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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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April 5, 2010

Sickened by an Engineered Virus?

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Posted by Derek

What to make of the case of Becky McClain? She's a former Pfizer scientist who sued the company, claiming that she had been injured by exposure to engineered biological materials at work. She's just won her case in court, although Pfizer may well appeal the verdict. It's important to note that her most damaging claim, that the company engaged in willful misconduct, was thrown out at the beginning. The jury found that Pfizer had violated whistleblower laws and wrongfully terminated McClain as an employee.

But what I'd most like to know is whether the claim at the core of her case is true, and I don't think anyone knows that yet. McClain says that she was exposed to embryonic stem cells and to various engineered lentiviruses (due to poor lab technique on the part of co-workers, if I'm following the story correctly), and that this gave her a chronic, debilitating condition that has led to intermittent paralysis. More specifically, the theory that I've seen her legal team floating is that the lentivirus caused her tissues to express a new potassium channel, and that she has improved after taking "massive doses" of potassium. (Query: how massive are we talking here?).

Now, that's a potentially alarming thing. But that should also be potentially subject to scientific proof. This trial didn't address any of these issues, and McClain has been unable to get any traction with the court system or with OSHA on these claims. Looking around the internet, you find that some people are convinced that this is a cover-up, but (having seen OSHA in action) I'm more likely to think that if you can't get them to bite, then you probably don't have much for them to get their teeth into. I also note that the symptoms that have been described in this case are similar to many that have been ascribed in the past to psychosomatic illness. I can't say that that's what's going on here, of course, but it does complicate the issue.

The other problem I have is that such human illness from a biotech viral vector is actually a very rare event, with every case that I can think of being a deliberate attempt at gene therapy. Industry scientists don't work with human-infectious viruses without good cause, but there's still an awful lot of work that goes on with agents that most certainly can infect people (hepatitis and so on). And although I'm sure that there have been cases (accidental needle sticks and the like), I don't know of any research infections with wild-type viruses, much less engineered ones.

Well, we may yet hear more about this, and I'll rethink the issue if more information becomes available. But for now, I have to say, whatever the other issues in the case, I'm inclined to doubt the engineered-viral-infection part of this story.

Comments (18) + TrackBacks (0) | Category: Biological News


COMMENTS

1. Sili on April 5, 2010 7:39 AM writes...

Well, ERV is a virologist (if some follows the link, she'll see the trackback, I suspect).

The 'problem' with psyschosomatic illnesses is of course that they do indeed give physical symptoms. But I have no clue if excess K-channels can be one such natural response of the body to stress.

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2. Keith Robison on April 5, 2010 7:51 AM writes...

Lentiviruses integrate. If she really has been sickened by one, then standard molecular biology techniques should be able to find the junction sequence between the lenti and her own DNA.

But, that does raise some broader questions -- how much of a fishing expedition can a civil defendants lawyers go on within the plaintiff's body?

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3. RickW on April 5, 2010 8:32 AM writes...

I agree with #2, if there are enough infected cells to cause these symptoms in the way they are claiming, it should be trivial to detect the integrated virus.

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4. darwin on April 5, 2010 8:37 AM writes...

what jury will understand any of this science explanation?

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5. Brian Baldridge on April 5, 2010 8:47 AM writes...

I'm confused by: "...I don't know of any research infections with wild-type viruses, much less engineered ones."

This cite: http://www.jstor.org/pss/30112440 describes laboratory acquired Hantaan Virus infections probably due to aerosols from the vectors.

The literature is replete with others, including a fatal laboratory acquired smallpox case in the UK in 1978.

So, obviously, I've missed something. Unless you meant no purposeful research infections?

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6. Anonymous on April 5, 2010 8:56 AM writes...

I think it's pretty clearly a psychosomatic illness, if she isn't outright faking it. I've worked with lenti vectors for gene therapy, and the infection rates in animal simply don't come anywhere near the levels that would give the symptoms she claims. Lenti particles pseudotyped with VSV-G are quite large, and don't really diffuse freely through tissues. Virus won't penetrate uncompromised skin, so there is no easy way for it to access nerves. It might infect the lung mucosa if she breathed it in, but is very unlikely to enter the bloodstream. She could have probably jumped into an industrial vat of lenti, and not infected a single neuron.

This was almost certainly a virus pseudotyped with an envelope that was not neuron specific. Therefore, it would also infect the first cell it comes across, most of which will be things like endothelial cells or hepatocytes. Those would be an enormous sink to absorb large amounts of virus. In order for significant numbers of her neurons to be infected, I'd guess she would need MASSIVE doses of virus INJECTED into her bloodstream. Even then, I'm not so sure that you'd get many neurons. Typically when people are trying to directly infect neurons, they have to inject large doses of lentivirus directly into the brain.

This also doesn't pass a simple logic smell test. If a coworker using lenti on his bench caused her to have such horrible symptoms, why is the coworker himself not dead or writhing on the ground in unspeakable agony right now? His exposure level should have been many orders of magnitude higher.

I know of one case where a lab worker was accidentally infected with a virus, with symptomatic results. This virus was SV-40, though, and was replication competent. She got a benign brain tumor that contained her lab strain of SV40, many years after she worked with it. Insult to injury: she was only middle author on the paper describing it. http://www.ncbi.nlm.nih.gov/pubmed/14676832

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7. RTW on April 5, 2010 9:34 AM writes...

My experience with Pfizer management is that they took laboratory safety very seriously. At least in Ann Arbor. So much so that if you didn't wear proper personal protective gear, you were sent home. This applied to everyone working in a lab, tech to lab directors, and VP visitors. Had constant inspections.

As much as I really deplore Pfizer right now, I am not really buying this particular instance. She faults others as being rather cavalier about safety. Well then why were they not infected? Seems pretty unlikely they wouldn't be under those circumstances. Sounds to me if this did indeed occur, then her own technique in the lab was more at fault. A lab of any kind is a dangerous place to work. Everyone should approach one as though its out to get you. Especially a biology lab containing pathogens of any kind!

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8. Anonymous on April 5, 2010 9:35 AM writes...

I also forgot to mention that this is almost certainly a replication incompetent lenti vector they were dealing with. That means there is no secondary infection from it. If you want to infect a million cells, you need to dump more than a million viruses on them. Usually a LOT more than a million. This is important. It means that normal rules about viral infection don't really apply. A single particle of hantavirus or smallpox or SV40 can theoretically give you a full-blown infection that infects many cells. You can get infection results that are exponentially worse than the exposure. For replication defective viruses, infection is linear with exposure. One virus results in the ultimate infection of one cell (at most).

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9. barry on April 5, 2010 10:42 AM writes...

Who can explain to a simple chemist what it would take to detect such an infection? How many cells would have to be infected to give symptoms? How large a biopsy would be needed to detect integration of the lentivirus or its products?

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10. Anonymous on April 5, 2010 10:58 AM writes...

ypically when people are trying to directly infect neurons, they have to inject large doses of lentivirus directly into the brain.
Perhaps she was just that annoying. I've known people like that.
This applied to everyone working in a lab, tech to lab directors, and VP visitors. Had constant inspections.
Awesome. Now if only they could stop VPs from personally 'inspecting' new facilities built on another continent for the express purpose of avoiding contamination by new and more stable polymorphs. Permalink to Comment

11. Chrispy on April 5, 2010 11:39 AM writes...

You can see a video of Becky McLain here .

Permalink to Comment

12. qetzal on April 5, 2010 11:58 AM writes...

barry (#9):

We used to do qPCR studies of gene therapy vector biodistribution. IIRC, a typical amplification would include ~ 200 ng of total DNA (e.g. isolated from blood or tissue), and could reliably detect down to about 10 copies of the vector. Obviously, some PCR assays will detect down to 1 copy per reaction, but 10 copies is more realistic.

A single human cell contains ~ 6 pg of DNA, so a decent PCR assay should detect the vector even if only 1 cell in ~ 3000 is infected. To put that into context, 1 microliter of blood normally contains 4000-11000 WBCs. (RBCs aren't relevant since they have no nucleus.)

I don't know how that compares to the number of infected cells that might be symptomatic, but my guess is such an infection would be readily detectable if you can biopsy the presumed target tissue.

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13. barry on April 5, 2010 1:06 PM writes...

re: Qetzal (#12) of course getting the relevant biopsy is problematic when they symptoms are neurological

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14. Hap on April 5, 2010 1:27 PM writes...

#10: How do you manage to keep a less stable polymorph from forming spontaneously? You don't need the VPs tramping around playing "let's seed the wrong polymorph so we can drive our people nuts" but isn't the most stable polymorph going to appear eventually, and be (nearly) impossible to remove completely? Can you actually keep the more stable polymorph away indefinitely?

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15. Larry Rose on April 5, 2010 11:40 PM writes...

If this laboratory based viral infection did not occur why wouldn't Pfizer management give complete information to Ms McLain's evaluating physician? A number of tests could then be done eg. matching antibodies. Pfizer claiming "proprietary information" and withholding genetic sequencing information does not allow for a full investigation. Of course there have been many laboratory induced viral infections that are not necessarily restricted to blood borne routes of infection.

Permalink to Comment

16. K on April 6, 2010 2:59 AM writes...

Hap, you're correct the more stable polymorph will always show itself eventually. However I think what the original poster was getting at was by allowing management to visit various sites (both contaminated and uncontaminated) all they achieved was to spread the new polymorph around liberally and quickly, making it almost impossible to study the two polymorphs side by side (because the less stable one couldn't then be synthesized). This would have made the scientists job a great deal more difficult. This example (Ritonavir) is particularly interesting as the difference in the polymorphic relative stabilities is huge, leading to the well documented disasters that followed (Abbott's withdrawal of the drug).

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17. Silis on April 6, 2010 8:12 AM writes...

Sorry about the lack of name at #10.

And, yes, as K pointed out I was thinking of Ritonavir (but couldn't recall the name ...). It's the curse of the disappearing polymorph, and of course it cannot be staved off forever. But the handling in this case was particularly stupid as I understand it.

The original polymorph was metastable and as such it could be isolated. Until the ice-9 of the real lowest energy structure appeared on the field.

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18. bmartinmd on April 6, 2010 10:57 AM writes...

If the NYT is reliable, McClain has been diagnosed with hypokalemic periodic paralysis--a well-known, but very rare, genetically determined disorder (specifically an autosomal dominant "channelopathy.")

It is highly unusual for Hypo PP to present itself after the second decade of life--but it is possible. I suspect that McClain and her lawyers are arguing that Pfizer's engineered lentivirus somehow caused or exacerbated her paralytic disorder, which is a dubious proposition.

What would be nice to know is whether McClain harbors one of the identified calcium- or sodium-channel mutations for Hypo PP. Existence of a mutation would certainly undermine any lentivirus-causation claim.

It is also possible that McClain is "elaborating" an extant disorder, like Hypo PP, for the sake of litigation.

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