Tag Archives: alternatives

All in a day’s work: Scientists promote alternatives

Once upon a time, the medication BoTox (made by a company called Allergan) was tested for its potency, on a batch by batch basis, in living animals. This medication, which is really a protein derived from bacteria, has many important therapeutic purposes. For example, it has been shown to be very effective in the treatment of chronic migraine headaches – a condition that can have disabling effects on those who suffer from it. It is used to treat disorders in which people sweat profusely (hyperhidrosis) or have overactive bladders, both of which affect people’s qualities of life by impairing normal social functioning. It has also been used in the treatment of motor disorders like spasticity and dystonia, preventing the irregular and disruptive involuntary movements that are found in these disorders, thereby reducing the physical pain that is so often a consequence of them. Of course, it has also been used for aesthetic reasons, an arguably less compelling medical use.

BoTox is used to treat patients with spastic cerebral palsy, lesseing the pain they suffer as a result of their uncontrolled movements

Because the potency of individual batches of BoTox produced vary, the Food and Drug Administration (FDA) in the United States required Allergan to test each batch on live animals. For each batch, studies were conducted in which the amount of BoTox that was required to produce a specific toxic effect was evaluated in live animals, and the dose was adjusted to ensure that the potency of the drug across batches could be accounted for (roughly, if the batch was half as potent, this can be accounted for by giving twice the dose, ensuring that clinical effects were stable over time). This testing involved a lot of animals, mostly mice.

However, earlier this summer, the FDA changed its mind. It was approached by an organization that had – at considerable expense – developed a test that could determine BoTox potency just as well as the animal tests – but without involving live animals. The test is conducted on cells in a dish.

The organization spent millions of dollars to develop the test and to petition the FDA to consider this replacement for live animal use based upon its empirical results. They were successful.

Who was this organization? Was it the Humane Society of the United States? Perhaps it was People for the Ethical Treatment of Animals, or the Physicians Committee for Responsible Medicine?

It was none of these. Indeed, since none of these organizations spend their operating budgets on the laboratory research that is required to develop alternatives to live animal studies, it couldn’t have been any of them.

So, who accomplished this? It was Allergan itself. Biomedical researchers at the company who used animals in their tests became determined to find a model system that could replace living animals, and they didn’t stop until they found one. They did this though it came at a huge expense to the company. They were committed to producing medicines that people need and to use the fewest animals in the process, and they accomplished that. As the Allergen press release notes, there have been several attempts, using a variety of methods, over the past two decades to develop a replacement for the LD50 test, but until now all these have fallen short.  A report from a 2008 scientific workshop convened by the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM)  and the National Toxicology Program Interagency Program for the Evaluation of Alternative Toxicological Methods (NICEATM) provides a good overview of many of the challenges involved in delevoling a replacement for the LD50 test, and the different approaches used to address them.

As always, the alternatives that exist for animal use in biomedical science came from the very scientists who are otherwise roundly criticized by the anti-animal research movement. Maybe the irony is lost on organizations like PCRM, HSUS and PeTA, but not on us. At UCLA, our administration has instituted a funding program that provides seed funding to scientists to promote work on refinement, reduction and replacement. What have the leading anti-research groups done? Nothing, but complain. Perhaps instead of criticizing scientists, these organizations should join with us in attempting to discover alternatives and reduce animal use.

Regards,

David Jentsch

The Limits of Computer Simulations

Following on from the last post about the limits of fMRI technology, we will now look further at the limits of another so called “alternative” – computer simulations.

Animal rights groups also argue (Warning: AR website) that advanced computer simulations can replace the use of animals in our research.  This position, again, reflects the poor understanding of what goes into a computer simulation and the limitation of the results.

Simply put, computer simulations produce the results of mathematical models (a set of equations) that investigators postulate capture the basic laws governing a physical system.  We can be successful at simulating how air flows across the profile of an airplane because physicists have developed good mathematical models of how matter behaves at these scales (the field of classical mechanics).   Such physical ‘laws’ are developed by scientists by first observing patterns in experimental data (note the emphasis on experimental) and try to envision a simple set of mathematical equations that could capture these patterns.  The postulated laws are then tested by predicting how systems would behave under different conditions, and experiments are conducted to test their validity.  When predictions fail, it sends scientists back to the drawing board.  It is the interplay between mathematical models and experimental work that allows scientists to refine our models, both in physics and in life sciences.

The Blue Gene Supercomputer was used to approximate brain function

The Blue Gene Supercomputer was used to approximate brain function

Neuroscientists are following on the steps of physicists in trying to come up with mathematical models for brain function.  An example is the successful development of a mathematical theory for the generation of action potentials by neurons, the so called Hodgkin-Huxley equations.  These equations have been successfully tested in a multitude of new experimental paradigms and we now consider it a well established law.  This work, done largely in the squid giant axon, and led them to share the Nobel prize in Medicine in 1963.

As important as this development was, it only provides a tiny amount of information about the workings of the brain.  The brain is composed of around 100 billion neurons, each with approximately 100,000 connections.  To simulate how a brain behaves it is not enough to understand how axons propagate action potentials, we also need to understand how neurons are connected to each other, measure the ‘strength’ of such connections, and figure out how is that each neuron (which is rather ‘dumb’ by itself) can cooperate with thousand of others to perform the computations we take for granted every day, such as reaching out for a cup of coffee, recognizing faces, and so on.  Even if we had full knowledge of the working of individual neurons, we would still not know how a brain really works.  To argue the opposite, would be to argue that just by knowing how a transistor works, we would have full knowledge of how a computer operates.

Science aims at explaining complex phenomena by describing them using a simple set of mathematical equations or laws.  Neuroscientists are building up their knowledge bottom up, by first developing models of how individual neurons work and how they communicate.   From a modest beginning of trying to understand how cells generate action potentials, theoretical neuroscience has advanced tremendously in the last few decades and into a field of itself.  We have reached the point where models of how neuronal populations code for information in certain areas of the brain are being applied to the development of neural prostheses that will allow paralyzed or amputated patients to control artificial limbs.   This work, developed in electrophysiological studies with monkeys, is now being successfully translated into humans.

However, we are still many, many years away at being able to develop models and simulations that capture the working of large neuronal circuits, let alone the entire brain.  As we work towards this goal, the interaction between models and experiments is critical.  We cannot verify the correctness of a model without comparing its predictions to actual data.   As a consequence, both computer simulations and animal work will be required to advance our knowledge of brain function in years to come.

Regards

Dario Ringach

The limits of fMRI

Animal rights groups often argue (Warning: AR Website) that new imaging technologies, such as fMRI, provide an alternative to invasive brain research in animals, accusing those doing animal work of failing to adopt these modern methods.  Such a position reflects a misunderstanding of what these instruments measure and their limitation in studying how the brain works. [More information on the limitations of replacement technologies can be found in the “Alternatives?” Section]

Our perceptions, thoughts, speech and decisions are carried out by a complex network of neurons that communicate through brief electrical impulses about one millisecond in duration (so called action potentials or ‘spikes’).  These electrical impulses allows the brain to perform all its amazing computations in real time, such as recognizing faces, keeping your balance, and understanding speech.  In other words, spikes are the currency of computation in the brain.  To study how the brain is capable of these feats we need, therefore, to measure directly how populations of neurons communicate with each other by means of spiking activity.

fMRI

fMRI

A central problem here is that neurons are very small (their bodies are about 25 micro-meters in diameter) and they are tightly packed together.  As an analogy, consider a football stadium full of spectators.  The problem is akin to developing a method to listening to the conversation of two individuals in the middle of this noisy crowd.  Clearly, without getting a microphone close enough to them, the background noise would make the measurement nearly impossible.  You cannot listen to an individual conversation with a microphone hanging in the middle of the stadium.  The micro-electrode, an insulated wire with a diameter smaller than a human hair, is such a “microphone” that allows us to record the spikes of individual cells in the working brain by getting close enough to the individual cells.

Is there a way to measure the activity of single neurons non-invasively?  The short answer is no.  What about fMRI?  fMRI does not measure neural activity directly, but instead relies on indirect changes in blood flow and volume triggered by modulation in neural activity.  To begin with, one problem is that we still do not know how fMRI measurements relate to neural activity.  Clearly, to be able to understand how fMRI signals relate to neural activity we need to measure both simultaneously, work that will also require the use of animals.  This exemplifies that without animal research there will be no alternatives either.  In addition, fMRI has a limited spatial resolution of about a cubic millimeter.  In such a volume, one can find 100,000 neurons.  In other words, the ‘fMRI microphone’ cannot listen to individual cells, but to a whole stadium full of them.  Finally, we already know that fMRI signals are much slower than neuronal activity, as the time course of hemodynamic signals is in the order of 5 seconds.  As neurons work tens of times faster (you can recognize an image in about 200 ms), the dynamics of fMRI signals are too slow to understand how brains compute in real time.  Instead, fMRI provides useful information about what brain areas might be involved in certain tasks.  After these areas are identified, electrophysiological measurements can be used to measure the activity of single neurons in those areas.  Such a strategy is now proving extremely useful in neuroscience research.

When animal rights activists demonstrate at UCLA carrying a sign stating “Support alternatives to animal research” they don’t need to convince us.  We fully support  and work towards the development of alternative, non-invasive methods.  Their sign is designed to suggest to the public that such methods currently exist and some scientists refuse to use them.   As we explained above this is not true.  Furthermore, the development of alternatives cannot be done without the use of animals.  The relationship between neural activity and the BOLD response in fMRI signals is one example of this process.   Only after such validation takes place, could one then proceed to apply the method with confidence in humans.

Regards

Prof. Dario Ringach (bio)

Animal Liberation Front Press Office become desperate

In a pathetic attempt to be noticed, North American Animal Liberation Press Officer (NAALPO), Jason S. Miller, decided to send an email to a group of researchers, research institutions and pro-research groups (including SR).

In an email containing links to typical AR pseudo-science, misinformation and misanthropic philosophy, Jason kindly explained our future:

Your newly formed “vivisector resistance movement,” as exemplified by Speaking of Research and other whoring shills for your cozy little industry, will quickly sink into the moral cesspool over which it is constructed. Your blatant speciesism, torture, murder, and anachronistic scientific practices are doomed to extinction.

Charming. I must confess I almost feel honored that Speaking of Research gets a mention – could it be we’ve hit a nerve? With animal research helping develop the medicines of tomorrow (fighting swine flu, combating HIV and offering hope for DMD patients) it would seem that such methods are far from anachronistic. I also wonder if Miller has ever seen the inside of a lab? Animal welfare is of the highest priority as you can read in our “Why Animal Welfare Matters” blog post. Oh, and what on earth is a “vivisector resistance movement”?

The Vivisector Resistance Movement?

The Vivisector Resistance Movement?

So who is this Jason Miller? Other than a member of NAALPO, an organization which reports on the violent actions of the Animal Liberation Front and the Animal Rights Militia, Miller is the founder of the “anarcho-veganist” website, Thomas Paine’s Corner (TPC):

[TPC] approaches anti-capitalism and total liberation from an essentially anarcho-veganist position, as portrayed in the graphic above by the juxtaposition of the Boy Scout–a victim of one of the indoctrinating mechanisms for our imperialist, patriarchal, faux Christian, corporatist, statist, speciesist society–against the anarchist symbol.

TPC Logo

It’s only missing “military industrial complex” and “marxism” to complete the hand (no, wait, there’s sections on the website for both of those…). Miller’s email might also have something to do with us ignoring his last hissy-fit written on TPC. Talking about the UCLA Pro-Test rally:

In that nauseating spectacle the unapologetic monkey-torturer, David Jentsch, and industry shill Tom Holder, the “founder” of Speaking of Research and a “founding member” of Pro-Test in the UK, whipped a crowd of adoring sycophants into a frenzy with a chant calling for animal testing.

Having seen some of Prof. Jentsch’s vervet monkeys I was impressed at the high standards of welfare – as well as the personal care and responsibility that Jentsch felt towards his animals. A far cry from Miller’s claims of “monkey torture”. However Miller falls into the mistaken belief that we could switch to “alternatives” tomorrow:

We have multiple other means by which we can advance our medical and scientific knowledge, including epidemiology, clinical testing, autopsies, biopsies, genetics, post-marketing drug research, computer modeling, tissue cultures, microdosing on human animals, personalized medicine, and nanotechnology

Check the “alternatives” page for scientific a deconstruction of this argument. A few intersting choices in his list – much genetics are  studied in animals, particularly mice, where you can “knock out” a certain gene to see its effect on the animal and thus the phenotype of the gene. Such work offers hope to sufferers of genetic conditions such as Cystic Fibrosis and Duchennes Muscular Dystropy. Biopsies are done on animals except the animal rights movement tends to rebrand it “vivisection”. Personalized medicine is an ideal which will certainly require animal research in its creation. The fact is these methods are complementary on animal research, not alternatives.

Well Jason, I hope you’ve learnt something – and please stop emailing large groups of people to make spurious and misanthropic claims about the research you appear to know so little about.

Regards

Tom Holder