that a lot of people read it and think it’s making specific predictions about biological systems,” Reinitz said. “The main thing he was concerned about was just demonstrating that you could form patterns from non-patterns. He wanted to show with chemistry that you can have patterns form spontaneously.”

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A cell is full of language. There’s the four-letter code of DNA, the slightly different four-letter dialect of RNA, and the three-letter words that direct the construction of proteins, which are built out of an alphabet of 20 amino acids. In recent years, scientists have slowly revealed another vocabulary superimposed on top of this language, comprised of chemical groups attached to genes and proteins. When groups such as methyl or phosphate are stuck to various places on a protein or gene, they can dramatically change its function, switching it on or off or marking it for transport or destruction. On a disease level, these changes can contribute to cancer, aging, and other conditions, making them an enticing target for drug design.

One area where protein modification is making a big splash is the relatively new field of epigenetics, which looks at how changes to DNA and DNA-related proteins can affect gene expression. The methylation of DNA is known to turn genes off, and a number of modifications to histones - proteins that package and organize DNA - can also have functional consequences. Scientists suspected that they hadn’t found all of the modifications possible on histones, but discovering each new modification and proving its role was considered a painstaking process requiring years of experiments. Finding a new modification, such as Yingming Zhao’s 2010 discovery of lysine succinylation, is an achievement worthy of publication in a high-ranking journal.

So what happened when Zhao’s laboratory discovered sixty-seven new modifications to histones in one paper? The research not only was published in the esteemed journal Cell, but was featured by the journal as one of its top five 2011 highlights.

Zhao, a professor in the Ben May Department of Cancer Research at the University of Chicago Medicine, said he believes the extra accolades reflect the volume of his laboratory’s latest breakthrough, and the paper’s expected influence on how scientists will understand the language of protein modification and epigenetic mechanism.

“If we are going to understand epigenetics and its role in disease we need to identify the full vocabulary of the histone modifications, a major group of epigenetic marks,” Zhao said. ” We thought we had a comprehensive histone vocabulary because of extensive studies by the whole research community in the past 3-4 decades, but in our study, in a single paper, we increased it by 70 percent.”

The laboratory put the pedal to the floor on histone modification discovery by developing new technologies and improving the resolution of pre-existing methods. By using the staple lab method of mass spectometry, which measures the mass and charge of particles, and an algorithm of their own design called PTMap, the researchers could scan the entire histone at once and detect more protein modifications than ever before. Their scan yielded a total of 130 different modification sites — 63 that had previously been observed and reported, and 67 that were new to science.

So large was the yield of new modifications that the current paper wasn’t big enough to fully explore the dynamics and function of all of them. The research team chose to more thoroughly study the novel modification that appeared the most: lysine crotonylation, where a crotonyl group is added to the amino acid lysine. Experiments determined that histone lysine crotonylation is evolutionarily conserved (found in yeast, flies, and humans), is often found in promoter or enhancer regions upstream of genes, suggesting a role in transcriptional control. Furthermore, histone lysine crotonylation was found to be enriched on sex chromosomes, specifically marking testis-specific genes, which implies a role in spermatogenesis.

As for what the other never-before-seen modifications are doing in cells, that will have to wait for future papers, Zhao said.

“This is still a very preliminary study,” Zhao said. “Hopefully, we and the research community will figure out if these modifications have a role in cancer and other diseases. Given the fact that lysine methylation and acetylation pathways are already popular drug targets, I assume these new modifications and the enzymes that regulate these modifications and pathways are highly likely to be drug targets for diseases.”

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An enzyme from three different species is compared, with structural "flaws" shown in green. (From Fernández & Lynch, Nature, 2011)

One common misconception about evolution is that it produces “better” organisms with time - a seductive opinion to humans who would like to think of themselves as the pinnacle of natural selection. In a way, it’s an easy error to make, for who would look at a single-celled bacterium next to a human and think that the four billion years of evolution between the two species hadn’t produced some improvements? But when Ariel Fernández and Michael Lynch compared the proteins that bacteria and humans share, they found that the unicellular organisms held a surprising advantage. Though the overall shape of the proteins were the same, the human proteins were leakier, more vulnerable to the destabilizing effects of water than those of the bacteria.

But according to the paper published yesterday by Fernández and Lynch in Nature, those protein flaws may have been the key spark that led to the evolution of complex organisms.

“We hate to hear that our structures are actually lousier,” said Fernández, a visiting scholar at the University of Chicago and senior researcher at the Mathematics Institute of Argentina (IAM) in Buenos Aires . “But that has a good side to it. Because they are lousier, they are more likely to participate in complexes, and we have a much better chance of achieving more sophisticated function through teamwork. Instead of being a loner, the protein is a team player.”

The engineering advantage of bacteria over humans boils down to one simple fact: they will always far outnumber us. Billions of bacterial organisms can fit into a single Petri dish, and in a single human body there are over 100 times more bacterial cells than there are humans on Earth . When a genetic mutation with a negative effect pops into existence in these huge populations, natural selection quickly disposes of it, preserving the integrity of the protein that gene encodes. But when a mildly negative mutation appears in a relatively small population, such as that of humans or elephants or pine trees, selection is less efficient and the mutation may spread - a phenomenon called genetic drift.

The direct effect of these mild mutations would be to introduce minor flaws into the structure of proteins. If the change in protein function was too severe, it would cease to function and likely kill the organism. But if the change was just a small nick in the armor of the protein, making it chemically more vulnerable to water, the mutation might stick around long enough to be passed on to offspring. That theory informed Fernández and Lynch’s hypothesis: proteins from species with small population sizes would contain more of these flaws than those from species with large populations.

Their idea was proven true: compare the same protein between, say, humans, flatworms, and bacteria, and you’ll find a descending frequency of protein flaws. Even within a single species, the difference can be measured. Some bacteria have both endosymbiotic populations that live inside other organisms and larger, free-living populations, and the proteins from the endosymbiotes were found to contain more structural errors than their free-living peers.

But the exciting part is what happens after those errors accumulate. read more