Some drug development has undergone a transformation this decade. Until now, preclinical studies have mainly relied on two-dimensional cell cultures and animal models, which often do not faithfully reproduce human biology. Since 2023, the US Food and Drug Administration will not require animal testing thanks also to organoids, which Professor Hans Clevers (Eindhoven, Netherlands, 68 years old), professor of Molecular Genetics at Utrecht University, has been researching since the beginning of the century. Last week he was awarded the ABARCA PRIZE, the Doctor Juan Abarca International Medical Sciences Prize. He received EL PAÍS in a hotel in the center of Madrid.
Ask. Let’s start from the basics: what is an organoid?
Answer. As the name suggests, it is something that resembles an organ. They are really small. We create them from stem cells in a culture dish. They constantly grow, divide into small fragments, grow again, divide again and reproduce the key functions and characteristics of an organ. For example, if I extract stem cells from a liver, I create a liver organoid with the main functions of the liver. If it were the lung, it would have those of the lung.
Q. How are they created?
R. We place the stem cells in the right environment, where they feel comfortable and begin to develop fully. Three or four additional components are generally required for each fabric. For example, for the prostate, we need to add testosterone. For breast tissue, estrogen. Once you understand it, it’s easy: you take a tissue, you cut it into small pieces, you put it in a gel, so it’s three-dimensional, then you add the growth factors and that’s how you create the organoid.
Q. Are you working with organoids of all organs?
R. Yes, we originally discovered them in the intestine, where the intestinal mucosa renews itself most rapidly. Every week the entire inside of the intestine is replaced by stem cells. We thought they were really special because of their hyperactivity. This inspired us to try to grow them, and that’s how we created mini intestines, the intestinal organoids. Then we realized that it is actually possible to do this with any organ by experimenting a little with the conditions. There are some organs that we cannot grow, such as the brain, heart muscle, retina and back of the eye, because they are tissues without stem cells.
Q. Many of the steps in drug development using other platforms, animals and cell lines, can be replaced with these human organoid models. Could this mean the end of animal testing?
R. This is what some people think. The FDA (American Drug Administration) has proposed to stop using them in the United States, not to allow us within five years to use more animals for the development of large molecule drugs, which represent about half of drugs. I think he’s too optimistic. Furthermore, the strength of organoids, but also their weakness, is that they are very simple.
Q. Interaction in the whole organism cannot be demonstrated.
R. Exact. If a drug has to be absorbed from the gut, reaches the liver, is modified and then reaches the brain and exerts its effect, how is this modeled? With three organoids? But how do they connect? Surprising and unexpected effects of drugs often occur in organs never seen before. I think organoids can help to be more specific and safer, but I doubt we will ever get rid of the animals completely.
Q. Are there any diseases for which this technology is particularly promising?
R. Yes, cancer. Numerous studies are underway that allow healthy tissue from the lung, liver or intestine to be taken and, using CRISPR, transformed into cancerous tissue. Organoids can be created from tumors, virtually any human tumor. With them we can test drugs and use them for personalized medicine. If I had colon cancer, I could grow my tumor, test it with various oncology drugs, and see which one kills the cancer cells. Even in cystic fibrosis. We have been using it in the Netherlands for about 10 years. We created organoids, and if they responded well, the patient could be cured. It was a simple process: if the organoid indicated it would work, it worked in the patient.
Q. Is it routinely used for this disease?
R. YES. There are around 18 million inhabitants in the Netherlands, around a third of Spain. We have 1,500 patients with cystic fibrosis and 50 new cases are born every year. So the numbers are very small. And they are treated in a few centers, where doctors are highly specialized and know about organoids. So it was quite simple, because we could do everything manually. The same can be done with cancer. Today this process is carried out manually by highly specialized personnel and can take four to six weeks. Several companies are designing machines and instruments that allow the procedure to be performed much faster, on a small scale and with the push of a few buttons, so that any technician can use them in a standard laboratory. The difference is that for cystic fibrosis there were no alternatives. It was an easy decision for regulators. But there are already many truly effective treatments for cancer. So if you propose a better treatment, you have to validate it. And this must also be accepted by the FDA, the EMA (European Medicines Agency) and doctors. So it requires a lot of work. It’s a continuous process, but much slower.
Q. Which cancer types can benefit most from this technology?
R. The most common tumors are those of the lung, breast and colon. Research is being carried out for all of them on organoids, as well as on liver and stomach cancer.
Q. And what is missing for it to reach hospital practice?
R. When you don’t respond to the first line of treatment, nor to the second or third, the doctor usually has some freedom to start using other things. In these cases, organoids could be used.
Q. Do you think this will happen in the near future?
R. Yes, but the machines that various companies are developing are needed. With them it is possible to create organoids and administer drugs. For example, for colon cancer, there are perhaps eight drugs that can be given to a patient. Basically, the machine would take the patient’s tissue, turn it into organoids, test them with those drugs, and deliver a result.
Q. In childhood tumors, with fewer therapeutic possibilities, it could prove very useful.
R. Yes, there are tumors, they are very rare; Sometimes there is one case per year across the country. So now they all end up in one center. We create organoids and there we can learn from them, since we do not know the appropriate treatment for these patients due to their scarcity. And these are usually deadly cancers that devastate young children who suffer from them. That’s why we use organoids to inspire doctors. There are drugs that cannot be tested on children, because there are very few of them, but they can be tested on organoids.
Q. Is there anything you’re researching that you’re particularly excited about?
R. In our pediatric oncology hospital we are creating biobanks of very rare tumors for which, ultimately, we don’t know what treatments to administer to these patients. So we will have 10 cases of this particular disease and 10 of that, accumulated over several years. And then we can start testing. Because there are hundreds of anticancer drugs that have never been tested on these children, but tests can be done on organoids. Now this is something I’m really interested in understanding: these rare childhood cancers, how they start and what can be done to treat them.
We also work intensively with intestinal cells. Ozempic relies on a hormone produced by a very specialized cell type, but there are about 20 others produced in the gut. When you eat, they start to be secreted, they make you stop feeling hungry, insulin is secreted. And this has never been thoroughly studied. Now we are doing it with organoids and perhaps in a few years we will have much more specific knowledge that will allow us to create more perfect drugs. We have also made great progress in the field of infectious diseases.
Q. For example?
R. An interesting case is covid. Two months after its appearance in Europe, we demonstrated that it not only affects the lungs, but also the intestine, through the use of hormones, thanks to the human organoids that we used. Then we started talking about hydroxychloroquine, which worked on standard cell lines in virology laboratories. That’s why it has become so popular. But it doesn’t work on patients. And not even in organoids. So if the virology labs had analyzed the organoids, we could have said, “No, that will never work.”
Q. Could testing animal viruses potentially capable of transmitting to humans serve to prevent a new pandemic?
R. Many viruses come from bats. We can create bat organoids and experiment with them, but governments are afraid to do so because failures could occur and they could accidentally jump to humans.
