Who would have thought a gut could look so handsome? If the doctor Hans Clevers talks about his work, so intestinal mucosal cells migrate in purple, orange and blue on the screen of his computer, forming stripes, beating wrinkles in red and green. As a painter with a brush, the researcher at the Hubrecht Institute in Utrecht created works of art in his stem cell laboratory: human organs in miniature.
What Clevers and his colleagues portray in color photos should one day help repair liver damage, heal diseased lungs, and inflame intestinal loops. Mini-organs provide unprecedented opportunities to explore diseases and test drugs.
To do this, human mini-organs grow in mice, while researchers see colored tumors grow, infect the cell structures with viruses, bacteria or parasites. One day, it is expected, lab copies could even serve as a substitute for organs.
Artificial human organs. (Video: Youtube / EPOfilms)
In technical terms, mini-organs are called organoids, and physicians are increasingly joining bioengineers and material scientists, molecular biologists, and computer scientists to create larger and more mature specimens.
As the different disciplines and lines of research complement each other, one can observe particularly well in Utrecht. "Many scientists today plunge into organoids to better understand the origins of human life and to simulate and fight disease," says the physician and immunologist Clevers.
Mini intestines of a stem cell
In the entrance hall of the Hubrecht Institute for Developmental Biology, there is an immense white cardboard cell in which curious visitors can enter, large windows hold embryos of historical animals and ancient microscopes. Just behind, a shiny red mini-organ appears on a canvas, looks like a precious painting from an art gallery. Hubrecht Art – Hubrecht Art – stands beside him in large letters.
Above, on the first floor, Hans Clevers reports the first brushstrokes of his research. He is considered one of the great artists among the researchers of Organoid, he achieved years ago for the first time, only those mini-organs in the laboratory to reproduce. From a single mini-stem cell intestine had grown, which appeared many colleagues such as magic or humbug at the time. "At first, no one wanted to believe in us," recalls Clevers.
With many dogmas at the same time, the doctor had broken: first, biologists were so convinced that in the mature human body only stem cells were present in the gut were completely unknown. Secondly, it was agreed that the body's cells outside the human body would die after a few days.
But now Clevers claims to have found a bunch of those adult stem cells in the gut. In addition, he was able to procreate from mini-organs of stem cells that survive in the laboratory for months. Twice the reviewers of Nature magazine have rejected his article, reports Clevers. In 2009, the study finally appeared, heralding the era of organoid research.
Hans Clevers points to the cells of a mini-Därmchens on the computer, looks a bit like a starfish, which is hollow inside. In other images, intestinal organoids are marked in green and red, sometimes even in even larger colors, as if someone had painted colored stripes on a black paper. The markers help researchers look at the behavior of stem cells under the microscope and join a cocktail of messengers, which drives the growth of organoids.
Above all, the Clevers must incorporate the stem cells into a gel so they form three-dimensional structures. In the Clever lab, containers with these gel cells are in the incubators, each about the size of a Smartie.
What looks spectacular in the microscopic colored images, looks more like a crumb of dust in the gel with the naked eye. Organoids are so small that they can only be recognized as black spots. How will these little things help patients?
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 at Wilhelmina Children's Hospital and met Fabian when the boy was 16, a smart, sporting and entertaining teenager.
In fact. If it were not for this condition, the cystic fibrosis that obstructed his trachea with viscous mucus, prevented him from breathing, threatened to steal him from his future. A girl of the same age as Kors van der Ent had died under her hands as a junior medical assistant. This should not happen to him again. Kors van der Ent decided to create mini-organs from the Fabians of intestinal tissue.
Cystic fibrosis is the most common hereditary disease and often leads to death in the first decades of life. A patient's gene is defective, more than 2,000 different mutations occur in patients with cystic fibrosis, some are common, others are very rare. A few years ago, new drugs are on the market and may help some patients with frequent gene mutations.
Genetic defect that occurs only twice in the world
Or rather, doctors know what genetic mutations drugs often work because they have been tested. Other genetic mutations, however, are so rare that expensive tests are not worthwhile for the pharmaceutical industry. Fabian, for example, suffers from a genetic defect known only twice around the world: with him and his aunt.
Typically, doctors have to test new drugs in animal studies and clinical trials. Kors van der Ent, on the other hand, took a shortcut: his colleagues created the boy's miniature intestines and added the new drugs in the laboratory. "Fabian's mini-intestines responded very well to therapy," says Kors van der Ent. As a result, the pulmonologist prescribes the medication to the patient. Within a few days, Fabian's shortness of breath died, he soon played hockey again. "Fabian was finally able to enjoy the wildlife of a teenager," says Kors van der Ent.
Mini-organ drug testing
But the doctor was not alone with the young patient. Instead, he and Hans Clevers would like to answer one of the most pressing questions of organoid research: whether the mini-organs actually describe the inner workings of real organs. In a study across Europe, they want to investigate this in mini-dummies of 500 patients with cystic fibrosis.
After all, researchers around Georgios Vlachogiannis of the Cancer Research Institute in London in the journal Science reported that mini-organs of cancer patients predicted the success or failure of chemotherapy very reliably. "An excellent study," says Hans Clevers aptly. In her group, for example, PhD student Else Driehuis is also working on cancer therapies. She is currently 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 established a tissue bank and, not far from its institute, employees of a non-profit organization can test drugs in large-scale mini-organs, in their own projects or for pharmaceutical companies. Jasper Mullender, one of the leaders in the startups group, wears thick gloves before taking frozen samples from a silver cooling tank. At minus 180 degrees Celsius, thousands of mini organs are stored here. Separated into small plastic containers, separated in white drawers, are healthy tissue organoids and patient patients, especially those with cancer and also with cystic fibrosis.
Understand parasites and malaria better
And samples of new tissue types are constantly added. In Hans Clevers' lab, his employees have already created so many that they need to take a break to remember the latest achievements. From the pancreas they have gained organoids and the urinary bladder, the lungs and the lacrimal gland.
And, yes, the mini-organs of liver cells were particularly elaborate, and one of the officials will soon publish his success in the renowned magazine Cell. One of the new organoids of liver cells is shown as a work of art in red, on the screen of the institute's entrance hall.
Clevers, on the other hand, is looking for black and white micrographs this time, but the pale organoids of liver cells carry a very special charge: Clevers officials infected the structures with a parasite. "Until now, we did not know what stages of the pathogen are going through the liver. We can now observe that in the organoids," says the doctor. The researchers also injected malaria parasites into the mini-organs to better understand the course of the disease.
Some genetic defects can fix them
As if Hans Clevers had initially painted only one sketch, his collaborators and other researchers are now drawing an increasingly detailed picture of the inner workings of organoids. Not far from the Hubrecht Institute is the Princes Maxima Center for Children with Cancer, located in front of Wilhelmina Hospital, where the lung specialist Kors van der Ent works. A transition with stained glass windows connects the buildings, as if the architecture of the clinics wanted to remind how research on organoids converges here.
In the Princes Máxima, Centrum Florijn Dekkers folds his laptop and shows images almost as colorful as the transition to the outside. Years ago, the stem cell researcher developed the drug test for patients with mucositis, such as Fabian; Meanwhile, she prefers to focus on organoids that arise from breast tumors. She shines in blue, red and green on her screen. In spectacular three-dimensional images she shows the thin branches in the mini-organs of breast cancer patients, they look a bit like colored corals.
With the help of these detailed photos, Florijn Dekkers can not only test drugs for the treatment of cancer. One can see exactly where blood vessels are growing in tumors, which milk ducts form in breast tissue, may even observe the growth of breast cancer in experimental mice and thus discover which cell groups in a tumor respond to therapy and which do not.
The ETH researcher helps
But what if you did not have to settle for the small organoids? What if larger, more mature structures were created in the laboratory? To achieve this, Hans Clevers works in conjunction with EPFL bioengineer and material researcher Matthias Lütolf. Lütolf combines new biomaterials with microchips to simulate the three-dimensional structure of real organs in the best possible way. "We want to control the growth of stem cells and their development in organoids," says Lütolf. In contrast to the laboratory, in the human body, not only growth factors play a role in the development of organs, but also influences the neighboring tissue.
In small channels of microchips, for example, it can simulate the blood flow of the real organs. Unlike the tiny shapes in Clever's lab, the mini intestines created by Lütolf are one centimeter long and are tubular, like the real intestine. So far, the bioengineer has managed to create the intestinal tubes only with stem cells from mice, but now he also works with human cells.
3-D Print Body Structure
One day, Clevers says, bioengineers could print a type of 3-D cell-free organ scaffold; Together with his colleagues, he would place the correct organoids in the appropriate places of the structure, for a lung, for example, for the alveoli, for the trachea and for the blood vessels. For Hans Clevers, it is 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 has found an unusual source of organ scaffolds. In August, the University of Texas researcher made it to the front page of Science Translational Medicine. She took the donor lung from a dead pig and removed all living cells, leaving only the scaffolding of the connective tissue. The scaffold then colonized them with lung cells from the future recipient organ, another pig, and placed the structure and cells in a bioreactor for 30 days. Then she transplanted the organ.
Four pigs underwent the procedure, and microscopic alveoli and a thin network of blood vessels formed in the body of all animals – an important prerequisite for gas exchange. "It would be interesting to colonize these lung scaffolds with organoids and blood vessel precursor cells," says Hans Clevers.
Skin of the laboratory
Sometimes, however, scaffolding is not required to develop an organ in the laboratory. Italian and German researchers around plastic surgeon Tobias Hirsch reported last year in the journal Nature. They transplanted a boy into the skin of the University Hospital Bochum, who had grown up in the laboratory.
"A spectacular work," enthuses Hans Clevers, reminding him of the early days of his research on the organoid. The first attempts at skin creation made him, at that moment, look for stem cells in the gut. This time, doctors managed to cover 80 percent of the surface of the patient's body, the boy suffered from a serious hereditary disease, his skin had largely resolved into blisters, suffered from septicemia, was dying.
But the researchers did not replace only the dissolved skin. They also corrected the genetic defect in the stem cells of the skin using gene therapy. Healthy skin has grown. It was a new organza work and gave the patient a new life. (Editors Tamedia)
Created: 03/11/2018, 21:01 clock