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 failed to accurately replicate human biology. Since 2023, the US Food and Drug Administration (FDA) will not impose animal testing, also thanks 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 Prize in Medical Sciences. He met EL PAÍS in a hotel in the center of Madrid.
Request. 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 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?
TO. 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 this, it’s easy: you take a tissue, you cut it into small pieces, you put it in a gel so that it has three dimensions, then you add growth factors, and that’s how you create the organoid.
Q. Are you working with organoids of all organs?
TO. 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 found them very special due to their hyperactivity. This inspired us to try culturing 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 drug development steps using other platforms – animals – and cell lines can be replaced with these human organoid models. Could this mean the end of animal testing?
TO. That’s what some people think. The FDA has proposed to stop using them in the United States and that within five years we will no longer be allowed to use animals in the development of large molecule drugs, which account for about half of all drugs. 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 entire organism.
TO. Exactly. 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 do you model this? 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 us be more specific and safer, but I doubt we will ever get rid of animals completely.
Q. Are there any diseases for which this technology shows particular promise?
TO. 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 cancer drugs, and see which one kills the cancer cells. The same goes for 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?
TO. Forks. The Netherlands has about 18 million inhabitants, about a third of the population 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 only in a few centers, where doctors are highly specialized and know about organoids. Therefore 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 need 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?
TO. The most common cancers are lung, breast and colon cancer. Organoids are being studied for all these disorders, as well as for liver and stomach cancer.
Q. And what does it take for it to be implemented in hospitals?
TO. When you don’t respond to the first line of treatment, or the second or third, your doctor usually has some leeway to start using other things. In these cases, organoids could be used.
Q. Do you think this will happen in the near future?
TO. Yes, but we need the machines that several companies are developing. With them it is possible to create organoids and administer drugs to them. 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, convert it into organoids, test them with those drugs, and provide a result.
Q. In childhood cancers, with fewer therapeutic options, it could prove very useful.
TO. Yes, there are very rare tumors; sometimes there is only one case per year in the entire country. That’s why they all end up in one center now. 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, typically, these are deadly tumors 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 few of them, but they can be tested on organoids.
Q. Is there anything you’re researching that you’re particularly excited about?
TO. In our pediatric oncology hospital we are creating biobanks of very rare tumors, for which we practically do not know what treatment to give 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 cancer drugs that have never been tested on these children, but can be tested on organoids. Now, this is something that I am very interested in understanding: these rare childhood tumors, how they originate and what can be done to combat them.
We also work intensively with intestinal cells. Ozempic is based on a hormone produced by a highly specialized cell type, but there are about 20 other hormones produced in the gut. When we eat, these hormones begin to be secreted, suppressing hunger and releasing insulin. This process has never been thoroughly studied before. Now we’re doing it with organoids, and maybe in a few years we’ll have a much more specific understanding that will allow us to create more precise drugs. We have also made significant progress in the field of infectious diseases.
Q. For example?
TO. An interesting case is that of Covid-19. Two months after it appeared in Europe, we showed that it affected not only the lungs but also the intestine, through the use of hormones, thanks to the human organoids that we were using. Then people started talking about hydroxychloroquine, which worked in standard cell lines in virology labs. That’s why it has become so popular. But it doesn’t work on patients. And it doesn’t work with organoids either. So if the virology labs had analyzed the organoids, we could have said, “No, that will never work.”
Q. Could testing animal viruses that have the potential to transmit to humans help prevent a new pandemic?
TO. 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.
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