I've been doing a bit of research on the human genome in preparation for a book. This led me to an article published in 2003 by Francis Collins, former head of the Human Genome Consortium (Collins, 2003). It's mostly about how he deals with science and religion but there was an interesting description of what he learned from completing the human genome sequence.
Here's what he said ....
We discovered some pretty surprising things in reading out the human genome sequence. Here are four highlights.
1. Humans have fewer genes than expected. My definition of a gene here—because different people use different terminology—is a stretch of DNA that codes for a particular protein. There are probably stretches of DNA that code for RNAs that do not go on to make proteins. That understanding is only now beginning to emerge and may be fairly complicated. But the standard definition of “a segment of DNA that codes for a protein” gives one a surprisingly small number of about 30,000 for the number of human genes. Considering that we’ve been talking about 100,000 genes for the last fifteen years (that’s what most of the textbooks still say), this was a bit of a shock. In fact, some people took it quite personally. I think they were particularly distressed because the gene count for some other simpler organisms had been previously determined. After all, a roundworm has 19,000 genes, and mustard weed has 25,000 genes, and we only have 30,000? Does that seem fair? Even worse, when they decoded the genome of the rice, it looks as if rice has about 55,000 genes. So you need to have more respect for dinner tonight! What does that mean? Surely, an alien coming from outer space looking at a human being and looking at a rice plant would say the human being is biologically more complex. I don’t think there’s much doubt about that. So gene count must not be the whole story. So what is going on?
2. Human genes make more proteins than those of other critters. One of the things going on is that we begin to realize that one gene does not just make one protein in humans and other mammals. On the average, it makes about three, using the phenomenon of alternative splicing to create proteins with different architectures. One is beginning to recover some sense of pride here in our genome, which was briefly under attack, because now we can say, “Well, we don’t have very many genes but boy are they clever genes. Look what they can do!”
3. The male mutation rate is twice that of females. We also discovered that simply by looking at the Y chromosome and comparing it to the rest of the genome—of course, the Y chromosome only passes from fathers to sons, so it only travels through males—you can get a fix on the mutation rate in males compared to females. This was not particularly good news for the boys in this project because it seems that we make mistakes about twice as often as the women do in passing our DNA to the next generation. That means, guys, we have to take responsibility for the majority of genetic disease. It has to start somewhere; the majority of the time, it starts in us. If you are feeling depressed about that, let me also point out we can take credit for the majority of evolutionary progress, which after all is the same phenomenon.
4. “Junk” DNA may not be junk after all. I have been troubled for a long time about the way in which we dismissed about 95% of the genome as being junk because we didn’t know what its function was. We did not think it had one because we had not discovered one yet. I found it quite gratifying to discover that when you have the whole genome in front of you, it is pretty clear that a lot of the stuff we call “junk” has the fingerprints of being a DNA sequence that is actually doing something, at least, judging by the way evolution has treated it. So I think we should probably remove the term “junk” from the genome. At least most of it looks like it may very well have some kind of function.
The folks at Evolution News & Views (sic) can serve a very useful purpose. They are constantly scanning the scientific literature for any hint of evidence to support their claim about junk DNA. Recall that Intelligent Design Creationists have declared that if most of our genome is junk then intelligent design is falsified since one of the main predictions of intelligent design is that most of our genome will be functional.
THEME
Genomes & Junk DNA They must be getting worried because their most recent posts sounds quite desperate. The last one is: The Un-Junk Industry. It quotes a popular press report on a paper published recently in Procedings of the National Academy of Sciences (USA). The creationists concede that the paper itself doesn't even mention junk DNA but the article in EurekAlert does.
Günther Witzany is one of those people who think the Modern Synthesis needs to be overthrown but he missed the real revolution that took place in the late 1960s. He's part of The Third Way crowd that includes Denis Noble and Jim Shapiro [see Physiologists fall for the Third Way and The Third Fourth Way].
Susan Mazur interviews him for the Huffington Post [Günther Witzany: Modern Synthesis "Must Be Replaced," Communication Key to Evolution]. Recall that Susan Mazur is fixated on the Altenburg 16 and their attempts to radically revise evolutionary theory without understanding anything about Neutral Theory and random genetic drift. Günther Witzany is a philosopher. He was not one of the Altenberg 16 but he clearly wants to be part of the outer circle. It's not clear why anyone should consider him an expert on evolutionary biology.
Susan Mazur did us a great favor when she asked him if he would like to make a final point. His answer shows us why we can ignore him.
The older concepts we have now for a half century cannot sufficiently explain the complex tendency of the genetic code. They can't explain the functions of mobile genetic elements and the endogenous retroviruses and non-coding RNAs. Also, the central dogma of molecular biology has been falsified -- that is, the way is always from DNA to RNA to proteins to anything else, or the other "dogmas," e.g., replication errors drive evolutionary genetic variation, that one gene codes for one protein and that non-coding DNA is junk. All these concepts that dominated science for half a century are falsified now. ...
Thank-you Susan. Keep up the good work. Fools need to be exposed.
I find it very frustrating to read reports about RNA these days because the writers almost always misrepresent the history of the field and exaggerate the significance of recent discoveries. An article in the July 23, 2015 issue of Nature illustrates the problem. The article is written by Elie Dolgin (@ElieDolgin), a freelance science journalist based in Massachusetts (USA). He graduated from McGill University (Montreal, Quebec, Canada) with a degree in biology and obtained a Ph.D. in genetics and evolution from the University of Edinburgh (Edinburgh, Scotland, UK).
At 8:15 AM on August 6, 1945 an atomic bomb was detonated over Hiroshima, Japan. Approximately 78,000 civilians were killed on that day. Six months later the death toll had risen to about 140,000 people.
There are many arguments in favor of dropping the bomb, just as there are many arguments against it. What's clear is that in the context of 2015 we are not in a good position to judge the actions of countries that had been at war for many years.
The most important lesson of Hiroshima is that war is hell and many innocent people die. It's all very well to enter into a war with the best of intentions—as the Japanese did on December 7, 1941—but it's foolish to pretend that when you start a war there won't be any suffering. When you do that, you can really say that the victims of Hiroshima will have died in vain.
The killing and maiming of civilians is an inevitable outcome of war, no matter how hard you might try to restrict your targets to military objectives. Before going to war you need to take the consequences into account and decide whether the cost is worth it.
Hiroshima was not a glorious victory. It was ugly, heartbreaking, and avoidable. War is not an end in itself, it is the failure of peace. War is not an instrument of foreign policy—it is an admission that you don't have a foreign policy.
[The top photograph shows the mushroom cloud over Hiroshima on the morning of August 6, 1945 (Photo from Encyclopedia Britanica: Hiroshima: mushroom cloud over Hiroshima, 1945. [Photograph]. Retrieved August 7, 2007, from Encyclopædia Britannica Online.
The bottom image is taken from a Japanese postcard (Horoshima and Nagassaki 1945). It shows victims of the attack on Hiroshima.]
William ("Will") Provine is an emeritus professor of history and of evolution at Cornell University (Ithaca, New YOrk, USA). He is no friend of creationism. Here's what Wikipedia has to say about him ...
Provine is an atheist, philosopher, and critic of intelligent design. He has engaged in prominent debates with theist philosophers and scientists about the existence of God and the viability of intelligent design. He has debated the founder of the intelligent design movement Phillip E. Johnson and the two have a friendly relationship. Provine has stated that he starts his course on evolutionary biology by having his students read Johnson's book "Darwin on Trial."
Provine is a determinist in biology, but not a determinist in physics or chemistry, thus rejecting the idea of free will in humans. Provine believes that there is no evidence for God, there is no life after death, there is no absolute foundation for right and wrong, there is no ultimate meaning for life, and that humans don't have free will.
When someone likes that publishes a book with the title, The 'Random Genetic Drift' Fallacy, I pay attention.
From an academic pedagogical perspective, there’s nothing wrong with a course that has a reading list emphasizing quack medicine. This is the view that people outside of the university don’t understand. They appear to want to prevent students from ever learning about, or discussing, the anti-vax movement and how to deal with it.
Those of you who read the articles and have seen talks by supporters of science-based medicine like Steve Novella and myself will recognize this for the straw man that it is. We never say anything like this, that we want to prevent students from learning about or discussing the antivaccine movement. That is an assertion that is unsupported and, quite frankly, downright risible. So you should understand that I was more than a little pissed off when I read this part of Moran’s post. We never say that we don’t want alternative medicine to be taught or antivaccine views taught. (Indeed, I really wish that pediatrics residency programs, for instance, would do a better job of teaching antivaccine views, so that they don’t catch pediatricians by surprise when parents start expressing them.) What we complain about is the uncritical teaching of these topics, the teaching, for example, of alternative medicine modalities as though they had scientific merit. This is a massive problem in medical academia. I’ve lost track of how many times I’ve reiterated this very point going back at least a decade.
We agree. I wasn't referring to people like Orac who understand how universities should work. I was referring to those people outside of the university community who really do want to ban any mention of alternative medicine at universities. I guess I didn't make that clear.
I'm pretty sure that Orac knows about this crowd. They are totally opposed to the idea of teaching the controversy. They have some very strong views on what's right and what's wrong and they firmly believe that the only views that should ever be expressed in university classes are the ones they agree with.
In the end, my little fit of pique over Prof. Moran’s condescending and dismissive attitude towards those of us who were so outraged by this course being offered by U. of T. aside, we actually (mostly agree). Moran supports “teaching the controversy” with respect to evolution and with respect to alternative medicine. So do I. Where we disagree is over what “teaching the controversy” actually entails. Can Prof. Moran can honestly say that he wouldn’t be the least bit upset if his own department were to offer an entire course on “controversies in evolution” taught by Ken Ham, Casey Luskin, and a Discovery Institute fellow to be named later? That he would approve of such a class as a great way to “teach the controversy”? If he can, I’d say there’s a problem. If he can’t say that, I congratulate him. That’s the correct reaction. In that case, I also point out that he has no business being so contemptuous of our anger over a homeopath teaching a course in alternative medicine as a way of “teaching the controversy.”
As I said in my earlier post, the problem wasn't that an anti-vaccine point of view was being discussed in a university course. The problem was that the course was being taught by someone who wasn't qualified to offer a university course that encouraged critical thinking. That situation has been rectified.
I would love to invite Casey Luskin to come and give a few lectures on Intelligent Design Creationism to my students. It would be far better for them to hear the other side directly from the horse's mouth than filtered through me.
There's been a recent kerfluffle about a course called "Alternative Health: Practive and Theory" taught as part of a program in Health Studies at the University of Toronto's Scarborough campus (Toronto, Ontario, Canada).
Most of the readings in the course emphasized non-evidence-based medicine and health. The instructor was Beth Landau-Halpern, a homeopath who warns her patients about the dangers of vaccines [see Beth Landau-Halpern]. She's also the wife of Rick Halpern, the Dean and Vice-Principle of University of Toronto, Scarborough (UTSC). Ms. Landau-Halpern will no longer be teaching and the Dean has resigned [Rick Halpern Resigns].
This is the game my son, Gordon Moran, and his friends at IronOak Games are developing. Please send him lots of money when Kickstarter is activated in September.
I'm buying a university and a professor character for the game. The professor will battle the forces of evil and superstition. Ms. Sandwalk is contributing enough for a medieval faire with lots of games where you can win prizes.
The draft sequence of the human genome was published in 2001. The "finished" version was published a few years later but annotation continues.
A massive amount of data on complex genomes has been published, especially on the human genome. The next step is to decide what this data means. Here are the most important questions from my perspective.
I don't think scientific journals or scientific organizations should take a position on the conflict between science and religion but that doesn't mean they should stay away from the subject altogether. The journal Nature has just (July 28, 2015) published a defense of accomodationism written by David M. Lodge [Faith and science can find common ground]. Lodge describes himself as a "Protestant ecologist embedded for 30 years in a Roman Catholic university." The Catholic University is Notre Dame [see David M. Lodge].
His main argument is that the current Pope understands the science of the environment and has spoken out in favor of protecting the environment. David Lodge thinks this represents an accomomodation between science and religion.
Of the Five Things You Should Know if You Want to Participate in the Junk DNA Debate, the most difficult to explain is "Modern Evolutionary Theory." Most scientists think they understand evolution well enough to engage in the debate about junk DNA. However, sooner or later they will mention that junk DNA should have been deleted by selection if it ever existed. You can see that their worldview leads them to believe that everything in biology has an adaptive function.
It's been a few years since I posted Michael Lynch's scathing comments on panadaptationism and how it applies to understanding genomes [Michael Lynch on Adaptationism and A New View of Evolution]. You're in for a treat today.
Here's what you need to know about evolution in order to discuss junk DNA. The first quotation is from the preface to The Origins of Genome Architecture (pages xiii-xiv). The second quotations are from the last chapter (page 366 and pages 368-369.
Contrary to popular belief, evolution is not driven by natural selection alone. Many aspects of evolutionary change are indeed facilitated by natural selection, but all populations are influenced by nonadaptive forces of mutation, recombination, and random genetic drift. These additional forces are not simple embellishments around a primary axis of selection, but are quite the opposite—they dictate what natural selection can and cannot do. Although this basic principle has been known for a long time, it is quite remarkable that most biologists continue to interpret nearly aspect of biodiversity as an outcome of adaptive processes. This blind acceptance of natural selection as the only force relevant to evolution has led to a lot of sloppy thinking, and is probably the primary reason why evolution is viewed as a soft science by much of society.
A central point to be explained in this book is that most aspects of evolution at the genome level cannot be fully explained in adaptive terms, and moreover, that many features could not have emerged without a near-complete disengagement of the power of natural selection. This contention is supported by a wide array of comparative data, as well as by well-established principles of population genetics. However, even if such support did not exist, there is an important reason for pursuing nonadaptive (neutral) models of evolution. If one wants to confidently invoke a specific adaptive scenario to explain an observed pattern of comparative data, then an ability to reject a hypothesis based entirely on the nonadaptive forces of evolution is critical.
The blind worship of natural selection is not evolutionary biology. It is arguably not even science.
Michael Lynch
Despite the tremendous theoretical and physical resources now available, the field of evolutionary biology continues to be widely perceived as a soft science. Here I am referring not to the problems associated with those pushing the view that life was created by an intelligent designer, but to a more significant internal issue: a subset of academics who consider themselves strong advocates of evolution but who see no compelling reason to probe the substantial knowledge base of the field. Although this is a heavy charge, it is easy to document. For example, in his 2001 presidential address to the Society for the Study of Evolution, Nick Barton presented a survey that demonstrated that about half of the recent literature devoted to evolutionary issues is far removed from mainstream evolutionary biology.
With the possible exception of behavior, evolutionary biology is treated unlike any other science. Philosophers, sociologists, and ethicists expound on the central role of evolutionary theory in understanding our place in the world. Physicists excited about biocomplexity and computer scientists enamored with genetic algorithms promise a bold new understanding of evolution, and similar claims are made in the emerging field of evolutionary psychology (and its derivatives in political science, economics, and even the humanities). Numerous popularizers of evolution, some with careers focused on defending the teaching of evolution in public schools, are entirely satisfied that a blind adherence to the Darwinian concept of natural selection is a license for such activities. A commonality among all these groups is the near-absence of an appreciation of the most fundamental principles of evolution. Unfortunately, this list extends deep within the life sciences.
....
... the uncritical acceptance of natural selection as an explanatory force for all aspects of biodiversity (without any direct evidence) is not much different than invoking an intelligent designer (without any direct evidence). True, we have actually seen natural selection in action in a number of well-documented cases of phenotypic evolution (Endler 1986; Kingsolver et al. 2001), but it is a leap to assume that selection accounts for all evolutionary change, particularly at the molecular and cellular levels. The blind worship of natural selection is not evolutionary biology. It is arguably not even science. Natural selection is just one of several evolutionary mechanisms, and the failure to realize this is probably the most significant impediment to a fruitful integration of evolutionary theory with molecular, cellular, and developmental biology.
Natural selection is just one of several evolutionary mechanisms, and the failure to realize this is probably the most significant impediment to a fruitful integration of evolutionary theory with molecular, cellular, and developmental biology.It should be emphasized here that the sins of panselectionism are by no means restricted to developmental biology, but simply follow the tradition embraced by many areas of evolutionary biology itself, including paleontology and evolutionary ecology (as cogently articulated by Gould and Lewontin in 1979). The vast majority of evolutionary biologists studying morphological, physiological, and or behavioral traits almost always interpret the results in terms of adaptive mechanisms, and they are so convinced of the validity of this approach that virtually no attention is given to the null hypothesis of neutral evolution, despite the availability of methods to do so (Lande 1976; Lynch and Hill 1986; Lynch 1994). For example, in a substantial series of books addressed to the general public, Dawkins (e,g., 1976, 1986, 1996, 2004) has deftly explained a bewildering array of observations in terms of hypothetical selection scenarios. Dawkins's effort to spread the gospel of the awesome power of natural selection has been quite successful, but it has come at the expense of reference to any other mechanisms, and because more people have probably read Dawkins than Darwin, his words have in some ways been profoundly misleading. To his credit, Gould, who is also widely read by the general public, frequently railed against adaptive storytelling, but it can be difficult to understand what alternative mechanisms of evolution Gould had in mind.
Interviewed by The New Yorker earlier this year, the great novelist and journalist Tom Wolfe acknowledged that he's writing a book about evolution -- actually, "a history of the theory of evolution from the nineteenth century to the present." No indication of what his overall thesis might be, but he "invokes the Spanish Inquisition when discussing how academics have cast out proponents of intelligent design for 'not believing in evolution the right way.'"
If you were to line up all the DNA molecules from all the individuals in all the species on Earth, how long would it be? This is a kind of "Fermi question" or "Fermi problem." You should be able to estimate an answer based on what you know and reasonable assumptions.
Michael Lynch has a crude estimate in his book The Origins of Genome Architecture. Without reading the book, can you come up with an estimate of your own? Is it larger than the circumference of the Earth? Larger than the distance to Pluto? Longer than the distance to the nearest star (other than the sun) or the the center of the galaxy? Would the string of DNA molecules stretch to the nearest large galaxy (Andromeda)? Or, would it be even longer than that?
I'm re-reading The Inside Story edited by Jan Witkowski, the former editor-in-chief of Trends in Biochemical Sciences (TIBS). The book is a collection of essays that appeared in the journal. The collection centers around "the theme of the Central Dogma of molecular biology." Here's how Jan Witkowski describes the collection in the preface (page xii)...
When I came to look more closely, it was clear that the area the articles covered most comprehensively, where the most interesting selection could be made, was the Central Dogma, that is DNA, RNA, and protein synthesis. And the number of relevant articles was just right for the size of book we had in mind.
This explains the subtitle of the book, "DNA to RNA to Protein."
This is not going to be another complaint about misinterpretations of the Central Dogma. Quite the contrary, as we shall see.
The Forward was written by Tim Hunt who was the editor-in-chief from 1992-2000. He refers to "The General Idea."
"Jim, you might say, had it first. DNA makes RNA makes protein. That became the general idea." Thus did Francis Crick explain to Horace Judson years later, long after he had written with such clarity and force on the subject of protein synthesis in the 1958 Symposium on "The Biological Replication of Macromolecules" [see Crick, 1959). This article is celebrated for its prediction of the existence of tRNA (although by the time the article appeared in print, tRNA had been discovered), but it is chiefly worth reading and rereading, even today, for its enunciation of the two principles that together constitute the "General Idea." The first principle is the Sequence Hypothesis; the idea that the sequence of amino acids in proteins is specified by the sequence of bases in DNA and RNA. The second principle is the famous "Central Dogma"; not DNA makes RNA makes Protein, but the assertion that "Once information has passed into protein it cannot get out again." It isn't completely clear why one is a hypothesis and the other a dogma and the two together an idea. The Dogma stuck in some throats, mainly because it was called a dogma, with heavy religious overtones.
Crick explains that calling it a dogma was a misunderstanding on his part: he thought the word stood for "an idea for which there was no reasonable evidence," blaming his "curious religious upbringing" for the error. But it probably wasn't that much of a mistake after all, for the Oxford Dictionary allows dogma to mean simply a principle, although the alternative "Arrogant declaration of opinion" is probably how most people who were not molecular biologists took it, considering its never modest author. That is probably how they were meant to take it, too. It was the most important article of faith among the circle of biologists centered on Watson and Crick and remained so for quite a long time until the mechanism of protein synthesis became clear. Crick said that if you did not subscribe to the sequence hypothesis and the central dogma "you generally ended up in the wilderness," although he did not offer alternative scenarios for public consumption, even though they probably played an important part in convincing him of the dogmatic status of the General Idea's second component.
This is the concept that I "grew up" with as a graduate student in the late 1960s. We saw the "General Idea" as an important concept and a way of understanding the data that was coming out of many labs working on DNA replication, transcription, and protein synthesis. We knew, especially after 1970 (Crick, 1970), that RNA could be used as a template to make DNA and that there were many types of RNA other than messenger RNA. We also knew that Francis Crick was a very smart man and it was unwise to disagree with him because he was usually right about big ideas.
Fig. 1. Information flow and the sequence hypothesis. These diagrams of potential information flow were used by Crick (1958) to illustrate all possible transfers of information (left) and those that are permitted (right). The sequence hypothesis refers to the idea that information encoded in the sequence of nucleotides specifies the sequence of amino acids in the protein.
At some point in the last 40 year the "General Idea" has been subverted in two ways.
The Sequence Hypothesis has come to be interpreted as the Central Dogma. This is mostly due to Jim Watson who propagated this misinterpretation in his Molecular Biology of the Gene textbook.
The Central Dogma is taken to mean that the ONLY important information in the genome is that which encodes proteins. It's assumed, incorrectly, that Crick meant to say that the role of all genes is to encode proteins.
One of the essays in The Inside Story is "Forty Years under the Central Dogma," published in 1998. The authors are Denis Thieffry and Sahotra Sarkar (Thieffry and Sarkar, 1998).
Here's how they explain some of the confusion about the Central Dogma ...
The most obvious interpretation of Crick’s original (1958) formulation of the Central Dogma is in negative terms. The Central Dogma only forbids a few types of information transfer, namely, from proteins to proteins and from proteins to nucleic acids. However, after its rapid adoption by most of the biologists interested in protein synthesis, it was most often interpreted or reformulated in a more restrictive way, constricting the flow of information from DNA to RNA and from RNA to protein (Fig. 1).
Figure 1 The Central Dogma as envisioned by Watson in 1965. ‘We should first look at the evidence that DNA itself is not the direct template that orders amino acid sequences. Instead, the genetic information of DNA is transferred to another class of molecules, which then serve as the protein templates. These intermediate templates are molecules of ribonucleic acid (RNA)...Their relation to DNA and protein is usually summarised by the formula (often called the central dogma).'
According to Watson’s autobiography, he had already derived this ‘formula’ (Fig. 1) in 1952. In fact, such schemes were commonly entertained during the early 1950s, at least among the biologists interested in protein synthesis. ... Much more restrictive than Crick’s original statement, Watson’s formula was immediately confronted with a series of possible exceptions, some of which are mentioned below. Crick, meanwhile, remained rather cautious in his interpretation of the Central Dogma. On several occasions, he felt it necessary to come back to his original idea and explicate what he thought to be its correct interpretation. For example, in 1970, Crick devoted a paper specifically to the Central Dogma, including a diagram reportedly conceived (but not published) in 1958.[see the figure at the top of this page]
The authors recognize several challenges to the Central Dogma, at least to the version preferred by Watson. There were two discoveries in the 1960s that seemed to threaten the Central Dogma. The first was the discovery that the genetic material of some viruses (e.g. TMV) was RNA, not DNA. The second was the discovery that RNA could be copied into DNA by reverse transcriptase. This was not a problem for Crick ....
These findings prompted Crick to write his 1970 piece for Nature, in which he explicitly showed how the new facts fitted into his scheme.
It's difficult to evaluate the importance of the Central Dogma in the 21st century because so many scientists don't understand it. The incorrect version seems to mostly serve as a whipping boy to promote "new" ideas that overthrow the strawman version of the Central Dogma.
Back in 1998, the authors of this article asked Crick what he thought of the Central Dogma ...
In a recent answer to a question addressing the relevance of these challenges, Crick stated that he still believes in the value of the Central Dogma today (F.H.C. Crick, pers. commun.). However, he also acknowledges the existence of various exceptions, most of which he regards as minor. For him, the most significant exception is RNA editing. Still, according to Crick, simplifications of the Central Dogma in terms such as ‘DNA makes RNA and RNA makes protein’ were clearly inadequate from the beginning.
Crick, F.H.C. (1958) On protein synthesis. Symp. Soc. Exp. Biol. XII:138-163. [PDF]
Crick, F. (1970) Central Dogma of Molecular Biology. Nature 227, 561-563. [PDF file]
Thieffry, D. and Sarkar, S. (1998) "Forty years under the central dogma." Trends in Biochemical Sciences 23:312–316. [doi: 10.1016/S0968-0004(98)01244-4}
