Inverview with Hans Clevers - summer 2015
Hans Clevers, ERC Advanced Grant
Hans Clevers grows organs in unique lab
Doctor and microbiologist Prof Hans Clevers has attracted countless research grants. His lab at the Hubrecht Institute is now world famous. The ERC even awarded him a second Advanced Grant. Clevers' team had already discovered stem cells and succeeded in culturing them outside the body. The team has now embarked upon a wide-ranging study into the role played by various bacteria in the development of intestinal diseases. They are also looking for answers to the question of why our immune system fails to leap into action when a tumour is forming. For the research, the Clevers Lab is using home-grown mini-intestines, known as organoids.
Prof Clevers has been given more or less carte blanche by the ERC. "We are now in a unique situation. We can grow mini-intestines and cells from other organs and have been given access to the 300 types of bacteria collected in a biobank by researcher Jeffrey Gordon of Washington University. Moreover, we have the technical know-how to chart cell development, enabling us to see what happens when bacteria infiltrate a healthy intestine. We are also investigating what happens when the stem cell division gets out of control and a tumour forms. Why doesn't our immune system spring into action then? We want to zoom in on this aspect and study it more closely."
From his work in immunology, Clevers' method is to study the healthy tissue first, before looking at the diseased tissue. This allows researchers to build up a thorough picture of the proper system before you study the deviations. More and more researchers all over the world are adopting this approach.
The scope of the ERC study is huge and Clevers is progressing in leaps and bounds. "Because we are growing cells from intestines and other organs outside the body, we don't need to carry out any animal testing or human clinical trials. We perform large-scale in vitro research in our lab, which also enables us to study the influence of two or three types of bacteria jointly on various types of human organ cells, for example. The computer processes all the data for us."
Influence of bacteria in our intestines
The research is set to reveal a great deal of useful information. "The use of probiotics and the like is not based on much actual knowledge. We are only just starting to unravel the real influence of various types of bacteria on our intestines. Our aim is to discover exactly how this works and to develop effective medication against the ensuing diseases." One particularly positive aspect of the research in Utrecht is the study's broad scope. "Most researchers focus on a single disease, for example Crohn's disease. But we are studying the entire system in which all kinds of diseases occur."
Clevers is glad to be back working in the lab after his years as president of the Royal Netherlands Academy of Arts and Sciences (KNAW). "The Hubrecht Institute is organised very horizontally, which means we can actually get down to hands-on research. My research team has now grown to 40 researchers, most of them young, from more than 15 countries. Five of them have already been awarded an NWO grant." Clevers proudly opens his laptop to show a film of an organoid. "These are the descendants of a single intestinal stem cell. You can see them dividing. Here they are creating a tiny cross-section of intestine." The stem cells are labelled. "We can return the tissue, transplant it into a mouse, where it is accepted and remains healthy. Just imagine that it the future we could do this in humans too, culture their own liver cells and transplant them. Or a kidney, skin, a lung."
Tumours switch off our immune system
Clevers looks contentedly at the dividing cells. "Besides bacteria, we are also studying how tumours form. It is normal for the intestinal epithelium to renew itself every four days. But sometimes the stem cells get out of control and division increases sharply. One tiny error in replicating the DNA during division is followed by yet another and another and, before you know it, the person has developed a tumour."
This takes us back to immunology. "We used to think that the development of cancer had nothing to do with our immune system since, after all, cancer is formed from the body's own cells. But now we know better. Tumours have found the switch to disable our immune system – that much is clear. So we need to protect that switch. One researcher, Jim Allison – who in my opinion is worthy of a Nobel Prize – has discovered that it is possible, in theory. A test involving melanoma patients revealed that 15 per cent of them were still cancer-free after six years. We are now investigating how various so-called 'checkpoint regulators' interfere with our immune response during the development of tumours and what we can do to counter this. When does our immune response fail? Is there more than one on/off switch?"
Clevers will soon also be able to predict whether certain types of medicine will work for a particular patient. Major treatments such as chemotherapy are very expensive and, for many patients, turn out to be ineffective. "Now we can culture the patient's cells to see whether the treatment will be worthwhile." Personalised medication lies within our grasp, but perhaps we can go even further. One statement by Prof Clevers continues to resonate: "Just imagine if we could succeed in getting our own immune system to attack the tumour."