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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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August 13, 2013

Druggability: A Philosophical Investigation

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Posted by Derek

I had a very interesting email the other day, and my reply to it started getting so long that I thought I'd just turn it into a blog post. Here's the question:

How long can we expect to keep finding new drugs?

By way of analogy, consider software development. In general, it's pretty hard to think of a computer-based task that you couldn't write a program to do, at least in principle. It may be expensive, or may be unreasonably slow, but physical possibility implies that a program exists to accomplish it.

Engineering is similar. If it's physically possible to do something, I can, in principle, build a machine to do it.

But it doesn't seem obvious that the same holds true for drug development. Something being physically possible (removing plaque from arteries, killing all cancerous cells, etc.) doesn't seem like it would guarantee that a drug will exist to accomplish it. No matter how much we'd like a drug for Alzheimer's, it's possible that there simply isn't one.

Is this accurate? Or is the language of chemistry expressive enough that if you can imagine a chemical solution to something, it (in principle) exists. (I don't really have a hard and fast definition of 'drug' here. Obviously all bets are off if your 'drug' is complicated enough to act like a living thing.)

And if it is accurate, what does that say about the long-term prospects for the drug industry? Is there any risk of "running out" of new drugs? Is drug discovery destined to be a stepping-stone until more advanced medical techniques are available?

That's an interesting philosophical point, and one that had never occurred to me in quite that way. I think that's because programming is much more of a branch of mathematics. If you've got a Universal Turing Machine and enough tape to run through it, then you can, in theory, run any program that ever could be run. And any process that can be broken down into handling ones and zeros can be the subject of a program, so the Church-Turing thesis would say that yes, you can calculate it.

But biochemistry is most definitely a different thing, and this is where a lot of people who come into it from the math/CS/engineering side run into trouble. There's a famous (infamous) essay called "Can A Biologist Fix A Radio" that illustrates the point well. The author actually has some good arguments, and some legitimate complaints about the way biochemistry/molecular biology has been approached. But I think that his thesis breaks down eventually, and I've been thinking on and off for years about just where that happens and how to explain what makes things go haywire. My best guess is algorithmic complexity. It's very hard to reduce the behavior of biochemical systems to mathematical formalism. The whole point of formal notation is to express things in the most compact and information-rich way possible, but trying to compress biochemistry in this manner doesn't give you much of an advantage, at least not in the ways we've tried to do it so far.

To get back to the question at hand, let's get philosophical. I'd say that at the most macro level, there are solutions to all the medical problems. After all, we have the example of people who don't have multiple sclerosis, who don't have malaria, who don't have diabetes or pancreatic cancer or what have you. We know that there are biochemical states where these things do not exist; the problem is then to get an individual patient's state back to that situation. Note that this argument does not apply to things like life extension, limb regeneration, and so on: we don't know if humans are capable of these things or not yet, even if there may be some good arguments to be made in their favor. But we know that there are human brains without Alzheimer's.

To move down a level from this, though, the next question is whether there are ways to put a patient's cells and organs back into a disease-free state. In some cases, I think that the answer has to be, for all practical purposes, "No". I tend to think that the later stages of Alzheimer's (for example) are in fact incurable. Neurons are dead and damaged, what was contained in them and in their arrangement is gone, and any repair system can only go so far. Too much information has been lost and too much entropy has been let in. I would like to be wrong about this, but I don't think I am.

But for less severe states and diseases, you can imagine various interventions - chemical, surgical, genetic - that could restore things. So the question here becomes whether there are drug-like solutions. The answer is tricky. If you look at a biochemical mechanism and can see that there's a particular pathway involving small molecules, then certainly, you can say that there could be a molecule to be found as a treatment, even if we haven't found it yet. But the first part of that last sentence has to be unpacked.

Take diabetes. Type I diabetes is proximately caused by lack of insulin, so the solution is to take insulin. And that works, although it's certainly not a cure, since you have to take insuin for the rest of your life, and it's impossible to take it in a way that perfectly mimics the way your body would adminster it, etc. A cure would be to have working beta-cells again that respond just the way they're supposed to, and that's less likely to be achieved through a drug therapy. (Although you could imagine some small molecule that affects a certain class of stem cell, causing it to start the program to differentiate into a fully-formed beta cell, and so on). You'd also want to know why the original population of cells died in the first place, and how to keep that from happening again, which might also take you to some immunological and cell-cycle pathways that could be modulated by drug molecules. But all of these avenues might just as easily take you into genetically modified cloned cell lines and surgical implantation, too, rather than anything involving small-molecule chemistry.

Here's another level of complexity, then: insulin is certainly a drug, but it's not a small molecule of the kind I'd be making. Is there a small molecular that can replace it? You'd do very well with that indeed, but the answer (I think) is "probably not". If you look at the receptor proteins that insulin binds to, the recognition surfaces that are used are probably larger than small molecules can mimic. No one's ever found a small molecule insulin mimetic, and I don't think anyone is likely to. (On the other hand, if you're trying to disrupt a protein-protein interaction, you have more hope, although that's still an extremely difficult target. We can disrupt things a lot more easily than we can make them work). Even if you found a small-molecule-insulin, you'd be faced with the problem of dosing it appropriately, which is no small challenge for a tightly and continuously regulated system like that one. (It's no small challenge for administering insulin itself, either).

And even for mechanisms that do involve small-molecule signaling, like the G-protein coupled receptors, there are still things to worry about. Take schizophrenia. You can definitely see problems with neural systems in the brain when you study that disease, and these neurons respond to, among other things, small-molecue neurotransmitters that the body makes and uses itself - dopamine, serotonin, acetylcholine and others. There are a certain number of receptors for each of those, and although we don't have all the combinations yet, I could imagine, on a philosophical level, that we could eventually have selective drugs that are agonists, antagonists, partial agonists, inverse agonists, what have you at all the subtypes. We have quite a few of them now, for some of the families. And I can even imagine that we could eventually have most or all of the combinations: a molecule that's a dopamine D2 agonist and a muscarinic M4 antagonist, all in one, and so on and so on. That's a lot more of a stretch, to be honest, but I'll stipulate that it's possible.

So you have them all. Now, which ones do you give to help a schizophrenic? We don't know. We have guesses and theories, but most of them are surely wrong. Every biochemical theory about schizophrenia is either wrong or incomplete. We don't know what goes wrong, or why, or how, or what might be done to bend things back in the right direction. It might be that we're in the same area as Alzheimer's: perhaps once a person's brain has developed in such a way that it slips into schizophrenia, that there is no way at all to rewire things, in the same way that we can't ungrow a tree in order to change the shape of its canopy. I've no idea, and we're going to know a lot more about the brain by the time we can answer that one.

So one problem with answering this question is that it's bounded not so much by chemistry as by biology. Lots and lots of biology, most of it unknown. But thinking in terms of sheer chemistry is interesting, too. Consider "The Library of Babel", the famous story by Jorge Luis Borges. It takes place in some sort of universe that is no more (and no less) than a vast library containing every possible book that can be be produced with a 25-character set of letters and punctuation marks. This is, as a bit of reflection will show, a very, very large number, one large enough to contain everything that can possibly be written down. And all the slight variations. And all the misprints. And all the scrambled coded versions of everything, and so on and so on. (W. v. O. Quine extended this idea to binary coding, which brings you back to computability).

Now think about the universe of drug-like molecules. It is also very large, although it is absolutely insignificant compared to the terrifying Library of Babel. (It's worth noting that the Library contains all of the molecules that can ever exist, coded in SMILES strings - that thought just occurred to me at this very moment, and gives me the shivers). The universe of proteins works that way, too - an alphabet of twenty-odd letters for amino acids gives you the exact same situation as the Library, and if you imagine some hideous notation for coding in all the folding variants and post-translational modifications, all the proteins are written down as well.

These, then, encompass everything chemical compound up to some arbitrary size, and the original question is, is this enough? Are there questions for which none of these words are the answer? That takes you into even colder and deeper philosophical waters. Wittgenstein (among many others) wondered the same thing about our own human languages, and seems to have decided that there are indeed things that cannot be expressed, and that this marks the boundary of philosophy itself. Famously, his Tractacus ends with the line "Wovon man nicht sprechen kann, darüber muss man schweigen": whereof we cannot speak, we must pass over in silence.

We're not at that point in the language of chemistry and pharmacology yet, and it's going to be a long, long time before we ever might be. Just the fact, though, that computability seems like such a more reasonable proposition in computer science than druggability does in biochemistry tells you a great deal about how different the two fields are.

Update: On the subject of computabiity, I'm not sure how I missed the chance to bring Gödel's Incompleteness Theorem into this, just to make it a complete stewpot of math and philosophy. But the comments to this post point out that even if you can write a program, you cannot be sure whether it will ever finish the calculation. This Halting Problem is one of the first things ever to be proved formally undecidable, and the issues it raises are very close to those explored by Gödel. But as I understand it, this is decidable for a machine with a finite amount of memory, running a deterministic program. The problem is, though, that it still might take longer than the expected lifetime of the universe to "halt", which leaves you, for, uh, practical purposes, in pretty much the same place as before. This is getting pretty far afield from questions of druggability, though. I think.

Comments (40) + TrackBacks (0) | Category: Drug Development | Drug Industry History | In Silico


COMMENTS

1. David Formerly Known as a Chemist on August 13, 2013 12:16 PM writes...

The email raises a really interesting question. I like to believe that, like engineering, if something is physically possible then it's possible to design a drug that will achieve the intended outcome. The key difference between engineering and biochemistry/medicinal chemistry is that engineering, by and large, is based on well-studied and well-understood principles of classic Newtonian physics and electromagnetism. Engineers understand the systems they're working with, they can quickly build and test prototypes, and can quickly come up with solutions that are "good enough". Developing a drug is immensely more complex because we have a much poorer understanding of the systems and networks underlying the disease, we cannot quickly build and test prototypes (if you consider human clinical trials part of the prototype testing phase), and the bar for "good enough" is pretty high (the drug must actually do some good without doing much harm). Given long time periods and unlimited finances I believe a drug could be developed for most if not all diseases. But the time periods and amounts of money required are enormous and impractical, so there will certainly be diseases that just don't get solved.

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2. Anonymous on August 13, 2013 12:19 PM writes...

Can't see the forest for the trees. Drug discovery has to break away from the idea that complex diseases can be cured by focusing on a single target.

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3. Vanzetti on August 13, 2013 12:58 PM writes...

>>>Drug discovery has to break away from the idea that complex diseases can be cured by focusing on a single target.

And then what? If you have 2 targets, you need 2 drugs. For twice the money.

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4. Casual Observer on August 13, 2013 1:14 PM writes...

For all the complexity of drug chemistry, it's still much more constrained than most of what we usually think of as engineering. To make, say, a car engine, you have a lot of options in materials, sizes of components, subsystems that have complicated behaviors in their own right (think of fuel injectors for instance). But with med chem, you're stuck with the atoms and bond lengths and reactions that nature has given us.

So I'd bet that what we can do with that is much more limited than the wide open range of things we can do with macroscale mechanical engineering, or electrical engineering. But very interested to hear what the real practitioners think (not being a chemist myself).

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5. Anon on August 13, 2013 1:17 PM writes...

I think that a distinction should be made here between the semi-specific term of drugs and the broader term of therapy (Encompassing drugs, radiation, gene therapy, small molecules, etc.)

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6. Extinct NJ chemist on August 13, 2013 1:23 PM writes...

Vanzetti - some of the best drugs hit multiple targets. Polypharmacology, while possibly a necessary approach to many complex diseases, is difficult for us trained in the 'single target' rational approach. I wonder if there will be a shift in pharma companies to be more accepting of 'dirty compounds' in the future. Only time will tell.

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7. Anonymous on August 13, 2013 1:30 PM writes...

Agree with the above: chemistry (geometry and synthetic routes) is actually quite limited, as is everything, ultimately. And then there is the law of diminishing returns.

But nothing is more limiting than the "one drug-one target-one disease" hypothesis. Time to open our minds, and get out of this rut.

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8. Chemist on August 13, 2013 1:55 PM writes...

@4&7
Chemistry may be considered somewhat limited, but the point is the complexity of biology far outstrips engineering.

when we build something from scratch its far easier to tinker with than reverse engineering a malfunction of something for which you know only a tiny fraction about how it works.

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9. Biotechie on August 13, 2013 2:31 PM writes...

This is a slight aside, but is prompted by #2 and #3; but does it make sense anymore to keep on looking for single new molecular entities, particularly when the existing pharmacopeia is now so big and perhaps underexploited? Given that a good proportion of approved drugs have now been used safely in humans for some time and work reasonably well in a subset of individuals, perhaps combinations of existing agents could be better investigated. Sure the trials are more complicated, there is a potential for drug-drug interactions etc, but companies like Gilead seem to have had spectacular success putting together existing single agents against HIV into one pill. If you can combine several treatments the advantages for patient compliance are clear, which probably means payers will support this type of innovation as well. All a bit mundane compared with Derek's more expansive original question and philosophical meanderings!

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10. BioAnon on August 13, 2013 2:58 PM writes...

Really interesting question. In addition to the question of whether or not solutions exist is whether or not the biochemical version of P=NP exists?

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11. J. Peterson on August 13, 2013 3:09 PM writes...

The related question is: When does the diminishing returns of drug investment get to the point where it's not worth looking for new drugs? When costs get beyond three commas to develop and verify a drug, is it still worth looking? Or would the money be better spent on other forms of care?

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12. @CountTheBricks on August 13, 2013 3:09 PM writes...

i have been reading this blog for about 7 years now and this is the best entry i have seen. i have so many questions and comments i dont know where to begin!

1) if i can draw it without breaking immutable laws of chemistry and physics, it can be made, i just havent figured out how to do it yet

2) if it can be made, it may serve a purpose to improve a malfunction, i just dont know what purpose that is yet

3) if it can serve a purpose, then i can turn it into a drug, i just havent figured out how to do it yet

this process will repeat and repeat forever, with the bars for success getting ever higher. the drug industry will change with the economics of scientific research capabilities and we will find cures for things that are currently thought to be incurable

we will learn to regenerate neurons to treat late stage AD, and we will learn to regrow the tree of Scizophrenia, we just havent figured out how yet

humans have unparalleled capacity Derek, do not ever forget how far we have come and where we can go if we want to. we looked out of the cave and saw fire, we crossed an ocean, pioneered the west and took to the skies. the evolution of man is hung on a timeline of discovery this is part of that timeline (#tww)

keep up the good work everyone, there is plenty left to discover

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13. @CountTheBricks on August 13, 2013 3:11 PM writes...

i have been reading this blog for about 7 years now and this is the best entry i have seen. i have so many questions and comments i dont know where to begin!

1) if i can draw it without breaking immutable laws of chemistry and physics, it can be made, i just havent figured out how to do it yet

2) if it can be made, it may serve a purpose to improve a malfunction, i just dont know what purpose that is yet

3) if it can serve a purpose, then i can turn it into a drug, i just havent figured out how to do it yet

this process will repeat and repeat forever, with the bars for success getting ever higher. the drug industry will change with the economics of scientific research capabilities and we will find cures for things that are currently thought to be incurable

we will learn to regenerate neurons to treat late stage AD, and we will learn to regrow the tree of Scizophrenia, we just havent figured out how yet

humans have unparalleled capacity Derek, do not ever forget how far we have come and where we can go if we want to. we looked out of the cave and saw fire, we crossed an ocean, pioneered the west and took to the skies. the evolution of man is hung on a timeline of discovery this is part of that timeline (#tww)

keep up the good work everyone, there is plenty left to discover

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14. Anonymous on August 13, 2013 3:17 PM writes...

How long can we expect to keep finding new drugs?

Until investors realize that drug R&D generates a negative ROI, and/or payers realize that new drugs are no better than generics. So about 10 years.

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15. weirdo on August 13, 2013 3:28 PM writes...

Biotechie:

That has been tried multiple times, and led to the formation of at least one company (Combinatorix) that mercifully imploded a couple years ago. If you thought single-agent discovery was difficult, try polypharmacology.

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16. Prog Chem on August 13, 2013 3:31 PM writes...

@CountTheBricks

You're failing to take into account the rather massive constraint of biology. Just because you can draw and synthesize a molecule that can hit a target, doesn't mean that the molecule can be a drug due to all the traditional med chem problems (tox, permeability, etc.). In addition, it is entirely possible that there may be proteins that simply cannot be targeted due to a variety of reasons, yet are still key parts of a disease. In those cases, a small molecule drug would simply be impossible, and other methods would have to be used.

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17. Anonymous on August 13, 2013 4:38 PM writes...

I am in the camp that there can be a molecular solution to any medical condition. People are just bags of chemicals doing chemistry and with the right constellation of drugs we should be able to normalize or otherwise alter at will the chemistry of life in whatever direction we choose. With the right molecules we could reconstruct a viable properly functioning brain from a partially dead brain. However the prior environmental impact on that brain will no doubt be erased. Amphibians, starfish and lizards can regrow appendages, and with the right molecular cues we should be able to grow new limbs as well. The hardest thing to do will be to replace missing biology that leads to pathology, but even for this problem clever people might be able to identify a chemical-based work around solution.

Today, we have a molecular solution for wrinkles using the most poisonous organic substance known. We can chemically alter thought processes and create vivid hallucinations, and we could just as easily chemically alter personalities if we wished to do so.

We have locked our psychology into the near worthless concept of drug-like molecules. We have a pill market centric view of medicine. In so doing we are limiting our imaginations when thinking about molecular solutions to biological problems. What is drug-like about lithium, Fosamax or w-conotoxin?

Cancer, Alzheimer's disease, schizophrenia, etc. are the output of chemistry. These diseases may just be the symptoms of multiple molecular pathologies each requiring a unique set of molecular solutions. None of this will be easy, cheap or happen in my lifetime, but starting from what we know today, imagine what we can dream up over 100,000 years, 10,000,000 years, 165 million years or until the next big comet shows up.

Note: several non-peptide organic molecules have been invented that mimic insulin and activate the insulin receptor. If chemistry, not magic, is involved nothing is impossible.

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18. Biotechie on August 13, 2013 4:50 PM writes...

Hmmm good point weirdo...riffing a little off some of Derek's thoughts about disease states and therapeutic modalities, it does seem rather miraculous that something as tiny as a small molecule can act on just a few protein targets within a complex system like the body and then reverse (sometimes in a matter of days) a disease phenotype that might have taken years to emerge. I guess most drugs found today are biased to those that rapidly tip the balance back to the non-disease state and our systems for finding drugs throw away those that would reverse phenotypes in longer timelines (and perhaps would work for diseases that are thought of as untractable). As to the original question, there is so much biological serendipity in how NMEs are found today (even in the age of shiny omics technology) that there doesn't seem to be any reason why we should be reaching a limit on finding new drugs (the question as others have written above is whether short-term investor sentiment and regulatory hurdles will stymie the the process of looking). Perhaps what we're looking at going forward is a process in which small molecule drugs become less important and other intervenions such as incentives to lifestyle change are used to address complex diseases (e.g. Alzheimer's) which (for the most part) require long timelines to manifest symptoms and thus might take a long time to reverse (if indeed they can be). As familiarity grows with more radical treatments such as cell or gene therpies, perhaps they will be used to radically reorient diseased biological systems that currently are too difficult to address using a tiny little small molecule. I guess surgery is the most radical treatment of all.

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19. luysii on August 13, 2013 5:14 PM writes...

"It's very hard to reduce the behavior of biochemical systems to mathematical formalism. "

The problem is that, even if you did, it is impossible to explicitly solve the equations, because they all involve feedback.

For a bit more elaboration on this point (including that of a former editor of Nature) please see

http://luysii.wordpress.com/2011/11/20/life-may-not-be-like-a-well-but-control-of-events-in-the-cell-is-like-a-box-spring-mattress/

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20. Curious Wavefunction on August 13, 2013 5:28 PM writes...

Personally I feel optimistic about druggability, at least in principle.

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21. Dr. Manhattan on August 13, 2013 5:39 PM writes...

I always find it interesting as to how many compounds were discovered back in the Empirical Days of the 1940-70's. A lot of major classes track back to that period. In those cases, much of the pharmacology was relatively crude, often animal based phenotypic modification experiments. When we got "molecular" and added biochemistry and molecular biology, genomics, and other target sophistications, in fact it has been a very modest success at best. I'm not advocating "going backwards" and I was part of the molecular crowd that thought we could solve diseases. I think that some of the current movement toward more cell-based screening is a step in the right direction, but will it be a big enough step? When it comes to some disease states (Alzheimer's, diabetes, cancer)as many have pointed out, the problems are so complicated, it is hard to know what is the best path forward (despite some success) to new therapies. Even an area so "well understood" and seemingly straightforward as antibiotic discovery & development has been challenging.

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22. Futuriist on August 13, 2013 5:40 PM writes...

Maybe some time around the year 2200 the next Copernicus/Newton/Einstein will come along and in time our current perceptions will come to be seen as primitive as witches, leeches and the Inquisition...

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23. Historiian on August 13, 2013 5:46 PM writes...

@21 I'm with Futuriist on this one!

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24. Anonymous on August 13, 2013 5:58 PM writes...

Most of the drugs we developed in the past worked by screwing up some fully functional biological protein or system, like a bacterial/viral protein, or some over-active human enzyme.

Then we had biologicals which replaced proteins missing from the blood, like insulin and factor VIII.

The problem is the remaining diseases we now face require fixing biological systems that are broken, often in difficult-to-reach tissues, and how is any foreign molecule supposed to do that?

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25. John Wayne on August 13, 2013 6:20 PM writes...

@23: Serendipitously

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26. Anonymous on August 13, 2013 6:35 PM writes...

@24: That rules out most current approaches, which are based on hubris.

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27. annon too on August 13, 2013 7:08 PM writes...

#1 and some others----

What I think you are trying to say is easily summarized: If you know enough, it can be modeled, predicted, made, constructed, cost-predicted and managed. With the task of making new drugs, we plain & simply just don't know enough.

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28. John Thacker on August 13, 2013 7:20 PM writes...

"I think that's because programming is much more of a branch of mathematics. If you've got a Universal Turing Machine and enough tape to run through it, then you can, in theory, run any program that ever could be run. And any process that can be broken down into handling ones and zeros can be the subject of a program, so the Church-Turing thesis would say that yes, you can calculate it."

Yes, but that's not precisely the same as what your interlocutor wrote. Contrary to "In general, it's pretty hard to think of a computer-based task that you couldn't write a program to do, at least in principle," I think that the halting problem is pretty simple to describe, and yet it is undecidable. All computable programs are decideable by a Universal Turing Machine, but some relatively simple ideas are not computable.

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29. Avraham on August 13, 2013 7:31 PM writes...

Long time lurker; first time poster. Excellent and thought-provoking post. I am reminded of Goedels incompleteness theorem. To abuse your analogy, the fact that a drug exists in the library does not mean that there exists a process to create it, in the way that a sufficiently complex set of axioms can be neither consistent and complete simultaneously.

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30. pete on August 13, 2013 10:03 PM writes...

very nicely written, Derek

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31. InSilicoConsulting on August 13, 2013 10:55 PM writes...

Derek,

Glad Avraham brought up Godel's theorem.


No Uiversal Turing machine can prove all mathematical statements and provide all proofs. This is the well known Godel's proof. Even arithmetic statements can't be proven by a UTM using only arithmetic. There's a difference between running/computing forever and providing a definite answer. (This is known as the halting problem)

By extrapolating this rigorous mathematical result to chemistry and biology arent you too guilty of playing to the audience much like the journalists we all like to hate :-)

Diseases are complex physical multivariate processes and where the fundamental causes of diseases may not be known (is it finally all related to telomere shortening in some way?). There simply is no parallel to computing here. Even for philosophy, this is Skating on very thin ice.

I do believe that will be at least a few molecules that can in principle affect each disease pathway/process.

Ever seen the American program where "the Count" restores old cars, part by part, stage by stage? Each stage involving multiple parts?

A stage by stage treatment modality is necessary to treat most diseases like Alzheimer and even cancer. This where medical treatment meets drug discovery and clinicians, biologists, chemists and other tinkerers will have to work together.

Unfortunately we haven't got the right molecules to target each stage. No single molecule/drug can CURE many of the toughest diseases.


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32. Vanzetti on August 14, 2013 2:10 AM writes...

@24
>>>The problem is the remaining diseases we now face require fixing biological systems that are broken, often in difficult-to-reach tissues, and how is any foreign molecule supposed to do that?

Gene Therapy is a solution for that. Theoretically, there is no problem. Our own cell can navigate toward specific tissues and viruses can edit genomes.

I just takes a lot of time to develop...

PS. What's up with Glybera, BTW? Will they be the pioneers?

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33. Poul-Henning Kamp on August 14, 2013 2:17 AM writes...

The theoretical answer is "yes", and it's been proven by one of the most brilliant minds in human history.

Molecules and in particular proteins are Von Neumann Automata, and Von Neumann Automata have been proven to be Turing Complete. QED.

The important footnote is: The human body is of finite size, blood vessels even more, so there may not be sufficient space for the infinite length of paper tape, or the potentially infinite number of automatons/molecules necessary to perform a particular task.

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34. Anonymous on August 14, 2013 3:51 AM writes...

2nd Law of Thermodynamics?

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35. Vanzetti on August 14, 2013 9:54 AM writes...

@34
>>2nd Law of Thermodynamics?

Is irrelevant. Human bodies are not isolated systems.

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36. Suleman on August 14, 2013 10:59 AM writes...

I don't think the Alzheimer's example is a good one. The fact you have irretrievable information loss does not means you cannot cure a person. As long as one reconstructed the neurones to be functional again, then the person would be cured, but minus a few memories.

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37. Ken Seidenman on August 17, 2013 1:56 PM writes...

I think this is a very interesting discussion/topic. In thinking about a disease as a "state," and health/proper homeostasis as another state, it always seems to me that quite often we are really asking a lot for one small molecule to alter a sufficient number of factors to mediate a transition from a disease state to a healthy state. Obviously, there are examples of this, but I do wonder if these will not turn out to be exceptions rather than the rule, especially for chronic diseases where it is likely that at any given point in time there are various subpopulations of cells that really need different molecular "problems" solved, which in aggregate manifest as "the disease."

I think polypharmacology goes some ways to addressing this issue, but I think another interesting paradigm is the way various groups are going about looking for ways of converting cells from one lineage ("state") to another by the use of small molecules (e.g., pluripotent stem cells to pancreatic beta cells). I think a key point is that no one, to my knowledge, ever attempts to identify a single molecule that will, BAM!, convert a pluripotent stem cell to a full-blown pancreatic beta cell (or pick your favorite terminally-differentiated cell), but rather the screening paradigm is usually in steps. First, a small molecule that induces a key transcription factor/factors associated with a precursor. Afterwards, molecules are sought that can further "move" cells treated with the identified molecule further down the lineage etc...In fact, a "holy grail" of cellular reprogramming used to be converting somatic cells to pluripotency with only small molecules-some were skeptical that this could ever be achieved, but it was just achieved within the past week or so for mouse cells by using a cocktail of 7 small molecules ( http://www.sciencemag.org/content/341/6146/651 ). By analogy, I think it may be worth while trying to approach screening for therapies by screening for serial combinations of small molecules that induce a transition from disease state(s) to a healthy state.

I realize, of course, that looking for combinations (simultaneous/serial) of small molecules to treat disease is fraught with incredible complexity scientific, safety, regulatory, commercial, etc...but somewhere between polypharmacology and the boundaries of the language of (drug) chemistry as alluded to in your article, I think we will need to start exploring more step-wise/combinatorial approaches to disease therapeutics. Sorry for the long post!

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38. simpl on August 19, 2013 8:56 AM writes...

this post resonates on so many wavelengths that blogbites can't do justice - thanks.
Picking out the polypharmacy one, a top grandfather drug in the 70s in Europe was sidelined in USA because it had more components than could be justified by science. The marketing arguments varied, but included the idea that the components boosted different neurotransmitters - as a dementia drug could become fashionable again? It was certainly interesting that the toxicologists supported it, and there were rumors of higher management taking it, to ward off tiring meetings, perhaps?

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39. simpl on August 19, 2013 9:10 AM writes...

I'm not really keen on the results of Ludwig Wittgenstein's approach: he did to philosophers what CDOs did for financiers.

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40. Eric on August 20, 2013 8:13 AM writes...

One can define philosophy as the art of taking a massive step back from our usual/comfortable ways of thinking. If so, and within the topic of this post, I strongly recommend writings in medical anthropology, especially the sub-field addressing "representations of disease". I went through this myself and discovered that the way I (scientist and biotech CEO) was understanding disease was mightily influenced by a positivist medical culture formed in the 19th century by the likes of Claude Bernard and Auguste Comte. In horribly abbreviated form, this culture stipulates that disease is ab-normal, that the destiny of humankind is to be healthy, and therefore medicine is there to fight disease. We are all complicit in using this military analogy in our everyday drug discovery vocabulary ("target", "off-target effects", etc.) The world of oncology is rife with 'good cells' and 'bad cells'. Kill most of the latter while sparing most of the former, and the patient will 'respond'.
Medical anthropology tells us that alternative approaches have been developed in other times and places. When we hear about 'restoring balance' and 'energy fluxes', the first 'scientific' reaction is to scoff at some kind of Asian-inspired quackery. Look again. Homeostasis is a Western medical concept. But I have not heard the word used once in over 20 years of academic research, Pharma and Biotech. And the highly scientific theory of complex systems teaches that a few descriptors mixing a huge quantity of micro-variables may explain macro-phenotypes. "Energy fluxes" may be just that ... should we find ways to measure them.
Bottom-line. Reading selected works of medical anthropology taught me to look critically at my representations, and to seek other perspectives.Two illustrative examples
(i) Mesenchymal stem cells may be what Nature found to detect tissues made unbalanced by local inflammation and restore their balance. Which chemokines they secrete in what conditions (the object of much research) may be a secondary consideration ; (ii) Many diseases may take their root in an altered interface with our environment (antibiotics in our intestinal tract, not to mention excessive use of detergents on our skin). The 'shoot-em-up' approach (be it one or several targets) of modern pharmacology has proven its value (especially to fight infections, and to a certain degree with cancer). But at a time when the low-hanging fruits for targets and pathways appear somewhat depleted, maybe it should be complemented by other, radically orthogonal approaches.

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