'Non-invasive measurement in humans is the new Holy Grail'
'In the Healthy Living unit, we look at lifestyle-related diseases, such as metabolic imbalance. What are the processes that cause diseases, and what can be done about them? We also look at people’s behaviour, as many conditions are related to lifestyle. Biomedical research has traditionally involved the use of laboratory animals. Our long-term ambition is to do more medical research involving human subjects, so without using animals, obviously without exposing test subjects to any risks.'
Peter van Dijken, director of the Healthy Living unit at the Netherlands Organisation for Applied Scientific Research (TNO), has a degree in chemistry. Before joining TNO, he worked in the business sector for the multinational Procter & Gamble and for Pepscan, an innovative company in the biotechnology industry. Economic and social interests intersect at TNO.
“Our work in the Healthy Living unit is aimed at improving people’s health and employability. We look at the bigger picture, as we want to help young people in the Netherlands grow up in good health and become productive labour market participants. But we also work on interventions to facilitate a healthy lifestyle, and we look at disease and health from the perspective of human physiology. To me, the most interesting aspect of working for TNO is helping the business community increase its innovative prowess to achieve social benefits. We support existing companies and start-ups until they are really large scale, at which point TNO’s involvement come to an end. We are, after all, a knowledge institution. For example, TNO supported the establishment of companies like Batavia BioSciences and Dutch DNA and also played a role in the founding of IntroGene, later renamed to Crucell and now known as Janssen Vaccines.”
According to Peter, research without the use of laboratory animals is unfortunately not yet universally possible. Therefore, we are not fundamentally opposed to animal studies, which we use to gain insight into disease processes in order to facilitate the development of safe and effective medicines. “But in addition to our laboratory animal research, we are doing a lot of work on developing animal-free models, such as computer models, organ-on-a-chip technology and ex vivo models, which can improve and accelerate the development process for new medicines and other health interventions. For TNO, it’s essential to know for all preclinical models which parts of the human physiology are adequately mimicked by these models and which are not.”
“TNO has a long tradition of reducing the use of laboratory animals, refining animal studies and replacing animal studies by other methods. In this context, we have developed a number of in vitro models in the area of kinetics and metabolism. In this same area, we started working on the development of microtracing combined with accelerator mass spectrometry (AMS) around 10 years ago. One of our senior scientists put forward the brilliant idea to use AMS technology in medicines development. To be honest, our main focus was on driving innovation in areas of medicines development. But I’m obviously happy that we soon recognised that this technology would remove the need to use laboratory animals in this area. This technology was developed for radiocarbon dating, for which Libby was awarded the Nobel Prize in Chemistry in 1960. In radiocarbon dating, the age of objects is determined based on the amount of radioactive carbon-14 they contain. This method enabled scientists to establish the age of the glacier mummy Ötzi, for example. Radiocarbon dating makes use of mass spectrometry, a versatile technology that can assist in the identification, quantification and profiling of isotopes, molecules and molecular complexes present in tiny amounts of chemical and biological mixtures.”
“The development of our AMS technology, which builds on the knowledge originally developed by Libby, involved an investment of 2.5 million euros with a long preparatory stage. The fact that a number of large pharmaceuticals companies have become convinced of the significant benefits of this technology is a huge breakthrough. This will create a real transition in the workflow of pharmaceutical companies. The benefits are enormous, as this method enables them to avoid delays of up to two years.”
New Holy Grail
“Microtracers are formulations of a drug candidate with an extremely low radioactive dose. The extremely low radioactive load makes it possible to safely conduct legally required safety studies into the bodily distribution and drug metabolism of drug candidates in humans. This provides information on the drug metabolism of medicines in humans at an early stage, reducing the need for animal studies and making them more efficient.”
“It’s a combination of cutting-edge technologies. The accelerator mass spectrometer, a kind of mini CERN, is a machine capable of performing extremely sensitive measurements of individual atoms. This provides a clear view of the impact of medicines in the human body, even when they are administered in extremely low doses. This technology also helps us safely determine the required dose of a particular medicine for children. That is currently very difficult, as medicines are not tested on children. For example, you cannot simply calculate the required dose for a baby on the basis of its body weight alone, because most of the test subjects in the clinical trials were young men. Non-invasive measurement in humans is the new Holy Grail.”
“As we now have insight into drug metabolism in humans at an earlier stage, we no longer have to use laboratory animals in radioactive metabolism studies. That means we can reduce the use of animals in this type of research into metabolites.”
Source of inspiration
“Together with Leiden University Medical Centre (LUMC) and HU University of Applied Sciences Utrecht, we are now working on an instrument to help institutions benchmark their innovations in the area of animal-free medical research. This Beyond Animal Testing Index will serve as a transparent, objective and independent benchmark against which the efforts and performance of public research organisations in this area can be assessed. It will give organisations and their stakeholders better insight into their opportunities and the progress they have made towards research that goes beyond animal testing. This benchmark is inspired by the Access To Medicine Index. Three Dutch university medical centres are currently working on the first version of the Beyond Animal Testing Index. Another great initiative is VitalTissue, which helps to provide vital residual human tissue to researchers in the Netherlands. Conducting research with this tissue enables us to gain more insight into the workings of the human body in health and illness. This can help to accelerate and improve the development of new products, including medicines. For example, this could involve research into the safety and efficacy of medicines.”
“At TNO, we particularly focus on developing screening models for kinetics and metabolism and disease models for non-alcoholic fatty liver disease (NAFLD). This disease is the reason behind most of the liver transplants in the Netherlands. Together with clinical centres, we also do research on the diseased livers removed in these operations, which are then kept viable for some time outside the body (ex vivo).”
Continue to invest
“While the COVID-19 pandemic has caused a lot of misery, I also see some positive effects. Only minimum animal studies were carried out to obtain market authorisation for the recently developed vaccines. The pharmaceutical companies handled this well. There was no time to run numerous animal studies. Moreover, due to the urgency of vaccine development, it was possible to organise regulatory processes differently. This also shows that we will have to continue to invest in innovation. The current regular funding will not suffice. If you want to foster certain types of research, there needs to a firm prospect of future funding to keep this research going. And you need to be willing to accept that research can end in failure. Because failures can actually offer a lot of lessons.”