Please read carefully the following story and answer all the questions.

You have 15 min.

One Saturday morning Dr. X was walking her dog thinking about some recent results in her field when it dawned on her that she might actually have the key to explaining all those findings.  If she was correct, she could go on to develop a new therapy for a terrible disease.

Being a scientist, Dr. X rapidly turned that idea into a specific hypothesis with testable predictions.  She ran back to her laboratory, gathered her students, told them the idea, and got to work.  They were excited when their first test (T1) yielded a positive result.  This simply meant that the implications of her hypothesis were corroborated by the experiment.  Good job everyone!

The next day her students were up all night running the second test (T2).  Dr. X arrived at the laboratory after dropping her kids in school to find very tired students, but with big smiles on their faces.  The second test, she correctly guessed, gave them another positive result.  Hurrah!

That night, at the dinner table, she shared the excitement with her family. Even the dog appeared to notice something important was going on. Next morning, one of her postdoctoral students came up with, what appeared to be, a direct test of the central idea.  It was agreed at the Lab meeting that this would be the next experiment (T3).

It was a difficult experiment.  Dr. X’s husband agreed to pick up the kids instead and let her finish her work.  Close to midnight the results came in.  Everyone in the lab ran to see the results.   They stared at each other in disappointment.  The result was clearly negative — what this meant is that the outcome contradicted a key prediction of the hypothesis.

Dr. X’s Lab had a difficult month.  They went over the data over and over again — nothing was obviously wrong; but they decided not to give up.  Instead, they brainstormed about how they could come up with a new hypothesis that may explain the data they had collected so far.  And yes, Dr. X explained, this must include a reason for the outcome of the negative experiment as well.

One night, Dr. X was awoken by the sound of the phone. She was startled, it was unusual that anyone would call at 3 am to her home. Understandably, Dr. X answered the phone with some apprehension.  She was relieved to hear one of her students, which after calming himself down and apologizing for the time, described to her a new idea that, he said, came to him out of nowhere in the middle of his sleep.  She grumbles, but listened…  her sleepy eyes slowly widening as the student went on.  When he was done Dr. X immediately knew that there was no doubt her student could explain the diverse findings.

Everyone gathered in the laboratory next morning and started to test again based on the new concept over the week.  T4… positive!  T5….positive!  T6… negative…  Negative?!  Oh no…  Again?!

Yes, again.  But Dr. X gathered her students and explain to them that this is how science works.  New ideas emerge from old ones in an effort to account for all the data their community gathered so far.  And that negative findings were important for science too. They all felt a bit better as they went home… just a little bit.  But more than Dr. X’s words, it was a group feeling that they were getting closer to the truth.

It took her Lab a few more iterations of this difficult game called science, but one day they knew they had nailed it.  They had a new idea that not only explained all past results but stood many additional tests, including replications by her colleagues.  Their work delivered a medical breakthrough that allowed them to develop a new medical treatment that saved uncountable human lives.

Questions:

Assume that in this story, from beginning to end, including her experiments those of her colleagues, scientists performed 20 experimental tests that yielded positive results, 15 experimental tests that yielded negative results, and that each test required the use of exactly one mouse.

Q1. How many mice were scientifically necessary to develop this medical breakthrough?

Q2. Which experimental tests were more important in developing this breakthrough?  The tests yielding positive results or the ones yielding negative results?  Explain.

Q3. Given the end result was that uncountable human lives are being saved.  Which test was morally justifiable and which was not?  Were positive tests in any way more justifiable than negative ones?  Were experiments used in replicating Dr. X’s findings necessary and justified?  Or is it only the final experiment directly preceding the development of the new therapy that was justified?

Q4. Five years after her discovery, and with the new knowledge acquired, one of Dr. X’s colleagues comments that it was obvious some of the ideas she had tried could not have worked.  With 20/20 vision, Dr. X agrees.  Does her admission mean the experiments testing those ideas were scientifically unnecessary or ethically indefensible?

Submit your answers in the comments section below!

Today on the Neurophilosophy blog Mo Costandi has another great example of how our knowledge of developmental biology is being advanced through animal research. In a post entitled “Astrocytes build blood vessel scaffolds for long distance neuron migrations” he discusses how a research team led by Dr Armen Saghatelyan  used  Green Fluorescent Protein labeling and genetic modification to track the processes that control the migration of nerve cells to their correct location in the developing mouse brain.

It’s fascinating work, and you can read about it on the Neurophilosophy blog here.

So what does this basic research in developmental biology mean to medicine?

Scientists have known for some time that the brain has a limited ability to repair itself following injury, for example after a stroke, and more recent studies have identified a critical role for adult neuronal precursor cells in this recovery.  But the process by these adult neuronal precursor cells migrate to the site of injury and integrate into the damaged brain circuitry is very inefficient, with only a small number of cells reaching the correct location, so scientists are working on a variety of approaches to boost the brain’s ability to repair itself.

One approach to doing this is the use of exogenous stem cells, such as the human embryonic stem cell derived neuronal precursor cells developed by the UK-based company ReNeuron that entered clinical trials for stroke in 2011.

Another avenue being pursued by several research groups around the world is to improve the efficiency with which the endogenous neuronal precursor cells migrate to and repair damaged regions of the brain. In order to develop therapies that improve endogenous brain repair scientists first need to understand the processes that drive – and limit – neuronal precursor production, migration and integration in the developing and adult brain, so that they can modify and enhance those processes to safely  optimize repair.  The work of Dr Saghatelyan and his colleagues has provided medical science with another important piece of a puzzle that when solved will benefit many thousands of stroke victims around the world.

Paul Browne

On Jan. 25 both Beutler, who works at the University of Texas in Dallas, and Hoffmann of the University of Strabourg, France, were at the University of California, Davis talking to a packed house about their work. Joining them on stage was UC Davis plant pathologist Pam Ronald, who studies rice, and Luke O’Neill of Trinity College Dublin, Ireland, who talked about human medicine.

(Watch the presentations here: http://ccm.ucdavis.edu/immunity.html)

L to R symposium speakers Bruce Beutler, Jules Hoffmann, Luke O'Neill and Pamela Ronald, with (far right) symposium sponsor Murray Gardner.

Work in these very different organisms can give insights that advances human medicine. From the basic discoveries in mice, flies and even rice could come new drugs and new approaches to treat heart disease, rheumatoid arthritis, inflammatory bowel disease and other conditions.

Our immune system has two lines of defense. The innate immune system reacts first, attacking invading microbes and triggering inflammation. If that response fails, the adaptive immune system fights back with antibodies and specialized killer cells. Afterward, the adaptive immune system retains a memory that allows a more rapid and powerful response if the same virus, bacterium or parasite comes back.

Only animals with backbones, from fish to humans, have an adaptive immune system. But all animals, including insects, as well as plants, have innate immune systems.

In the 1990s, Ronald (working with rice), Hoffmann (with Drosophila flies) and Beutler (with mice) identified genes for immune receptors that triggered innate immunity in the rice, flies and mice, and found that the genes were remarkably similar despite hundreds of millions of years of evolution.

From this common trigger, plants, insects and animals develop different types of response to invaders.

Activation of the immune system is not always a good thing. It can lead to allergy, inflammatory diseases such as rheumatoid arthritis or autoimmunity, when the body starts attacking its own tissues.

In his talk, for example, Beutler described how his team, working with mice, has isolated genes related to inflammatory bowel disease, while O’Neill talked about the possibility of being able to develop drugs to treat a wide range of diseases linked to inflammation.

The symposium is an annual event sponsored by a fund created by AIDS pioneer and UC Davis professor emeritus Murray Gardner, who previewed in an interview for Sacramento Public Radio Jan. 24 [http://www.capradio.org/168919] At the beginning of the AIDS epidemic in the 1980s, Gardner helped discover viruses similar to HIV in monkeys and cats – animal models that have been of vital importance in discovering drugs to treat and prevent HIV/AIDS.

– Andy Fell

This goal encompasses all aspects of laboratory animal care— their participation in ethical scientific studies, their humane treatment during daily care and maintenance, and their receipt of the highest standard of clinical care. Do scientists engaged in animal research perform all of these duties?  No. In fact, by law, it is not scientists who have the ultimate responsibility for oversight of all issues involved in animal welfare, but the attending veterinarian and institutional officials.

In practice, there are a range of individuals who share in the responsibility to provide for animal welfare. Many different types of expertise are needed to provide the best management of a laboratory animal research facility. Scientists working with animals have expertise in the topic their research addresses, in the activities that research requires, and in use of animals in research. Depending on their research area, background, and training they may have tremendous depth and breadth of knowledge about the animals’ behavior, psychology, physiology, and other systems. But it takes more than this to accomplish all that is needed to maintain an animal research program.

Animal research programs always include veterinary staff to provide the animals with clinical care. They typically also include animal care staff to provide daily husbandry; behavioral management staff to provide environmental enrichment and animal training; and facility management staff who work with engineers and others to maintain clean and safe environments for the animals. In addition to facility management, clinical care, and daily husbandry there are also divisions of personnel charged with evaluation and oversight of the research, including the Institutional Animal Care and Use Committee, associated staff, and compliance officers. Oversight for the entirety of the animal research program typically rests at the level of university administration.

In sum, the number of individuals and divisions now involved in ensuring laboratory animals’ welfare and humane treatment in ethical scientific studies extends far beyond the scientists most identified with animal research.  What does this mean? It means that there is a great deal of shared responsibility for both successes and the occasional failures in the conduct of laboratory animal science.  It also means that any discussion of continued improvements in the daily activities that affect animal welfare, as well as changes in policies that govern the conduct of animal research, should benefit from teamwork among these different stakeholders.

A huge number of people are involved in animal welfare in laboratories

Finally, it should mean that in public dialogue the voices of scientists and research advocates are routinely joined by laboratory animal veterinarians, university officials, and others who play important roles in laboratory animal research.  This is true even when that research is controversial and has the potential to elicit attention from animal rights activists. All too often, however, few of these voices are raised when the public eye is turned to issues of concern in animal facilities. Rather, in place of thoughtful answers to questions raised by a range of parties—by the press, by animal rights activists, by other scientists, by USDA reports— what is often offered are generic statements that contribute little to understanding of the events and the context in which they occurred. For example, in response to virtually any type of incident, an institution’s response might be along the lines of:  “We follow all regulations and hold animal welfare in highest regard and priority…”

It is long past the time that our community should have abandoned this approach and required more from each of its members and divisions.  To accept anything less is a mistake.  Absence of accurate information, accompanied by the failure of institutions and their representatives to engage in public dialogue, only further erodes public trust.

The intent of the AWA, subsequent legislation and policies, accreditation programs, revisions of guidelines, and continued increases in regulatory oversight is to ensure the best animal welfare and humane treatment possible.  In the rare cases where the apparatuses put in place to achieve this goal fail, sometimes from accident or human error, two things must happen.  First, it is contingent upon all of those involved to immediately work together to identify the reason for the failure and ways to minimize the possibility that it occurs again.  Second, those ultimately responsible for oversight should provide the public with accurate information, explanation, and opportunity for discussion.  At the very least, they should be able to articulate the rationale and their support for the research programs and their contribution to scientific and medical progress.

Are we suggesting that attending veterinarians and institutional officials open their doors for daily chats with animal rights activists?  No, but we do believe that addressing legitimate public concerns and questions about their animal research programs are among the key obligations of those charged with oversight and conduct of those programs.

While scientists can address questions about the scientific side of animal research, we need the laboratory animal care and veterinary staff to provide their expertise in service of addressing public questions about clinical care and husbandry.  If they do not, it will be no surprise if the public view of animal research is disproportionately colored by the relatively rare adverse events and the misrepresentations of animal rights activists. Many believe that it is possible—and perhaps acceptable—to ignore this part of reality in order to focus on more immediate demands for time, energy, and resources. Consider, however, that a fundamental part of the AWA, accreditation, regulation, and professional obligation is actually to ensure communication with the public that supports animal research.  Thus, it is our entire community who share a primary obligation to engage in the dialogue that surrounds us.

Speaking of Research Committee

Apparently, by 2050 we can expect the complete elimination of animal use in science.

At least, this is the prediction made by Dr. Andrew Rowan, Chief Scientific Officer of the Humane Society of the United States (HSUS) in a recent article that appeared in The Scientist.

The title of the piece was “Avoiding Animal Testing.  Advances in cell-culture technologies are paving the way to the complete elimination of animals from laboratories”.

The first half of the article focuses on the development and adoption of alternatives to the use of animals in toxicology.  Our public health officials and the FDA have long made the sensible decision to require any company that introduces new chemicals or drugs into the market to provide an initial experimental assessment of their potential toxicity to humans.

This use of animals for such safety screening is typically called animal testing.

Dr. Rowan correctly points out that advances in the development toxicology methods may allow us eventually to relax the regulations that require the use of animals in testing.  But he rapidly moves to insinuate such advances imply that by 2050 we could see the end of animal use in laboratories:

This overall decline in animal use can be attributed to the advent of novel technologies such as improved cell-culture systems and micro-analytic techniques; more sophisticated model systems; improved understanding of signaling and metabolic pathways; and a host of other new methods that allow scientists to answer important questions about the functioning of healthy and diseased tissues without subjecting whole animals to harmful procedures. With a 50 percent decline in animal research since 1975, we are roughly at the halfway point towards the complete elimination of animal research. Thus, we argue that, by 2050, we might finally see the last of animal use in the laboratory, particularly if all stakeholders put their minds to it.

First, the assertion that the total use of animals is systematically declining is not supported by the data.  The slide below, for example, was taken from a recent talk Dr. Rowan gave at the University of Wisconsin.  It shows the total number of animals used has been stable since the mid 80s, with the number of non-genetically modified (Non-GM, faint dashed line) animals decreasing and stabilizing in the 90s (see also data here), while the number of  genetically modified (GM) animals, which are largely mice, has been systematically increasing.

Second, even if correctly asserting that we can expect a diminished need for animals in toxicology testing, Dr. Rowan’s generalization of such trend from a such narrow field to all of biomedical research is groundless and misleading.

Let us be clear, our universities do not engage in animal testing, but in animal research.

What’s the difference?

Scientists are largely concerned with elucidating the basic mechanisms of biological processes in health and disease.  We want to study how cells in our bodies work, how they communicate, how they develop, how they age and how they die.   We want to understand how the brain, our immune system, and internal organs work and how they fail.  And so on…

Why is it critical we develop such an understanding?

Because without this knowledge there will be no hope to combat disease. Indeed, the mission of the National Institutes of Health (NIH) recognizes this fundamental fact in its opening statement,

NIH’s mission is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life and reduce the burdens of illness and disability.

Implicit in such declaration is the acknowledgment that it is basic knowledge that drives advancements in human health and well-being.  Basic knowledge of nature is what drives progress.  This point is critical –   translational or applied research would not exist without basic knowledge as the raw material.  Without knowledge there would be nothing to translate nor apply.

Those that declare an imminent end to the use of animals in science are effectively implying that they envisage all basic knowledge needed will be acquired by a certain date, or that we will have methods that would allow us to proceed with studies non-invasively in human volunteers. Dr. Rowan’s statement that “Advances in cell-culture technologies are paving the way to the complete elimination of animals from laboratories” is nothing short of utter scientific nonsense.

Is it possible for Dr. Rowan to be ignorant of the role of animals in scientific research?  Could he legitimately be confused about the difference between safety testing on one hand and the development of therapies and basic research on the other?

This seems highly unlikely giving his academic credentials and the fact that he has served on IACUCs before.  In fact, another slide from his talk, shows him delineating these different uses of animals, and illustrating that animal testing for human safety accounts for merely ~25% of total animal use.

No, Dr. Rowan is not confused at all.  He knows what he is talking about.  This is unfortunate as one can only conclude his article is simply a misguided attempt to deceive the public about the fields in which we might realistically expect science to successfully replace animals in the near future.

And I emphasized science above for a good reason.

As difficult as it is for animal advocates to understand, scientists also believe we will see a day when we can eliminate the use of animals in all animal research.  And the day will arrive because of the hard work, progress and achievements of dedicated scientists, such as this one, and not because of deception of those that want to oppose animal research at all cost.

For HSUS to suggest that all animal research could be eliminated by 2050 is  flatly wrong from a scientific point of view, and utterly irresponsible from a public health perspective.

Studies in mice were key to developing gene therapy for hemophilia B

Clearly a more permanent solution to factor IX deficiency is highly desirable, and to develop one scientists at University College London and the St Jude Children’s Research Hospital in Memphis turned to a technology that we have discussed on several occasions on this blog in recent years – gene therapy. The results of their clinical trial, published in NEJM, were impressive, all the patients were able to stop regular factor IX injections to maintain adequate factor IX levels, or to greatly reduce the frequency of injections.

As the NEJM editorial points out, this therapy has the potential to not only improve the lives of people with hemophilia B, but also to save millions of dollars over their lifetime.

In an excellent post discussing the clinical trial science blogger ERV notes that:

This treatment is not perfect yet– but its a huge step in a right direction, and only possible because of viruses.”

A very good point, in medicine we usually think of viruses as the enemy, but when it comes to gene therapy they are an ally.

But they are not always the easiest of allies to campaign alongside, and that is where another scientific technique without which this advance would not have been possible comes in – animal research!

A key choice when developing any virus-based gene therapy is the vector used to deliver the replacement gene to the cells of the body.  The vector must deliver enough copies of the gene to the target tissue to be effective, enable the gene to express in sufficient quantity to ameliorate the condition, and do so safely. Adenoviruses are often chosen for this task, with the serotype AAV 2 being the most widely studied in animals and humans. But there is a serious problem with AAV2, roughly half the population have been exposed to AAV2 naturally, and mount an immune response that clears the vector from the bloodstream before it can deliver its gene cargo to the target tissue.

The researchers addressed this problem by turning to another adenovirus serotype AAV8, which was isolated from rhesus monkeys a decade ago.  They chose AAV8 for three reasons, firstly earlier studies in mice showed that AAV8 injected into a peripheral vein delivered genes to the liver – the natural site of factor IX production – much more efficiently than AAV2, secondly the mouse studies also showed that AAV8 uncoats and delivers its  gene payload to cells more swiftly that AAV2, helping to ensure that the gene is delivered before the body can mount an immune response, and thirdly prior immunity is far less common in the human population than immunity to AAV8.

The AAV8 vector wasn’t perfect though, it would still require a large number of virus particles to be injected – potentially enough to trigger liver damage or stimulate a larger and more rapid immune response – so they designed a modified AAV8 vector known as a self-complementary (SC) vector that delivers the gene to liver cells even more efficiently.  Injection of mice with an SC vector containing the factor IX gene was found to lead to a 20-fold increase in liver of factor IX expression compared to the same amount of standard AAV8 vector, with no increase in toxicity. Since the ability of vectors developed from different adenovirus serotypes to target gene expression to particular tissues can vary between mice and primates, they then evaluated this vector in rhesus monkeys, finding that the SC vector could drive safely therapeutic levels of factor IX production in the monkey liver, and that prior immunity to one adenovirus serotype did not diminish the efficiency of factor IX production by a vector based on another serotype.

These studies paved the way for the clinical trial that caused so much excitement in the scientific and popular press earlier this month. Hopefully further development and larger clinical trials in people with hemophilia B will confirm the potential of this exciting new therapy, a therapy that was developed thanks to viruses and to animal research!

* after a patient named Stephen Christmas from whom factor IX was first isolated.

Paul Browne

I have been an advocate for biomedical research, specifically involving animals, for decades. I go to work each and every day supporting researchers involved with discovering new cures or treatments. I dedicate time outside of those duties to promote education regarding the use of animals in such research. I want people to be able to make up their own minds free of rhetoric and sound bites empty of any real information. Research is part of who I am.

All of this became intensely personal for me, more so than it was, in February of 2010 when my husband was diagnosed. They did not need to explain to me how serious his diagnosis was. I already knew. I knew it was going to be a tough battle but he was a fighter. He was not ready to leave me or his daughters or the life we built. Not now. Not to cancer. No way.

He remained a fighter until his very last day on this earth. In our last conversation he told me cancer had only taken his body but he was still free and he will be waiting for me when the time comes for me to shed my body too. I still work in the same hospital where all his treatments had taken place and I eat at the same cafeteria where I bought all his food when he was in the hospital. I still see some of his caregivers in the hallways and they always ask me how I am. They are very caring people and I am sure each and every one of them would applaud an end to cancer. I know I would. I am pretty sure everyone that has been touched by this horrible disease would love to see an end to it, just as I am sure people were very happy to see an end to polio or small pox.

On Monday, author Sharon Begley published an article in The Daily Beast entitled “Could This Be The End Of Cancer?”outlining some of the new developments in the fight against cancer, particularly using vaccines. It is detailed but easy to read, and it was nice to see more information on some of the treatments my husband received. Research for cancer and many other diseases go on each and every day by thousands of people. Some of those people remember what life was like before the current vaccines we take for granted were widely used. In reading the evaluation results for the polio vaccine, you can see how many children were affected and see pictures of them in iron lungs. My generation has never known a friend confined to one of those thanks to those who continued the research that lead to the vaccine. The mortality rates for small pox were up to 35% and yet according to the WHO this disease was eradicated in 1979, thanks to those who developed the first vaccine. I doubt anyone who was born after 1975 could really tell you what small pox looked like without looking it up thanks to those who continued to search and refine the current vaccine.

Immunotherapy – developed through animal research – offers new hope to patients with Chronic Lymphocytic Leukemia, and is an example of recent advances in cancer treatment discussed by Sharon Bagley

Without research, both with animals and humans, or those dedicated to searching for answers, no cures are possible. Will we see vaccines for all cancers in the next 30 years? No one can answer that, just like no one can give you a date when the human race will finally stop wars. But does that mean we should stop looking? Stop striving? Stop hoping for a cure? Absolutely not. Polio and small pox are simple diseases if compared with the complexity of cancer. It is going to take lots of time, lots of man hours and a lot of dedication from a lot of people to finally put this monstrous disease in the “eradicated” file.

It is also going to take a lot of money. On Ms. Begley’s article page is a comment regarding this money. The poster states:

This is a nice read, but … this will never happen. At least not in our life time as Cancer has become a big business. I am a ovarian 3 cancer survivor and I can tell you that there would be a lot of people out of work if there ever was a cure. The Government would fail. “

Do you suppose she is happy about the treatments she received for her disease that has extended her life? Would she reject a vaccine in favor of current treatments if her cancer was to reappear? Somehow I think she would take the easier treatment.

Is finding cures and treatments expensive? You bet it is. Is funding from the government and charities vital to this research? Absolutely. Without it we would not be able to hire the scientists, the biologists, the doctors or the nurses who work tirelessly each and every day, not only to find a cure, but to make every day in the life of a cancer patient the best it can be. And believe me, we are not a rich bunch. We shop at dollar stores and check the clearance section too just like so many people do in our current economic state.

However…

Do you think any one of us would give up their job to find that cure tomorrow? I know I would. In a heartbeat. It is too late to save my husband. But if I could save everyone else, every kid, mother, father, wife, husband and friend, from having to go through what I just went through, I would collect my last paycheck today. Right now.

But until that cure happens, we are going to come to work and continue searching, perfecting, refining and aiming for that day to come. And it will come.

Pamela Bass

The experiment consisted of having a rat placed in an arena (the free rat) who is able to see and interact  with a companion that is trapped in a cylindrical restrainer with a door (the trapped rat).  It was found that the free rat learned over time to free the trapped rat by intentionally opening the door.  In control experiments, rats did not open empty tubes or ones containing an inanimate object.  When given a choice between getting access to chocolate and freeing the trapped rat, they would often free the rat even before eating the chocolate, suggesting that the motivation to liberate its companion trumped even its desire for the chocolate, a potential sign of altruism.

The authors concluded that “the free rat was not simply empathically sensitive to another rat’s distress but acted intentionally to liberate a trapped conspecific.”

The media reported on the finding by declaring science has shown altruistic behavior in rats.  Some media titles include “Rats: Holiday spirit in rodent form”, “If someone calls you a rat, take it as a compliment”, “Rats kind-hearted, generous creatures”, “Rats show Empathy and Altruistic Behavior”, “Rats are as compassionate as humans” and so on.

It appears that both the press, and perhaps even the authors, interpret the findings as implying the following:

1. The free rat has a mental state that represents the well-being of a conspecific.
2. This representation generates a distressful response in the free rat.
3. The free rat learns it can act in a way to relieve the distress of the caged rat by opening the door of the cage.
4. The rat intentionally acts to relieve the caged rat from distress even when there it has nothing to gain from the action.

Dr. Daniel Povinelli, in a Nature coverage of the paper, had a different view, saying that “This work is not evidence of empathy — defined as the ability to mentally put oneself into another being’s emotional shoes.”

Though the view that rats exhibit empathic behavior may be consistent with the data, we must ask if there could be alternative, simpler explanations that do not necessarily involve invoking assumptions 1-4, above.

One possibility is that the trapped animal is generating an alarm signal, either in the form of vocalizations or pheromones, that generates stress in the free rat.  The free rat may then learn it can stop the distressing signal by opening the door (so-called negative reinforcement).  In acting in such a way, the free rat would then be relieving its own distress rather than the perceived and shared stress of a conspecific.

Is this possible?

The authors did not measure chemical signals but did measure vocalizations during their experiments and found that “significantly more alarm calls were recorded during the trapped condition (13%) than during the empty and object conditions.”

So this alternative scenario is, in principle, a possibility.  The authors dismissed this alternative explanation because the rate of alarm calls was relatively low and yet they remained open to the possibility when they concluded:

Thus, the most parsimonious interpretation of the observed helping behavior is that rats free their cage-mate in order to end distress, either their own or that of the trapped rat [...] This emotional motivation, arguably the rodent homolog of empathy, appears to drive the pro-social behavior observed in the present study.

This is a bit confusing and requires clarification.

There are at least two different interpretations of the data.  Not one.

Either the rat is freeing the companion to end its own stress (caused by an alarm signal) or it is doing it to end the perceived stress of the caged rat.   The interpretation of a pro-social, empathically motivated, altruistic behavior is only applicable to the second interpretation and not the first one.

To differentiate among these possibilities one can conduct some additional control experiments.  One could, for example, just play alarm calls that are stopped once a rat presses a lever once placed in the arena.  Or we could use chemical signaling if we learn the behavior is mediated by pheromones and identify the pheromone in question. One could have offered the free rat the option to leave the arena to a dark, quiet place, potentially ending its own distress and leaving the companion trapped.  Or the free rat could be offered the possibility of a “personal sacrifice” (such as a mild shock) to free the other rat, thus paying a price to help his companion.  These are all doable experiments that would help tease apart the different interpretations of these data.

Another potential explanation of the data is raised by video records of these experiments provided as part of the Science article shown below.

In this example, taken after the rat has learned to free its counterpart, we see the free rat going right into the restraint immediately after opening the door.  Why would the rat enter the tube if it truly felt and understood the distress the other rat experienced by being confined?

If one has ever seen rats at the pet store, you know that you will often find them snuggled up together in tubes and tight spaces because they apparently enjoy the safety and security of these types of experiences. This view was raised in an online discussion of the data:

Rats enjoy access to tight enclosures.  We routinely put plastic tubes in home cages for “environmental enrichment” and the rats are often found “snuggled” together in them, especially when resting – presumably an inherent protective response.  In fact, if you try to grab a rat in a cage with a tube, the rat will immediately go for the tube and try to stay in it.  Thus the “trapped” rat could also be seen by the “free” rat as enjoying a protected situation, and the free rat could in fact be displaying “envy” by freeing his companion so that he can enjoy the same protection and/or being motivated for social reasons to have a companion to “snuggle” with.  Indeed, the first thing the free rat did in the video after opening the enclosure was to go right into the tube with the other rat! 

So the basic question is, does the free rat want to get in, believing that his cagemate enjoys the privilege of a protected space, or does he fear for his cagemate and want to release him?   

Again, only additional experiments can address this. Resolution of these alternative views is crucial in terms of both of the prevailing motivations for conducting the study. Either rats are acting to relieve their own distress, or that of another – the difference bears strongly on our understanding of their mental abilities. In addition, if the former, but not latter, phenomena is correct, the value of studying the biology of empathy using rats is significantly challenged.

Still, we are left with a provocative phenomena —  rats freeing one another, invoking similarities with human behavior. There are plenty of other examples in nature where individuals of a species cooperate and interact in ways that could be described in terms of our own (human) mental states as altruistic or empathic behavior.  The examples range from bonobos, to bats, to even single-cell organisms, such as social amoeba (see here and here.)  The behavior is essentially the same across all these species and yet one would be hard pressed to argue that single-cell organisms have a notion of altruism and empathy in the same sense humans do.

Our brains (including those of scientists) are wired in such a way that they readily interpret the behavior of others in terms of our own mental states.  Such ability is useful in many situations, form navigating daily social interactions and even in the description of scientific data.  Care must be exercise in descriptions based on our own mental states when the outcome can have clear moral and scientific consequences.

Scientists must always keep an open mind.  But before rushing to declare that humans must seek moral guidance from rats, we should pause and try to understand exactly what the data say.  As new experiments are done and more information is available, we will surely be able to discern which of the alternative explanations is the correct one. If additional work confirms the (premature) conclusions of the authors, it will lay the ground work for developing new animal models for human psychological disorders, which will be a welcome development. For now, however, we must await that conclusive work.

J. David Jentsch and Dario Ringach

08/12/11: Facts must inform discussion of future of chimpanzee research.

10/13/11: Joseph M. Erwin, PhD Efforts to ban chimpanzee research are misguided.

11/21/11: A closer look at the Great Ape Protection Act.

Previous posts and other discussions of chimpanzee research have focused on ethical questions, animal welfare, and ongoing evaluation of the role chimpanzees do play, or should play, in scientific research.  These are the most important issues to address in discussion of the future of great apes in the U.S. At the same time, this year’s version of the Great Ape Protection Act has included a new focus, with addition of the phrase “and Cost Savings.”  The new language and the calculations given as basis for its assertions have received relatively little careful broad discussion or evaluation.

According to cost analysis for the legislation compiled by the Humane Society of the United States, the majority of cost-savings from GAPA – 76% – would result from ending federal grants for projects involving chimpanzees.  Of the “nearly $30 million saved annually” over $22 million reflects funds committed to support research projects that involve chimpanzees and are funded by the National Institutes of Health (NIH).

HSUS GAPA Cost Analysis

It appears that this number was arrived at by summing the cost of all NIH grants that involve chimpanzees, regardless of their topic or the types of activities in which the animals are engaged. Whether this number could reflect the total funds invested in what is commonly considered invasive research is not readily apparent. Some of these grants may involve noninvasive studies, others may be dedicated to studies that require as little as samples of DNA—something commonly done in human studies. It does appear that the underlying assumption for the cost analysis is a complete block on any NIH research grants that involve chimpanzees. (We welcome correction if this is not an assumption of the HSUS analysis or any cost analysis used to support the claims associated with GAPA.)

The remaining savings are projected from reduction in care costs if the animals were moved to sanctuaries.  Whether sanctuaries provide lower-cost care than research facilities is subject to some debate, in part because care costs vary across facilities. This is illustrated in the most recent data published by the National Center for Research Resources (NCRR) October 31, 2011 “Costs for Maintaining Humane Care and Welfare of Chimpanzees:”

Based on the most recent awards and payments, NIH is spending an average of $35 per day per chimpanzee in research facilities; $67.00 per day per chimpanzee in the research reserve facility at Alamogordo Primate Facility (APF); and $47 per day per chimpanzee in the federal sanctuary facility operated by Chimp Haven. The average for research facilities becomes $44 per day if the research reserve facility at APF is included. See Table 1 for detailed figures.”

The reasons for variance in costs are complex. Among other things, they do not reflect differences in housing, clinical care, or health status of the animals (e.g., older animals or animals with chronic health problems may require more expensive treatment and care). But overall, the numbers reported by NCRR show a rough equivalence in care costs at the federal sanctuary and many research facilities.

Table 1 “Costs for Maintaining Humane Care and Welfare of Chimpanzees, October 31, 2011“

What is not shown by these numbers or by most of the discussion of GAPA are the number of other issues that should accompany thoughtful consideration of the long-term care and housing of chimpanzees.  Dr. Joseph Erwin provided commentary on many of these in a previous guest post, among them concerns about ensuring the highest quality of care for the animals:

Most chimpanzees in scientific and educational institutions (research colonies and zoological gardens) live in spacious, social, and secure environments, where they are provided with excellent professional healthcare, and are afforded protection under the Animal Welfare Act, through inspection by the USDA, and publicly available reports of those inspections. The legislative ban would require removal of chimpanzees from decent facilities that were built at great public expense, and would deposit hundreds of chimpanzees in “sanctuaries” that provide no assurance of competent professional care, are not subject to Animal Welfare Act protection, and are not publicly transparent.”

One of the biggest unanswered (and virtually unmentioned in public spheres) questions surrounding the effects of this legislation is where it is that these chimpanzees would go? Is the intent that they would stay in current facilities? That new facilities would be constructed? While some animal rights groups have advocated for moving chimpanzees from their current research facilities to Chimp Haven, there is little information that would indicate that is a feasible option. Nor do the discussions of cost-savings and future plans include information about projected costs to build sufficient sanctuary space that could accommodate the number of animals currently housed in research facilities.

This is a non-trivial issue. For example, the publicly-available NCRR cost information informs us that the cost to construct the only federally-funded chimpanzee sanctuary, Chimp Haven, was $11.8 million. Chimp Haven houses 130 animals.  In other words, the initial construction cost was just over $90,000 per chimpanzee.

There are an additional 594 NIH-supported chimpanzees currently housed in research facilities. There are also hundreds of privately-owned chimpanzees. Thus, on even rough calculation based on the construction cost of Chimp Haven, it would appear that at least many millions of dollars would be required to extend the capacity for sanctuary housing to these animals. 

The cost, feasibility, and plan for constructing additional facilities that could provide care for these chimpanzees does not seem apparent in the cost calculations for the current legislation. Nor is it an issue raised much in public discussion.  It is a relatively easy thing to call for an end to chimpanzee research and to encourage public support by appealing to fiscal conservatism. What is far more challenging is to include consideration of real factors that significantly influence the outcomes for the animals, including an accurate assessment of where they can be housed, how best practices for care can be supported, real costs and dedicated sources of funding for long-term maintenance and facilities. Those details matter and deserve far more attention than they currently receive by those claiming to have chimpanzees’ welfare as the utmost priority.

Allyson J. Bennett

The disease has claimed over 25 million lives.  Worldwide, over 33 million people are now living with HIV/AIDS.

This year marks the 30^th anniversary of the first report of the disease, published in the CDC’s Morbidity and Mortality Weekly Report of June 5, 1981. By 1984 scientists had isolated the virus that caused the disease – human immunodeficiency virus, HIV.

It was a terrifying and frustrating time.  A diagnosis was considered a death sentence.  There were few treatments and little hope.   “All our patients died – 100 percent,” said one clinician about the era.

In 1985 the first diagnostic test was licensed and in 1987 AZT, the first anti-HIV drug, was approved. Over the past two decades, scientific progress in developing new treatments has been steady as dozens of new drugs were developed and several new methods of prevention were proven to be effective.

Jeff Getty - a hero of the fight against HIV/AIDS

In a bold experiment in 1995, Jeff Getty, a prominent HIV/AIDS activist and research advocate, received the first bone marrow transplant from a baboon.  The hope was that the animal’s natural resistance to HIV-1 would develop in his system.

I’m going to die anyway,” Jeff told a reporter. “Let’s get on with finding some answers about the disease.  If this saves me, then I got lucky.”

Despite approval by the FDA after extensive deliberation, many researchers had concerns about the procedure.  The physician who carried out the marrow transplant, Steven Deeks, an HIV/AIDS researcher at UCSF acknowledged, “We have been accused of being desperate, and to some extent we are,” he said. “We’re seeing people die every day and the therapies that are currently available and those that are predicted to be available over the next several years aren’t going to substantially slow that down.”

Ultimately, the baboon cells did not engraft, but Jeff’s health improved greatly.  His doctors thought some treatments, including radiation and chemotherapy, that he received in preparation for the transplant, were likely responsible for his upswing. Jeff felt the procedure ‘bought some time’ – and indeed, he lived long enough to benefit from another novel treatment he was receiving at the time: combination antiviral therapy.

The development from the mid-1990’s of the first generations of antiviral drug combinations known as Highly Active Anti-Retroviral Therapy (HAART) was a breakthrough  that was to have a profound effect on the prognosis for HIV positive people, and was spurred by the arrival of HIV protease inhibitors, whose development depended in part on animal studies.

Jeff lived with HIV/AIDS for a total of 26 years, until October, 2006 when he died of heart failure.

While he was recovering in San Francisco General Hospital in December 1995 after the transplant, Jeff received a number of death threats from animal rights activists.  Jeff perceived PETA and other animal rights groups that opposed the use of laboratory animals as a direct threat to AIDS research.  He was not wrong: at the time PeTA had allied itself with ACT UP San Francisco* a malevolent organization that embraced HIV/AIDS denialism and attacked both HIV/AIDS researchers and other AIDS activists, including Jeff.

The following June, Jeff travelled to Washington DC  to work with Americans for Medical Progress in effectively speaking out against PETA’s anti-research stance, and the hypocrisy of Hollywood celebrities who supported PETA while wearing red ribbons in support of HIV/AIDS research.

He wrote the following commentary for the Wall Street Journal during that visit, and we reprint it in his honor on this World AIDS Day.

Sadly, while the options for successfully treating HIV/AIDS have improved dramatically since 1995 thanks to the efforts of scientists and of activists like Jeff, the animal rights anti-research agenda remains unchanged.

THE TRAGIC HYPOCRISY OF ‘ANIMAL RIGHTS’

by Jeff Getty
The Wall Street Journal, June 13, 1996

Without animal research there will be no cure for AIDS. My life and the lives of millions of people with HIV/AIDS depend on scientists working with animals to develop new therapies.

Every single drug we are taking right now to stay alive until a cure is found has come about only because of animal research. Yet the advocacy group People for the Ethical Treatment for Animals (PETA) says it would oppose any cure for AIDS that involved research with animals.

Such extremists do not simply make animal research a matter of polite debate. One need not look far to find people with HIV or AIDS who have been targeted by the animal rights zealots. When I was fighting for my life in the hospital this winter, I received death wishes from so-called animal lovers. Cleve Jones, founder of the Names Project, received death threats after being a grand marshal for a gay rodeo. Peter Stahley of Treatment Action Group recently said that PETA is a direct threat to his life. He is right.

Using tactics of distortion, intimidation, harassment and in some cases even violence, animal rights extremists have effectively delayed significant AIDS research. Here are some examples:

• AIDS researchers at Stanford University in California were forced to build labs and complexes underground following attacks on university property carried out in the name of animal rights. According to one researcher there, the violent tactics of the animal rights fanatics’ violent tactics have added great costs to AIDS research, slowed certain projects and blocked other AIDS experiments from happening altogether due to high costs.

• Recently, a prominent immunologist in the Northeast who is researching important immune restoration therapies for people with AIDS said that the biggest obstacle to his research was over-restrictive animal rights laws. In his research, this AIDS scientist is transplanting thymus tissue from infants to adults. After transplants are performed on animals, researchers are prohibited from conductnig further biopsies on any of these animals. On the other hand, human study subjects can and will receive biopsies over and over, as needed.

• An animal rights group’s complaint to the National Institute of Health (NIH) about the appropriateness of the xenotransplant I received in December led to an expensive, time consuming paper chase for researchers. The NIH responded that there was no wrongdoing and that the experiment was approved to move forward. This bogus complaint caused people with AIDS needless waste of time and money.

• The Progressive Animal Welfare Society, an animal rights group, targeted a Washington State researcher and successfully shut down, for a time, research involving mother-to-child transmission of simian immunodeficiency virus among macaque monkeys. This work later turned out to be the foundation for treatment of human newborns with AZT to block HIV. How many children are now needlessly dying of AIDS because information that could have prevented their disease was obstructed by animal rights extremists?

Certain Hollywood celebrities like to wear red AIDS ribbons while also supporting groups like PETA. It is time for the hypocrisy to end. You can’t be for AIDS, breast cancer and diabetes research and also support militant animal rights groups.

The only productive research approach is intensive, well-funded biomedical experimentation performed by scientists free to use animals in their work. Contrary to PETA’s rhetoric, computers have not replaced animals for drug safety testing and research. It will be many years before such a computer is ever programmed, simply because we now only dimly understand how the immune system works.

Meanwhile, animal rights groups continue to take donors’ money, promising to fight “for the animals.” In fact, their agenda is to stop all animal research forever, no matter what the human cost. Dan Mathews, an openly gay employee of PETA, has said publicly that he agrees with the group’s opposition to a cure for AIDS if it came through animal research. When asked about the fate of those currently dying of the disease, he said “Don’t get the disease in the first place, schmo.” Dan does not have AIDS, but he has shown that he has contempt for the men, women and children who do.

Many of the cures for diseases that are now long gone and out of the way came from animal research. If PETA had it way 50 years ago, we’d be talking today about hundreds of thousands of people dying from polio, as well as AIDS.

*ACT UP San Francisco should not be confused with the other groups within the ACT UP network who did much and more to raise awareness of the HIV/AIDS crisis, drive forward research on new therapies, and improve access to effective treatment.

Speaking of Research