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Who would have thought that the gut might look so beautiful? If doctor Hans Clevers talks about his work, and then the cells of the intestinal mucosa migrate in purple, orange and blue on the computer screen, creating stripes, beating wrinkles in red and green. Just like a painter with a brush, the researcher of the Hubreck Institute in Utrecht created works of art in his laboratory of stem cells: human organs in miniature.
What Clevers and colleagues depict on colored pictures is to help fix the liver damage one day, cure the diseased lungs and inflammatory intestinal loops. Mini-bodies provide unprecedented possibilities to study diseases and test drugs.
To do this, human mini-organs grow on mice, while scientists see colored tumors, infect cell structures with viruses, bacteria or parasites. One day, we hope, copies from the laboratory could even replace the organs.
Artificial human organs. (Film: Youtube / EPOfilms)
In technical terms, mini-organs are called organoids, and doctors increasingly combine forces with bioengineers and scientists dealing with materials, molecular biologists and computer scientists to grow larger and more mature specimens.
How different disciplines and research branches complement each other can be observed particularly well in Utrecht. "Today, many scientists are sinking into organoids to better understand the origin of human life and to simulate and fight disease," says Clevers physician and immunologist.
Mini intestines with stem cells
In the entrance hall of the Institute for Developmental Biology Hubrecka hangs a huge cell built of white cardboard, in which interesting visitors can fall into, in large display cases rest the historical embryos of animals and old microscopes. Just behind him, a mini-organ appears in the screen in a bright red color that looks like a valuable picture of an art gallery. Hubrer's art – Hubrecht's art – stands next to it in large letters.
Above, on the first floor, Hans Clevers informs about the first brush strokes in his research. He is considered one of the great artists among the Organoid scientists, for the first time he succeeded in years, only those mini-organs in the laboratory to grow. Single mini stem cells have grown from a single stem cell, and many colleagues such as magic or humbugs have appeared at this time. "At the beginning no one wanted to believe us," says Clevers.
With too many dogmas, the doctor broke: First, biologists have so far been convinced that in a mature human body, almost no stem cells are present in the intestine, they were completely unknown. Second, it was established that the cells of the body outside the human body would die after a few days.
But now Clevers claimed to have found a whole lot of these adult stem cells in the intestine. In addition, he was able to grow from mini-organs stem cells that survived in the laboratory for many months. Twice the reviewers of the journal Nature rejected his article, Clevers reports. In 2009, the research finally appeared, announcing the era of organoid research.
Hans Clevers points to the mini-Därmchens on his computer, looks a bit like a starfish that's empty inside. In other paintings intestinal organoids are marked in green and red, sometimes even in more colors, as if someone painted colored stripes on black paper. Markers help researchers observe the behavior of stem cells under a microscope and assemble a cocktail of messengers that pushes the growth of organoids.
First of all, Clevers needs to embed the stem cells in the gel so that they form three-dimensional structures. In the Clever laboratory, incubators contain containers with such stacks of gel, each with a size of Smartie.
What looks spectacularly on microscopic colored images looks worse as pollen in the gel with the naked eye. Organoids are so small that they can only be recognized as black dots. How can these small things help patients?
The defective gene leads to mutations
To explain this, Hans Clevers likes to talk about Fabian and his colleague Kors van der Ent. The pulmonologist works near the Hubrecht Institute in the Children's Hospital of Wilhelmina and met Fabian, when the boy was 16, he was an intelligent, sporty and fun teenager.
Actually. Were it not for this condition, cystic fibrosis, which blocked his windpipe with sticky mucus, prevented him from breathing, threatened to rob him of his future. A girl of the same age in which Kors van der Ent died under her hands as a younger medical assistant. This should not happen to him anymore. Kors van der Ent decided to grow mini-organs from Fabian's intestinal tissue.
Cystic fibrosis is the most common hereditary disease and often leads to death in the first decades of life. One patient's gene is damaged, more than 2,000 different mutations occur in patients with cystic fibrosis, some of them are common, others are very rare. New drugs have appeared on the market for several years, which may help some patients with frequent gene mutations.
A genetic defect that occurs only twice in the world
Or rather, doctors know which frequent genetic mutations work because they tested them. Other gene mutations, however, are so rare that costly tests are not viable for the pharmaceutical industry. Fabian, for example, suffers from a genetic defect known only twice in the world: with him and his aunt.
Usually doctors have to test new drugs in animal studies and clinical trials. On the other hand, Kors van der Ent took a shortcut: his colleagues bred the boy's miniature intestines and added new drugs to the laboratory. "Fabiana's mini-intestines reacted very well to therapy," says Kors van der Ent. As a result, the pulmonologist prescribed the drug to the patient. Fabian died breathlessly in a few days, soon he played hockey again. "Fabian was finally able to enjoy the wild life of a teenager," says Kors van der Ent.
Test drugs on mini-organs
But the doctor was not alone with the young patient. On the contrary, he and Hans Clevers would like to answer one of the most urgent questions related to the study of organoids: are the mini-organs actually reflecting the internal functioning of real organs. In a pan-European study, they want to study it on mini-mannequins of 500 CF patients.
Finally, researchers from Georgios Vlachogiannis of the Cancer Research Institute in London this year in the journal Science report that the mini-organs of cancer patients very reliably predicted the success or failure of chemotherapy. "Excellent research," says Hans Clevers with appreciation. In her group, for example, doctoral student Else Driehuis is also working on anti-cancer therapies. Currently, he is preparing a study to test drugs for patients with head and neck tumors in mini-organs and compare them with the course of treatment of patients.
Clevers has long created a tissue bank, and not far from its institute, non-profit workers can test drugs on large-scale miniature bodies in their own projects or pharmaceutical companies. Jasper Mullender, one of the leaders of the startup group, puts on thick gloves and then pulls out frozen samples from the silver cooling tank. At minus 180 degrees Celsius there are thousands of mini bodies stored here. Torn in small plastic containers, sorted in white drawers, there are organoids from healthy and diseased tissue of patients, especially cancer patients, as well as cystic fibrosis.
Understand better parasites and malaria
And samples of new types of tissues are constantly added. In the laboratory of Hans Clevers, his employees have grown so many people that he must stop to remember the latest achievements. The pancreas obtained organoids and bladder, lungs and lacrimal gland.
And, yes, the mini-organs from the liver cells were particularly sophisticated, and one of the employees will soon publish success in the renowned journal Cell. One of the new organoids from liver cells is shown as a work of art in red on the screen in the entrance hall of the institute.
While Clevers is looking for black and white photomicrographs at the moment, the pale organoids from liver cells have a very special charge: Clevers employees infect the parasite structure. "Until now, we did not know which stages of the pathogen break through the liver. We can now observe that in organoids," says the doctor. Researchers also injected malarial parasites into mini-organs to better understand the course of the disease.
Some genetic defects may already correct them
As if Hans Clevers initially only painted a sketch, his collaborators and other researchers are now drawing a more and more detailed picture of the internal actions of organoids. Near the Hubreck Institute, there is the Children's Center for Children with Cancer, Princes Máxima, opposite the Wilhelmina Hospital, where a specialist from the lungs of Kors van der Ent works. The passage with the colorful glass windows connects the buildings, as if the architecture of the clinic wanted to remind you how research on organoids is collected here.
At Princes Máxima, the Florijn Dekkers Center folds a laptop and shows pictures that are almost as colorful as on the outside. Years ago a stem cell researcher developed a drug test for patients with mucositis, such as Fabian; meanwhile, he prefers to sacrifice himself with organoids that arise from breast cancer. It shines in blue, red and green on the screen. In spectacular three-dimensional images shows delicate branches in the mini-organs of patients with breast cancer, they look a bit like colorful beads.
Using these detailed approaches, Florijn Dekkers can not only test drugs for the treatment of cancer. You can see exactly where the blood vessels grow in tumors that form dairy channels in breast tissue, can even observe the growth of breast cancer in experimental mice, and thus find out which groups of tumor cells respond to treatment and which do not.
ETH researcher helps
But what if you did not have to settle for tiny organoids? What will happen if larger, more mature constructions are created in the laboratory? To achieve this, Hans Clevers collaborates with the bioengineer and material researcher Matthias Lütolf of the EPFL. Lütolf combines new biomaterials with microchips to best simulate the three-dimensional structure of real organs. "We want to control the growth of stem cells and their growth in organoids," says Lütolf. In contrast to the laboratory, in the human body not only growth factors play a role in the development of the organ, but also affect the neighboring tissue.
For example, in small channels microchips can simulate the flow of blood in real organs. Unlike the tiny shapes in the Clever lab, the mini intestines grown by Lütolf are one centimeter long and are tubular like the real intestine. So far, the bioengineer has managed to grow intestinal tubes only with mouse stem cells, but is now also working with human cells.
Print organ structure in 3-D
One day, according to Clevers, bioengineers can print a type of organ scaffold without cells in 3D; Together with his colleagues, he placed appropriate organoids in the right places of the skeleton, on the lungs, for example on the blebs, on the trachea and blood vessels. For Hans Clevers, it's only a matter of time before science is ready: "I think everything that nature has created can be imitated, it is never extremely complicated."
Internist Joan Nichols discovered an unusual source of organ scaffolding, in August a researcher from the University of Texas found himself on the front page of the journal Science Translational Medicine. She took the donor's lung of a dead pig and removed all living cells, leaving only the scaffolding of the connective tissue. The scaffold was then colonized with the lung cells of the future organ recipient, another pig, and the skeleton and cells were inserted into the bioreactor for 30 days. Then she transplanted the organs.
Four pigs have been treated, and microscopically small bubbles and a fine network of blood vessels formed in the body of all animals – an important prerequisite for gas exchange. "It would be interesting to colonize such lung scaffolds with organoids and blood vessel precursor cells," says Hans Clevers.
Skin from the laboratory
Sometimes, however, scaffolding is not needed to grow an organ in a laboratory. Italian and German researchers around the plastic surgeon, Tobias Hirsch, noted last year in the journal Nature. They transplanted the boy on the skin of the Bochum university hospital that had grown up in the laboratory.
"Spectacular work" – enthusiastic Hans Clevers, reminding him of the beginnings of his organoidal research. The first attempts to grow the skin caused that during this time he was looking for stem cells in the intestine. This time, the doctors managed to cover 80 percent of the patient's body area, the boy suffered from a serious hereditary disease, his skin largely disintegrated into blisters, suffered from sepsis, died.
But scientists have not only replaced the dissolved skin. They also improved the gene defect in skin stem cells by gene therapy. Healthy skin has increased. It was a new organza work and gave the patient a new life. (Editorial Tamedia)
Created on: 03/11/2018, 21:01 clock
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