Prof. Thomas Hartung – former head of ECVAM, currently Professor at the Public Health Faculty of Jhon Hopkins University in Baltimore
The presentation of Prof. Hartung at the Conference held at Palazzo Montecitorio for the 30 anniversary of LIMAV – Analysis and proposals for alternative methods of scientific research specific-species:
“Good morning and than you for the invitation to speak. I know my Italian took a bit of rust after past last eight years out of the country, but coming back in Italy is always a great pleasure for me: we used to pass, every years, summer time at Lake Maggiore where I worked with the European Commission for eight years.
When I arrived in Italy in 2002, I was a young pharmacology professor, and we used animals. We also used cells, patients and healty people too, to test the different substances.
We know very well that animals give only a small contribution to information, but so many different experiments, give us an idea about what works or what doesn’t.
The very important thing is that 97% of experiments that give a positive results in animals, fail in humans. Think about it: 97%! This is already a demonstration, but there are also so many studies on substances that are almost identical!
Probably, the percentage of success in humans about substances that work very well in animals, is 2%. And this is almost the normality in our job.
When the European Commission offered me the Alternative Validation Center’s responsability (ECVAM), I considered that like a great chance. It really was an opportunity to change something in our field. And I was positively surprised about the interest for toxicology.
The issue was obviously about cosmetics which made their Big-Bang exactly when I arrived.
The project to ban animal testing for cosmetics was really an opportunity for development alternative methods.
For the last 15 years also the REACH program has been developed to test 40.000 chemicals (currently on the market). These are very huge projects who rapresent the opportunity for new scientific approaches in order to develop alternative methods.
It is important to note how little is the knowledge about these substances. We have more or less 100.000 chemical substances in products we habitually use and about 3.000 have been intensively used as drugs or pesticides; 10.000 substances have been tested and 90.000 are not tested at all: there is no public data. This means that understand what we put into our food and what we find in products that we usaullay use, has to be our primary goal.
Since the beginning, I understood that the result that was expected from me was the introduction of a new methodology, principally because of ethics.
In the fileld of ethics, Europe is really one step ahead compared to all other countries. Since 1986 we have in Europe a legislation that says: If an alternative method exists, without using animals, we must use it. No other country has a similar legislation.
Now I am a professor at Johns Hopkins University in Baltimora. In U.S. we have a law for animal protection unmodified since 1967 and legislation says that 90% of the animals we use in the lab are not protected. In the United States, a child, at school, can use animals in experiments without restriction, and this is what really happens.
This already means that we are lucky, because in Europe we have been a legislation ffor more than thirty years, which establishes a stronger protection for animals. We did not get to the goal, but something was done.
Indeed, the development of alternative methods has started before the ECVAM. What I have prepared during the years at ECVAM’s management was a method change. There are many things we have to cut or abandon completely. Animal experiments belong to these, not only for ethical aspects. The ethical aspect, however, is important.
It is so clear to me that a person who execute unnecessary experiment on animals, it’s just insane. I am a doctor and I can’t accept unnecessary, unscientific uneconomic cruelty, let me say to my colleagues.
I also want to emphasize that exists some economic aspects, beyond ethical and scientific.
Animal experimentation is a method that is too expensive and takes long time. An animal experiment to test whether a chemical is or not carcinogenic, costs 1 million euros. This is the amount to test only a substance! And in takes four years to get results! This method does not produce the necessary information quickly in order to choose the right substance for our products.
In this way, we tested only 3.000 substances out of 100.000 that are currently on the market, but this is just one aspect of the issue: the information we have obtained is valid for rat cancer, for mouse cancer but not for human cancer.
If we do the same experiment with mice and rats to test a substance for cancer, we only have 57% correlation between the two species. Only 57% in mice and rats which are genetically very similar, while human is very different!
However, no one says that one of these results is better, more predictive of what will happen to human; human reaction can not be predicted.
This leads us to believe that there are ethical and scientific, but also economic aspects.
We can not test 100.000 substances by using this method: we have no time! We can’t wait so long and moreover the results obtained with this method are uncertain.
Certainly a little knwoledge about rats cancer is better than no learning at all, but that doesn’t mean that we know what we need to know.
My first lesson was that animal experimentation is not a reference point for human, due to uncertainty of the results obtained. The modern methods we are developing, are better than this.Over the last 15 years the researchers vision has changed.
We could understand the limits of animal testing thanks to databases, wich demonstrate the uncertainty of data obtained with animal experiment. One of these banks was created by ECHA, the European Chemicals Agency in Helsinki that is holding by REACH.
Europe’s REACH regulation is a huge advantage for us: it is the first worldwide legislation able to publish the main chemical substances validation results: we now have a database of the top 10.000 registered chemicals: these substances have been tested on animal 800.000 times. Imagine! 800.000 different studies for 10.000 substances!
In this new situation we could analyze the reproducibility of animal tests. One of the most known experiments in toxicology is to put a chemical on the rabbit’s cornea. This is terrible for rabbits, but it was the ordinary method used in tests and it was introduced after a dramatic event that triggered a reaction in public opinion: in 1930 there was a scandal in the U.S. due to a chemical contained in a cosmetic product (p-phenylenediamine) that caused 3.000 cases of “unexpected” reactions: five people went blind and a person dead. The consequence of these events was that FDA after the promulation of a new law, introduced tests on rabbits.
John Draize, a researcher, developed a method by using 1930’s technology and devised Draize Test in 1943, that is courrently used.
The first thing that scocked us working with the database was finding over-use of animal tests: 2 substances had been tested over 90 times on rabbit’s eyes! Another 69 substances had been tested more than 45 times; this is a tremendous waste of animals, a completely unnecessary damage! Why does this happened? Because no one knew that someone else had already done the same test.
Don’t forget that before the 1980, each substance had to be registered in each countries providing experimental data. Fortunately, a German company, registered a product in Germany, France, Italy and England and it was not necessary to produce experimental data in all the countries because the results of the owner country was accepted. This was one of the great steps forward. Now we have the Organization for Economic Cooperation and Development (OECD). In 1980 a new principle was also established: the acceptance of quality data.
In ECHA database we found that for 3.000 substancmore than 9.000 tests had been conducted on rabbit eyes.
Moreover, we mustn’t underestimate the importance of psychological aspect: if a substance has had a positive result, this may lead us to think that that method is correct. The restult is that huge damages are produced and the reproduction of the same tests several times.
This habit, useless and damaging, provided us the argument against animal experiments. By repeating the same experiments, only a percentage of 70% has the same result; a percentage of 20% has a lower effect and a percentage of 10% has no effect.
This is the reproducibility of an experiment, if repeated. This is a very important step, also because it represents what we want to replace.
Since 1990 we found methods with a reproducibility of 85%. but the required percentage was at least 90%. We must reproduce, but experiment on animals are not reproducible, and this is what we understood over the last few years.
Converserly, chemical methods in toxicology, are more reproducible than animal experimentation.
Now, with quality control we can compare animal experimentation with chemical methods. We have something very standardized about the effects of exposure to high doses of chemicals. We don’t need a disease to do new study and research. Also in the field of pharmaceuticals there is the same issue.
There are 2 very important studies published in REACH in 2011 and 2012. In 2011, a team from Bayer analyzed the percentage of studies taken from scientific publications in order to examine the degree of reproducibility of experiments: well, a percentage from 25% to 75% of published studies didn’t work! Only 20 to 25 percent of the studies they tried to reproduce, came to results “completely in line” with those of the original publications.
Even worse, in 2012 a US firm analyzed 53 publications that are really considered very important for cancer’s research and only 6 out of 53 studies (11%) were reproducible!
This means there is a problem we call “reproducibility crisis“.
There has been widespread debate among the researchers about means and the quality control, still considered not effective enough. This is the reason why in many other countries we are now trying to improve quality controls and this is a very important for us because it may opens the door to new methods that are better controlled, of better quality and were no animals are needed.
If there are fools that prefer don’t use a concrete opportunity, then we need to open an objective debate. We must avoid to discussing the ethical aspect, because we can have different values and a child’s life may seem more important than animal’s life. But quality is indisputable: data are objective. If something is not reproducible, it is not scientific.
We have developed in Italy a program named “Evidence-Based Toxicology“. This is a evidence-based medicine that is a revolutionary model, who use objective and transparent methods to developed means that can lead us to decide if a new treatment is better than the traditional, or not.
A renowned researcher says that using genuinely objective data, is the right way. We organised the first Conference in Lake of Como in 2007 with 170 experts and researchers. We developed the idea of ”evidence-based toxicology”.
Two years later, I received a prestigious invited from JOHN HOPKINS, one of the best universities in the world. An university of only 20.000 students with 10 billion turnover, and the first chair for Evidence-Based Toxicology was created at Johns Hopkins in 2009. I’m so proud the EBT idea has been institutionalized by major agencies in the last 8 years. Converserly, when I left the European Committee European, nobody wanted to continue in that direction.
Today we work with EFSA, the European Food Safety Authority in Rome where I am the Vice-President for the Evidence-Based Toxicology collaboration. We organize events also in collaboration with EPA FBA. EBT method has become a new standard. It is an objective approach, that leaves out any other aspects and relying only on the facts. This is very important for the change we want: objectivity.
The third lesson was that we also need to increase cell experimentation: these are young technologies and we still have so many limits, so many artifacts and the quality control of cells is a very important project. We have created a system to check and realize good quality reports about cellular methods. The project had a stop but were resumed two years ago. We also started an international collaboration and we are working on the new statute of stem cells. Today we are able to reproduce organs and tissues of the uman body: not only cells, but also tissues with functionality and organ-architecture. This was my fourth lesson: we must use new technologies to create organs and human tissues. Always checking the quality.
Another very important opportunity that is the power of computers. Computational toxicology is really impressive, but we need big data. As I’ve already said, we have created a database that is now the biggest in the world. A year ago there were 10.000 chemicals tested and 800.000 studies! Today we have a very large database with 70 million structures: 300.000 have biological data and 20.000 of these have animals data.
We are now able to analyze them: for a substance that has no data, we can look for similar substances that have data. I did not believe it! But my student demonstrated me in his thesis, that chemical approach works at same level of quality of animal experimentation. We are making progress. Today, we are able to identify toxic substances in 80% of cases, better than animal experimentation. This method is working for more than 70% of chemicals and this percentage is growing with the growth of our database: in this way, it was possible to start a partnership with a non-profit company in the United States. Something very similar has happened in Germany, the Netherlands and Italy. These organizations pursue the objective of create a standard for security and then testing and evaluating each tested product. I hope so much, because they don’t have a product to sell, they only have to search for security.
In just seven months, we have created a product that is now available on the Internet. You can write the formula of the first substance that comes into your mind and get the result, which is required for REACH 2018 registration. We can therefore predict whether a substance will be useful or harmful. The main toxicologist of the American Chemical Society Association said that thanks to these results, he will no longer do experiments on animals! Moreover, the cost is much less than the animal experimentation!
And this is just the beginning, because we can now spread to public and teach to students about this program. Furthermore, companies can use, behind a firewall, the same program. And this shows the impressively progress managed in our field.
In the field of organ culture, in example, a year ago, we shown our project. We have beautiful images that show how, starting from a patient’s stem cells, we’ve got a human mini-brain, of the size of a fly eye. Visible, albeit tiny, but functional: the nerves communicate at the neuro-electric level, so that we can record the communication. There are also cells that help these nerves. For experts, this really creates a brain architecture, built in the lab. This is very important. We have standardized this process and we can create millions of these cells that cost very little, less than an animal. This mini-brain is a human model now really available.
It takes about a year to introduce this technology into a new lab, former the reasercher, but now we have a Hopkins firm, that’s named Organ. We want to make these cells available, in order to compare cells of healthy person with those of a Parkinson’s case.
Nobody has now a valid reason for continuing use animal-based model instead human-based model. There is a development at the level of technology that really produced a leap in quality. This development is based on human cells and computerized research. Today we have computers whose power is growing steadily, but there is also a change due to two remarks we have put and understood. We have created objective validation method instead of subjective method.
These new methods and new technologies together with a new mentality, create synergy. And I am very optimistic: there is a real change and all that we have been expecting for so many years, will be realized. This will be the achievement of a long-term project. We will have a true change in a future, now not so far.
Thank you allof you, I hope my Italian has been comprehensible. Thank you.”