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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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June 14, 2010

Looking Back at the Genome

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Posted by Derek

The New York Times reminded its readers the other day about something that people in medical research have known for quite some time: the human genome has not exactly turned out to be an open book full of readily usable data about human diseases.

It does make a person cringe to go back and read the press releases and speeches that were made back when the genome was first announced. How about Bill Clinton's statement that the genome sequence would "revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases"? Or Francis Collins, predicting "a complete transformation in therapeutic medicine"? He's got about five more years on that one, but I'm not holding my breath.

As I've written here before, though, there was already a deep sense of nervousness among the people searching the sequences for disease clues - not to mention the nervousness among the people who had given them huge piles of money to do so. When the total estimated number of genes came out far lower than most people expected, there was a collective "Hmmm. . ." across the field. That number meant that the simpler possibilities for gene sequence-protein-disease linkage could already be ruled out - complicated things were clearly going on in transcription, translation, and further downstream.

That certainly doesn't mean that genomic sequencing has been a waste of time. It's been a tremendous boon, actually, because this complexity was out there waiting to be uncovered and understood. It's no one's fault that it hasn't led to speedy drug discovery; biology isn't set up for our convenience. And the further improvements that we've seen in sequencing speed and accuracy are going to be crucial if we're to have any chance of figuring out what's going on.

Comments (25) + TrackBacks (0) | Category: Drug Industry History


COMMENTS

1. CMCguy on June 14, 2010 9:45 AM writes...

Just another example of over-hyped technology that was supposed to lead immediately to quicker and easier drugs/treatments. I think you are correct genomics has increased understanding and ultimately will provide benefits in a few areas however as with other such "paradigm shifts" it has been largely another diversion or distraction that provided justification for management to reduce or eliminate resources that could have been discovering and developing drugs by somewhat more traditional efforts.

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2. wei on June 14, 2010 10:08 AM writes...

this feels like a part of the difference between science and business as discussed a few days ago in "The Truth Shall Make Ye. . .Unhappy?"

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3. CB on June 14, 2010 10:16 AM writes...

I completely disagree. The traunch of money supplied for the human genome initiative revolutionized gene sequencing. I doubt that we would currently have the ability to rapidly sequence genes that we now have without government funding in this areas. Secondly it has opened up gene sequencing of multiple organisms providing significant insight gene function through comparative studies between organisms. Finally this has lead to a revolution in diagnosis and identification of cancer genes.

Prior to the human genome initiative there was really no market for high throughput gene sequencing, hand read DNA sequencing gels were the standard. There were no drivers for developing the high end sequencing machines and databases that we currently have access to.

This is an example of government spending, having a huge multiplier effect.

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4. Evorich on June 14, 2010 10:21 AM writes...

Linked to this is this article I read this morning:

http://seekingalpha.com/article/209854-digital-pathology-will-usher-in-a-new-era-of-personalized-medicine?source=email

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5. Daniel Newby on June 14, 2010 11:23 AM writes...

The technology is only now getting cheap enough to sequence the millions of people needed to get enough data. It will take 5-10 years from today to gather the data, then another 5-10 years to start finding final common disease pathways. Only then will we have the targets to develop therapies in earnest.

Did people seriously think that having Craig Ventner's genome would be an instant magic cure for all diseases?

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6. RandDChemist on June 14, 2010 11:27 AM writes...

Pharmaceutical Development: Tough Road Ahead

http://www.policymed.com/2010/06/pharmaceutical-development-tough-road-ahead.html

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7. ProteinChemist on June 14, 2010 1:12 PM writes...

I read the NYT article yesterday and was pretty irritated by it, to tell the truth. I think that it draws some unfair conclusions, or at least hints at them. One quote in particular: "Indeed, after 10 years of effort, geneticists are almost back to square one in knowing where to look for the roots of common disease." I would strongly disagree. IMHO we have instead reached a point where a greater understanding of signaling has been/is being achieved. Instead of this immense gene pool (I think in high school they told us 100,000 plus!) where every gene has a specific function, we have a complicated signaling mechanism where each point can affect and be affected by multiple stimuli. Just understanding this and being able to manipulate it should generate new treatments. I think that the 'combo' drugs hitting the market are evidence of this.

In short, I think that the complicated picture that developed mostly as a result of the genome sequence will take time to detangle. Is it the beautiful end of all disease utopia that was predicted? Obviously not, but more knowledge that points us in the right direction has been a very clear result.

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8. anon on June 14, 2010 2:46 PM writes...

I believe in "right hyping". Too little hype; you don't get funded. Too much; you poison the waters.

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9. King of Rings on June 14, 2010 3:30 PM writes...

One problem with the whole pharma industry is too many biologists which overrun the graduate schools at a 10 to 1 ratio with chemists.

Now transpose number to the industry and you see why "omics" has ruled for the past 20 years and ruined an industry.

We chemists need to take back the role of discovery.

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10. anon too on June 14, 2010 4:46 PM writes...

I think it's mostly the incredibly long cycle time for something as complex as the genome to yield results that are easy to explain in the New York Times. For example, the EGF receptor was cloned in roughly the mid 1980's, ID'd as an oncogene and then the related erbB2 was discovered and Herceptin hit the market in (?) late 1990's, small molecules followed and still follow... >20 years from a single potential starting point to diagnostics + drugs + improved drugs. This is just how long it takes to connect the dots. You probably can't get funded if you are realistic though - 'right-hyping' is probably correct about that

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11. dearieme on June 14, 2010 5:30 PM writes...

I assume that virtually all public statements by Scientists written in the future tense are lies. It's a pretty good approximation.

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12. JasonP on June 14, 2010 5:34 PM writes...

"One problem with the whole pharma industry is too many biologists which overrun the graduate schools at a 10 to 1 ratio with chemists.

Now transpose number to the industry and you see why "omics" has ruled for the past 20 years and ruined an industry.

We chemists need to take back the role of discovery"

Hahaha...good old fashion organic chemist arrogance. You're like a blast from the past, I thought this sort of thinking was humbled by the recent times. In my experience, it is a very rare breed of chemist that can bridge the divide between chemistry and biology, whereas it is rather easy for biologists to understand the boring project presentations of chemist's synthesis and rationales.

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13. Thumperska on June 14, 2010 6:03 PM writes...

@JasonP. Ouch, but you have a point. A limited audience cares about how a molecule was made; most care about what it does and doesn't do biologically.

Back on topic... Remember that when the whole human genome project was started no one knew the extent of post transcriptional control. Few had dreamed that RNAi was so
important and what the use of 3' untranslated regions on mRNA are.

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14. Matt Random on June 14, 2010 7:33 PM writes...

An analogy... (Metaphor? Parable?)

Hiking out of the Grand Canyon, you look up and see a tall rock wall, with only the sky above it. Far ahead and above, you can make out the trail winding back and forth on its way to the top. That's the task, and you set to it, measuring your progress with how close you are to the top, and perhaps a glance back to see how far you've come.

Ah, but some time later at the top of that wall, you see a short flat mesa, and another tall rock wall set back enough to be hidden from view until now. Far ahead and above, you see the trail winding back and forth on its way to the top. Looks like there's a lot more to go, and no guarantees that that top is THE top.

Weary feet groan that you are back to square one. Hope that soon a promised reward would be in reach fades, at least temporarily. Looking back, most of the progress made seems to have faded from view below the mesa, but not faded from the memory of the feet and legs and back of the ones walking. An observer suddenly spirited into this location might conclude you have just started, and think you have been wasting time thus far.

Looking around you, though, you see staggering beauty. You may find valuable companionship in your fellow travelers. One moment you treasure these things, the next you just want to be over and out.

Back to the regularly scheduled discussion.

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15. Jose on June 15, 2010 2:26 AM writes...

"...we have a complicated signaling mechanism where each point can affect and be affected by multiple stimuli. Just understanding this and being able to manipulate it should generate new treatments."

I think sums up exactly why the genomics hype is just laughable, and NYT article is dead on.... we are dealing with so many previously unsuspected layers of interconnected complexity we can't even *begin, guess or hypothesize* how to untangle it for even the most *basic* of diseases- do you really think that state of affairs is going to change anytime in the next 30 years???

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16. AR on June 15, 2010 7:13 AM writes...

#5: 'Did people seriously think that having Craig Ventner's genome would be an instant magic cure for all diseases?'

Yes. They did. I lost a job when senior managers drank from the genmoics kool-aid.

Genes to Products was the mantra. You didn't need the stuff - nor the people - in-between.

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17. MIMD on June 15, 2010 7:26 AM writes...

#5 Did people seriously think that having Craig Ventner's genome would be an instant magic cure for all diseases?

Unfortunately, I think many did.

While the ranks of medicinal chemists are being thinned, and a belief prevails that cybernetic miracles will discover new drugs, I think it's worth asking if bioinformatics has hit a hard wall of stagnation.

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18. King of Zings on June 15, 2010 8:49 AM writes...

No organic chermistry arrogance here. We all know that it's easier for a chemist to learn biology than the other way around.

But the good geneticists know the genome is 25% flawed and meanwhile the chemists that get laid off from generating IP and comnpounds are eating from trash cans these days.

10 to 1 biologists to chemists means more control over an industry that is sorely lacking...think about it.... or not.

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19. anon too on June 15, 2010 9:04 AM writes...

Having worked on and/or managed three projects that delivered FDA approved drugs, I have to interject into the 'King of Zings' and 'JasonP' exchange. Great chemistry w/o great biology in drug discovery is usually one hand clapping. The best scientists (i.e. - those having an impact on drug discovery) in both domains understand a lot about both areas. This does not imply that biologists need to know synthesis or that chemists need to know how to culture cells - these are means to ends - it's understanding the issues at the interface that matter the most.

The best discovery projects I've seen were led by a talented chemist and a talented biologist.

A long-term view of the value of the genome is required - because we are not as smart as we thought we were (and this is always true)

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20. JasonP on June 15, 2010 3:55 PM writes...

"10 to 1 biologists to chemists means more control over an industry that is sorely lacking...think about it.... or not. "

You're right about the numbers but I think you are reading too much into them. I think a tremendous number of people get into biology for reasons other than drug discovery, whereas if you are getting into organic chemistry, you are 99% of the time heading for that pharma job.

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21. JasonP on June 15, 2010 3:57 PM writes...

By the way, reading too much into numbers and not taking in the whole picture is a classic chemist thing to do....

:)

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22. King of Zings on June 15, 2010 5:04 PM writes...

Jason, We could keep this going but who has time? As an educator the students tell me that biology is much easier and I walk in many worlds.

Hence, the 10:1 ratio.

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23. King of Zings on June 15, 2010 5:23 PM writes...

One more thing, just to let you know I am part biologist--

Did you hear about the farmer's daughter and the molecular biolgist?

They both thought restriction enzymes were reagents not commercially available!

Enjoy!

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24. Science is hard, deal with it on June 16, 2010 4:22 PM writes...

The "failure" of the human genome to deliver is not a failure of the sequencing of the genome, it's a failure of HapMap and GWAS technologies to identify COMMON VARIANTS associated with complex, non-Mendelian diseases. What is clear from the "disappointing" results thus far is that GWAS/HapMap's ability to approximate the extent of genetic variation was vastly overestimated (or overstated) by proponents of the technology. A recent GWAS effort in a common disease from a consortium looking at 10,000 cases and 16,000 controls (probably not money well spent - 10M GBP) concluded that only 4% of the heritability of the disease could be explained by GWAS. That leaves two likely (non-mutually exclusive) possibilities to explain the remaining 96%: 1) rare variants, which may be addressed by emerging "cheap" whole genome sequencing technologies and 2) epigenetics, which we really don't understand very well at a genomic level.

For complex diseases with evident, if complex, heritability, genetic approaches are unlikely to identify causal variants that are directly targetable with new therapeutics; more likely (and this is how we should be thinking about it) they will help us identify dysregulated pathways that we can target, and in most cases the "target" itself may not be mutated. Thus we need to have some fairly detailed understanding of biological pathways in addition to statistical genetics. Furthermore, these pathways will not likely be implicated in everyone with a given disease, hence understanding in whom they are implicated will be necessary to show efficacy in therapeutic trials.

Or for the short version of this comment: we will not be able to make sense of complex datasets with statistics alone; we need to actually understand the biology too.

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25. Shazz on June 16, 2010 9:45 PM writes...

Another gorilla in the room is the impact of all the unidentified and unstudied viruses, bacteria and parasites that call the human body home (plus the health impacts of them being absent when they were having some positive role).

Much of what we currently consider to be genetic or environmental disease may in fact be sparked by a subtle pathogen (like Helicobacter and stomach ulcers).

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