Serendipity and Animal Research

Dr. Alberto Ferrari is a member of the managing board and of the scientific Committee of Pro-Test Italia, an association dedicated to correct scientific information on the topic of animal research in Italy. He has a Ph.D. in molecular medicine; during his training he has worked on animal models of psychiatric disorders. Currently, he is specializing in biostatistics and collaborates with the unity of medical statistics at the University of Pavia, Italy.

Animal experimentation has always drawn criticism from an ethical standpoint; but while concerns about animal welfare or good laboratory practice are legitimate (if not always easy to agree on), we know that the position of those who deem animal testing useless or dispensable from a strictly scientific point of view is much less acceptable.

“Scientific” criticism of animal experimentation deals mainly with the ability of animal models to be predictive of human responses to drugs or other therapeutic treatments. Clearly, attacks of this kind are mostly deceptive, and there is no way that they can justify the request to abandon animal research tout court. Despite the fact that in some cases animal models might fail in predicting undesired responses, in many other cases they do predict potential outcomes and help in this way to refine the candidate treatment or drug. It has to be acknowledged that critics are right in saying that this predictive ability is less than perfect, which means that animal models are to some extent heuristic. And this is precisely what scientific research is. Most of the time, scientists do not know what will come out of their next experiment. Well, why would they experiment at all, if they already knew the results?

As scientists, we should not be ashamed of admitting the role luck has in our work. As the headline of a 2008 article on the Financial Times said, “drug research needs serendipity”. We hope that the scientific community will be able to reduce the role of chance in drug discovery more and more as time passes; but in the meantime, we should not fall for the tricks of pseudoscientific propaganda, which would like us to believe that the need for serendipity neutralizes the importance of the scientific method, reasoning and modelling. Indeed, it is quite the opposite.

“God helps those who help themselves”, and the awareness that we need a little luck to succeed doesn’t exempt us from researching, hypothesizing and experimenting. Winning the lottery needs luck, but if you wish to win, you should at least buy a ticket. There are a lot of interesting cases of drug discovery that required serendipity to happen; but in most of them, good chance met with the brilliant minds of researchers ready to understand what was facing them and to grasp the opportunity.

A few examples of drug discovered by serendipity are chemotherapeutics, such as Metothrexate and Cisplatin; the immunosuppressant Ciclosporin, used to prevent rejection in organ transplantation; antidepressants and mood stabilizer drugs, such as Imipramine and Valproic Acid; and antibiotics, including Streptomycine and, most importantly, Penicillin, the first discovered antibiotic in history. All of these discoveries were made possible by a stroke of luck. Nevertheless, they all happened in the context of research laboratories. As an example, I will deal shortly with the case of a serendipitous discovery that is particularly interesting when it comes to talk about animal research: the one of benzodiazepines.

My education as a neuroscientist has made me particularly aware of the importance of benzodiazepines, but I believe it would be safe to assume that almost everyone has used benzodiazepines once in their life, or knows someone who has.

Benzodiazepines are a class of drugs that act as anxiolytics, hypnotics, muscle relaxants and anticonvulsants. These properties allow for a range of different therapeutic uses, from treatment of epileptic seizures, to alcohol withdrawal, to insomnia. Still, their most widespread application is in the treatment of anxiety disorder.

Before their discovery, the drugs of choice for the treatment of anxiety or sleep disorders were barbiturates. Barbiturates have a mechanism of action akin to benzodiazepines (they act on the same receptors in the central nervous system), but they are much more powerful. One could say, too powerful: a barbiturate overdose can easily lead to death by respiratory arrest. Indeed, when their use was more common, they were quite often used to commit suicide: Marilyn Monroe is perhaps the most famous victim of barbiturates.

In contrast to barbiturates, benzodiazepines have a higher therapeutic index (they are much safer), they don’t interfere with sleep patterns and liver metabolism, and they are less prone to cause addiction. In fact, given all of these advantages, it’s very common nowadays to find a small bottle of Valium or Xanax in one’s medicine cabinet.

The history of these valuable medicaments is quite bizarre, serendipitous … and it involves animal testing.

The man credited with the discovery of the first benzodiazepine is Leo Sternbach, a, Croatian-born Polish-American chemist of Jewish origin. In the 1930s, Sternbach had been working in Poland under the supervision of Karol Dziewonski; during this period, he studied the synthesis of a compound called hept-1,2,6-oxodiazine. Unfortunately, the social climate in Poland in those years wasn’t very comfortable to Jews, thus, in 1937, Sternbach moved to Switzerland where he started working for Roche. Out of caution, he left again in 1941 for the USA, and there he continued his research. It was at the Roche labs in New Jersey that, in 1954, about 20 years after he had first dealt with hept-1,2,6-oxodiazine, he decided to further explore its pharmacological properties. He synthesized about 40 derivatives of the compound in the hope of finding among them a potential drug with tranquilizer properties, an aspect that pharmaceutical companies were very interested in at the time.

His method can be summarized effectively as random screening, but we should not be surprised by this: at the time drug design as we know it these days was pretty much science fiction; back then, pharmaceutical companies used to evaluate vast libraries of compounds in generic screenings, in search for drugs with the properties they were interested in. Sternbach just sent all of the chemicals he had produced to the Roche pharmacology labs for animal testing. Unfortunately, all of them proved pharmacologically inert, and that line of research was abandoned.

That was until 1957, when, during a lab clean-up, he noticed one of the compounds he had synthesized had been forgotten on the shelf. He sent it to pharmacological testing, without any great expectation about the results.

But a big surprise was waiting: the compound, chlordiazepoxide, had hypnotic and sedative effects in mice, it was a powerful muscle relaxant in cats and showed a taming effect on monkeys. More preclinical analysis was carried on, until, in 1958, clinical trials started. Not only did the drug show a clear anxiolytic effect, but also caused no detectable clouding of consciousness (a common side effect of tranquilizers at the time). The compound in question, a benzodiazepine, was sold under the name of Librium, and it was the first of many of its family.

Once the first compound of the class had been discovered, it paved the way for a series of even more effective tranquillizers with a similar chemical structure. Nowadays, benzodiazepines are among the most widespread psychiatric medications, and as we have mentioned before, they are important in the treatment of a series of different conditions, including, but not limited to, anxiety and insomnia.

This story stimulates a couple of very interesting reflections:

Firstly, we should notice that one of the greatest successes in drug research was indeed highly favored by chance. But as one of the fathers of modern medicine, Louis Pasteur, said: “In the fields of observation, chance favours only the prepared mind”.

Librium’s discovery was surely favoured by chance, but first and foremost, it was made possible by scientific curiosity. The research that had led to the synthesis of hept-1,2,6-oxodiazine and its derivatives was purely speculative in the first place, and the screening method was highly heuristic. Chance? Yes, Sternbach probably won the lottery. But he could achieve that since he had bought lots of tickets, otherwise he would not have won anything.

Secondly, all of this was made possible by animal testing.

In spite of those critics who claim that, due to interspecies differences, no inference on the effect of a drug on humans could ever be drawn from animal testing, benzodiazepines have shown practically the same properties on all the species they were tested on.

Was it just a lucky event? Was it just an extreme coincidence? This is what some animal right activists claim. But if that was the case, we should admit that it was a highly unlikely coincidence. And the history of medicine is full of such unlikely “coincidences”.

What is beyond doubt is that without a little serendipity, most biomedical research would not have accomplished results able to impact human health as deeply as benzodiazepines, or chemotherapies, or many other drugs. But let’s not forget that this also holds the other way around: without research, method and scientific curiosity, chance alone would be totally useless. We may have been lucky in finding out the interesting properties of Librium, but chlordiazepoxide was not going to pop out of the soil by itself.

It is becoming more and more common to hear critics of animal research attacking not only routine animal testing, but also the use of animals in basic research or in heuristic modelling. It happens more and more to hear that basic research is “pointless” because it so “rarely” leads to meaningful improvements in human health.

I am not going to call into question that the discovery of a cure for cancer is not an everyday happening; but we must be aware that successes are not going to become more common if we stop research. It should be self-evident that this kind of criticism, if deemed acceptable, would end up proving too much. Indeed, if scientific curiosity is “pointless”, if not making a groundbreaking medical discovery every other week makes the search for knowledge “pointless”, then it is not just animal research that is on trial here: scientific and medical research in their entirety are accused of futility.

But could we honestly think that biomedical research has not led to any meaningful improvement in human health? Could we seriously believe such a thing, while having a bottle of Valium in our medicines cabinet?

As far as I am concerned, the answer to this question is no.

Dr. Alberto Ferrari


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