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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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April 17, 2009

Genes to Diseases: Hard Work, You Say?

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Posted by Derek

So I see that the headlines are that it’s proving difficult to relate gene sequences to specific diseases. (Here's the NEJM, free full-text). I can tell you that the reaction around the drug industry to this news is a weary roll of the eyes and a muttered “Ya don’t say. . .”

That’s because we put our money down early on the whole gene-to-disease paradigm, and in a big way. As I’ve written here before, there was a real frenzy in the industry back in the late 1990s as the genomics efforts started really revving up. Everyone had the fear that all the drug targets that ever were, or ever could be, were about to be discovered, annotated, patented – and licensed to the competition, who were out there fearless on the cutting edge, ready to leap into the future, while we (on the other hand) lounged around like dinosaurs looking sleepily at that big asteroidy thing up there in the sky.

No, that’s really how it felt. Every day brought another press release about another big genomics deal. The train (all the trains!) were loudly leaving the station. A lot of very expensive deals were cut, sometimes in great haste, but (as far as I can tell) they yielded next to nothing – at least in terms of drug candidates, or even real drug targets themselves.

So yeah, we’ve already had a very expensive lesson in how hard it is to associate specific gene sequences with specific diseases. The cases where you can draw a dark, clear line between the two increasingly look like exceptions. There are a lot of these (you can read about them
in these texts
), but they tend to affect small groups of people at a time. The biggest diseases (diabetes, cardiovascular in general, Alzheimer’s, most cancers) seem to be associated with a vast number of genetic factors, most of them fairly fuzzy, and hardly any of them strong enough on their own to make a big difference one way or another. Combine that with the nongenetic (or epigenetic) factors like nutrition, lifestyle, immune response, and so on, and you have a real brew.

On that point, I like E. O. Wilson’s metaphor for nature versus nurture. He likened a person’s genetic inheritance to a photographic negative. Depending on how it’s developed and printed, the resulting picture can turn out a lot of different ways – but there’s never going to be more than was in there to start with. (These days, I suppose that we’re going to have to hunt for another simile – Photoshop is perhaps a bit too powerful to let loose inside that one).

But I've been talking mostly about variations in proteins as set by their corresponding DNA sequences. The real headscratcher has been this:

One observation that has taken many observers by surprise is that most loci that have been discovered through genomewide association analysis do not map to amino acid changes in proteins. Indeed, many of the loci do not even map to recognizable protein open reading frames but rather may act in the RNA world by altering either transcriptional or translational efficiency. They are thus predicted to affect gene expression. Effects on expression may be quite varied and include temporal and spatial effects on gene expression that may be broadly characterized as those that alter transcript levels in a constitutive manner, those that modulate transcript expression in response to stimuli, and those that affect splicing.

That's really going to be a major effort to understand, because we clearly don't understand it very well now. RNA effects have been coming on for the last ten or fifteen years as a major factor in living systems that we really weren't aware of, and it would be foolish to think that the last fireworks have gone off.

Comments (27) + TrackBacks (0) | Category: Biological News | Drug Industry History


COMMENTS

1. The epidemiologist on April 17, 2009 10:28 AM writes...

The presumption has always been that the 2% or so of the genome which was transcribed into protein would provide the keys to understand malignant transformation and other pathophysiologic processes. The fact that 98% of DNA was termed "junk" says a lot. Now we're beginning to understand that the 98% isn't "junk" but contains regulatory information or perhaps offseting reading windows, etc. It's important (or, as my professor used to put it, "Nature isn't stupid--it doesn't waste anything."). We need to figure out what it means. Whether it's in terms of DNA or RNA, we need to understand it.

The problem with our current situation is that we've bet the farm on genomics without understanding what we were really doing. The financial equivalent of betting the bank on subprime loans in 2004/5. It looks like the thing to do, even if the textbooks say to diversify to minimize risk. Now we're coming up short and everyone seems amazed. This is the predictable result, though.

In the 1970s, we bet the farm in cancer on viruses. Wonder why we didn't "win the war on cancer" (now going on for 38+ years)? In the 1990s, we bet on SNPs in a big way. Now it's GWAS which are all the rage. Unfortunately, this isn't how normative science progresses, and our insistence on funding it to the exclusion of other biomedical disciplines will most likely yield the same results as the bolus of money wagered on oncogenic viruses in the 1970s. I'm not suggesting we shouldn't invest in the area--just in moderation as with everything else.

Has anyone noticed that GSK, which tried to make money off genomics, seems to have given up on that area? Perhaps it's time to go back to tried and true models of discovery which produced drugs doing $500M to $1 billion per year. Not blockbusters, I know, but if you add enough of them together, pretty soon, you get a lot of revenue.

david

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2. Muruga on April 17, 2009 10:43 AM writes...

The increasing difficulty of relating gene sequences to specific diseases is a hard reality that we need to accept. Most of the diseases are polygenic disorders and hence the association of single gene to single disease does not augur well. Also, the individual genetic profiles for diseases vary (where pharmacogenomics has a role) and this complicates the matter further. Finally, several genes are pleiotropic. This means a single protein gets expressed in various part of the body with different functions.

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3. CF on April 17, 2009 11:30 AM writes...

Waddington's ideas about the epigenetic landscape were published over sixty years ago.

In my view we discount dynamical state as an inherited trait because we discount the energy barriers separating these states.

The genomics community continues to ignore basic concepts of dynamics. See the recent Nature review on cancer genomics, the authors mention that several mutations are required for a cancerous phenotype but do not see any need to discuss the importance of the individual or collective advantages of the mutations in their persistence.

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4. Eric on April 17, 2009 11:51 AM writes...

I once heard a talk in which Eric Lander made an interesting point: genome-wide association studies aren't that good for finding diagnostic and predictive markers, but they're probably much better at finding drug targets for treating diseases. HMG-CoA reductase was his example; the linkage of HMG-CoA reductase to cardiovascular disease is surprisingly low (statistically significant, but not accounting for a huge percentage of disease occurrence), but targeting it for therapy has been very successful, due to the fact that we can modulate its activity drastically with drugs.

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5. retread on April 17, 2009 12:44 PM writes...

If you want to get up to speed on all the things RNA is doing in the cell -- look at the 20 February '09 issue of Cell -- this includes splicing, mRNA formation and destruction, microRNAs, long nonCoding RNAs etc. etc. It's all there in 227 action packed pages.

To the epidemiologist -- couldn't agree with you more. I posted the following (excuse the length) on the late lamented ChemBark over a year ago. Here it is again, since the site has since died.

Consider the following terms from molecular biology: nonsense codon, noncoding DNA, Junk DNA. 2 of them are downright pejorative. All imply that anything in our DNA not coding for an amino acid going into a protein is unimportant. As most of you probably know, the 4 bases of DNA (A, T, G, and C) are read in groups of three (these are the codons) giving 64 possibilities. The 3/64 not coding for an amino acid are called nonsense codons. They tell the protein making machinery (the ribosome) to stop and start on another protein. The 3 codons are just as vital for life as the other 61, or we'd just be one big protein. Calling them nonsense always seemed peculiar to me.

Noncoding DNA means DNA which doesn't code for an amino acid going into a protein. The implication is that it doesn't code for anything else. Of our 3.2 billion positions in DNA, perhaps 2% codes for amino acids going into proteins. The rest has been called 'junk DNA' -- again the implication is that it does nothing.

You have doubtless heard that we are 98.5% chimpanzee. What this means is that our proteins are 98.5% similar (e.g. they have the same sequence of amino acids in 98.5% of positions). Again, the proteincentric view is dominant here -- proteins are all that you have to know.

Now we all love chemistry or we wouldn't be here reading this. Consider Independence Hall and Monticello from the chemical point of view. They're both made of bricks, and a chemical analysis of them could certainly figure out that one set of bricks came from South Jersey and the other came from the Virginia piedmont. However, the most sophisticated chemical analysis can not tell us why the two buildings look so different. Why not? Chemistry can't deal with the way the bricks are put together. You can do a lot with bricks if you stack them just right (and the chemical nature of the bricks doesn't matter very much for this).

However, for at least 30 years, minor differences in proteins were thought to determine the differences between a man and chimp. In fact, it was seriously stated at one point, that chemically man and chimp weren't different enough (as far as their proteins were concerned) to be considered separate species.

Well we are and the determining difference lies in the 98% of the DNA which does NOT code for protein. In some way (which we are just beginning to find out) it determines which protein is made where, how much of it is made, and when it is made.

Retread

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6. Cellbio on April 17, 2009 12:45 PM writes...

It strikes me that, as usual, the promises are oversold in the sense that the parties central to the newest technology discount the value of other information/technology that makes the realization of value iomportant. So too do the detractors simplify the argument. I would put people like Eric Lander, Francis Collins and every VC in the category of self promoting, straw men defeating extraordinaires.

I read the NEJM papers, thanks for the heads up Derek. I think the outlook is reasonably informed in those papers, and deals fairly with the limitations and additional needs. In particular, evaluating the GWAS information in the context of gene expression, biological pathways and disease physiology is discussed. In this context, the genetic association, coupled with important data such as clinical history and treatment outcome, can indeed be another valuable tool.

However, if the expectation is that a single SNP, or haplotype, reads the future disease risk and clinical history for a healthy person, without other biological data, then yes the success of this approach will be low, unless you are a series A investor in 23andme. Bigger fools will come along and provide return.

I wonder if there is a SNP that can distinguish between the first VC fool and the bigger fools that follow their folly?

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7. Cellbio on April 17, 2009 1:01 PM writes...

Retread,

You should read about regions of DNA which have rapidly evolved from the time that the chimp/human common ancestor walked the earth. There are variations in non-coding regions, but also in coding regions responsible for key distinguishing attributes. A recent, good quality read exists in the latest Scientific American.

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8. petros on April 17, 2009 2:40 PM writes...

Look what's happened to all the genomics (and proteomics) companies that raised shedloads of dollars from IPO.

Celera acquired Axys and haven't delivered anything
Millennium bought a couple of companies and then got purchased by Takeda
Incyte, Lexicon and Oxagen all become drug discovery companies, and have promising pipelines

HGS has perhaps remained truer to the model

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9. Retread on April 17, 2009 2:42 PM writes...

Cellbio -- quite true -- one of the most interesting ones is the foxp2 gene (particularly to me as a neurologist). It was found in a human family with speech problems [ Nature vol. 413 pp. 465 - 466, 519 - 523 '01 ]. More importantly, the gene is among the 5% most conserved genes between man and rodent, yet there are 2 amino acid changes since the divergence of man and chimp 6 million years ago. Contrast this with the 3 amino acid changes since the divergence of man and mouse 70 million years ago [ Science vol. 297 p. 1105 '02, Nature vol. 418 pp. 869 - 872 '02]. Interestingly two of the amino changes (arginine 325 --> serine && threonine 303 --> asparagine) change the ability of the protein to be regulated by phosphorylation (I'm not sure this was picked up in the original papers, and I don't have them available presently).

Another interesting protein coding gene to look at is HAR1 [ Nature vol. 443 pp. 149 - 150, 167 - 172 '06 ] which is involved in brain development and which shows changes between man and chimp.

Disappointingly, many of the changes in proteins between man and chimp involve the immune system (not that suprising if you consider the different selective pressures from infectious agents the two species have been under since divergence). Monkeys don't get infected with HIV1 (the AIDS virus) because they have a protein called TRIM5alpha [ Science vol. 303 p. 1275 '04 ]. We have one too but our TRIM5alpha is slightly different and doesn't protect us from HIV1, their TRIM5alpha doesn't protect them from simian immunodeficiency virus (SIV).

All very nice, but I think the main differences between man and chimp will be found in the 98% of the genome called junk, back in the day when molecular biologists considered themselves masters of the universe. The NEJM paper is another salutory wakeup call for them. A third will be found in an upcoming post on the Skeptical Chymist.

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10. Cellbio on April 17, 2009 3:02 PM writes...

Great comments retread! Thanks for the references.

Oh, and as a former mol biologist, I'm not a master of the universe!? Damn, what a bad day. Maybe that is why I moved over to pharmacology. I didn't even have the wisdom to call myself a systems biologist, today's masters of the universe, if I'm not mistaken.

I am not so sure that our non-chimpness will be mainly in the 98%, thinking instead that a few key changes can amount to profound difference, but I'll enjoy reading about the importance of the 98%, whether I am right or wrong.

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11. MedResearcher on April 17, 2009 7:49 PM writes...

There is definitely an association [yes, inverse], between the exponential rise of Big Pharma spending in this area and the decline in the discovery rate of new drugs over the past decade.
Many industry scientists believe that the immense amount of funds that have been siphoned away from proven drug discovery methods, into the glitzy rathole of genomics and gene expression studies, actually is a significant cause for the dismal productivity of Big Pharma these days.
As companies begin to abandon this malarky and return to funding drug discovery paradigms already proven to work, perhaps a causal relationship can formally be established.
Unfortunately, it will take awhile to make up for a decade lost to the gene jockeys. Hopefully, for the sake of the patients, the industry can survive in some form.

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12. RKN on April 17, 2009 8:48 PM writes...

I don't find it very surprising that genome-wide association studies (GWAS) or traditional microarray approaches for finding candidate genes, or even panels of genes, have produced so few clinically useful markers of disease. For one, protein is the immediate effector molecule of phenotype, not DNA. And two, diseases like cancer are complicated -- gene expression patterns reveal only one small part of the molecular dynamics in disease. And when you consider that 20K+ genes may code for over 1 million proteins [1], any or all of which may be post-translationally modified to become active or inactive...well, is it any wonder that GWAS have fallen short?

Our lab and many others are showing that the activity of small networks are more accurate classifiers of disease compared to markers based on traditional gene expression approaches.

Dawkins was wrong; the gene isn't the unit of selection, more likely networks of proteins are.

1. http://www.expasy.ch/sprot/hpi/

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13. dave on April 17, 2009 10:57 PM writes...

The development analogy is great for describing the disparity between general "epigenetics" between each person.

It is interesting to look at the successes along side the "thing in the sky" we are all staring at. Like almost every other industry it comes down to pairing a need with novel application. This is the biggest no shit statement to everyone, but it still rings true, and honestly I think our industry is huge to pulling us out of this...sorry to get off base, but I believe it.

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14. Ellert on April 18, 2009 8:12 AM writes...

Another wrinkle to add to the fabric is the heterogeneity of the individual proteins that are involved. Although still a field of uncertain practical application, demonstrations that individual proteins are heterogeneous with respect to binding properties, catalytic rate etc. underscores how tangly things are at the sub-cellular level.

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15. provocateufr on April 18, 2009 9:29 AM writes...

I have always wondered whether the scientists from the biological sides were less rigorous in their scientific discourses.I have a very simple question.
If you believe in evolution and survival of the fittest how could you make such a sweeping statement that 98% of genes are 'junk' or such a arbitrary claim that one gene -one enzyme theories which go and demolish the very heart of the evolution argument!totally made-up science and how could you be so arrogant when you do not so much abt this thing called 'life' in general!

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16. Vanilla on April 18, 2009 12:19 PM writes...

Muscle injuries are very difficult to control especially for the constant pain that occur as low back pain, or a tear, there are medicines that control these pains and found findrxonline..com indications and contraindications as Vicodin, Lortab, flunitrazepam, and so on. medicines that have a high content of which is codeine which minimizes pain.

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17. Anon on April 18, 2009 2:38 PM writes...

Provocateufr.

You're probably right evolutionary theory is complete nonsense.

Maybe you should refuse medicines developed with these 'theories' in mind. Just to be safe.

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18. Provocateufr on April 18, 2009 8:36 PM writes...

Anon
I am no anti-evolution,intelligent design guy...I think there is overwhelming proof for evolution theory and natural selection.But believing in these I cannot make sense when the scientists involved in the research tell me that 98% of our genes are 'junk'!why would evolution stand such inefficiency...why would evolution support a one gene-one enzyme theory because it would try to utilize more of one gene over the evolution process for more than producing one enzyme...Can you care to explain the above rather than attacking me personally...Always know that you know less than what you think you know..

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19. Cellbio on April 19, 2009 12:07 AM writes...

So Provocateur, I will try, with respect to comment on your questions. Science deals well with how, less well with why. Why often implies a why-not comparison. These questions may prove valuable in thinking about theories, but can, without rigor applied, rapidly turn into questions of philosophy or religion.

Second, with life sciences, worse yet in psychology, the general public has a keen interest but little scientific literacy, so complex messages are boiled down to quick sound bites, like "junk DNA". The common language does spill back into the lab. As an example, Magic Johnson introduced the phrase HIV virus instead of AIDS virus, and this is not uncommon in scientific language now. It drives me nuts, but this is linguistic sloppiness and the evolution of language, not the biological side displaying less rigor.

Some points for you to consider to strengthen your thinking... the "junk" part is DNA, not genes. Don't generalize, there is no group singing harmony, "the scientists involved", that speaks with uniformity. You ask 'why would nature stand such inefficiency'. Nature is not an animate object, let alone a stern headmaster at a boarding school who is intolerant of waste. And, inefficiency is a requirement for and by-product of evolution.

Finally, the human mind, even the very good, does on occasion, and too often, mistake our ignorance of something for the lack of its existence. But all science is about moving into that space. If an academic scientist tells you on one day that something is junk, only to turn around and tell you that it is vitally important, don't get your panties in a knot. Either they are the true leaders and innovators, or they suck, or it is merely time to do a new grant funding dance, and they realize the tune has changed. It is up to you to figure it out. If you don't have the scientific training to make the judgment, which is too common these days, then take it upon yourself to become educated instead of insulting well trained scientists who work hard at illuminating the edges of our knowledge.

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20. retread on April 19, 2009 7:44 AM writes...

Some charity should be shown to the one gene enzyme hypothesis. It goes back to the (very) early days of molecular biology and was proposed by Beadle and Tatum in 1941. The fact that DNA was the actual chemical substrate of heredity wasn't proved until the work of Avery and McLeod 3 years later.

No such charity should be shown to Junk DNA which has been around since 1972 (although you should check out the C value paradox etc. etc.). I never bought it, based on my military experience. Here's how the post cited in #5 actually began (again with apologies for length -- but the blog it was posted on (ChemBark) is no longer with us).

In 1968 the USA had half a million men in Vietnam. The Army needed lots of docs to take care of them and their motto was "If you can practice medicine outside the army you can practice it inside the army". There was no 4F for docs nor were there medical excuses. There were excuses for individuals of exceptional value, and as chemists you should know where this arose (see the end of this post if you don't). This meant that all newly minted MDs would spend two years during or after residency training in the service. Fortunately (for me) the Army was short of neurologists in 1968, so with just one year of residency (instead of the usual 3) under my belt I was sent to one of their best hospitals (Fitzsimons) to work under an excellent and seasoned neurologist (Col. Halbert Herman Schwamb -- whose name alone scared the hell out of me).

The tour of duty in Vietnam was 1 year for everyone, so docs who had been there for their first of two years got their pick of where to go for their final year. Naturally, Fitzsimons was one of their top picks, so the place was full of them.

What in the world does this have to do with molecular biology? The army had something called the 'body count' which meant the number of Viet Cong (and possibly civilian) bodies they could find. It gave a number, which was increasing with each passing month. It showed we were winning. However not one of the returning 2 year docs I talked to (and I talked to a lot of them) thought we were winning. Most thought we were losing, and badly. They were of course right. The point is that what we could not measure was far more important than what we could.

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21. Anon on April 19, 2009 9:30 AM writes...

Provocateufr.

My apologies for assuming the worst. But saying a one gene one protein relationship "demolish[s] the very heart of the evolution argument" was completely hysterical. Evolutionary pressure acts predominantly on function rather than mechanism.

Also evolution is an ongoing process, so suboptimality is only a strong criticism at infinity in an unchanging environment, additionally there may be limited functional disadvantage with having sizable segments of inert DNA. You seem to discount functional advantages associated with redundancy.

The other major area worth considering (which I know very little about) is the available mechanisms for creating new function (gene duplication, protein moonlighting, etc). These options are limited and their viability is unlikely to be weighted equally, or constantly, throughout time.

Fun topic, sorry for jumping to the wrong conclusion.

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22. provocateur on April 19, 2009 9:31 AM writes...

Thanks to CellBio and retread for the efforts...Some key thoughts were ..'the human mind, even the very good, does on occasion, and too often, mistake our ignorance of something for the lack of its existence'...'is that what we could not measure was far more important than what we could'..

But I am not 'insulting' anybody ....I am criticizing which as both of you admitted are relevant here..I just felt that 'the scientists involved' tend to go out on a limb and claim even a lot of 'too good to be true' stuff with limited data..I do not see any such parallels in my field of that sort(organic chemistry)...

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23. provocateur on April 19, 2009 9:39 AM writes...

Anon
No probs..:)))

I was saying that since I believe there is overwhelming proof of evolution, the one gene-one enzyme theory cannot be true..(reverse of what you assumed from my comments)

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24. retread on April 19, 2009 10:54 AM writes...

Provocateur #22

Organic chemistry Yesss ! ! ! Compared to the work in molecular biology organic is sooo much cleaner intellectually. That's why it's such fun reading about what's been happening in the field, since I left it 47 years ago (I recommend Clayden, Anslyn and Berry -- all et. al. ).

However, organic chemistry is also relatively trivial in the larger scheme of things which matter to living people -- disease, disability and death -- which is why I left the field. Not completely trivial, as new drug classes however discovered will require the ministrations of Derek and friends to make them selective and clinically effective, and this can't even begin without what they know about organic chemistry, and the unteachable art of knowing what is likely to work and what is not. See the Chemiotics post of 5 March '08 "Is Math harder than Organic Chemistry ?"

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25. provocateur on April 19, 2009 11:24 AM writes...

Retread
...Organic chemistry focused so much on only 'reagent' chemistry ..that's why I like the new approach of late now...tying it more with the biology side of it...just think of the advances we would hv made if we would have taken 'organocatalysis' more seriously...by the way I love Anslyn..

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26. Keith Roibison on April 21, 2009 9:35 AM writes...

WRT to one-gene, one-enzyme, it is certainly a useful model for teaching but nobody I've every met (certainly in genomics) takes it as dogma. I don't see why the one provocateur is so hung up on it.

Well known deviations from the one-gene, one enzyme (or structural protein) model, and these are well known


  • Multiple enzyme activites from one polypeptide, such as Fatty Acid Synthase

  • Multiple signalling proteins via proteolysis, such as many bioactive peptides in vertebrates

  • One protein, multiple functional categories. Enzymatically active proteins which also are lens proteins (crystallins); aconitase also serving as redox/iron-sensing transcription factor

Concepts such as 'gene' are very useful, but nature wasn't interested in making things easy for us. The ultimate sort of case is a set of mRNAs in human (I forget the locus at the moment) which share exons, but there are cases of pairs of mRNAs from that locus that share no exons between themselves.

As a colleague of mine commented once, Nature is a hacker! Whatever works is what is used.

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27. mark on April 24, 2009 9:21 AM writes...

Getting back to the original point, and supporting comment 4, there is a big difference between trying to understand the genetic basis of common diseases and finding viable drug targets for those diseases. We are a long way from the former, but already quite good at the latter. When it comes to identifying a viable drug target, genetics functions as a sort of surrogate chemical modulator. Genetic variation in a gene that changes its level of activity is (with some caveats) equivalent to chemically modulating the activity of that gene. The example of HMGCoR and statins is good, but those are subtle variants. High penetrance severe mutations of the HMGCoaR gene are not known in humans, but mutations in the LDL receptor cause familial hypercholesterolemia, and upregulation of the LDLR is the ultimate effect of statins in the body. Rare mutations in the GPCR-family gene member P2RY12 cause a clotting disorder, and this is the direct gene target of Plavix, a major anti-clotting drug. Similarly, rare familial mutations in the sulfonylurea receptor genes can cause either diabetes or severe hypoglycemia, acting very much like the channel blockers or openers which are used currently to treat diabetes or insulinomas. Rare monogenic disorders as well as common low penetrance SNPs are useful for defining new drug target candidates, even though they are of limited value in 'personalized medicine'. The human genome encodes about 3000 classically druggable gene products (enzymes, receptors, channels, etc) only a small fraction of which are actual targets of drugs on the market. So there are lots of potentially druggable genes for which no clear function is known; any of these could be a target for new drugs if we could draw the appropriate genotype/phenotype correlations.

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