The development of some drugs has undergone a transformation this decade. Until now, preclinical trials relied primarily on two-dimensional cell cultures and animal models, which often failed to accurately replicate human biology. Since 2023, the U.S. Food and Drug Administration (FDA) has not required animal testing, thanks in part to organoids, which Hans Clevers (Eindhoven, 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 Doctor Juan Abarca International Award in Medical Sciences. He met with EL PAÍS at a centrally located hotel in Madrid.

Question. Let’s start with the basics: what is an organoid?

Answer. As the name suggests, it’s something that resembles an organ. They’re really small. We create them from stem cells in a culture dish. They grow constantly, divide into small fragments, grow again, divide again, and replicate 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 a lung, it would have the functions of the lung.

**Q. **How are they created?

A. We place the stem cells in the right environment, where they feel comfortable and begin to fully develop. For each tissue, we typically need three or four additional components. For example, for the prostate, we need to add testosterone. For breast tissue, estrogen. Once you understand that, it’s easy: you take some tissue, cut it into small pieces, place it in a gel so that it has three dimensions, and then add the growth factors, and that’s how you create the organoid.

Q. Are you working with organoids of all organs?

A. Yes, we originally discovered them in the gut, where the intestinal mucosa self-renews most rapidly. Every week, the entire inside of the gut is replaced by stem cells. We found them very special because of their hyperactivity. That prompted us to try to cultivate them, and that’s how we created the mini-guts, the intestinal organoids. Then we realized that, actually, you can do it with any organ by experimenting a bit with the conditions. There are some organs that we can’t cultivate, such as the brain, the heart muscle, the retina, and the back of the eye, because they are tissues that lack stem cells.

Q. Many of the steps in drug development that use other platforms — animals — and cell lines can be replaced with these human organoid models. Could this mean the end of animal experimentation?

A. That’s what some people think. The FDA has proposed that we stop using them in the United States, that within five years we will no longer be allowed to use animals for the development of large-molecule drugs, which account for approximately half of all medications. I think that’s overly optimistic. Furthermore, the strength of organoids, but also their weakness, is that they are very simple.

Q. The interaction cannot be verified in the whole organism.

A. Exactly. If a drug needs to be absorbed by the gut, reaches the liver, is modified, and then reaches the brain and exerts its effect, how do you model this? With three organoids? But how do they connect? Surprising and unexpected drug effects often occur in organs that have never been observed before. I think organoids can help us be more specific and safer, but I doubt we’ll ever completely get rid of animals.

Q. Are there any diseases for which this technology shows particular promise?

A. Yes, cancer. Numerous studies are underway that allow us to take healthy lung, liver, or intestinal tissue and, using CRISPR, transform it 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 own tumor, test it with various cancer drugs, and see which one eliminates the tumor cells. The same applies to cystic fibrosis. We’ve been using it in the Netherlands for about 10 years. We created organoids, and if they responded well, the patient could be treated. 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?

A. Yes. The Netherlands has about 18 million inhabitants, roughly a third of the population of Spain. We have 1,500 patients with cystic fibrosis, and 50 new cases are born each year. So the numbers are very small. And they are treated in just a few centers, where the doctors are highly specialized and understand organoids. Therefore, it was quite easy, 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 between four and six weeks. Several companies are designing machines and instruments that allow the procedure to be performed much faster, on a small scale, and with just 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 the regulatory authorities. But for cancer, there are already many really good treatments. So if you propose a better treatment, you have to validate it. And that also has to be accepted by the FDA, the EMA [European Medicines Agency], and the doctors. So it requires a lot of work. It’s an ongoing process, but much slower.

**Q. **What types of cancer can benefit most from this technology?

A. The most common cancers are lung, breast, and colon cancer. Organoids are being researched for all of these, as well as for liver and stomach cancer.

Q. And what’s needed for it to be implemented in hospitals?

A. When you don’t respond to the first line of treatment, nor to the second or third, the doctor usually has some leeway to start using other things. In those cases, organoids could be used.

Q. Do you think this will happen in the near future?

A. Yes, but we need the machines that several companies are developing. With them, organoids can be created and medications administered to them. For example, for colon cancer, there are perhaps eight medications that can be given to a patient. Basically, the machine would take in the patient’s tissue, convert it into organoids, test them with those drugs, and give a result.

Q. In childhood cancer, with fewer therapeutic options, it could be very useful.

A. Yes, there are cancers that are very rare; sometimes only one case is registered per year in the entire country. That’s why now they all end up in a single center. We create organoids, and there we can learn from them, since we don’t know the appropriate treatment for these patients due to their scarcity. And, generally, these are deadly tumors that devastate the young children who suffer from them. That’s why we use organoids to inspire doctors. There are drugs that can’t be tested in children because there are so few of them, but they can be tested in organoids.

Q. Is there anything you’re researching that you’re particularly excited about?

A. At our children’s oncology hospital, we’re creating biobanks of very rare tumors, for which we basically don’t know what treatment to give these patients. So we’ll have 10 cases of this particular disease and 10 of that one, accumulated over several years. And then we can start doing trials. Because there are hundreds of cancer drugs that have never been tested on these children, but they can be tested on the organoids. So that’s something I’m very interested in understanding: these rare childhood cancers, how they originate, and what can be done about them.

We are also working intensively with intestinal cells. Ozempic is based on a hormone produced by a highly specialized cell type, but there are approximately 20 other hormones produced in the intestine. When we eat, these hormones begin to be secreted, suppressing hunger, and insulin is released. This process has never been thoroughly studied before. Now we are doing so with organoids, and perhaps in a few years we will have a much more specific understanding that will allow us to create more precise drugs. We have also made significant progress in infectious diseases.

Q. For example?

**A. **An interesting case is Covid-19. Two months after its emergence in Europe, we demonstrated that it affected not only the lungs but also the intestines, through the use of hormones, thanks to the human organoids we were using. Then people started talking about hydroxychloroquine, which worked in standard cell lines in virology labs. That’s why it became so popular. But it doesn’t work in patients. And it doesn’t work in organoids either. So, if virology labs had analyzed the organoids, we could have said, “No, this will never work.”

Q. Could experimenting with animal viruses that have the potential to jump to humans help prevent a new pandemic?

A. Many viruses come from bats. We can create bat organoids and experiment with them, but governments are afraid to do so because there could be failures and they could accidentally jump to humans.

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