Skip to main content

Drug Industry History

Jargon Will Save Us All

Moore’s Law: number of semiconductors on a chip doubling every 18 months or so, etc. Everyone’s heard of it. But can we agree that anyone who uses it as a metaphor or perscription for drug research doesn’t know what they’re talking about?
I first came across the comparison back during the genomics frenzy. One company that had bought into the craze in a big way press-released (after a rather interval) that they’d advanced their first compound to the clinic based on this wonderful genomics information. I remember rolling my eyes and thinking “Oh, yeah”, but on a hunch I went to the Yahoo! stock message boards (often a teeming heap of crazy, then as now). And there I found people just levitating with delight at this news. “This is Moore’s Law as applied to drug discovery!” shouted one enthusiast. “Do you people realize what this means?” What it meant, apparently, was not only that this announcement had come rather quickly. It also meant that this genomics stuff was going to discover twice as many drugs as this real soon. And real soon after that, twice as many more, and so on until the guy posting the comment was as rich as Warren Buffet, because he was a visionary who’d been smart enough to load himself into the catapult and help cut the rope. (For those who don’t know how that story ended, the answer is Not Well: the stock that occasioned all this hyperventilation ended up dropping by a factor of nearly a hundred over the next couple of years. The press-released clinical candidate was never, ever, heard of again).
I bring this up because a reader in the industry forwarded me this column from Bio-IT World, entitled, yes, “Only Moore’s Law Can Save Big Pharma”. I’ve read it three times now, and I still have only the vaguest idea of what it’s talking about. Let’s see if any of you can do better.
The author starts off by talking about the pressures that the drug industry is under, and I have no problem with him there. That is, until he gets to the scientific pressures, which he sketches out thusly:

Scientifically, the classic drug discovery paradigm has reached the end of its long road. Penicillin, stumbled on by accident, was a bona fide magic bullet. The industry has since been organized to conduct programs of discovery, not design. The most that can be said for modern pharmaceutical research, with its hundreds of thousands of candidate molecules being shoveled through high-throughput screening, is that it is an organized accident. This approach is perhaps best characterized by the Chief Scientific Officer of a prominent biotech company who recently said, “Drug discovery is all about passion and faith. It has nothing to do with analytics.”
The problem with faith-based drug discovery is that the low hanging fruit has already been plucked, driving would be discoverers further afield. Searching for the next miracle drug in some witch doctor’s jungle brew is not science. It’s desperation.
The only way to escape this downward spiral is new science. Fortunately, the fuzzy outlines of a revolution are just emerging. For lack of a better word, call it Digital Chemistry.

And when the man says “fuzzy outline”, well, you’d better take him at his word. What, I know you’re all asking, is this Digital Chemistry stuff? Here, wade into this:

Tomorrow’s drug companies will build rationally engineered multi-component molecular machines, not small molecule drugs isolated from tree bark or bread mold. These molecular machines will be assembled from discrete interchangeable modules designed using hierarchical simulation tools that resemble the tool chains used to build complex integrated circuits from simple nanoscale components. Guess-and-check wet chemistry can’t scale. Hit or miss discovery lacks cross-product synergy. Digital Chemistry will change that.

Honestly, if I start talking like this, I hope that onlookers will forgo taking notes and catch on quickly enough to call the ambulance. I know that I’m quoting too much, but I have to tell you more about how all this is going to work:

But modeling protein-protein interaction is computationally intractable, you say? True. But the kinetic behavior of the component molecules that will one day constitute the expanding design library for Digital Chemistry will be synthetically constrained. This will allow engineers to deliver ever more complex functional behavior as the drugs and the tools used to design them co-evolve.
How will drugs of the future function? Intracellular microtherapeutic action will be triggered if and only if precisely targeted DNA or RNA pathologies are detected within individual sick cells. Normal cells will be unaffected. Corrective action shutting down only malfunctioning cells will have the potential of delivering 99% cure rates. Some therapies will be broad based and others will be personalized, programmed using DNA from the patient’s own tumor that has been extracted, sequenced, and used to configure “target codes” that can be custom loaded into the detection module of these molecular machines.

Look, I know where this is coming from. And I freely admit that I hope that, eventually, a really detailed molecular-level knowledge of disease pathology, coupled with a really robust nanotechnology, will allow us to treat disease in ways that we can’t even approach now. Speed the day! But the day is not sped by acting as if this is the short-term solution for the ills of the drug industry, or by talking as if we already have any idea at all about how to go about these things. We don’t.
And what does that paragraph up there mean? “The kinetic behavior. . .will be synthetically constrained”? Honestly, I should be qualified to make sense of that, but I can’t. And how do we go from protein-protein interactions at the beginning of all that to DNA and RNA pathologies at the end, anyway? If all the genomics business has taught us anything, it’s that these are two very, very different worlds – both important, but separated by a rather wide zone of very lightly-filled-in knowledge.
Let’s take this step by step; there’s no other way. In the future, according to this piece, we will detect pathologies by detecting cell-by-cell variations in DNA and/or RNA. How will we do that? At present, you have to rip open cells and kill them to sequence their nucleic acids, and the sensitivities are not good enough to do it one cell at a time. So we’re going to find some way to do that in a specific non-lethal way, either from the outside of the cells (by a technology that we cannot even yet envision) or by getting inside them (by a technology that we cannot even envision) and reading off their sequences in situ (by a technology that we cannot even envision). Moreover, we’re going to do that not only with the permanent DNA, but with the various transiently expressed RNA species, which are localized to all sort of different cell compartments, present in minute amounts and often for short periods of time, and handled in ways that we’re only beginning to grasp and for purposes that are not at all yet clear. Right.
Then. . .then we’re going to take “corrective action”. By this I presume that we’re either going to selectively kill those cells or alter them through gene therapy. I should note that gene therapy, though incredibly promising as ever, is something that so far we have been unable, in most cases, to get to work. Never mind. We’re going to do this cell by cell, selectively picking out just the ones we want out of the trillions of possibilities in the living organism, using technologies that, I cannot emphasize enough, we do not yet have. We do not yet know how to find most individual cells types in a complex living tissue; huge arguments ensue about whether certain rare types (such as stem cells) are present at all. We cannot find and pick out, for example, every precancerous cell in a given volume of tissue, not even by slicing pieces out of it, taking it out into the lab, and using all the modern techniques of instrumental analysis and molecular biology.
What will we use to do any of this inside the living organism? What will such things be made of? How will you dose them, whatever they are? Will they be taken up though the gut? Doesn’t seem likely, given the size and complexity we’re talking about. So, intravenous then, fine – how will they distribute through the body? Everything spreads out a bit differently, you know. How do you keep them from sticking to all kinds of proteins and surfaces that you’re not interested in? How long will they last in vivo? How will you keep them from being cleared out by the liver, or from setting off a potentially deadly immune response? All of these could vary from patient to patient, just to make things more interesting. How will we get any of these things into cells, when we only roughly understand the dozens of different transport mechanisms involved? And how will we keep the cells from pumping them right back out? They do that, you know. And when it’s time to kill the cells, how do you make absolutely sure that you’re only killing the ones you want? And when it’s time to do the gene therapy, what’s the energy source for all the chemistry involved, as we cut out some sequences and splice in the others? Are we absolutely sure that we’re only doing that in just the right places in just the right cells, or will we (disastrously) be sticking in copies into the DNA of a quarter of a per cent of all the others?
And what does all this nucleic acid focus have to do with protein expression and processing? You can’t fix a lot of things at the DNA level. Misfolding, misglycosylation, defects in transport and removal – a lot of this stuff is post-genomic. Are we going to be able to sequence proteins in vivo, cell by cell, as well? Detect tertiary structure problems? How? And fix them, how?
Alright, you get the idea. The thing is, and this may be surprising considering those last few paragraphs, that I don’t consider all of this to be intrinsically impossible. Many people who beat up on nanotechnology would disagree, but I think that some of these things are, at least in broad hazy theory, possibly doable. But they will require technologies that we are nowhere close to owning. Babbling, as the Bio-IT World piece does, about “detection modules” and “target codes” and “corrective action” is absolutely no help at all. Every one of those phrases unpacks into a gigantic tangle of incredibly complex details and total unknowns. I’m not ready to rule some of this stuff out. But I’m not ready to rule it in just by waving my hands.

46 comments on “Jargon Will Save Us All”

  1. alig says:

    Maybe the time interval for the doubling is different for pharmaceutical Moore law. Instead of 18 months maybe its 50 years. Compare the number of drugs discovered in the 1900s to the 1950s to 2000s.

  2. Orthogon says:

    I think the protein-protein interaction/kinetic behavior/synthetically constrained business is a result of his/her vague familiarity with Aileron and stapled peptides.

  3. RB Woodweird says:

    “The most that can be said for modern pharmaceutical research, with its hundreds of thousands of candidate molecules being shoveled through high-throughput screening, is that it is an organized accident.”
    Well, that part is true. It is only the degree and type of organization that we have control over.
    “These molecular machines will be assembled from discrete interchangeable modules designed using hierarchical simulation tools that resemble the tool chains used to build complex integrated circuits from simple nanoscale components.”
    My head asplode. No mention of quantum or a paradigm shift? -2 clue points.
    “Honestly, I should be qualified to make sense of that, but I can’t.”
    Need that sentence on a T-shirt.

  4. You know, the idea of nanomachines etc… reminds me of the book Moon War by Ben Bova. He draws heavily on nanomedicine-machine things.

  5. Hap says:

    Since the article seems to have no intellectual basis [no understanding of the problems involved with drug design, no idea of the technology necessary to solve them (or how to find such technologies), no idea of the costs of said technologies], my guess is that the methodology (and I use that term loosely) is destined for a business methods book for pharmaceutical executives and naive/lobotomized reporters on the pharmaceutical industry. The book will sell like hotcakes, be repeated by pharmaceutical excutives endlessly in six months, have jumped the shark in two years, and leave a mess in R+D that will take at least five years to fix.
    Anything is easy for the one who doesn’t have to do it himself.

  6. Ty says:

    sigh… too much TV, I guess…

  7. Anonymous says:

    This is like a basketball coach saying the most efficient way to win an NBA championship is to find a player who is 10 times more talented than Michael Jordan.

  8. Seehecht says:

    At the moment we did not even know how simple proteins are being folded also the interactions between a drug and its target is unclear on the atomistic scale.
    > But modeling protein-protein interaction is
    > computationally intractable, you say? True.
    Here, Moore’s law will help us, but it think it will still takes at least 5-10 years.
    > But the kinetic behavior of the component
    > molecules that will one day constitute the
    > expanding design library for Digital Chemistry
    > will be synthetically constrained.
    Digital Chemistry = Computational Chemistry 2.0?

  9. weirdo says:

    It sounds like this guy sat next to Stu Schreiber on a plane trip (from Basel to Boston, in First Class) last week.

  10. RTW says:

    A Bio-IT guy trying to elicit funding…. The CADD, Bio-IT guys always think they know how to develop drugs better mor rationally than the Synthetic/Medchemist. I don’t think I have ever seen a beleivable case of CADD being responsible forthe discovery of a drug that has made it out the door. Even if it made it to a clinical trial, I suspect it had a lot of medicinal chemistry, PK/PD support to get there.
    As a former synthetic chemist that worked the bench in Big Pharma for more than 20 years, and now doing Cheminformatics and knowledge management, I have a much more realistic view. From my perspective we have a great deal of KNOWLEDGE to create and manage. Just managing that knowledge is going to be a major undertaking.
    This is indeed something out of a futuristic SyFi broadcast.

  11. anon says:

    I read that same article and thought WTF…

  12. Sleepless in SSF says:

    Looking up the author, I find that he has BS/MS in electrical engineering and a BS in biology. He has spent his career working for in the wireless phone and set-top box industries. No wonder the article is vague and nonsensical — his training and experience look to be completely irrelevant to the subject at hand.

  13. Nick k says:

    The article is wishful thinking of the highest order. Clearly, the author is completely clueless about drug discovery and medchem.

  14. hibob says:

    @RTW, @Sleepless:
    I think this guy is angling for a job with Andy Groves, the Intel chief who knows how to fix all of Pharma’s problems:
    “Why is the speed of progress so different in semiconductor research and drug development?”
    “The fundamental tenet that drives us all in the semiconductor industry is a deeply felt conviction that what matters is time to market, or time to money. But you never hear an executive from a pharmaceutical company say, “Before the end of the year I’m going to have xyz drug,” the way Steve Jobs said the iPhone would be out on schedule. The heart of every high-tech executive has been, get the product into customers’ hands and ramp up production. That drive is just not present in pharma; the drive to get sufficient understanding and go for it is missing.”

  15. np_chemist says:

    Even “Saint Stuart” at his worst would not try to perpetrate such a fraudulent series of statements, and I do not love “SS”!!

  16. DevicesRus says:

    I think this is related to a recent business week article on innovation. The authors make the argument that in recent years innovation in America means innovation in either computer hardware or software and that there is an apparent lack of innovation in areas like biomedical science and drug therapies. They just don’t get how hard it is. On the other hand medchem folks don’t get the same push for nano that us poor device folks get. We hear every day “why don’t you make my device look like an Ipod, small and cute”. When you point out that the device needs to hold 3 ml of drug or a battery to last 10 years without recharging they say “just use some of those nanotechnology gizmos to make it work”. If only we knew how.

  17. theo says:

    Sorry to see the BIO-IT World article perpetuating the myth of penicillin’s supposedly serendipitous discovery. As detailed in, “Alexander Fleming: The Man and the Myth,” Howard Florey painstakingly developed penicillin as a useful antibiotic. Fleming’s happening upon the mold led to fleeting interest on his part, and some furtive use of it by him as a reagent.

  18. partial agonist says:

    RTW:” I don’t think I have ever seen a beleivable case of CADD being responsible forthe discovery of a drug that has made it out the door. Even if it made it to a clinical trial, I suspect it had a lot of medicinal chemistry, PK/PD support to get there.”
    Well, somebody has to “put 10 grams of it in a bottle” you know. Then a kilo, then the big scale… It’s kind of hard to feed the rats the sdf files (or pdb files, or whatever) and see any effect. 😉
    Like everything else that was (or is) a fad and gets overhyped, CADD is a tool. It has been used effectively many times to speed things to market, though far less effectively than those who were (and are) championing it loudest have predicted.

  19. milkshake says:

    So far the pharma industry is following the inverse Moore law – precisely because the management and investors act irresponsibly and fool themselves and each other with pretentious gorp. Jargon lends the semblance of solidity to crazy and inane ideas.

  20. JC says:

    One doesn’t have to do expensive clinical trials & get FDA aprroval to sell buggy software or iPods that overheat.

  21. DerekF says:

    I think someone has modified Scigen (see some of Derek’s earlier posts, most recently 12 June) to add some more biobabble terms and turned it loose.

  22. Hap says:

    Oh, look – another drug spammer! (post 20)
    You must be so proud.

  23. anon the II says:

    The pharma world isn’t the only place that has morons. Listen to this guy and he’s a director with NASA. He should know better.

  24. lost in translation says:

    the article reads like an accidentally misplaced, particularly ill-translated instruction manual (heaven forbid for pharma executives!)…

  25. Tok says:

    That Andy Groves quote burns me up.
    Imagine if every time an intel chip (either CPU, wireless, northbridge, etc) on the market died, so did a human being. Somehow I think Moore’s law would quickly come screeching to a halt. It’s tough to “get the product into conusmers’ hands and ramp up production” when it has to be pretty much perfect out the door.

  26. JC says:

    Look Hap – another drug spammer (post 25)

  27. Mr. Gunn says:

    Tok – You nailed it. Don’t compare pharma to the semiconductor industry, compare it to space exploration.
    I know the EEs at the biotech I work for are probably reading this, nodding their heads, and thinking “poor little biologists …” Can’t wait for one of them to bring it up in conversation.

  28. Dylan says:

    Reading this reminded me of an old joke about economists.
    3 college professors are stranded on a desert island after the ship they are on capsizes. The only thing they managed to save was one of those giant cans of baked beans from the galley…but of course had no way to open it. The physics professor starts with some equations in the sand about the amount of force that can be generated by dropping coconuts onto the can…but the others reject the idea as being too likely to cause half the beans to go flying. The chemist suggest that the can be set in salt water where it will eventually rust away to the point that it will be easy to open…but they decide that this will take too long. Then the economics professor steps up and says to the other two, “look, you’re making this too hard, let’s just assume a can opener…” [/groan]
    But seriously, as an economics trained individual, my take is always that someone else can do the hard work as long as the incentives are right. So what the heck is taking you so long…

  29. Ben T says:

    Well… we’re getting there:

  30. Ben T says:

    Whoops… missing the quote from Derek’s post:
    “At present, you have to rip open cells and kill them to sequence their nucleic acids, and the sensitivities are not good enough to do it one cell at a time.”

  31. Clueless says:

    What is a “drug spammer”?

  32. Brok says:

    Re: comment 28
    Okay, what are my incentives? Or, better question- what’s my budget? If you’re in economics, take a look at what has been happening with funding in the scientific community over the last 10-15 years. More time is being wasted by people fighting to get money, rather than actually trying to conduct their research. Not all innovations come from industry- in fact, more of the really out of left-field stuff comes from private researchers and institutes and universities.

  33. sawtheplace says:

    Stapled peptides, yeah right, when I visited the place there was NO ONE working in the lab, not even one.
    And who’s the CFO……
    So we’re supposed to believe that years of making constrained peptides to no effect, will be eclipsed by ones made via RCM?
    More grabbing at straws

  34. S Silverstein says:

    I thought the Electronic Medical Record was the cybernetic miracle that was going to revolutionize medicine and save the pharmaceutical industry, too. Now I find out it’s digital chemistry.
    Who knew?

  35. OxFrog says:

    hey, what’s all the fuzz ?
    So there’s an editor who needs to fill his (advert-financed) pages who asks someone for a commentary. This other guys is qualified, because he did a BS in Biology at MIT at the time Craig Venter did his PhD on the other coast, and because he read “The Lazarus Vendetta” not too long ago. But then he went into el. engineering and spent a good part of his life building visionary products that nobody wanted ( and now sits on the dark side looking for (presumably other people’s) money to finance start-ups that build visionary stuff for the next century. Of course he agrees to the free advertisement of himself as the one in the know, takes a piece he wrote for RealClearMarkets (, cuts out the juicy bits and now enjoys the storm on this blog and others – free publicity.
    This piece of BS didn’t appear in WSJ or FT, it didn’t come from Witty or Obama, and it certainly doesn’t deserve half of the attention or 10 minutes of our time.
    Back to the bench (or the computer 🙂 and start doing the real visionary stuff that will bring our industry a success to get excited about !

  36. Conrad says:

    It’s deeply insulting to compare this man to a schizophrenic. Schizophrenics are more coherent.

  37. Dr. Manhattan says:

    This reminds me of one of the lines from that classic Mel Brooks film “Blazing Saddles”. To paraphase:
    “I’m happy these youngster were present to hear this example of authentic scientific gibberish!”

  38. milkshake says:

    the problem is that some VP debil will read it and recycle it into a brand new meeting lingo.
    A colleague blogger once heard their pointy-haired boss musing on the meeting whether they should use water-based ionic liquid chemistry “to greenify our methodology”. When someone pointed out that butyl lithium in that step would not mix too well with water, the boss smiled and said “I bet you could try it with cyclodextrins”

  39. Jan Teller Jr says:

    If I were that guy I would have excused myself to go out from the meeting to the nearest card cash machine, I would have taken everything out, even grandma´s jewelry, and then would have put all on the table to accept that bet from such a nefarious…

  40. Hap says:

    #31: A drug site likes to post pretend comments with their URL to get people to buy drugs from them – they usually don’t make any sense with respect to the topic but take a second to parse and realize that the comment is just a way to get their URL out there. It’s not spam in the sense that it’s not being mass emailed, but it’s close enough to be some sort of relative whose authors are deserving of the same treatment as spammers.

  41. Clueless says:

    @#40: I see. But neither #20 nor #25 are ‘drug spams’. They both support Derek’s argument against Moore’s Law in pharma.

  42. Jack says:

    “Hit or miss discovery lacks cross-product synergy”
    I just found my new favorite Name For A Band.

  43. alig says:

    The drugs spams were removed. The current #20 & 25 are not the spams.

  44. srp says:

    The worst part of the article, from my bus/econ point of view, is not even the egregious scientific/technological ignorance it displays. The business analysis, *assuming his fantasy were to come true*, is fatuous. If we could design drugs the way we design cars, the rate of return on investment in drug design would plummet because of the lower risk premium and greater competition. The day drug discovery becomes semi-routine is the day its extraordinary historical ROI goes bye-bye forever.

  45. Hap says:

    #20 and #25 were drug spams, but Dr. Lowe or whoever else maintains the site nuked them quickly. Usually I put “soon-to-be-ex” or something so that when they are removed and sent to hell (a fate too good for them), the messages aren’t so confusing.
    On one hand, I’d like to nuke the spammers and their paymasters from orbit. On the other hand, if someone is stupid enough to buy heavy-duty pain medication from someone paying online spammers for advertising, the purchaser deserves some of what they’re going to get.

  46. Rich Rostrom says:

    In 1950, Robert Heinlein wrote:
    “When chemistry becomes a discipline, mathematical chemists will design new materials, predict their properties, and tell engineers how to make them – without ever entering a laboratory.”

Comments are closed.