Epigenetics

Epigenetics is one of those words that means entirely different things to different people. P.Z. Myers has put up a nice description of the term on his blog [Epigenetics]. Here's how he defines epigenetics ...

Epigenetics is the study of heritable traits that are not dependent on the primary sequence of DNA.

In fairness, he then goes on to explain that this is an unsatisfactory definition. That's an understatement.

Now, as it turns out, those scientists who work on animal development employ a definition of epigenetics that looks very much like what we used to call developmental regulation of gene expression. That's why PZ can say ...

... developmental biology basically takes epigenetics entirely for granted — development is epigenetics in action! Compare an epidermal keratinocyte and a pancreatic acinar cell, and you will discover that they have exactly the same genome, and that their profound morphological, physiological, and biochemical differences are entirely the product of epigenetic modification. Development is a hierarchical process, with progressive epigenetic restriction of the fates of cells in a lineage — a dividing population of cells proceeds from totipotency to pluripotency to multipotency to a commitment to a specific cell type by heritable changes in gene expression; those cases where there is modification of the DNA, as in the immune system, are the exception.

Here's the problem. If this is epigenetics then what's the point? When I was growing up we had a perfectly good term for these phenomena—it was regulation of gene expression. Why is there a movement among animal developmental biologists to use "epigenetics" to refer to a well-understood phenomenon?

I've been bugging my colleagues today by asking them to tell me whether certain examples of gene regulation are epigenetic or not.¹ The answers are mixed so I thought I'd submit the questions to Sandwalk readers. Which of the following are "epigenetic"?

1. Consider an E. coli cell that grows and divides for hundreds of generations in the absence of any exogenous β-galactosides (e.g. lactose). Under those conditions the lac operon is repressed and this state is heritable from generation to generation due to the presence of lac repressor.
2. Consider mating type in yeast. In an α cell the a gene is suppressed from generation to generation. This is heritable regulation of gene expression. All daughter cells inherit the ability to express the α gene and suppress the a gene.
3. During a bacteriophage infection certain genes are turned on in a definite sequence. In the simplest cases there is a set of "early" genes that are expressed as soon as the 'phage DNA enters the cell. After a few minutes the expression of the "early" genes triggers the expression of the "late" genes. Note that the "late" genes are not transcribed initially even though they are present.
4. Right now your major heat shock genes (e.g. Hsp70 genes) are transcriptionally silent. However, if you are stressed by heat those genes will become active and will be transcribed at a very high rate.
5. During oogenesis in fruit flies the bicoid gene is expressed in nurse cells and bicoid mRNA is deposited in the egg. In males, the bicoid gene is never expressed.
6. One of the nucleotides at an EcoR1 restriction endonuclease site in E. coli is methylated. This blocks cleavage at that site, thus protecting the bacteria from degrading its own genome. The methylation pattern is inherited from generation to generation by the action of a methylase enzyme.
7. Globin genes are expressed in erythroblasts but not in brain cells. During development the globin genes are activated in erythroblast stem cells because certain activator proteins are synthesized. The globin genes are not activated in any other tissues.
8. During development in mammalian females one of the X-chromosomes is randomly inactivated [Calico Cats]. Once this occurs the pattern is inherited in (almost) all cells that descend from the initial embryonic cell where the inactivation first occurred. The same X-chromosome is inactivated in all daughter cells.

I'm interested in two questions. First, is it possible to define epigenetics in a rigorous manner so that we can decide whether certain cases are "epigenetic" or not? Second, what, if anything, is the difference between "epigenetics" and "developmental regulation of gene expression"?

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1. And they are quite annoyed about it. Many of them are avoiding me because they don't know how to answer the questions.

[Image Credit: The cartoon is from Mark Hill's website at the University of New South Wales, Australia. It appeared originally in Nature. The figure represents a different definition of "epigenetics"—one that focuses on modifications to DNA and histones.]

Climbing Mount Improbable as Metaphor

 
One of my postings, Good Science Writers: Richard Dawkins, has been re-posted on RichardDawkins.net. This doesn't happen very often—in fact this may be the very first time. I can't imagine why they would have selected this particular posting.

I mentioned that some of the Dawkins metaphors are misleading and I suggested that Climbing Mount Improbable was one example. That prompted a comment from Richard Dawkins so I replied on his website. In case anyone is interested, I'm reproducing it here.

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Richard Dawkins asks,

I am interested in the suggestion that Climbing Mount Improbable might not be an ideal title.

Richard, we've been over this ground before but for the benefit of the lurkers let me explain why I think the metaphor is inappropriate.

To begin with, you use the Mt. Improbable image as a metaphor for evolution. This is misleading since evolution encompasses more than just adaptation. It would be difficult to apply the "Climbing Mt. Improbable" metaphor to the organization of our genome, for example, since it's clearly not well-designed and could never be characterized as the peak of an adaptive landscape.

But even as a metaphor for adaptation the image is less than perfect. Most readers will see the peak of Mt. Improbable as a goal of adaptation, implying that evolution somehow recognizes that there is an ultimate perfection that all organisms seek to achieve by reaching the summit. As you well know (I hope) there are very few (any?) species that are perfectly adapted to their environment. If this were true, adaptation would cease because the species resides on the summit of Mt. Improbable.

Thus, in the real world, species tend to move about in the foothills rather than attempt to scale the highest peak. As long as they are good enough to survive and reproduce that's all that's required.

Yes, some individuals within the population might acquire a mutation that makes them a little more fit but in most cases the selective advantage will be too small to make much of a difference. I don't believe there's any great pressure to get to the top of Mt. Improbable. That's why we usually don't see perfection in nature. And it explains why most organisms do not look as though they have been designed by some intelligent being. If anything the "design" looks more like a Rube Goldberg creation, and I doubt that anyone would say that those creations represent the peak of perfection.

I prefer a different view of evolution, one that emphasizes chance and accident [Evolution by Accident]. For me, the metaphor of "Climbing Mt. Improbable" is quite wrong as a metaphor of evolution.

Now, I understand that you disagree about the role of chance and accident. You say, for example, on page 326 of Climbing Mt. Improbable, "It is all the product of an unconscious Darwinian fine-tuning, whose intricate perfection we should not believe if it were not before our eyes" (referring to the evolution of figs and fig wasps). For someone who believes that such a description is characteristic of most evolution (adaptation) the "Climbing" metaphor may seem quite appropriate.

BTW, I agree with you that your case for adaptationism is much stronger in Climbing Mt. Improbable than in The Blind Watchmaker. I especially like the chapter you mention, The Museum of All Shells, where you discuss - among other things - the contrast between your view of evolution and the mutationist view. Ironically, you begin that discussion by pointing out that this is a sophisticated controversy, "... and Mount Improbable, even in its multiple-peaked version, isn't a powerful enough metaphor to explore it."

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Nobel Laureate: George de Hevesy

 

The Nobel Prize in Chemistry 1943.

"for his work on the use of isotopes as tracers in the study of chemical processes"


George de Hevesy (1885 - 1966) received the 1943 Nobel Prize in Chemistry for his work on tracing the synthesis of biological molecules using radioactive isotopes, such as ³²P.

He was able to show, for example, that ³²P is readily incorporated into phosphatides (lipids) in chickens and mammals (including humans) but that incorporation into nucleic acids was much slower unless the tissues were growing rapidly. de Hevesy also showed that ³²P from labeled ATP could be incorporated into fructose-1,6-bisphosphate during glycolysis. This was the beginning of studies using radioisotopes to elucidate biochemical pathways.

The presentation speech was delivered by Professor A. Westgren, member of the Nobel Committee for Chemistry of the Royal Swedish Academy of Sciences in a radio address on December 10, 1943. The situation in Europe at the time made travel to Sweden quite difficult so there was no formal awards ceremony, even though de Hevesy was at Stockholm University.

When, in 1913, de Hevesy was working with Rutherford in Manchester, this young scientist had been commissioned to isolate radium D from radioactive lead. His efforts were unsuccessful. It had in fact become apparent that radioactive radium D differed so little from inactive radium G, the last of the series of descendants of radium, that all attempts to isolate them from each other seemed destined to failure. The reason for this was at the same time discovered. Radium D and radium G are isotopes and constitute different species of lead. They differ in their atomic weight whilst their atoms have the same nuclear charge. The shells of their electrons, shells which determine their chemical properties, are therefore more or less identical.

Although unsuccessful, de Hevesy's efforts were not wasted. They gave him the idea for a new method of chemical research.

If it is impossible to isolate chemically a radioactive isotope from an element of which it is part, it must be possible to use this peculiarity to follow in its details the behaviour of this element during chemical reactions and physical processes of different kinds. The active atoms are recognized by their radiation and, being faithful companions of the inactive atoms of an element, they serve as markers for them. Since the intensity of radiation can be determined with such precision that imponderable quantities can be measured in this way, extremely small quantities of a marker of this kind are sufficient.

By using radium D as a marker, de Hevesy determined the solubility of highly insoluble lead compounds. He succeeded in determining exactly the quantity of lead sulphide or of lead chromate taken up under different conditions from solvents of different types. He studied the exchangeability of lead atoms into the dissolved substances and was able to confirm that it corresponded to the behaviour of the lead atoms as ions. The movements of the atoms in solid lead, i.e. the self-diffusion which occurs in this metal, would be determined; it had previously been impossible to measure this process. By precipitating thorium B, a very active isotope of lead, on the surface of a lead crystal and by following the reduction in radiation intensity brought about by the changes in place of the active atoms with the inactive lead atoms of the lower layer, and hence with the penetrations which took place in the crystal, he was able to measure the energy needed to liberate an atom from the crystallised part of the lead, in other words the dissociation energy of the crystal lattice. This energy was found to be of the same order of magnitude as the heat of vaporisation of lead. This latter research is particularly interesting from the physico-chemical point of view.

The new method has also enabled biological processes to be studied. Beans placed in solutions containing lead salts with a mixture of active lead atoms absorbed a part of these salts but the distribution of the metal was not the same in the root, the stem and the leaves. Most of the lead, which does not favour natural biological development but on the contrary acts as a poison, stays in the root. Relatively more lead was extracted from dilute than from more concentrated solutions. Absorption and elimination of lead, bismuth and thallium salts by animal organisms was studied in this way. A knowledge of the distribution of bismuth compounds introduced into an animal organism is valuable from the medical point of view, since some of these compounds, as we know, are used therapeutically.

So long as natural radioactive elements only were used as markers, use of the new method was inevitably very limited. In fact the method could be applied only in the case of heavy metals - lead, thorium, bismuth and thallium - and their compounds. The situation was to be very different when Frédéric and Irène Joliot-Curie, and Fermi succeeded in producing radioactive isotopes from any element by bombarding it with particles. This discovery was made some ten years ago and the study of chemical processes by means of radioactive markers has since then been carried to such a point that it is now widely used in laboratories throughout the world. De Hevesy has remained the prime mover in this new field of activity and much first-class and important research has been carried out by him and his co-workers.

Exceptionally valuable results have thus been obtained in biology. An isotope of radioactive phosphorus, which can be obtained by exposing sulphur to neutron radiation or ordinary phosphorus to radiation from nuclei of heavy hydrogen, has mostly been used. This radioactive phosphorus is sufficiently long-lasting for tests of this nature. It has a half-life of approximately 14.8 days. De Hevesy produced physiological solutions of sodium phosphate containing this marker and injected them into animals and humans. The distribution of the phosphorus was determined at certain intervals. A study of blood samples showed that the phosphorus thus introduced quickly left the blood. In human blood the radio-phosphorus content had fallen after only 2 hours to a mere 2% of its initial value. It diffuses into the extra-cellular body fluid and gradually changes places with the phosphorus atoms of the tissues, organs and skeleton. After some time it can even be found, though in very small quantities, in the enamel of the teeth. Exchanges small and slow as they may be, therefore occur between the outer hard parts of the teeth and the inner tissues of the bones and the lymph. Most of the phosphorus introduced, finds its way into the skeleton, muscles, liver and gastro-intestinal organs. Elimination of phosphorus from living organisms has also been studied by this method.

Phosphorus is an extremely important element in biological processes. The knowledge of its functions in living organisms which has been acquired thanks to the use of radioactive markers is therefore of the very greatest interest. De Hevesy succeeded in detecting where and at what speed the various organic compounds of phosphorus are able to form and the paths which they take in the animal organism. In order to form from a phosphate which has been injected into the blood they must first penetrate into the cells. Acid-soluble compounds of phosphorus form rapidly, whereas phosphatides closely related to fatty substances are slower-forming. These latter form mainly in the liver, whence they are carried by the blood plasma to the places where they will be consumed. De Hevesy showed that the phosphatides of the chicken embryo are produced in the embryo itself and that they cannot be extracted from the egg yolk.

De Hevesy also carried out several investigations with radioactive sodium and potassium. He studied how physiological saline containing radioactive sodium which was injected into a human subject first spread into the blood and then slowly penetrated into the cells; he also studied the manner in which it is excreted. After 24 hours the blood corpuscles had lost approximately half their sodium content.

In addition to the above-mentioned markers, several other active isotopes, such as magnesium, sulphur, calcium, chlorine, manganese, iron, copper and zinc, have been used for this type of research. In the case of the lighter elements it has also been possible to use inactive isotopes such as heavy hydrogen, with an atomic weight of 2, nitrogen, with an atomic weight of 15, and oxygen, with an atomic weight of 18. It is of course less easy to determine the content of an inactive than of an active marker, but this can be done by determinations of density or mass-spectrographically. To determine the concentration of deuterium, or heavy hydrogen, which is twice as heavy as ordinary hydrogen, is a relatively easy matter. De Hevesy used deuterium as marker in many tests. He then noticed that a person who has drunk water containing heavy hydrogen excretes deuterium in the urine after only 26 minutes. Frogs and fishes swimming in water containing deuterium absorb it and, after about 4 hours, are in equilibrium with the medium as far as the deuterium is concerned. Heavy nitrogen and heavy oxygen have also been used in many investigations.

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New Greek Font: Renaissance Greek with Ligatures

Renaissance Greek with Ligatures (or, for short, RGreekL2) is a font that will allow anyone easily to write Greek in the style of the Renaissance. For example, an editor of Greek texts may use it to reproduce a ligatured word in the manuscript that could be interpreted in different ways. Since the first printers adopted this style of writing for their type, the font can also be used to represent, say, an incunabulum. Many ligatures and abbreviations remained in use up until the eighteenth century.

Does not appear to work with Macs, however.

Source: Digital Classicist discussion list and Usama Gad.

Stanford Papyri News Item

Stanford Report, July 23, 2008

New life given to ancient Egyptian texts stored at Stanford for decades

BY ADAM GORLICK

They're torn and faded and have the woven texture of a flattened Triscuit. At first glance, the ancient Egyptian texts look like scraps of garbage. And more than 2,000 years ago, that's exactly what they were—discarded documents, useless contracts and unwanted letters that were recycled into material needed to plaster over mummies, like some precursor to papier-mâché.

Now they are priceless clues to everyday life in the Ptolemaic Era, bits of history recently cleaned and sandwiched between pieces of glass so researchers at Stanford could begin translating the Greek writing and Egyptian script while studying the worn papyrus it is scribbled on. Etc at Stanford news

The Goal of a Science Education

We've recently been debating the purpose of our undergraduate program in biochemistry. There are some who think that the main goal is to teach students how to do biochemistry. Those biochemists want as many lab courses as possible and they want to provide plenty of opportunities for students to carry out research projects in a research lab. In some cases, they want to minimize the number of formal lectures. These are the biochemists who want undergraduates to read the primary literature instead of textbooks.

On the other hand, there are biochemists who want to emphasize the basic concepts and principles of biochemistry. They want to teach student about biochemistry. They believe that students need the latest knowledge of how cells work at the molecular level before they learn how to do research at the frontiers.

The first group wants to train students for a career in biochemistry while the second group tends to think that most students will not go on to be biochemists.

Eva Amsen, a graduate student in our department, has some comments. You should read her posting on her Nature Network blog [What will you be?]. Here's some of the interesting part ...

The problem is not that a science undergraduate degree is not a career-oriented degree. It shouldn’t be. History, English, Philosophy, and some of the social sciences aren’t career paths either. But for those fields people seem to know that, and yet people associate science with something that leads to a job. They picture a scientist in a lab somewhere, and don’t realize that the people at the bench are either lab techs with a degree from a technical college or university students or -graduates at some point in their training. It’s all training, it never ends. A select few will eventually have their own lab, and if their grandmother lives to experience this they can tell her that they now are a scientist. Finally, at the age of 35-40 they have what the family would consider a job. And then they spend the next few decades struggling to get grants and write papers just to be able to keep that job.

The problem is that science programs pretend to be career-oriented. They train you for the job of research scientist, but there are way more students than ever needed to fill these jobs. I’d guess that about 10% of PhD students end up with their own lab. Everyone else has to find an alternative career. But if 90% of the graduates of a science program need to find an alternative career, is it still alternative, or is that just what people do with their degrees?

I agree with Eva. Science programs often pretend to be career oriented but they should be knowledge oriented. The main goal should be to teach students how to think and not how to work at a bench. Thus, students who graduate from an undergraduate—or graduate—program will have valuable skills that they can use in any career they choose.

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Good Science Writers: Richard Dawkins

 
Richard Dawkins was not included in Richard Dawkins' book: The Oxford Book of Modern Science Writing. The reason for the omission is obvious, so I rectify the "oversight" by including him in my list of good science writers.

I don't always agree with what Dawkins writes but there's no controversy about his ability to explain biology to the general public. He has a clear, crisp style that's easy to read and his arguments are well constructed. Part of his success is achieved by simplifying difficult concepts but this is also part of the problem since, in some cases, an over-simplification leads to misinterpretations.

Dawkins is also a master of metaphor but, sometimes the metaphors are misleading and can give an incorrect view of evolution (e.g. Climbing Mt. Improbable). I've chosen an excerpt from The Ancestor's Tale to illustrate Dawkins' skill at writing about science. This book is somewhat less polemical than his others, although it still has its fair share of strongly voiced personal opinions about evolution.

The passage below addresses "convergence," a favorite topic of theistic evolutionists such as Simon Conway Morris and Ken Miller. Dawkins has his own spin on the subject. He begins by addressing a question posed by Stuart Kauffman in 1985. Kauffman asked whether there are certain features of life that are easy to evolve. If so, we might expect these features to appear whenever life evolves. On the other hand ....

Those biologists who could be said to take their lead from the late Stephen Jay Gould regard all of evolution, including post-Cambrian evolution, as massively contingent—lucky, unlikely to be repeated in a Kauffman rerun. Calling it "rewinding the tape of evolution," Gould independently evolved Kauffman's thought experiment. The chance of anything remotely resembling humans on a second rerun is widely seen as vanishingly small, and Gould voiced it persuasively in Wonderful Life. It was this orthodoxy that led me to the cautious self-denying ordinance of my opening chapter; led me, indeed, to undertake my backwards pilgrimage, and now leads me to forsake my pilgrim companion at Canterbury and return alone. And yet ... I have long wondered whether the hectoring orthodoxy of contingency might have gone too far. My review of Gould's Full House (reprinted in The Devil's Chaplain) defended the unpopular notion of progress in evolution: not progress towards humanity—Darwin forfend!—but progress in directions that are at least predictable enough to justify the word. As I shall argue in a moment, the cumulative build-up of complex adaptations like eyes, strongly suggests a version of progress—especially when coupled in imagination with some of the wonderful products of convergent evolution.

Convergent evolution also inspired the Cambridge geologist Simon Conway Morris, whose provocative book Life's Solution: Inevitable Humans in a Lonely Universe presents exactly the opposite case to Gould's "contingency." Conway Morris means his subtitle in a sense which is not far from literal. He really thinks that a rerun of evolution would result in a second coming of man: or something extremely close to man. And, for such an unpopular thesis, he mounts a defiantly courageous case. The two witnesses he repeatedly calls are convergence and constraint.

Convergence we have met again and again in this book, including in this chapter. Similar problems call forth similar solutions, not just twice or three times but, in many cases, dozens of times. I thought I was pretty extreme in my enthusiasm for convergent evolution, but I have met my match in Conway Morris, who presents a stunning array of examples, many of which I had not met before. But whereas I usually explain convergence by invoking similar selection pressures, Conway Morris adds the testimony of his second witness, constraint. The materials of life, and the processes of embryonic development, allow only a limited range of solutions to a particular problem. Given any particular evolutionary starting situation, there is only a limited number of ways out of the box. So if two reruns of a Kauffman experiment encounter anything like similar selection pressures, developmental constraints will enhance the tendency to arrive at the same solution.

You can see how a skilled advocate could deploy these two witnesses in defence of the daring belief that a rerun of evolution would be positively likely to converge on a large-brained biped with two skilled hands, forward-pointing camera eyes and other human features. Unfortunately, it has only happened once on this planet, but I suppose there has to be a first time. I admit that I was impressed by Conway Morris's parallel case for the predictability of the evolution of insects.

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