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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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June 22, 2009

Genzyme's Virus Problems

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Posted by Derek

We organic chemists have it easy compared to the cell culture people. After all, our reactions aren't alive. If we cool them down, they slow down, and if we heat them up, they'll often pick up where they left off. They don't grow, they don't get infected, and they don't have to be fed.

Cells, though, are a major pain. You can't turn your back on 'em. Part of the problem is that there are, as yet, no cells that have evolved to grow in a dish or a culture bottle. Everything we do to them is artificial, and a lot of it what we ask cultured cells to do is clearly not playing to their strengths. Ask Genzyme: they use the workhorse CHO (Chinese Hamster Ovary) cells to produce their biologics, but they've been having variable yield problems over the past few months. Now it turns out that their production facilities are infected with Vesivirus 2117 - I'd never heard of that one, but it interferes with CHO growth, and that's bringing Genzyme's workflow to a halt. (No one's ever reported human infection with that one, just to make that clear).

I assume that the next step is a complete, painstaking cleanup and decontamination. That's going to affect supplies of Cerezyme (imiglucarase) and Frabazyme (agalsidase) late in the summer and into the fall, although it's not clear yet how long the outage will be. Any cell culture lab that's had to toss things due to mycoplasms or other nasties will sympathize, and shudder at the thought of cleaning things up on this scale.

Comments (21) + TrackBacks (0) | Category: Biological News | Drug Development


COMMENTS

1. SP on June 22, 2009 7:48 AM writes...

They don't get infected? You've never had some trace metal contaminant from some reagent mess up a reaction?

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2. CC on June 22, 2009 8:41 AM writes...

There is a significant difference between the removal of a trace metal, even on a very large scale, and having to decontaminate a GMP facility of a viral contamination. Your chemical reaction may be 'messed up' but it is certainly not infected. In regard to chemistry/biochemistry, I do not belieive that it is accurate to call a contaminant an infection unless it is a biologic...

Infect
1: to contaminate with a disease-producing substance or agent (as bacteria)
2a) to communicate a pathogen or a disease to 2b) of a pathogenic organism: to invade (an individual or organ) usually by penetration
2c) of a computer virus: to become transmitted and copied to (as a computer)

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3. Chemjobber on June 22, 2009 8:50 AM writes...

Not to anthropomorphize too much, but can you imagine the sheer glee of the virii when they happened upon so many hapless cells?

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4. Hap on June 22, 2009 9:50 AM writes...

Getting rid of a metal is likely annoying, but metals don't multiply - if you get rid of a metal to 1e-12M, it won't end up at 1e-6M when you try to restart the process. You don't have an immune system in a drug plant, so you have to get rid of all the virii in your plant (and in your materials sources as well) or you're screwed. The only thing that might be comparable would be enantioselective recrystallizations - if the other enantiomer contaminates something and starts initiating crystallization of the wrong enantiomer, you might have to nuke everything to make sure that the correct enantiomer only crystallizes from your process. (Someone - Milkshake? - mentioned this happening on plant scale.)

Everyone wants to make biologics because the lack of effective duplication means no (or few) generics and an effectively infinite patent life. Of course, there's also a reason (or lots of them) why biologics are so hard to reproduce.

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5. Chemist on June 22, 2009 10:12 AM writes...

While our stuff might not be alive, if we destroy our material in an unwise experiment, we can't really go back to frozen stock and grow more...

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6. NJBiologist on June 22, 2009 11:19 AM writes...

@Derek: "Part of the problem is that there are, as yet, no cells that have evolved to grow in a dish or a culture bottle."

I see your point, but I'd still propose the fairly horrific HeLa line as a possible exception. They grow like stink under culture conditions. Unfortunately for their original host, they grew just as fast in tumor form, and rapidly killed her. I'd propose that they're better adapted as cultured cells than as part of a human body.

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7. Heather on June 22, 2009 11:28 AM writes...

Definitely shudder in sympathy. At least they are not primary cell cultures - they should be able to bring in new lots of cells that are not contaminated - at least one hopes! Getting up to speed again will be painful, though.

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8. tgibbs on June 22, 2009 11:31 AM writes...

HeLa cells have been propagated in labs so long that they are very well adapted to culture, to the point that they have themselves become a problem as a contaminant of other cell lines.

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9. SP on June 22, 2009 12:19 PM writes...

The poor woman (Henrietta Lacks) who was the origin of the HeLa cell has the highest biomass of any human in history, despite having died from cervical cancer (the origin of the line) for 60 years.

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10. Bombauer on June 22, 2009 1:17 PM writes...

Possibly the closest problem that a synthetic plant could have would be a crystal polymorph switch.

Here's the intro from the OPRD special feature section in the September 2000 issue:

http://pubs.acs.org/doi/pdf/10.1021/op000090s

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11. Chemoptoplex on June 22, 2009 1:59 PM writes...

I do cell cultures (E. coli) to express proteins and synthetic chem to make other molecules for my project. When the cells work, they're a lot better than most synthetic procedures, but when they stop working they're way worse. I've mainly trained as a chemist so maybe I just find troubleshooting reactions easier. It involves degrees less voodoo than the cells do.

I've never experienced a mass infection firsthand, but if someone so much as mentions phage, all the biologists in the building go into lock down.

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12. Eric on June 22, 2009 2:29 PM writes...

I think the unique experimental difficulty of biology is the fact that most everything gets amplified exponentially (either biologically or biochemically), so that over time, small errors become dramatically worse, not only for infection, but also cross-contamination of cell lines, contamination of PCR reactions, and so on. I'd expect self-catalyzing chemistry to be just as troublesome to work with.

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13. Hap on June 22, 2009 3:33 PM writes...

10: I think that's what I was thinking of and got wrong. Sorry.

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14. CMCguy on June 22, 2009 5:09 PM writes...

I don't know much about everyday cell culture world but assume is similar with aseptic processing where generally the "personnel" that are traced back to as the source of majority of contamination, especially after full cleaning/sterilization of facilities lines.

Hap although polymorphism can be very bad occurrence, particularly at scale as OPRD anecdotes relate, I would think it can be more easily dealt with than if wrong enantiomers start being the favored isolate (polymorph can be changed via physical operation, enantiomers require chemical). I have seen this happen in labs where once one isomer/crystal entity is grown it dominates through "air seeding" and attempts to get other forms require significant efforts.

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15. T on June 23, 2009 2:33 AM writes...

Norvir is the case study that terrifies us crystallization bods - The occurance of a more stable polymorph on a plant scale is disasterous on numerous levels. If the new polymorph is more stable, it will be less soluble - ie potentially not dissolve in vivo in the developed formulation. As CMCguy suggests once a new more stable form is in existance, it is often very difficult to synthesise the original polymorph as a consequence of universal seeding.

If you guys are interested in the Norvir case take a look at Pharm Res, Vol 18, No 6, 2001 (page 859). This is a review penned by the guys at Abbott. I imagine their life was hell for a few months whilst trying to sort this one out...

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16. Michael on June 23, 2009 7:53 AM writes...

The contamination does mostly come from the people working in the plant. That is why many mouse facilites have rules (which usually aren't really enforced), that people working there shouldn't have rodents as pets at home, or at the very least not handle them in any way before coming to work. Sometimes, though, the contamination can come from outside sources. We had some kind of tropical rat mite infestation our mouse colony, and it's thought that the source was the giant upswing in the numbers of wild mice that were inhabiting our building. That really sucks for Genzyme. If it's a particularly hardy virus that can survive in the air or on surfaces for long periods of time, they might have to nuke the site from orbit.

Though it's not an animal virus, there's a famous story of dubious origin in phage genetics. Someone wanted a phage from another lab, who refused to give it out. In those days, people wrote letters, so the researcher who wanted the phage wrote a nice letter, knowing his request would be denied. When he got the denial letter back in the mail, he dipped it in luria broth, and cultured the plaques he got. One of them was the phage he wanted. It may not be true, but it probably *could* be true, the way phage can multiply and persist in the environment.

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17. Hap on June 23, 2009 9:13 AM writes...

I've heard the story told another way (target lab had bacterial strains desired by and denied to letter writer, letter writer dips letter in phage and mails to target lab, predictable events follow).

Yikes.

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18. Hap on June 23, 2009 9:15 AM writes...

I've heard the story told another way (target lab had bacterial strains desired by and denied to letter writer, letter writer dips letter in phage and mails to target lab, predictable events follow).

Yikes.

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19. madkathy on June 23, 2009 9:50 AM writes...

Cells would be a cakewalk compared to studies with human subjects. Messy, lack of control, contamination... ugh. Especially kids. Good luck if you ever have to do research involving minors.

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20. Alice Carmel on June 24, 2009 4:55 PM writes...

Around the same time that this virus story came out, another possibly related one came out in China--turns out that the rapid growth of the biotech industry in China has spawned the sale of cell culture media that are counterfeit, and are labeled with spurious lot numbers not related to the actual series of lot numbers produced by American cell culture media vendors --I forget if they were knockoffs of Invitrogen labels, but I think they were. If a huge amount of media could be bought more cheaply from an anonymous vendor, who is hiding behind the well-respected US vendor label on their product, we will most likely see more of this sort of story. It goes along with the previous comment about these contaminations usually being tracked back to personnel at the local plant, rather than due to outside saboteurs. In this case it may be a lot more random and due to greed on both the seller/purchaser axes than to intentional sabotage by a competitor.

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21. Dianna Hofbeck on December 27, 2010 4:31 PM writes...

Happy New Year Everyone!
Wow...back to 2009- cell cultures, China, horrific HeLa etc. I am doing research with the Amish & Mennonites population. Have large d base from my (as in I owned it-so info is issue-free). Orphan diseases & some very strange stuff. Yes, data from kids is tough but it is already captured. Question: anyone doing specific studies, contact me & see if your scenario is in the d base. This is purely non profit.

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