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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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December 18, 2012

Parabon's DNA Structures: What The Hey?

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Posted by Derek

I'm having a real problem understanding this press release from the NSF. I've been looking at it for a few days now (it's been sent to me a couple of times in e-mail), and I still can't get a handle on it. And I'm not the only one. I see just this morning that Chemobber is having the same problem. Here, try some. See how you do:

Using a simple "drag-and-drop" computer interface and DNA self-assembly techniques, researchers have developed a new approach for drug development that could drastically reduce the time required to create and test medications. . ."We can now 'print,' molecule by molecule, exactly the compound that we want," says Steven Armentrout, the principal investigator on the NSF grants and co-developer of Parabon's technology. "What differentiates our nanotechnology from others is our ability to rapidly, and precisely, specify the placement of every atom in a compound that we design."

Say what? Surely they don't mean what it sounds like they mean. But they apparently do:

"When designing a therapeutic compound, we combine knowledge of the cell receptors we are targeting or biological pathways we are trying to affect with an understanding of the linking chemistry that defines what is possible to assemble," says Hong Zhong, senior research scientist at Parabon and a collaborator on the grants. "It's a deliberate and methodical engineering process, which is quite different from most other drug development approaches in use today."

OK, enough. I'd love for atom-by-atom nanotech organic synthesis and precisely targeted drug discovery to be a reality, but they aren't. Not yet. The patent application referenced in the press release is a bit more grounded in reality, but not all that much more:

The present invention provides nanostructures that are particularly well suited for delivery of bioactive agents to organs, tissues, and cells of interest in vivo, and for diagnostic purposes. In exemplary embodiments, the nanostructures are complexes of DNA strands having fully defined nucleotide sequences that hybridize to each other in such a way as to provide a pre-designed three dimensional structure with binding sites for targeting molecules and bioactive agents. The nanostructures are of a pre-designed finite length and have a pre-defined three dimensional structure

Ah, and these complexes of DNA strands will survive after in vivo dosing just exactly how? And will be targeted, via that precisely defined structure, just how? And bind to what, exactly, and with what sort of affinities? And are the binding sites on these DNA thingies, or do they bind to other things, anyway? No, this is a mess. And this press release is an irresponsible mishmosh of hype. I'd be glad to hear about some real results with some real new technology, and I'd like to ask the Parabon people to cough some up. I'd be equally glad to feature them on this blog if they can do so, but not if they're going to start talking like they're from the future and come to save us all. Sheesh.

Update: the discussion on this press release features a number of interesting comments. It's now moved over to this post, for reasons explained there. Thanks!

Comments (37) + TrackBacks (0) | Category: Chemical Biology | Press Coverage


COMMENTS

1. Anonymous on December 18, 2012 11:46 AM writes...

Strike through fail,

Permalink to Comment

2. barry on December 18, 2012 12:39 PM writes...

well it would be:
1-Novel
2-non-obvious
and
3-utile

alas, it fails at the "reduction to practice" and--critically--it doesn't ENABLE. So it's not patentable and should only have been published in a journal of sci. fi.

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3. Hap on December 18, 2012 12:46 PM writes...

If there's a target DNA/RNA sequence in the desired cells (cancer cells, for example), then if it bound more effectively to the target sequence than to internal sequences, you could unfold your DNA and make the drug contained in it available to kill the cell, kind of like Neo opening his jacket in The Matrix. Of course, how you'd deliver DNA origami to a cell (or its nucleus) would seem nontrivial, since what makes it stable should also give it Chrysleresque solubility and permeability (without active import).

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4. MTK on December 18, 2012 12:57 PM writes...

Discovery News had an online story on this and my favorite part was that it touted the scalability of the process by stating that trillions of copies of the molecules could be made. And trillions was italicized for emphasis.

Let's see a trillion molecules would be what just over a femtomole. Oh yeah, that'll last awhile.

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5. Hap on December 18, 2012 1:02 PM writes...

I assume that the made on demand part involves sequencing target cancer DNA so that sequences for the corresponding origami can be generated by small-scale DNA synthesis. Maybe they have proprietary monomers with reductively-cleaveable protecting groups, but the origami will still be the size (and solubility?) of a Mack truck.

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6. anon the II on December 18, 2012 1:08 PM writes...

This is so reminiscent of past posts where computer world people think they can just walk over to the pharma world and solve all the problems 'cause they're so much smarter. Most of us thought they were smarter cause they went into computers and made a lot of money and still have jobs. But when they start talking about structural chemistry, they tend to be thinking about 2 orders of magnitude off scale (too big) and to those of us who know better, they seem more lucky (to be rich and employed) than smart. And the people that listen to them are just dumb.

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7. anchor on December 18, 2012 1:15 PM writes...

Sometimes I wish I could do the organic/medicinal chemistry, as was practiced by my senior colleagues and my peers-the old fashioned way! We know all along that the discovery of drug for a given therapy, that way was little bit arduous but very rewarding. You liked both the chemistry/biology and success/failure that went along with it as it was simple to understand and easy to execute it as well. By contrast, people these days have bundled the information we all new all along but repackaged them by initially filing a patent first and other preposterous claim that went along with it! In my life time I have seen/heard all these kind of techniques, but none has resulted in any accelerated drug discovery that their proponents claim. Given enough time and spotlight they all fall by the way side. From what little I understand "parabon" will not be paragon we all look up to!

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8. ScientistSailor on December 18, 2012 1:23 PM writes...

It's a real shame that scams like this distract the public and divert precious funds from projects that might actually work...

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9. keko on December 18, 2012 1:27 PM writes...

I am afraid you lot simply lack the required intellectual capacity to understand this groundbreaking technology.

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10. student on December 18, 2012 1:49 PM writes...

"cancer medicines are typically so expensive that a real price per molecule can be discussed using familiar numbers."

To give the example they used, cis-platin costs ~100/gram. It has a MW of 300 g/mol. Based on my calculations that means that the price per molecule is about one attocent. Yup, those are familiar numbers to me, by golly!

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11. patentgeek on December 18, 2012 2:11 PM writes...

The claims as filed have 112 paragraph 1 issues out the wazoo, as Barry notes.

I once asked someone at a biotech why they filed such nonsense, as no actual drug would come out of it. The response: "We don't sell drugs, we sell deals." Ka-ching!

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12. imatter on December 18, 2012 2:31 PM writes...

This is fascinating science. I'd like to know more because Janssen and NSF are liking it.

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13. ROGI on December 18, 2012 2:38 PM writes...

This is complete bullshit. What troubles me is that the NSF is party to this delusion. This is Alice in Wonderland stuff. Period, end of quote.

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14. Anonymous on December 18, 2012 2:57 PM writes...

NSF should return money to taxpayer if they support such a BS.

Permalink to Comment

15. weirdo on December 18, 2012 3:44 PM writes...

Paging Dr. La Clair!

Dr. J. J. La Clair!

Paging Dr. La Clair!

Permalink to Comment

16. eugene on December 18, 2012 5:26 PM writes...

Hey Derek,

It's been about two years since your last post on BlackLight Power and they were saying that they were about to revolutionize quantum chemical calculations and the production of energy. Now that they are officially 'snake oil', can you do a post on those guys? Whatever happened to Mills by the way? Did he get away with all the investor money, or is he going to end up in jail? I think he really believed in his new para-hydrogen too, as well.

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17. Anne on December 18, 2012 6:09 PM writes...

I... what?

That's what my brain keeps coming back to every time I try to read this load of rubbish. So... they're "printing" new compounds, but what they're actually making is DNA scaffolds to bind compounds, but those compounds still have to be synthesized by regular chemistry... right? And how exactly does slapping the compounds onto a slab of concrete - er, DNA - do to help test its efficacy any faster than current means?

I think what blows my mind most (and this is relative, because it ALL blows my mind) is this: "What differentiates our nanotechnology from others is our ability to rapidly, and precisely, specify the placement of every atom in a compound that we design." Wait - what? If he's talking about DNA, then uh, DNA synthesis and PCR are kinda old news, buddy. If he's talking about medicinal compounds, uhhh... there is no indication here that they actually have any method of doing that. ?!?!

I'm going to stop beating my head against this particular brick wall to save me some brain cells. Ow.

Permalink to Comment

18. matt on December 18, 2012 6:31 PM writes...

from the PR: "However, potential partners frequently demand technical specifications and require proof-of-concept data as a prerequisite for partnership, requirements that are beyond the scope of small businesses' initial objectives."

What could those initial objectives be, besides providing those most basic items? Oh,
1. file a worthless patent, as #11 above, and
2. securing money from [cough]a sucker[cough] an investor, then
3. $$$ profit!

Technical details and some indication that it's not complete snake oil is too much to ask of a startup without heavy additional NSF funding? I think the NSF should be asking for the same thing. Otherwise, they are funding the most prolific quackers. Oh. Yeah.

Without the sarcasm, I think the NSF makes better judgments about the use of its money than that, but you can't tell it from the quote. And I don't think this research is worthless, it's just worthless as an applied drug delivery framework described in the hype.

It seems there's a slippery slope from describing one's basic research as "could lead to" great things, to "enabling" great things, to "can do" great things [with a few provisos, quid pro quos, and limitations, check the fine print; but the fine print is left as an exercise for the reader]. Unfortunately, it seems sometimes there's a race to the bottom of that slope, that descent into pure bullshit.

Permalink to Comment

19. in vivo veritas on December 18, 2012 7:17 PM writes...

Geez... This stuff makes medicinal chemists look like "the man behind the curtain", simply pulling levers on a slot machine until random chance provides a drug for the Great and Powerful Pharma.

Permalink to Comment

20. newnickname on December 19, 2012 8:01 AM writes...

I wonder if they power their technology and devices with energy from Rossi's E-Cat cold fusion machine?

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21. Puff the Mutant Dragon on December 19, 2012 10:01 AM writes...

Press releases can be pretty inane, but man....this one takes the cake. I love it! way too cool

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22. Josh chamot on December 19, 2012 10:24 AM writes...

I wrote this press release, and I am a bit concerned that instead of discussing the research with myself, or more importantly the researchers, you decide to attack the text.

We presented information based on research that has been underway for some time, at least two years with NSF peer-reviewed support.

Additionally, we were careful to not overstate either the technology or the impact, but to present an illustration of what the technology can do in the limited space that a press release allows.

A journalist is expected to follow the initial reading of the press release with questions for the researchers involved -- not attack the limited text that we provide as an introduction.

In my eleven years at NSF, I have never had someone attack my work -- particularly without first getting their facts straight.

Please contact the researchers to discuss the technology and limit your criticism for those thongs for which you are informed.

Thank you.
Josh Chamot
Media Officer for Engineering
National Science Foundation

Permalink to Comment

23. Josh Chamot on December 19, 2012 10:37 AM writes...

To add, my supervisor pointed out a stellar typo in my last line.

I'm fear that's where the discussion will go next, but if you do wish to learn more about the actual research you are disparaging, please do contact the researchers to learn more about the technology and the approach.

Thank you.

Permalink to Comment

24. Hap on December 19, 2012 10:52 AM writes...

1) If you can't get the facts from your press release, then exactly how is someone supposed to "get the facts straight"?

2) If lots of people with technical backgrounds in the area of the research can't understand what you are saying, then your press release did it wrong. Sorry.

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25. David Formerly Known as a Chemist on December 19, 2012 10:57 AM writes...

Mr. Chamot, you need to realize that to a medicinal chemist the language in the press release sounds like overhyped nonsense that we've become too accustomed to reading. I don't know who your intended audience was, but as you can see from the response it generated on this blog (as well as others) it failed to resonate with experienced researchers in the drug discovery field who've encountered scores of overhyped technologies over the past two decades. Please realize this is a skeptical group of scientists that prefer science presented in a clear, realistic manner. This is early-stage technology that may be useful at some point, but is more likely to crash and burn (like most technologies). Using phrases like "could drastically reduce the time required to create and test medications" and "The process, from conception to production, can be performed in weeks, or even days--much faster than traditional drug discovery techniques that rely on trial and error for screening potentially useful compounds" do indeed overstate the technology and the impact because neither of these "could happen" scenarios have been shown to be the case. Believe me, the language in the press release reminds us of many overhyped technologies that have burned us and our industry before, so you should expect a skeptical response. Just the nature of this audience, so don't be personally offended.

Permalink to Comment

26. Chemjobber on December 19, 2012 11:02 AM writes...

Hi, Josh:

I think I understand the guts of the PIO process to understand that you're mostly innocent -- you're not the subject matter expert. Armentrout and company are responsible for making sure that press releases and the like are accurate and not overstated.

You say, "Additionally, we were careful to not overstate either the technology or the impact."

But the release says "The process, from conception to production, can be performed in weeks, or even days--much faster than traditional drug discovery techniques that rely on trial and error for screening potentially useful compounds."

I suspect that most commenters think this is a major overstatement.

Best wishes, Chemjobber

Permalink to Comment

27. Hap on December 19, 2012 11:13 AM writes...

Dr. Chamot,

I am sorry - I don't think I understand how you write your press releases and so it's not fair to criticize you for yours. Sorry.

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28. Anonymous on December 19, 2012 12:23 PM writes...


Mr. Chamot,

The medicinal chemists that frequent this blog are accustomed to breathless hype from companies trying to stoke investor interest. Often this hype is effective at raising money or selling a company of dubious value (I'm looking at you, Sirtris). In an industry that has been gutted by layoffs there is no shortage of cynicism for the Next Transformative Idea in drug discovery.

Frankly, we need transformative ideas in this business, and there may be more to Parabon than is evident from the press release and their patent. Derek has an open invitation -- perhaps this will be a teaching moment for all of us.

Permalink to Comment

29. ptm on December 19, 2012 12:28 PM writes...

Josh, let me clarify it for you in case you are genuinely confused. People attack your press release because your press realease is bloody terrible. For example I am a cell biologist with keen interest in nanotechnology and no link to drug industry at all (in case you think that may be skewing the reception) and after reading it I have no idea whatsoever about what it is that you are actually doing apart from the fact that it takes advantage of DNA selfassembly. Your press release is just choke full of cheap, empty, hype with zero supporting science. This is a great way to piss of all the experts among your readers since they will all undoubtly conclude that you've just wasted their time.

Permalink to Comment

30. Josh Chamot on December 19, 2012 12:34 PM writes...

Thank you for the thoughtful responses. This is exactly the engagement I was hoping for.

First, I agree that hype is never what we want to communicate -- and I appreciate that skepticism is critical to ensuring accuracy and the complete communication of news. However, I do hope many of you will explore the research further so that any skepticism is completely informed.

I want to be clear that I have no intention of misleading the research or pharma communities, nor do I want to give false hope to those who might need any of the treatments that we referenced. Our language was intended to convey that the breakthrough to date is exciting, but clearly more work is needed before this can start producing drugs for patients -- and I believe we stated this.

Through links to additional information (such as the full patent application) and clear contact information for the principal investigator, it is our hope that the primary audience for the press release (reporters) will present a thorough and complete account of the work.

We do not wish to mislead, but we also cannot convey a full news story in press release format. The intent is to serve as an alert, and importantly, an accurate one.

Journalists are the primary audience for the press releases, and our system of information is reliant on their services. To the best of my knowledge, the information we presented on Parabon is accurate and states only results that Parabon has demonstrated and announced in their patent application -- the starting point for a journalist to explore the story further.

As background, the pieces I work on cover research efforts that are originally proposed to NSF in a review process informed by peers in the community. Parabon has received both Phase I and Phase II NSF small business funding, so they had succeeded in that competitive peer review twice.

That setting served as a baseline to inform my office that the research approach was a valid starting point -- however, as with almost all NSF research, this is research at the very earliest stages. I can accept that while I wrote the release to reflect this, I was not successful in conveying this clearly. However, the assertions that data in support of the research effort do not exist are incorrect.

The company first came to our office (public affairs) more than two years ago, and it is only now that the company had enough publicly available information for us to pull together an announcement of the technology and some introduction of how it works.

I have some lessons learned here in how to try to clarify caveats, but I stand by my original assertion that the research is valid and exciting. While I have no way to predict Parabon's ultimate success, I do believe that public discussion of their technique can only prove of value to the broader drug development effort -- including the identification of any obstacles that this, or a similar technique, must overcome.

Best,
Josh Chamot

Permalink to Comment

31. Anonymous on December 19, 2012 12:52 PM writes...

Hi, Guys,

Face it! This is why we are only chemists, but people at Parabon can get rich and richer. We can't speak like they do, since we stick too much to the fact, and lose sight of the "big picture".

Best

Permalink to Comment

32. MoMo on December 19, 2012 12:59 PM writes...

Josh,

You are in a Brave New World where Article 19 of the Universal Declaration of Human Rights comes at you in the form snarling scientist-amoebas that smell blood in the water! So good luck but if are in the business of "Technology Pusher" you better grow a spine!

I personally think nucleic acid targeting is cool, and has been around for decades, so I hope the Parabon guys think outside the box or in this case, grid!

But tell me NSF grant reviewers, how does one get I and II grants without ever publishing anything in this area?

Inquiring Ameobas Want to Know!

Permalink to Comment

33. student on December 19, 2012 1:00 PM writes...

Josh, I think it's likely that the research is exciting and valid. However, I hope you can see from the response in the comments that you made a bloomer with the press release. Were the authors consulted before publishing it? If not, it is likely that they are mortified and/or embarrassed by it.

Permalink to Comment

34. newnickname on December 19, 2012 1:02 PM writes...

Parabon is heavy on the computer sci side.

"Drag and drop" drug building implies, to me at least, that you are using AFM or other single molecule (optical tweezers) method to manipulate physical entities into position for bond formation and continuation of the process to build "the house" and then "the city" (their analogy).

Apparently, Parabon's "drag and drop" must refer to their computer interface to design a DNA sequence that will then be synthesized by, almost certainly, conventional means. Trillions of copies? Almost certainly PCR. Drag and Drop! Sure beats having to type letters! That's got to be worth a big chunk of NSF change.

I think "drag and drop" has a great future in computing. So much so, that I think my Mac II already had it 20+ years ago.

Artificial (designed) DNA scaffolds! Now that's another exciting cutting edge topic. One of the earlier cuts that I'm thinking of was in the late 1980s or early 1990s: DNA 3D-cubic scaffolds.

A key piece of information would be in the actual principles underlying their design process. Are they building on X-ray or NMR structures of targets? Pharmacaphore mapping? If they really knew how to successfully design strong, selective stable binders, that would be great.

Parabon even talks about multiple drugs per DNA scaffold and multiple targeting so they can suppress off-target side effects. That would be another good trick, getting their DNA scaffold to deliver drug A to target A and then float away to deliver drug B to target B.

Drag and Drop, DNA scaffolds, ... I think they're milking the NSF to go after the glitzy easy stuff (computer graphics). Making a real drug?? DNA that will bind to the target AND bind to the drug molecules, deliver the drug molecules to the target, release the drug molecules at the target, address many other issues in making a real drug (ADMET) ... I see nothing in THE HYPE about their success with that.

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35. imatter on December 19, 2012 1:45 PM writes...

And yet, nothing. Nothing has been made clear. Is there a peer reviewed material available?

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36. Doug Steinman on December 19, 2012 1:55 PM writes...

The concept is certainly interesting and one that appears to be worth pursuing. Whether or not that concept is worthy of a patent is, however, questionable. Furthermore, until data confirming the validity of the concept appears in a peer-reviewed journal, it is not worth a press release nor is it worthy of serious discussion in this forum or any other. Maybe that is a harsh assessment but we have all seen the damage that hype can do to legitimate pharmaceutical research.

Permalink to Comment

37. querty on December 19, 2012 2:23 PM writes...

I believe all NSF (funded?) grant applications are available via FOIA request, right? Someone should be able to get hold of the grant if they want to?

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