gribskov@FCRFV1.NCIFCRF.GOV ("Gribskov, Michael") (02/12/91)
At the risk of once again incurring the fiery wrath and ridicule of Dr. Ellington, due to anyone who speaks favorably about the genome initiative, let me just train my antennae on his "tiny mind". He makes the following cogent arguments against the genome project: he doesn't like it he doesn't think it's real science he thinks it's really worthless Perhaps a more tightly reasoned argument would be more convincing? There are certainly quite a few people who see some value in the genome project, even if they don't agree entirely with its goals/or implementation. Not all of those people are fools. I would certainly like to know the names of the ofFfFensive person or persons who "would suggest I should just bag my ideals and go off to happily catalogue genes at random. And I am outraged that *alternative service* in science may come to mean just that." Furthermore, there is a big difference between systematically sequencing an entire genome, and sequencing genes at random. I would say they are opposite ends of a spectrum, in fact. Michael Gribskov gribskov@ncifcrf.gov
m.witten@CERBERUS.CHPC.UTEXAS.EDU (02/12/91)
I'm all for open discussion. But Im getting tired of the FLAME war. Can we cease this infantile behavior on all sides. If we want to get into philosophical flame wars, lets do it in usenet.sci.phil or somewhere like that. > > At the risk of once again incurring the fiery wrath and ridicule of > Dr. Ellington, due to anyone who speaks favorably about the genome > initiative, let me just train my antennae on his "tiny mind". He makes > the following cogent arguments against the genome project: > > he doesn't like it > he doesn't think it's real science > he thinks it's really worthless > > Perhaps a more tightly reasoned argument would be more convincing? There > are certainly quite a few people who see some value in the genome > project, even if they don't agree entirely with its goals/or > implementation. Not all of those people are fools. I would certainly > like to know the names of the ofFfFensive person or persons who "would > suggest I should just bag my ideals and go off to happily catalogue > genes at random. And I am outraged that *alternative service* in > science may come to mean just that." Furthermore, there is a big > difference between systematically sequencing an entire genome, and > sequencing genes at random. I would say they are opposite ends of a > spectrum, in fact. > > Michael Gribskov > gribskov@ncifcrf.gov > > -- _____________________________________________________________________ Matthew Witten, Ph.D. Director, Applications Research & Development Associate Director, UT System Center For High Performance Computing Balcones Research Center, 1.154 CMS 10100 Burnet Road, Austin, TX 78758-4497 USA Phone: (512) 471-2472 FAX: (512) 471-2445/2449 E-MAIL M.WITTEN@HERMES.CHPC.UTEXAS.EDU M.WITTEN@UTCHPC.BITNET "some intellectuals make their living by creating obscurities for the rest of us to puzzle over" _____________________________________________________________________
tone@biomath.mscs.mu.edu (Peter J. Tonellato) (02/12/91)
In article <9102111918.AA00663@morpheus.chpc.utexas.edu> m.witten@CERBERUS.CHPC.UTEXAS.EDU writes: >I'm all for open discussion. But Im getting tired of the FLAME war. Agreed. This newsgroup is an obvious forum for the discussion of the pro's and con's of scientific funding, emphasis, ... and (even) direction and validity. As such, we are all obligated to contain the personal attacks. I was disappointed that the nature of the discourse took the negative/critical track. I think it is important and useful to air the views and hear the arguments (both for and against any topic of interest) of researchers from such diverse backgrounds. My vote: Continue the discussion - without the nastiness. Peter J. Tonellato US Mail: Department of Mathematics, Statistics and Computer Science Marquette University Milwaukee, Wisconsin 53233 Voice: 414-288-5228 (Office) 414-288-7573 (Message) FAX: 414-288-5472 (FAX) Arpa: tone@biomath.mscs.mu.edu
Ellington@Frodo.MGH.Harvard.EDU (Deaddog) (02/12/91)
In article <9102111908.AA07006@genbank.bio.net> gribskov@FCRFV1.NCIFCRF.GOV ("Gribskov, Michael") writes: > Perhaps a more tightly reasoned argument would be more convincing? From my point of view, Michael, this is rather like trying to argue against N-rays or phlogiston: you point out that there is no evidence to support their existence, and that's about the end of it. I am sure that I will see justification for the project at some point, but so far none has appeared. I am truly mystified: given the ability to clone genes by a variety of methods (probing with oligos based on protein sequences, complementation, hybridization with homologous sequences, panning, subtraction cloning, etc.) I do not see a need to sequence the human genome. I do not see what information will be gained that cannot be garnered by other, more directed means. In terms of genetic disease, for example, the search for a given gene would still seem to be a directed search. You contend that sequencing genes at random and systematically sequencing a genome are opposites: I contend that they are both undirected searches and,in the current research climate, such undirected searches should not be funded to the detriment of research which has a higher probability of producing new insights into biology/chemistry/medicine. While there are genome mapping/sequencing projects whose goals I understand ("we want to know the sequences of all the genes in X, because we have a fantastic genetic map of organism X, we already know what many of the genes do, and we don't have to worry about the 95% of the genome that is essentially junk;therefore, the sequence of X's genome is just a way to get at a glut of information that we can immediately interpret"), these arguments do not seem to apply to humans. Even in this form, though, it is not sequencing "the genome" that is important, but sequencing "all the genes that we know are important." It seems as though anthrocentricity is driving this project, rather than a true quest for scientific knowledge. Consider: I remember when the sequence of all of SV40 was first determined; I also remember when the chloroplast genome was completed. What new lines of research have been opened up by this information? New lines mind you, that wouldn't have been available had not the sequence of the whole genome been available. For example, I am grateful for the sequences of additional Group I introns from the chloroplast genome, but a more diverse range of sequences has become available from directed searches of many different genomes. And if you defer to thinking about the sequence of the human genome as a tool, then it is a very, very expensive tool. And again I would suggest that finding the mechanism of one gene which causes MS is worth much more than knowing the sequences of all the genes together (when you don't know what the genes do and still have to go back and find out). > I would certainly > like to know the names of the ofFfFensive person or persons who "would > suggest I should just bag my ideals and go off to happily catalogue > genes at random. And I am outraged that *alternative service* in > science may come to mean just that." David Kristofferson (apologies for mis-spelling, if such is the case) makes the point that academics should consider industry as an option. A worthy point and one which I take to heart. However, he goes on to suggest that researchers should consider not doing 'real science,' and that a wealth of (not-'real-science'?) opportunities will be related (just how, we are not sure) to the Genome Project. Thus, my obviously fanciful statement is based on: (1) The contention that scientists should somehow be fulfilled "not doing real science," which seems like a self-contradictory sentence, and (2) The notion that the Genome Project will somehow provide opportunities in industry for real or unreal science. Again, I find this hard to imagine. IMO (obviously H would be a bit out of place here) the Human Genome Project does not have a direction or purpose that would make it more useful than a telephone book in a forgotten language. Non-woof (Look Ma, no flames! Yet.) (Michael, for someone who characterized my arguments as "he doesn't like it," you should do better than "9 out of 10 top docs support the Genome Initiative;" rather like a National Enquirer special report.)
chacko@hpuxa.ircc.ohio-state.edu (George W. Chacko) (02/12/91)
In article <9102111918.AA00663@morpheus.chpc.utexas.edu> m.witten@CERBERUS.CHPC.UTEXAS.EDU writes: >I'm all for open discussion. But Im getting tired of the FLAME war. >Can we cease this infantile behavior on all sides. If we want to >get into philosophical flame wars, lets do it in usenet.sci.phil >or somewhere like that. Hear! Hear! G
kristoff@genbank.bio.net (David Kristofferson) (02/13/91)
> (1) The contention that scientists should somehow be fulfilled "not doing > real science," which seems like a self-contradictory sentence, ARGGHHH 8-)!!!! Perhaps my writing is extremely unclear, but, after a couple of attempts at clarification, this "paraphrase" still shows a misunderstanding of my position. I hope others who did not have a direct involvement in this exchange understood what I was trying to say. It was never my intention to try and "convert" Dr. Ellington, but only to speak to those scientists who were *already* tired of "real science" and let them know that, despite the trauma one can experience in deciding to leave research, there are other fulfilling career options out there. Enough said on this topic. Dave Kristofferson
steeg@ai.toronto.edu ("Evan W. Steeg") (02/13/91)
In article <Feb.12.08.23.44.1991.3915@genbank.bio.net> kristoff@genbank.bio.net (David Kristofferson) writes: > >ARGGHHH 8-)!!!! Perhaps my writing is extremely unclear, but, after a >couple of attempts at clarification, this "paraphrase" still shows a >misunderstanding of my position. I hope others who did not have a >direct involvement in this exchange understood what I was trying to >say. It was never my intention to try and "convert" Dr. Ellington, >but only to speak to those scientists who were *already* tired of >"real science" and let them know that, despite the trauma one can >experience in deciding to leave research, there are other fulfilling >career options out there. Enough said on this topic. > >Dave Kristofferson Dr. Kristofferson, Good stuff! Keep the asbestos suit on for a while longer, but there are people out here who understand and appreciate what you've been trying to say. I did my degrees in math and CS and am now finishing my PhD in CS by working on problems in "computational biology" (sequence analysis and RNA/protein structure prediction). While I love "real science" and I know that my heart will always quicken when I open up a _Science_ or _Nature_, I am fed up and frustrated with many aspects of academic science. I will finish my doctorate and may even do a postdoc or some such if I get a really good offer, but I know that I might turn my attention before long to work in industry and also in science and technology policy. Just as I don't narrowly define myself as *only* a computer scientist, but rather as a *problem-solver* trained in a few fields for interesting interdisciplinary work, similarly I don't see myself as *just* a scientist but rather as a scientifically trained thinker (well, I try,), problem-solver, and world citizen. I, too, have seen the lives of friends in science *crumble* (temporarily, thank goodness,) when their ride on the Real Science Fast Track[tm] came to a sudden halt, due to personal or funding reasons, and they had *no* idea that there is anything else they could do with their intelligence, diligence, and energy. The narrow, all-or-nothing views of many of our colleagues sadden me, because their lack of breadth threatens not only to impoverish their own lives and careers but also diminishes the quality of scientific research, which increasingly requires diverse backgrounds, vivid imagination across disciplines, and flexibility w.r.t where and how science is done. -- Evan -- Evan W. Steeg (416) 978-7321 steeg@ai.toronto.edu (CSnet,UUCP,Bitnet) Dept of Computer Science steeg@ai.utoronto (other Bitnet) University of Toronto, steeg@ai.toronto.cdn (EAN X.400) Toronto, Canada M5S 1A4 {seismo,watmath}!ai.toronto.edu!steeg
frist@ccu.umanitoba.ca (02/13/91)
In article <5695@husc6.harvard.edu> Ellington@Frodo.MGH.Harvard.EDU (Deaddog) writes: > >I am sure that I will see justification for the project at some point, >but so far none has appeared. I am truly mystified: given the ability to >clone genes by a variety of methods (probing with oligos based on protein >sequences, complementation, hybridization with homologous sequences, >panning, subtraction cloning, etc.) I do not see a need to sequence >the human genome. I do not see what information will be gained that cannot >be garnered by other, more directed means. In terms of genetic disease, >for example, the search for a given gene would still seem to be a directed >search. > ....deleted stuff about genome project competing for funds w/other science ... deleted stuff about sequencing at random > >do, and we don't have to worry about the 95% of the genome that is essentially >junk;therefore, the sequence of X's genome is just a way to get at a glut of >information that we can immediately interpret"), these arguments do not seem >to apply to humans. But how do you KNOW it's junk? There are still lots of chromosomal functions that repetitive DNA could play, but we wouldn't have been able to detect for lack or a global picture. Such functions might include higher-order packaging of chromatin during chromosome condensation, facilitation of chiasma formation, attachment to the nuclear matrix or the definition of functional "domains" [Bodnar, 1988]. It should be obvious now that gene expression is _not_ just a question of having the right promoter or enhancer. These are clearly only one component of a much more complex mechanism for genome function that is made possible by the deliberate organization of the chromatin in the interphase nucleus. The importance of repetitive DNA is further underscored by evolutionary studies such as those done by Narayan with the plant genera Clarkia, Nicotiana, Lathyrus and Allium [Narayan (1985), Narayan (1982)]. Basically, Narayan has demonstrated that, in a wide range of genera examined, interspecific differences in genome sizes are in discrete increments, rather than being a continuous variation. Similarly, Flavell and colleagues have used hybridization kinetics to demonstrate that specific subsets of interspersed repetitive sequences can be selectively lost or gained as spec- iation occurs [Flavell et al. 1977]. I am a firm believer in "junk DNA" and I do think that a lot of the genome is junk. But not all of that 95%,` or whatever figure you wish to use. The Genome Project is an exploratory mission, like Darwin's voyage on the H.M.S. Beagle. Although Darwin was perhaps perceived as an unimportant crewman on this exploratory trip, the wealth of data obtained by Darwin served as his 'database' for thinking about biology from a global perspective. At first, his work was merely 'bookkeeping'. Who really cared how many types of finch were on each island? Nonetheless, it was these years of observation that made it possible for Darwin to obtain the global perspective necessary for the formulation of the most fundamental theory in biology: the theory of evolution. > >Even in this form, though, it is not sequencing "the genome" that is >important, but sequencing "all the genes that we know are important." It >seems as though anthrocentricity is driving this project, rather than a true >quest for scientific knowledge. Again, how do you KNOW which genes are important? At the present time, the sequence databases are largely biased towards highly-expressed genes, because those are the ones most likely to be detected and cloned. These are important, in the sense that the cell needs thousands of copies of their transcripts. But it is often the case that <25% of the mass of the mRNA represents >95% of the sequence diversity. There are literally thousands of genes for which only 1-10 copies of the transcript are present in the cell [Okamuro and Goldberg, 1989]. It is only by obtaining a clear view of what the cell does with these rare transcripts that we will have a complete understanding of how gene expression results in a differentiated organism. >Consider: I remember when the sequence of all of SV40 was first >determined; I also remember when the chloroplast genome was completed. What >new lines of research have been opened up by this information? New lines >mind you, that wouldn't have been available had not the sequence of the whole >genome been available. For example, I am grateful for the sequences of >additional Group I introns from the chloroplast genome, but a more diverse >range of sequences has become available from directed searches of many >different genomes. It took Darwin more than 20 years after his voyage to understand the meaning of the data he had collected, and publish Origin of Species. Getting the data is the easy part, and will take a finite time. Understanding it will take generations. I like to compare molecular biology to planetary astronomy. There is so much data from space probes (eg. Ranger, Surveyor, Mariner, Viking, Voyager, Pioneer) that it is reasonable to do an entire PhD thesis without ever touching a telescope. Sadly, much of this data is virtually inaccessible because NASA has not been able to do anything with it other than store the tapes in vaults. The advances that our database managers are making with biological sequence data should serve as a source of optimism that the same thing will not happen to newly-obtained sequence data. > >And if you defer to thinking about the sequence of the human genome as a >tool, then it is a very, very expensive tool. And again I would suggest >that finding the mechanism of one gene which causes MS is worth much more >than knowing the sequences of all the genes together (when you don't know >what the genes do and still have to go back and find out). Yes, it is cheaper to clone one gene than to sequence the human genome. But there are several hundred known genetic diseases in humans. With the entire genome sequenced, we will have all of them. It seems likely to me that sequencing the genome will be cost effective, as compared to hundreds of separate projects to clone individual genes. >Non-woof > References: Flavell, R.B., Rimpau, J. and Smith, D.B. (1977) Repeated sequence DNA rel- ationships in four cereal genomes. Chromosoma 63:205-222. Narayan, R.K.J. (1985) Discontinuous DNA variation in the evolution of plant species. (Indian) J. Genet. 64:101-109. Narayan, R.K.M. (1982) Discontinuous DNA variation in the evolution of plant species: the genus Lathyrus. Evolution 36:877-891. Okamuro, J.K. and Goldberg, R.B. (1989) Regulation of plant gene expression in Stumpf, P.K. and Conn, E.E. (eds.) The Biochemistry of Plants Vol 15 "Molecular Biology". Academic Press. Query: Is Deaddog (Non-woof) really playing devil's advocate here, challenging supporters of the genome project to justify it in a better way than has been done up to now? Further query: Was Darwin doing 'real science' during his voyage on the Beagle, or did that come only later, as he tilled the 'vegetable mould' in his garden, pondering the meaning of 'certain facts in the distribution of organic beings inhabiting South America'.? =============================================================================== Brian Fristensky | What can literature do against the pitiless Department of Plant Science | onslaught of naked violence? Let us not for- University of Manitoba | get that violence does not and cannot flourish Winnipeg, MB R3T 2N2 CANADA | by itself; it is inevitably intertwined with frist@ccu.umanitoba.ca | LYING... Lies can stand up against much in Office phone: 204-474-6085 | world, but not against art. FAX: 204-275-5128 | Alexander Solzhenitsyn, NOBEL LECTURE ===============================================================================
Ellington@Frodo.MGH.Harvard.EDU (Deaddog) (02/13/91)
I make several general comments, which I believe pertain to most
of the material in Dr. Fristensky's reply:
(1) None of the suggested benefits requires the complete sequence
of the genome. All of them could be realized by targeted sequencing.
(a) For example, domains that are attached to the nuclear matrix can
easily be isolated and sequenced. It is unnecessary to clone
them all to determine whether they are involved in higher order
chromosome structure, or in gene regulation. In fact, a great
deal of experimentation has already been done in this area
(see, for example, JMB, 200/101, 1988; TIGS, 3/16, 1987;
for those who care, the Bodnar reference is J. Theo Biol., 132/479).
(b) The interrelationship between speciation and repetitive
sequences is well established; see also, for example, Chromosoma,
78/137 (1980). In fact, plants aside, it has been well-studied
in the higher apes, including man (EMBO J., 6/1691 (1987),
PNAS, 83/3875 (1986)). The very fact that these studies can
be done suggests that sequencing the human genome is less than
necessary. If you are truly serious about learning about the role of
repetitive sequences in evolution, you would do well to do comparative
sequence analysis between related organisms (the approach that has
already been taken).
2. To the extent that these are worthy goals, they could be
carried out in other, more worthy eukaryotes (again,
Drosophila and C. elegans leap to mind).
3. No offense, but if you were to write a grant proposal
for these ideas ("I would like to sequence the human genome to
learn about how interspersed repetitive sequences affect
speciation.") you would receive a rotten priority score.
As I have said before, I would like to see the human genome
initiative in the same pool of grants as the science it
purports to do. I do not believe it would stand up to
the harsh scrutiny that everyone else is having to endure.
4. You write:
> There are literally thousands
> of genes for which only 1-10 copies of the transcript are present in the
> cell [Okamuro and Goldberg, 1989]. It is only by obtaining a clear view
> of what the cell does with these rare transcripts that we will have a
> complete understanding of how gene expression results in a differentiated
> organism.
Can you tell me exactly how the sequence of the human genome will address
this problem? I mean, what do you do: find which genes don't have high
abundance RNAs and then look for a function for these genes? If so, how
do you intend to look for function? And how is it different than just
looking for function in the first place without the sequence of the human
genome? One example will suffice.
Most genes are identified by phenotypes, which for the human genome will
mean RFLP mapping. Some genes will be identified by homology to genes
found in other higher organisms that we can ethically mutate all to hell,
like rats. In neither case is the sequence of the human genome likely
to make a difference in determining *function*.
I LIKE THE DARWIN ANALOGY! Good show!
Let's carry it a little further.
Two points:
(1) Was seeing the Finches of the Galapagos the only way
Darwin could have realized the wonders of natural selection?
(Analogy: even if sequencing the human genome will reveal
something unknown, is this the only mechanism by which
we can know this unknown thing?) Obviously not: Darwin
points out how pigeon and dog breeding are beautiful examples
of natural selection at work. Once the insight came, the evidence
was all around him. Wallace stumbled across natural selection
without ever going to the Galapagos. The DATA was there; the insight
was not. Think harder, sequence less.
(2) If Darwin had gone to the Royal Grantsmaster and said:
"I just know I can figure out how organisms change through
time; give me a fleet of ships and I will sail
to all the corners of the Earth and collect every piece of
biological data that I can find in hopes of finding an answer."
I submit that the Royal Grantsmaster would have bunged
young Charles out on his young ass.
The cost of the Beagle was justified because terrestrial
exploration had proven profitable to the English time and again
(e.g., the New World). Why not include a snot-nosed naturalist?
What justification is the genome initiative going to piggyback on?
I gave you the examples of the SV40 and
chloroplast genomes: these are what you are going to have
to take to the Royal Grantsmaster to justify your big
project. What have they yielded? And why is sequencing
the human genome a better bet than a hundred other bits
of proven science (for closure, why sequence the human genome
when we can fund Roy Britten and Eric Davidson to tell us all that
we desire about reptitive sequences?)
Finally, we have:
> It seems likely to me
> that sequencing the genome will be cost effective, as compared to
> hundreds of separate projects to clone individual genes.
Oh come now!
The separate projects are seldom directed at just "cloning
the individual genes." They are directed at "cloning and understanding
the individual genes," which is why they are much more useful than
the GeeWhiz approach of the genome initiative.
In addition, let's say that
the average gene of interest is, oh, 10,000 bases in length. For 100
odd genes that would be 1x10E6 bases, as compared to the human
genome size of 3.3x10E9. Are you trying to tell me that
it will cost more than 100x more to do directed cloning/sequencing
of these target genes than it will to do the whole genome (since you
must do a sizeable fraction of the genome to be sure of finding
most of the target genes)? And that the concommitant knowledge of what the
genes actually does not go a long way to actually justifying that cost
(knowledge which may or may not be the product of the genome initiative)?
> Query: Is Deaddog (Non-woof) really playing devil's advocate here,
> challenging supporters of the genome project to justify it in a better
> way than has been done up to now?
No, I'm really this much of a curmudgeon. Too much is at stake.
I don't actually worry so much about starting the human genome project.
Hell, Soviet science survived Lysenko. No, I'm worried about what
happens when we finish sequencing the genome, and Congress and the public
ask us to justify the cost. At least with the "War on Cancer" there
wasn't a defined endpoint staring us in the face. When that sad day
comes when the headlines blare "100% complete at a cost of N billion!"
there is going to be hell to pay.
Non-woof
(You know, you Matrix-teers aren't really trying. No one's even
mentioned "introns" yet, or "heterochromatin," or "gene
dosage," or "sub-telomeric sequences," or .... But of course
those are all already being studied in established labs fighting
desperately for funding, aren't they?) Ellington@Frodo.MGH.Harvard.EDU (Deaddog) (02/13/91)
In article <Feb.12.08.23.44.1991.3915@genbank.bio.net> kristoff@genbank.bio.net (David Kristofferson) writes: > Enough said on this topic. Except for one thing: I would like to go on record as saying that DAVE KRISTOFFERSON IS A GREAT GUY WHO IS TRYING REAL HARD TO HELP PEOPLE WITH TOUGH CAREER CHOICES. (and I hope the Genome Initiative is deep-sixed so that fewer people will have to make those tough career choices.) Non-woof
CCIPE%FRMOP53@PUCC.PRINCETON.EDU (02/14/91)
>But how do you KNOW it's junk? There are still lots of chromosomal >functions that repetitive DNA could play, but we wouldn't have been able to >detect for lack or a global picture. I can't agree more. The fact that no functions for "junk" DNA are known TODAY, does not mean that this will be the same in the future. A possible role for this DNA could be the interaction with functional or structural proteins. What I would like to say is that we are far from knowing everything about eukaryotic DNA, and the human DNA is a good example of that type of DNA. jean-rene ALATTIA