Archive for the 'Animals in Research' category

Blogrolling: unlikely activist

I invite you to put the new blog of Professor J. David Jentsch on your list. At the unlikely activist you will find fare such as:

The mystery of addictions, Part 1: Why spend money on addiction research at all?

If they are remarkably lucky and have proper medical and psychological support, they may return to a healthy life and never use again. But for most, their freedom is only temporary, and they will relapse again days, weeks, months or even years later, returning them to their suffering and to their fateful spiral. You see, drugs kill. They are powerful toxins that can stop breathing or a heart. If they are injected, they can bring infectious diseases like hepatitis and HIV along with them. And because they intoxicate the mind, they lead to reckless driving and other behaviors that risk the lives of the addict and those around them.

Ignoring science, from the bench

Put differently, juveniles and teens have a brain fully capable of feeling powerful emotions (like anger), but their ability to resist those emotions and to behave in a socially appropriate manner (like to inhibit aggressive reactions) is not at adult levels. The 5 justices who struck down harsh penalties for child offenders recognized this; it was a crucial part of their logic in this, and the earlier death penalty, case.

But like a frightening number of people in our society, the other 4 justices viewed the science as either being wrong or irrelevant. Their own ethical or philosophical views about crime and punishment appeared to trump their interest in scientific principles and facts. In this regard, they are not unlike strident animal rights activists opposed to biomedical and behavioral research involving animals.

A solemn voice in support of medical researchers

In the fall of 2010, an animal rights extremist sent me razor blades and heinous threats to cut my throat in the mail. It became a national news story, again highlighting the abject cruelty of some in the anti-vivisection movement. During this time, I turned on my phone one evening to see that I had received a voice mail. Anticipating the worst – yet another cruel, rabid and profane threat from my opponents – I found something quite different. I have kept this communication private for long enough. Now, at the wishes of the caller, I am sharing it with the broader community to demonstrate that support for humane animal research is everywhere…. It comes not from greed or ignorance, but from love and a hope that no one should ever suffer the same loss as the caller.

VoiceofSupport (click on this link to listen to this .wav file)

3 responses so far

On discovering new medicines

ResearchBlogging.orgA link from writedit pointed me to a review of drugs that were approved in the US with an eye to how they were identified. Swinney and Anthony (2011) identified 259 agents that were approved by the US FDA between 1999 and 2008. They then identified 75 which were "first in class", i.e., not just me-too drugs or new formulations of existing drugs or whatnot. There were 20 imaging agents, not further discussed, and 164 "follower" drugs.

The review also focused mostly on small molecule drugs instead of "biologics" because of an assumption that the latter are all exclusively "target based" discoveries. The main interest was in determining if the remaining small molecule drugs were discovered the smart way or the dumb way. That's my formulation of what the authors term "target based screening" (which may include "molecular mechanism of action") discovery and "phenotypic screening" type of discovery. As they put it:

The strengths of the target-based approach include the ability to apply molecular and chemical knowledge to investigate specific molecular hypotheses, and the ability to apply both small-molecule screening strategies (which can often be achieved using high-throughput formats) and biologic-based approaches, such as identifying monoclonal antibodies. A disadvantage of the target-based approach is that the solution to the specific molecular hypotheses may not be relevant to the disease pathogenesis or provide a sufficient therapeutic index.

A strength of the phenotypic approach is that the assays do not require prior understanding of the molecular mechanism of action (MMOA), and activity in such assays might be translated into therapeutic impact in a given disease state more effectively than in target-based assays, which are often more artificial. A disadvantage of phenotypic screening approaches is the challenge of optimizing the molecular properties of candidate drugs without the design parameters provided by prior knowledge of the MMOA.

You will note that this is related to some comments I made previously about mouse models of depression.

The authors found that 28 of the first-in-class new molecular entities (NMEs) were discovered via phenotypic screening, 17 via target based approaches and 5 via making synthetic mimics of existing natural compounds. To give you a flavor of what phenotypic screening means:

For example, the oxazolidinone antibiotics (such as linezolid) were initially discovered as inhibitors of Gram-positive bacteria but were subsequently shown to be protein synthesis inhibitors that target an early step in the binding of N-formylmethionyl-tRNA to the ribosome

and for target based approaches:

A computer-assisted drug design strategy that was based on the crystal structure of the influenza viral neuraminidase led to the identification of zanamivir

The authors even ventured to distinguish discovery approaches by disease area:

Evaluation of the discovery strategy by disease area showed that a phenotypic approach was the most successful for central nervous system disorders and infectious diseases, whereas target-based approaches were most successful in cancer, infectious diseases and metabolic diseases

Unsurprising of course, given that our state of understanding of nervous system disorders is, to most viewers, considerably less complete in comparison with some other health conditions. You would expect that if there are multiple targets or targets are essentially unknown, all you are left with are the predictive phenotypic models.

Of the follower drugs 51% were identified by target based discovery and 18% by phenotypic screening. This is perhaps slightly surprising given that in the cases of the me-too drugs, you would think target-based would be more heavily dominant. Perhaps we can think of a drug which initially looked to have property X that dominated but then in the phenotypic screening, it looked more like a property Y type of drug.

The authors take on this is that it is slightly surprising how poorly target-based discovery performed within a context of what they describe as a period in which there was a lot of effort and faith placed behind the target-based approaches. I suspect this is going to be in the eye of the beholder but I certainly agree. I can't really go into the details but there are areas where my professional career is...affected, let us say...by the smart/dumb axis of drug discovery. It should be obvious to my longer term readers that I align most closely with animal models of various things related to health and neurobiology and so therefore you may safely conclude that I have a bias for phenotypic screening. And even in the case of the target-based discovery:

at least three hypotheses that must be correct to result in a new drug. The first hypothesis, which also applies to other discovery approaches, is that activity in the preclinical screens that are used to select a drug candidate will translate effectively into clinically meaningful activity in patients. The other two hypotheses are that the target that is selected is important in human disease and that the MMOA of drug candidates at the target in question is one that is capable of achieving the desired biological response.

Right. You still need good phenotypic models and ultimately you are going to have to pass human clinical trials. The authors further worry that this higher burden, especially knowing the MMoA is going to lead to some misses.

in the case of phenotypic-based screening approaches, assuming that a screening assay that translates effectively to human disease is available or can be identified, a potential key advantage of this approach over target-based approaches is that there is no preconceived idea of the MMOA and target hypothesis.

Ultimately I think this review argues quite effectively for an "all hands on deck" approach to drug discovery but it can't help but come off as a strong caution to the folks that think that "smarter" (aka, "rational drug design") is the only solution. Yes, this points the finger at Francis Collins' big thrust for a new translational IC at the NIH but also at the BigPharma companies that seem to be shedding their traditional models-based, phenotypic discover research units as fast as they can. No matter which side you come down on, this is a great read with lots to think about for those of us who are interested in the discovery of new medicines.
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Swinney, D., & Anthony, J. (2011). How were new medicines discovered? Nature Reviews Drug Discovery, 10 (7), 507-519 DOI: 10.1038/nrd3480

4 responses so far

Consider the source, Ed Silverman

Oct 07 2010 Published by under Animals in Research

I admit I am not a highly regular reader of Ed Silverman's Pharmalot blog, although I do keep up with his Twitts and read the occasional post. So I have little knowledge of where he's coming from on this issue. But he had a post that basically parroted the animal rights extremist's party line without a smidgen of critical thought.

The background is that pictures of severely wounded monkeys got out from a scientific supply company. The animal rights extremist organizations are all over this. Dog bites man story. They are, of course, certain that these pictures provide smoking gun evidence indicting all of animal research and nonhuman primate research in particular, demonstrating the general incompetence and uncaring nature of the industry.

This is their a priori belief. The extremist organizations that want to halt all use of animals in research by any means necessary do not have their opinion changed by facts either supporting or undermining their arguments. They feel free to lie, misrepresent or otherwise play fast and loose with any situation. This is what they do.

Ed Silverman should know this.

In his blog post, Silverman makes at least two glaring mistakes. The most troubling one is this one because it is deployed by the author in a way that makes it sound as if he agrees with the charge.

Primate Products ceo Don Bradford recently told NBC that the conditions depicted in the photos were not caused by medical testing, but due to injuries caused by other animals, and the monkeys have since healed. But the Animal Rights Foundation of Florida does not seem to believe him

the second item is a direct quote from an extremist group- still troubling because it contains an unexamined accusation:

These serious injuries may have resulted from self-mutilation, experimental procedures, or fights between animals who had been improperly housed.

As if the beliefs of anti-research extremist groups have any bearing on anything of evidentiary or probative value. They are against research. They are against researchers. They are against medical advances that are made possible only through the use of animals in research. Period. There is nothing that can be said or proven with facts that will make them "believe" anything anyone who is in support of well regulated humane use of animals in research has to say. Facts are irrelevant.

Which is why, Ed Silverman, it is essential for those who are presumably interested in the facts of a matter to account properly for the opinions offered by the person who comes from an unfalsifiable, unassailable fundamentalist belief structure that is impervious to fact. In this case properly means "deeply suspicious".

Fortunately, the Speaking of Research organization has an excellent bit up on their blog which underlines something anyone might have come up with on only a moment's thought. Anyone who has a National Geographic level understanding of the natural world and the behavior of species, that is.

There are two observations relevant to my points about Ed Silverman's dismal coverage. First, that macaque monkeys are, at times, socially aggressive organisms in their natural social and environmental niche- this frequently results in major wounding and even death. Second, that this means that the only "proper" housing that can guarantee zero wounding is single housing. And we all know how the animal rights groups feel about the propriety of that choice.

In other words, the animal rights extremist reaction to this situation betrays their usual profound misunderstanding of the natural world. It also illustrates their theologically driven desire to make the world we actually live in conform to some Utopian ideal in which all species are somehow equivalently enlightened and interacting as truly sentient (in the real sense of the word) organisms.

Science fiction is a nice read, but it is just a fantasy.

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Additional reading is a mere PubMed click away.

Or you can visit the American Journal of Primatology and use the search box for macaque

It does not require much effort to turn half-baked opinion into even minimally-informed opinion...assuming one is unafraid to have one's uninformed views modified by facts, that is.

9 responses so far

Levi Leipheimer: Cyclist, Philanthropist....Idiot

Sep 27 2010 Published by under Animals in Research, Public Health

Of course there is no particular reason to think that bike racing celebrity types should be any smarter than your average Hollywood actor or even one of those ruthless self-promoting celebrities who you can't quite figure out why they are famous.

Levi Leipheimer is a US professional cyclist who has become, over the course of a long career, a top talent with a long list of accomplishments. Recently his accomplishments have been in association with Lance Armstrong who is an absolute pitbull when it comes to battling cancer. I've mentioned before that following his Twitter gives you a whole new appreciation for how much this guy works at the whole LiveStrong charity.

And it isn't like Levi is just a passive participant. He puts the name of some kid with "pineoblastomas, a rare and aggressive brain cancer that afflicts less than 2% of all juvenile brain cancer patients" on his bike. Or remembers the name of a junior high school counselor who fell to colon cancer in another race.

He sponsors and promotes "Levi's Gran Fondo", a charity ride to raise money for various causes including "The Lance Armstrong Foundation received a $10,000 donation from the GranFondo for their ongoing funding of cancer research".

Research.
So what in the hell is he doing
tweeting this?

Odesssa and I hanging w/ @richroll and @jaiseed at the 30th anniversary [famous ARA wackanut organization-DM] Gala. Great night http://yfrog.com/3upsxnj

I've said it before...we really need to get Lance Armstrong focused on including animal research as part of his message.

8 responses so far

Why Supposed Ethics Case Studies / Training Scenarios Are Idiotic

Aug 16 2010 Published by under Animals in Research, Ethics, Science Ethics

Dr. Isis has a post up responding to a Protocol Review question "Noncompliance in survival surgery technique" published in Lab Animal [2010; 39(8)] by Jerald Silverman, DVM. His column is supposed to be in the vein of practicum case studies that are a traditional part of the discussion of ethical issues. Given X scenario, how should person A act? What is the ethical course of action? Was there a violation? Should it be reported/evaluated/punished.

We see these sorts of examples all the time in the ethics training courses to which we subject our academic trainees, particularly graduate students and postdocs.

These exercises frequently annoy me and this IACUC / Animals-in-Research question is of the classic type. Continue Reading »

7 responses so far

Don't t-a-a-a-a-a-a-aze me bro!

BlackSheepDM_234.jpg
source
A report in Popular Science (authored by Jeremy Hsu) points to a recent paper published in Academic Emergency Medicine. In this, Dawes and colleagues report on an investigation on the effects of TASER on sheep intoxicated with methamphetamine (MA). I was alerted to this by Damn Good Technician who wanted a little bit of context for what would seem to be a WTF? kind of study.
ResearchBlogging.orgThe study was conducted in Dorset sheep who were anesthetized, and administered 0, 0.5, 1.0 or 1.5 mg/kg of methamphetamine HCl (curiously from dissolved Desoxyn, the approved pharmaceutical product) in an IV infusion. The drug treatment was a between subjects factor (N=4 per group) and animals were monitored for "continuous blood pressure, heart rhythm (one-lead), pulse oximetry, and capnography... Arterial blood sampling was performed at baseline, 30 minutes after the administration of the methamphetamine, and after each exposure from a TASER X26".
To answer the question of why?, and for appropriate background on the science try a PubMed search for "cardiac TASER". I note a study in which 5 sec of TASER didn't cause cardiac damage or symptoms in law enforcement trainees and another showing minimal cardiac effects on law enforcement volunteers after vigorous exercise. Also of interest are the case studies of atrial fibrillation in a previously healthy adolescent and recovery of a teen in TASER induced asystole. These, a mini-review by the Dawes group and other searched papers should give you some context and support from the feeling you might have from half-remembered MSM reports over the years that TASER is suspected of being somewhat less than "safe".
What I'm not finding right away is very much about the drug intoxicated suspect who might be TASER'd by law enforcement. Remember this guy? My best estimate was that he was acutely intoxicated with 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") although that might be one of my blog interests talking. You might also wish to consider some papers found by searching PubMed for "methamphetamine cardiac toxicity", "methamphetamine vetricular fibrillation" and "methamphetamine heart attack".
Together this background would seem to identify a situation crying out for additional study.

Continue Reading »

8 responses so far

Second annual rally in support of biomedical science at UCLA

Apr 08 2010 Published by under Animals in Research

Wow, has it really been a year? Time for the second annual rally in support of biomedical research. I'll quote liberally from the UCLA Pro-Test for Science bit hosted at Speaking of Research:

In 2009, Pro-Test for Science held an historic rally on the UCLA campus; bringing over 700 people onto the streets in support of the scientists and researchers who carry out lifesaving medical research using laboratory animals. Such research continues to advance scientific knowledge and plays a vital role in the development of innovative treatments for human disease. However, animal rights extremists have continued to escalate their threats against researchers and their families.
On Thursday April 8th Pro-Test for Science will respond by rallying students, scientists and members of the public to support the cause of medical science. We call on the community to stand together against the recent tide of animal rights activism which has worked to misrepresent research and coerce those that carry it out.

A video from the rally held last year.

If you cannot attend perhaps you might want to take a look around Janet Stemwedel's blog. She has a number of thoughtful entries on topic of Research with Animals that are fantastic starting points for your own discussions that you will be having with your friends, family and colleagues. My own posts on the topic are perhaps less fulfilling but you may find a nugget or two. I would point you specifically to the Lie of the Truncated Distribution, an introduction to the heavily regulated activity of animal research, a description of additional guidelines that carry the weight of law and regulation and why the use of mice and rats is well regulated despite the Helms amendment.
You might also read a computer guy demolishing the myth that animal research can be replaced with computer simulations and an extensive and link-heavy discussion of typical animal rights' extremist tropes from Orac.
Happy reading.

4 responses so far

CongressCritters, can you please get the left hand talking to the right hand?

Mar 25 2010 Published by under Animals in Research, Call yer CongressCritter

From this Op-Ed.

The Institute of Medicine has recently released a report outlining the ominous public-health threat of chronic hepatitis C, much of which is the result of unwitting infection through medically-necessary blood transfusions, leading to 350,000 deaths worldwide each year and infecting more than three to five times as many people in the United States as HIV.

Narsty isn't it? We should get right on that, don't you think? Any decent models for research?

Currently, chimpanzees are the only experimental animal, except for humans themselves, susceptible to infection with hepatitis C. The Great Ape Protection Act would end the use of chimpanzees in biomedical research, grinding promising studies to a halt and unconscionably delaying the release of anti-viral therapies and a vaccine for chronic hepatitis C.

Whoops.

Continue Reading »

27 responses so far

IACUC 101: Satisfying the erroneous inference by eyeball technique

I stumbled back onto something I've been meaning to get to. It touches on both the ethical use of animals in research, the oversight process for animal research and the way we think about scientific inference.

 

Now, as has been discussed here and there in the animal use discussions, one of the central tenets of the review process is that scientists attempt to reduce the number of animals wherever possible. Meaning without compromising the scientific outcome, the minimum number of subjects required should be used. No more.

physioprofitinErrBars-1.jpg

run more subjects..

We accept as more or less a bedrock that if a result meets the appropriate statistical test to the standard p < 0.05. Meaning that sampling the set of numbers that you have sampled 100 times from the same underlying population, fewer than five times will you get the result you did by chance. From which you conclude it is likely that the populations are in fact different.

 

There is an unfortunate tendency in science, however, to believe that if your statistical test returns p < 0.01 that this result is better. Somehow more significant, more reliable or more..real. On the part of the experimenter, on the part of his supervising lab head, on the part of paper reviewers and on the part of readers. Particularly the journal club variety.

False.

Continue Reading »

48 responses so far

Things White People Love: Comparing Black People to Monkeys

No, I don't mean the self-imagined political wag, nor those of a similarly fantastical oppressed ethnic subculture of the US. I mean the kind of (over)educated middle to upper-middle class, progressive liberal occasionally self-avowed skeptic, contrarian and/or scientific white folk.
I've seen the odd social justice action now and again in the US over the past decades. Whether at the local municipal level, the University level or on national TV. African-Americans are typically very well represented even when the issue at hand is not a "black issue" per se. When it comes to the incredible underrepresentative University campus population, it is particularly striking because you will find the black faces that you'd never known were on campus appearing in support of social justice causes.
There is one notable exception and that is the animal-rights campaign. The practitioners of animal rights theology would have you believe they are engaged in a social justice battle akin to many familiar ones. They never seem to look around and ask why their tiny band of followers are so unusually devoid of the black folks.
Perhaps it is because one of their favorite memes is viscerally offensive to African-Americans?

Continue Reading »

42 responses so far

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