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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 9, 2011

Drug Research Areas You Wish You'd Never Heard Of

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Posted by Derek

A conversation the other day got me to thinking: over the course of my career, I've worked in the following therapeutic areas (more or less in chronological order): CNS (dementia, then Alzheimer's), diabetes, osteoporosis, obesity, oncology, anti-bacterials, multiple sclerosis, and antivirals. That covers a fair amount of ground, but there are still areas I've never really touched on - not much that would qualify as cardiovascular and not much inflammation, for example. So I'm sure that there are readers out there who have seen more drug discovery territory than I have - anyone who thinks that they have the local record, feel free to leave details in the comments.

A second question is whether there are therapeutic areas that you'd always wanted to try but never have. (Anti-infectives would have been in that category for me until the last few years). The opposite of that is well worth asking, too: are there disease areas that you regret ever having touched on? For my part, I learned a lot doing my Alzheimer's work, but in retrospect, much of it was a ferocious waste of effort, considering the results, so I'd probably put that one at the top. Other candidates?

Comments (54) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. In Vivo Veritas on August 9, 2011 12:42 PM writes...

Obesity? I mean talk about an area where nothing will ever get approved. The FDA hates the indication. In the past 5 years more drugs have been withdrawn than approved for the indication!

And all signs point o the Agency making it HARDER to get obesity compounds approved in the future.

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2. Terry on August 9, 2011 12:49 PM writes...

It takes long time to develop Alzheimer drugs due the tough clinic and patients.
I would like to develop drug related with antifungal function or eye drop for inflamation, the reasons are that it is usually used as outside cream, and it can be observed clearly when there is a clinic trail. Also there are several drugs available already, me-too strategy will be easier than a complete new drug, such points has been approved by some pharmaceutical companies.

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3. johnnyboy on August 9, 2011 12:58 PM writes...

I'm thankful every day that I don't have to work on obesity. The futility of trying to develop a pill for a 'disease' for which the only cure is already known would be soul-crushing.

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4. anchor on August 9, 2011 1:00 PM writes...

I never wanted to work in the anti-inflammation programs. Previously worked in this areas, but never paid off. When it comes to anti-inflammation programs, Churchillian quote comes to my mind..." an enigma wrapped in mystery"..

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5. Rick on August 9, 2011 1:04 PM writes...

Call me a wet blanket, but one area I suspect a lot of followers would like to follow is employment.

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6. Derek Lowe on August 9, 2011 1:13 PM writes...

Obesity is indeed pretty high on my list, too. . .

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7. partial agonist on August 9, 2011 2:04 PM writes...

It's not a therapeutic area, but the biggest waste of time was when I was doing combichem to make screening libraries. There was lots of mindless building of molecules, making too many to even screen using the technologies we had in house in those days (early 90s).

"So let me get this straight, bossman, I'll make 10,000 compounds and then we will screen a "representative" set of these against only a few targets?"

Yuck. My head hurts just thinking about it.

Another chunk of time was lost working on protein phosphatases and following up HTS leads. 100% of them were false positives- trace impurities.

For a therapeutic area, respiratory diseases was a challenge and less enjoyable than CNS, cancer, or antiinfectives. Anticoagulants was a toughie too.

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8. DCRogers on August 9, 2011 2:16 PM writes...

Sepsis deserves a mention for a brutal reality slaying lots of pretty theories.

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9. You're Pfizered on August 9, 2011 2:33 PM writes...

Neuropathic Pain.

It goes under the big blanket of neuroscience, of course, and is one of those Holy Grails that everyone wants to get, but no-one can quite unravel.

Great activity, no BBB.
Great BBB, poor activity.

Bah.

I did a bit of library work as well on my sabbatical from Big Pharma. I often wonder if anything ever came out of those 5000 compounds....

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10. John Spevacek on August 9, 2011 2:39 PM writes...

As someone on the outside looking in, I'm confused. Is there something radically different about any therapeutic area from another? You're chemists after all, creating new chemicals. And I think you are so far removed from the clinical setting as to not be even remotely involved in seeing patients actually improve from a treatment you created.

I'm a polymer chemist and have worked in developing packaging films, adhesives, floor coatings, medical devices, etc...and it's still all just polymers and chemistry to me. I don't feel deprived that I am not working on...car fenders or airplane components or...

What am I missing?

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11. Respisci on August 9, 2011 2:46 PM writes...


Although really interesting from a pure research perspective, stem cell therapy (as a treatment for Parkinsons) gets my vote as "least likely to become a drug"

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12. Eponymous on August 9, 2011 2:53 PM writes...

Immunosuppression. Too many macrolides. Ick!

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13. Derek Lowe on August 9, 2011 2:55 PM writes...

John S., the big differences for medicinal chemists often have to do with (1) how relevant the animal models are to eventual success (CNS is a big loser here, where antiinfectives are a winner), (2) how tractable the molecular targets tend to be, as far as giving usable chemical hits (this varies a good deal according to the sort of targets you're screening against and not necessarily the therapeutic area, but bacterial targets have given notoriously poor starting points, for example), and (3) the properties that your molecules may need to have in order to be successful (where CNS is, once again, harder than usual).

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14. Toad on August 9, 2011 3:13 PM writes...

Bone.

Osteoporosis and other bone diseases have a dearth of good, tractable targets and the animal efficacy models are typically tough and take a long time. It also is an area that seems to garner a lot less research interest from the scientific community (I feel Europe leads the US in this area).

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15. petros on August 9, 2011 4:36 PM writes...

Derek

Don't forget CNS has tighter constraints, due to the BBB unless there is an obliging transporter, than other areas.

My med chem exposure was limited to respiratory/inflammation, so different constraints again

But while the chemistry, and constraints, may differ the same general principles should apply

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16. Anonymous on August 9, 2011 5:57 PM writes...

I agree with Derek, obesity is not where you want to go. Companies try to couple diabetes/obesity (Diabesity or metabolic syndrome). Keep them apart.

Look into chronic / acute kidney injury...there's an area that has a large unmet medical need. There's a small company in Irving Texas that's doing quite well in the field. Big bucks to be had if you can crack that nut!

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17. MoMo on August 9, 2011 6:48 PM writes...

Terry- For a poster that writes as poorly and has as harsh a criticism for US innovation in the pharmaceutical industry as yourself, you sure do pop up a lot lately. You said in the previous post on Munos many negative things about our Great Country, our science and our entrepreneurial spirit and I am here to call you on it.

This is the best country in the world, and you are here probably spying on us as we all tend to forget that you Socialists and Communists are the still the Enemy! Why the pharmceutical companies committed high treason and went to your tyrrannical and brainwashed country to outsource research, only years of therapy, litigation or exposure of the industry will tell. But some of us are on to you and your Communist ways! Your country has no respect for patent laws, the environment or the value of the individual, and in the end our values will win! And then we will charge you for our drugs far more than the American people are paying for overpriced medicine.

So challenge me and keep posting here, because as an American, free speech is important and because in this country you CAN speak freely, even if you are a Communist!

God Bless America! Regardless of the treason caused by the pharmceutical industry!

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18. Susurrus on August 9, 2011 7:11 PM writes...

I worked on a urinary incontinence project. The in vivo model was in 50 kg landrace pigs. Scale-up time was a hoot.

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19. Terry on August 9, 2011 7:39 PM writes...

To MoMO
I can’t agree more that America is a great country, probably the most important and fabulous country in the world in our era. Personally I like US’s politics, news freedom, stock market system and legal system, they are much advanced systems than India or China’s.

What I am claiming is that it is a little bit older now compared to these new fast developing countries such as India, China, Brazial and lots of other countries.
The argument here between china and US is not simply capitalism and socialism, if you still call china a socialism country. I would like to say it is the redistribution of benefit, the profit and the capitalism during the globalisation after WTO.

What you are talking here (..ism) seems yourself is brainwashed, I would like to remind you a reality, there is no socialism or communism in china now, there is only a unique china specialized ism there! The key issue between these two countries is the economic issue.

Indeed china respect patents after joining WTO, now the new drugs of the international companies can sale their products according to the patent and regulation of SFDA. There are only two cases went court between the international pharmaceutical companies and domestic companies, one is Viagra, another is …, which indicated that china do respect the patents and would like to protect the new drugs according to the law. Can u give me other cases that china doesn’t respect the patents of drugs?

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20. alf on August 9, 2011 8:11 PM writes...

To MoMO too,

Give our man Terry a break. He brings a unique perspective to this blog, as do you!

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21. Austin on August 9, 2011 9:09 PM writes...

Terry,

One child policy... forced abortion... brutal crackdowns on dissent... iron-fisted controls on internet access... forced labor camps... (but the nation is not communist!!!???) Sorry, but China does Communism better than the Soviet Union ever did.

I agree with you. Even during these rocky times, I'll take the USA over ANY other country.

p.s. China is still a more desirable place to live than North Korea. I'll give you that.

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22. MoMo on August 9, 2011 9:25 PM writes...

I did give Terry a break as I always do. But we in the US use blueing agents when whitening clothes, those in China use Red. A fun chemistry fact that all should remember, including Pharma executives.

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23. Terry on August 9, 2011 9:56 PM writes...

Those negative things will exist during any developing process, you can find these from the history book of ameica, there are lots of tough time and corruption, slave system, tycoons control the economy, the recession, bad bankers. Obviously a simple but fierce policy (big government, Roosevelt’s policy) will make the country better, and satisfying the majority’s request, however, on the other hand it will hurt the minority, these examples you listed here are just some of them.

In china we have more statues than in US, I mean that in US ppl can only be 0 or 100, for instance once you have a doctor degree you will end either with a decent high paid job or jobless, there is no other statues between them, such situation also reflected in the society, just few grey zone left due to the 200 years development of capitalism and legal system. In China there are still lots of grey zones as well as some grey policy, thus a well educated ppl can accept different level of salaries, thus everyone may have a job, low paid but enough for providing bread and milk to their family.

In deed most Chinese farmers have 2 or more children, in city if ppl can afford some fine they also can born more babies. For these dissent ppl, if they don’t really go on the street, no one will care. Go on street for a riot is unacceptable, the recent riot in London really made ppl upset, shouldn’t police to stop them by gun and armour? For internet users they can use VPN to reach any kinds of website as they like. The problem there is young kid spend too much time and put money into internet game developed by western game companies. In my perspective the labour force camp is a effective way to change criminals and cover the expenses of the management of the prison system, I would not show my sympathy to these criminals such as killer, guy rape women.

In my point the real problem in china is corruption and unstable political system.


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24. Alzeimist on August 9, 2011 10:18 PM writes...

To Austin and MoMo: maybe you guys should really visit China, even once. (China has its own problems, I admit.)

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25. WB on August 9, 2011 10:49 PM writes...

I'm not particularly fond of working on anything related to CNS. Ditto on obesity ("Take a hike, will ya?") Though I admire some researchers for their courage, I'd personally shy away from disease areas such as Rett's Syndrome as well.

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26. Fishy Fish on August 9, 2011 11:11 PM writes...

Austin and MoMo, #24 is correct. Your opinion of China would certainly change once you visit there. Don't think Big Brother is not watching over us here - remember the Patriots Act? I am pretty sure that you will be on FBI's radar in no time if you do one or more of the following things one time too many: visit/post at jihadist or Aryan nation/Nazi sites, child porn, or out of your kind hearts to send money to some "charity" organizations in Yemen to help "starved" children, etc. Another case in point: a convicted murder spends 15-20+ years on death row mocking our legal system with all kinds of ridiculous appeals and delays, costing tax payers tens and thousands dollars. Where are victims' rights in these cases?
China has their problems. And we get ours. Both countries are big boys. Let each country mind their own business, especially in social, political, and cultural area.

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27. johnnyboy on August 9, 2011 11:25 PM writes...

oh please, guys. Let's keep the sophomoric, "my country is better than yours" idiotic arguments where they belong, ie. anywhere but on this blog. Unless you want Derek to revise his recent opinion on the quality of the comments...

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28. Tim McDaniel on August 9, 2011 11:31 PM writes...

So obesity is a big fat waist of time?


I'll be here all week. Try the bacon-wrapped veal.

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29. China.bonding on August 10, 2011 1:14 AM writes...

ditto 24, 27

be happy to show you around...surprisingly good mexican food and burgers here, awesome happy hours. weather not so good.

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30. Ricardo Ros on August 10, 2011 2:08 AM writes...

Obesity and ion channels

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31. tuky tuky on August 10, 2011 5:02 AM writes...

what about neglected diseases? malaria, chagas, TB,...

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32. Cancer Vaccines on August 10, 2011 6:33 AM writes...

Hi Derek, this post is slightly related to someting I am currently wondering about. The recent drop in Dendreon's share price must be telling us something about cancer vaccines such as Provenge. It would be great to get a post on this subject, it is really fascinating!

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33. simpl on August 10, 2011 7:35 AM writes...

Some amazing choices here: malaria, cancer (and other) vaccines and immunosuppression offer good chances for improvement.
Osteoporosis has been a mainstay at Novartis for decades and we're still making advances, but in smaller increments. As recently discussed, H1 blockers show the end of that road is combinations with aspirin.
The hard ones are where the disease is unclear: agree with Alzheimer's and obesity on those grounds, also neuro-improvers or Parkinsons. Bed-wetting is for me a last try for CNS leads which do something but it's unclear what.
Nobody has yet touched on promising mechanisms that lead nowhere after years. Is that the part that hard-core researchers take on the chin?

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34. Austin on August 10, 2011 7:37 AM writes...

#27 johnnyboy

Terry started it! :)

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35. anchor on August 10, 2011 8:01 AM writes...

Terry, you should fund #17 (momo) and #21 (austin) their travel and stay to China and have them record the changes taking place in China (an explosive combo of communism + capitalism). This will be similar to, the way Tocqueville, a French citizen recorded the progress of democracy in the USA. Momo and Austin, you guys ready for the challenge?

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36. darwin on August 10, 2011 8:04 AM writes...

Didnt work on it, but the justification for eyelash thickening (Latisse)as a major unmet medical need, seems to me to be somewhat of a stretch.

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37. Anon on August 10, 2011 8:19 AM writes...

@36,

I think the Latisse indication for eyelashes was serendipity. The original intent was to treat an actual eye disease, but they found that topical administration produce significant eyelash growth. Can't blame them for actually doing what all those L'Oreal, etc TV commercials claim to do by gooping on cosmetics, when this one actually has biological activity. Now if only they could get other tissues to grow so that breast implants aren't necessary. Hmmmm....

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38. MoMo on August 10, 2011 8:21 AM writes...

Count me in Anchor! And now back to our regularly scheduled thread:

What about Matrix Metallo-protease Inhibitors? The path to ruin is paved with drug start-ups and big pharma programs on this one.

But its still a wonderful therapeutic area. That way we can cure all those aneurysms like Johnnyboy is about to have after he reads some of these posts.

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39. johnnyboy on August 10, 2011 8:22 AM writes...

@ 36 - On the same subject, aren't we all terribly excited by the first FDA-approved personalized cell therapy for treating...wrinkles ?

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40. anchor on August 10, 2011 8:55 AM writes...

#38, MoMo-I concur with you that MMP protease inhibitors are nasty area to work with. Many in our group were jarred while working on this program. For one, there were many subtypes (selectivity was an issue) and secondly,lack of efficacy, that was even bigger issue for many companies, post pre-clinical phase. I will tell you that when TNF-alpha sequesters (i.e. biologic' s) hit to the market, it was a tremendous relief and saved lot of blushes for many.

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41. Anonymous on August 10, 2011 8:58 AM writes...

@39, this is even better (though far-fetched a bit) - human cloning. You can clone yourself and re-live your "wonderful" life as a chemist starting from college days. Would you want to be a chemist again or become a MBA suit?

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42. Myma on August 10, 2011 9:00 AM writes...

I am glad I never had to work on kinases. There are only a couple hundred of them to avoid while trying to hit the one you do want. That's like walking down Main Street Disney World with a four year old and not being asked to buy something.

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43. Virgil on August 10, 2011 10:52 AM writes...

Cardiac is pretty intractable... we have no FDA approved drugs for lowering myocardial infarct size, and some very high profile failures in phase III (cariporide probably the biggest). All these things work great in large animal models, but then fail in humans. Acadesine, ANP, Ranolazine, etc. Some interesting stuff in the pipleline (nitrite, cyclosporin A), but another big issue in this field is getting the stuff into humans... You're basically limited to persuading cardiac surgeons (not an easily persuadable group) to try something new during bypass surgery. Here we are sitting in academia, looking thru a glass ceiling at the cardiac clinical field, and there's no clear path to getting our molecules up there. Some interesting new initiatives (www.nihceasar.org) might help things along, but I'd guess it'll still be te 2020s before we have a decent heart attack drug.

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44. Bunsen Honeydew on August 10, 2011 10:56 AM writes...

I find it very interesting that no-one has mentioned oncology under either of the headings of want to work on it or want it avoid it. Interesting...

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45. Drug Developer on August 10, 2011 12:55 PM writes...

How about acute stroke, the futile intersection of cardiovascular and CNS?

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46. Isaac on August 10, 2011 1:24 PM writes...

#44 - I agree with you about cancer, especially given the difficulties about getting valid animal models to predict human response.

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47. Anonymous on August 10, 2011 2:14 PM writes...

Hey, PFE just launched projects in Tourettes 'cos its the next best thing' according to their genius marketing department. Already on the tracking sheets.

I would like to joke and go 'no F**king way' but sadly it is true and lots of people are getting Pfired at the moment......

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48. Guppy on August 10, 2011 2:25 PM writes...

Regarding the FDA's extremely stringent requirements for obesity drug safety... funny thing is that without an effective drug, patients are moving towards bariatic surgery instead (huge hiring demand for bariatic surgeons right now).

With surgery carrying a mortality of 0.1-0.2% (and complications in something like 1/3rd of cases), any of the withdrawn pharmaceutical agents were safer. Yet even with the high level of danger, the math on the relative benefit/risk still works out in favor of allowing the surgery -- such is the huge impact of obesity on health.

We already have a perfect "cure" of course, which Public Health has been pushing for decades now, while obesity rates continue their march upwards. Unfortunately, concepts such as willpower and self-control only have meaning on the level of the individual. On the average population level, there is predictably an "average" level of willpower and an "average" level of failures at diet and exercise.

We keep pushing diet and exercise till we're blue in the face -- but the demographics tell us that whatever impact the message has, it's overwhelmed by stronger trends in lifestyle/culture and the food industry. Factors which I've (increasingly cynically) come to view as more intractable than the technical problems behind pharmaceuticals and surgery.

In short, I believe the FDA's position on diet drugs is, on the whole, costing more lives than it saves. Still, the agency has been referred to by politicians as "a slow target that bleeds easily", easily attacked to score political points. So, I can't blame them for their current overly-caution stance, either.

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49. Dave on August 10, 2011 3:23 PM writes...

Induction of immune tolerance is a holy grail, as it would cure/prevent rheumatoid arthritis, lupus, type 1 diabetes, multiple sclerosis, and a host of others in one fell swoop. It would also make immunosupressives irrelevant.

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50. Stubbie on August 10, 2011 10:42 PM writes...

Renin inhibitors. After 25 years, one lousy 5% bioavailable drug on the market. Sheesh.

They did, however, prove to be a training ground for the next aspartyl protease target to come along, HIV.

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51. Formerly UCB on August 11, 2011 6:45 AM writes...

Integrins (like VLA-4 and LFA-1)....even if we could get small, drug-like molecules which perturb those protein-protein interactions with all the requisite pharmaceutical properties, they never worked like the antibodies do....why, Oh why!?...

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52. JIAmom on August 12, 2011 8:00 AM writes...

I didn't see anything to give me any hope until the 49th comment. Immune suppression is a temporary fix for some, but all will pay a price for it eventually in one way or another.

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53. Jonadab on August 16, 2011 5:53 PM writes...

> Obesity? I mean talk about an area where
> nothing will ever get approved. The FDA
> hates the indication.

Maybe that's because every single obesity drug that ever HAS been approved doesn't bloody work for most of the people who take it.

(Note that I'm not exactly blaming the people who developed the drugs for this. The drugs probably even worked in clinic, when the trial ran for a limited amount of time and most of the participants were people who were desperate to lose weight and willing to cooperate with the other aspects of the program, such as the "in conjunction with diet and exercise" thing. But when you send obesity drugs out into the real world, where people expect them to just work on their own because they're medicine and should single-handedly fix the problem...)

> One child policy... forced abortion...
> brutal crackdowns on dissent... iron-fisted
> controls on internet access... forced labor
> camps... [...] Sorry, but China does
> Communism better than the Soviet Union ever did.

You've confused communism with totalitarianism in general. Communism is a *form* of totalitarianism, but it's more specific than that. The key feature that makes a nation communist (as an absolute monarchy or fascism or some other style of totalitarian government) is government ownership of all or nearly all business and industry. China has spent the last thirty-five years (gradually) moving away from that. Granted, they have made the changes slowly and still have more to do, but it is not fair to say that they are more communist than the Soviet Union was. More totalitarian in some other ways, *possibly*, *arguably* (although Stalin was pretty darned totalitarian as well), but definitely not more communist.

(The Chinese government, of course, would not say it this way. They would instead say that they are practicing communism in the Chinese way, rather than in the European way -- a semantic sophistry employed so that they can still pretend to be carrying out the vision of the late great chairman Mao, because it's not politically advantageous in China to admit that Mao was wrong about anything. It would be kind of like running for US President while starting your speeches with "Lincoln was wrong". It's more politically advantageous to pretend that Washington and Lincoln and both Roosevelts all firmly believed in whatever you're about to say we should do.)

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54. rtyecript on August 23, 2011 9:51 PM writes...

I really liked the article, and the very cool blog

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