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Archive for the ‘Research’ Category

Teleost fish are unique in that they are able to regenerate many different types of tissues throughout their lives, including cardiac, retinal, and renal (kidney) tissues.  Many of these regenerative abilities occur through the action of stem-cell like populations.  Identifying stem cells in fish may help researchers identify analogous cells in human tissues. 

The ability of some fish to regenerate renal tissues is particularly interesting because there is currently no known kidney or nephron (the functional unit of kidneys) “stem cell” in humans.  A recent paper looked at using zebrafish to try to identify nephron stem cells. 

To find out more, check out my latest post for the Stem Cell Network.

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My last post on rodent anesthesia looked at the use of chemical anesthesia, in particular, the use of ketamine-xylazine to attain surgical unconsciousness. I identified several issues with the use of this combination, most importantly the lack of dosage control and lack of predictability in response.

So what are the alternatives?

If ketamine-xylazine is not used, most often researchers will turn to an inhalent anesthetic. Inhalents use a vaporizer to deliver a gaseous form of a chemical directly to the rodent via a hose or face mask (or through intubation for larger animals) in combination with oxygen.  The most common inhalant used in rodents is isofluorane gas.

Isoflurane is a halogen-based gas which causes muscle relaxation and unconsciousness.  It used to be used in human medicine, but is now principally used in veterinary medicine and research.

Gaseous anesthetics require more equipment than injectible anesthetics.  In addition to the vaporizer and assorted tubes and hoses, a scavenging system must be used.  Scavengers gather up leftover gases to prevent worker exposure.  Charcoal canisters which absorb residual gases are a common form of passive scavenging, while various types of ventilated hoods can be used for active scavenging.  Never use anesthetics without a proper scavenging system!  Chronic isoflurane exposure has been linked to cognitive decline.

[Aside: I had some bad exposure to isoflurane in the past and it is like being in a fog – you just can’t think.  Little bit terrifying.  Thank God for new careers!  Computers can only ruin my posture and eye sight! … ]

But using all this complicated equipment has it’s advantages!  The vaporizer allows the technician to control precisely how much gas is being delivered to the animal.  If you need to increase or decrease it, you know exactly how much you are raising or decreasing the dosage.  It is much harder to accidentally cause an overdose.  As well, since the gas is being continually delivered, there is no risk that the animal might being to wake up in the middle of a procedure.

For the animals, recovery from isoflurane is much, much quicker than recovery from ketamine-zylazine.  Isoflurane is excreted entirely via the lungs – no residual chemical is left in the system.  So once an animal is removed from the gas flow, it beings to recover immediately.   Full recovery occurs in only a few minutes and aside from regular post-surgical care, rodents do not generally require additional monitoring.

Unfortunately, isoflurane does not provide any analgesic properties aside from unconsciousness during the procedure.  So, analgesic must still be given before and after surgical procedures.

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While in Canada, many universities and institutions remain mum on their animal research activities, researchers in Europe are taking a proactive approach.  There are a few possible reasons for this difference in attitude.  The European research atmosphere is slightly different than that of Canada’s: Certain groups of primates have a legislated right to “inherent value” for example, while no such rights exist in Canada.  Whatever the reason, scientists in Germany and Switzerland have launched an educational initiative called the Basel Declaration which pledges to be more open about research and to engage in public dialogue about research.

As Nature News reports:

“The public tends to have false perceptions about animal research, such as thinking they can always be replaced by alternative methods like cell culture,” says Stefan Treue, director of the German Primate Center in Göttingen. Treue co-chaired the Basel meeting, called ‘Research at a Crossroads’, with molecular biologist Michael Hengartner, dean of science at the University of Zurich, Switzerland. Outreach activities, such as inviting the public into universities to talk to scientists about animal research, “will be helpful to both sides”.

I think that this is a good point that Dr.Treue brings up – the importance of dialogue cannot be understated.  He also makes a good point, that alternatives like cell culture are not always viable or indeed, may not be the “alternative” that activists would hope for.  Growing cells requires a hodgepodge of media to keep the culture alive.  One important constituent of cell culture media is fetal bovine serum, or sometimes fetal calf serum, which as the name suggests, comes from cows.  [Note: FCS and FBS are by-products of the meat industry and would be otherwise wasted if not used by research].  But it is important to note that the absence of research on animals does not mean that animal products will not need to be used in research and is a prime example of how science does a poor job of communicating what it does.

[Note: it is possible to grow cells serum-free, but the cost remains prohibitive at the moment]

And, there is the simple fact that cells grown as tissue culture are just not quite the same as cells in a living body.  Just ask Mark Post, who’s trying to create lab-grown meat.  Using biopsies from donor animals and tissue culture techniques, he’s trying to grow enough meat to create a sausage that looks and tastes like the real thing.  Dr. Post’s long term goal is to create meat without needing to slaughter animals.  While he’s succeeded at growing a strip of pork muscle, the “meat” does not resemble anything from the grocery store.  The tissue is weak and prone to cell death due to lack of stimulation and without the support of a proper vascular system to deliver nutrients uniformly.

A similar case can be made for the use of computer modeling.  I think computer models are great – they drastically reduce the cost of research by allowing researchers to narrow the field of interest.  But at best, computer models only reduce the number of possibilities.  When it comes to testing drugs, for example, a computer model cannot predict all the effects on a substance on a whole body system.  We simply don’t have enough information about all the interactions that occur in the body.  Yet.

That is not to say we should not pursue new tissue culture or modeling techniques.  Quite the opposite – these techniques will improve with time and refinement.  In time, they may even be sophisticated enough that human clinical trials are less reliant on animal data for safety and efficacy testing.

But in the mean time, hopefully initiatives like the Basel  Declaration will foster more openness between the public and the animal research community.

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This post turned out a bit longer than I expected, so I broke it up into two parts.  Excuse my science-y jargon and please do leave comments if anything is unclear!

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Rodent anesthesia falls into two main types: Chemical or Inhalant.

Chemical anesthesia involves the administration of a drug or several drugs via subcutaneous injection.  The most common drug of choice is a combination of ketamine and xylazine.

Xylazine is an alpha-2-adrenergic agonist sedative with short lived analgesia. As a sedative, the drug depresses, or slows down, the respiratory and cardiovascular system and relaxes the muscles.  Too much “slowing down” can be dangerous, especially in mice, where surgeries are generally conducted be a single technician and changes in respiration and cardiovascular function are usually monitored only by visual inspection.  If a person is occupied with the technical aspects of the surgery, slight changes may be easy to miss.  When the respiratory or cardiovascular systems become over-depressed, this is an overdose and death can result.

Ketamine is a “dissociative anesthetic” which renders animals unable to move.  Lubrication of the eyes is absolutely required because the eyes remain open while the animal is in this dissociative state.  Failing to lubricate the eyes during surgery can result in blindness due to drying of the cornea.  Recovery from ketamine can take up to several hours and during this time, the animal must be monitored closely.

By combining the two drugs, you are able to produce a sedate animal which is unable to move.  This is suitable for short surgeries.  However, the recovery period is often rough.  Animals often appear “groggy” and may not resume normal activities for some time after.

Ketamine-xylazine is favoured because it is relatively cheap and non-technical, requiring only the drugs and needles with which to administer the injection.  As well, there are no wastes produced from these chemicals which may be dangerous to the animal or the handler.

However, it is not suitable for long or invasive surgeries and comes with a few complications:

Ketamine-xylazine injection also does not produce lasting analgesia, or pain relief.  Additional painkillers are generally recommended before and after the surgery.

Many animals react differently to ketamine-xylazine injection.  A dosage which works well in one strain of mice may not work well in another.  As well, individual mice may metabolize the drug at slightly different rates, such that a dose that results in 1 hour of anesthesia in one mouse may only give 45 minutes in its cagemate.  This can be disastrous if a surgery is predicated to take 50 minutes to complete.  As such, the appropriate dosage must always be tested for each new strain of mice and for each new experiment, and allowing plenty of time for unexpected results.  The technician should also always have extra drug ready, should the animal show signs of waking up.

The amount of cardiovascular and respiratory depression is also dangerous, as I mentioned, and this danger increases during longer or more complicated surgeries.  Every time you have to administer a bit of extra drug to keep the animal unconscious, you risk administrating an overdose.

Luckily, there are other methods for producing a surgical level of anesthesia, which I will discuss in the next post.

[Photo by Dale Tidy]

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There was another flurry articles appearing in student media this past week over UBC’s animal use.

UBC publication The Ubyssey published an article and a well written opinion piece, remarking on the difficult nature of the debate.  Indeed, they echo many of my own sentiments when they remark that “moderate, progressive voices” are needed in this debate.  Mud slinging and fear mongering on both sides does nothing for animal welfare.  Until people are willing to talk rationally about the issues, no real progress can be made for either side.

It’s gotten to the point where being concerned about animal welfare is enough to send people into a frenzy of recrimination and accusations, while being a biomedical researcher arouses suspicion and distrust.  No doubt this blog will get passed around in numerous clandestine emails where I will be alternately skewered or praised by people too afraid to talk about their own opinions.  And why are people afraid?  Part of it is because we have not done a good enough job of educating our researchers and technicians about ethics and educating our public about science.

That’s one of the reasons I found my university ethics classes to be so insightful – it taught you to leave the emotion aside, think critically about an issue, and look at the scientific, ethical and philosophical arguments on both sides of a debate.   This is an important skill that I feel a lot of people are lacking.

Unsurprisingly, I was the only science-oriented researcher present in a 40-person class on biomedical ethics.  😛

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I’ve been in writing over-drive as I realized that indeed, the more I write, the more views I get.  😛  Now I know that there’s a lot of you reading (thanks WordPress stats!) but many of you seem to be the strong and silent type. I would encourage everyone to leave comments if they have a question, suggestions, or just want to call bs on something I write.

Interesting stories from the past few days in science:

  1. You can’t seem to leave the house the last few weeks without hearing about a new feat in stem cell technology.  Most recently, Nature published a paper which describes the transformation of skin cells into blood cells without the need of first passing through a stem cell state. Crazy stuff – see a summary from Nature News here.
  2. If you haven’t heard about the Rockstars of Science initiative yet, check it out!  This campaign paired leading scientists with big name musicians in an attempt to demonstrate the importance of science to the public.  Interesting new idea, check it out in GQ’s December “Men of the Year” issue and read about it on The Intersection.
  3. It’s one of those eternal life mysteries you always wondered about… well here it is, the physics of cat lapping milk from Wired!

I have a few ideas in the works for blogs: look for a piece on rodent anesthesia coming up and also a few fish stories.  I’ve managed to find a few newsletter articles that I’ve done as well and may repost them here.

Cheers!

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During the course of research, rodents are commonly euthanized for tissue collection, to end suffering or to terminate surplus animals.  Several methods of euthanasia are possible, and out of these, CO2 euthanasia is most preferred.

An overview of the types of euthanasia available:

Cervical dislocation describes a method in which the head is separated from the spine.  If performed correctly, it can be a quick death.  However, it is technically demanding and any errors would result in suffering by the rodent.  Due to it’s technical nature and the potential for error, it is not a commonly used technique.

Decapitation describes the physical separation of the head from the body.  Some investigators may pursue this method of euthanasia because it does not contaminate the blood or the tissues, which may be of importance in some studies.  While the death itself is quick, again, it relies on the skill of the technician to perform the euthanasia quickly and flawlessly.  Additionally, the handling and restraint required to decapitate a rodent may cause unnecessary stress prior to death.

Chemical methods of euthanasia are generally brought about through the use of lethal injections, typically barbituates. These are generally administered through a subQ injection.  Chemical euthanasia does not require a lot of handling nor technical skill, but some chemicals may be controlled substances or be considered too costly and time consuming to use on large numbers of animals.

Finally, CO2 euthanasia is a form of gaseous euthanasia.  It is the most common form used in laboratory animal science.  It is cheap, requires little to no technical skills, and has some anesthetic properties.  In this form of euthanasia, carbon dioxide is allowed to gradually fill a chamber containing one or more rodents.  As the oxygen levels decline, the animals are rendered unconscious, followed by death from asphyxiation.

While CO2 euthanasia has been the go-to method in recent years, a 2006 thesis by a UBC Animal Welfare Program grad suggests that CO2 euthanasia may cause distress* in rodents due to the dyspnea (the sensation of “breathlessness”) that precedes unconsciousness.   The idea that CO2 euthanasia causes distress in rodents has been explored in other studies as well.

I will note that the UBC Animal Welfare Program does not harm animals used in it’s research nor does it breed animals for the purposes of research.  All animals used are “surplus” from other labs which would have otherwise been euthanized. I will also note that all information provided here is freely available from the above mentioned papers, Wikipedia, and other online sites.

References:
KM Conlee, ML Stephens, AN Rowan and LA King (2005) Carbon dioxide for euthanasia: concerns regarding pain and distress, with special reference to mice and rats. Lab Anim 39:137-161.

Lee Niel Ph.D. (2006) “Assessment of distress associated with carbon dioxide euthanasia of laboratory rats” (thesis)

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* “Distress” is one of those nebulous, poorly defined words used in animal research.  Much like “ethics”.  😉  For the purposes of this post, I use “distress” as defined by the author: “… an umbrella term that encompasses negative affect associated with more specific negative states such as pain, discomfort and fear”.

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