[ad_1]
Who would have thought that an intestine could be so beautiful? If the doctor Hans Clevers recounts his work, then cells from the intestinal lining migrate in purple, orange, and blue on his computer's screen, forming stripes, beating wrinkles in red and green. As a painter with a brush, the researcher at the Hubrecht Institute of Utrecht created works of art in his stem cell laboratory: miniature human organs.
What Clevers and his colleagues describe in colorful images is supposed to help one day repair liver damage, heal diseased lungs and inflamed bowel loops. The mini-organs offer unprecedented opportunities to explore diseases and test drugs.
To do this, human mini-organs develop in mice, while researchers see colored tumors develop, infect cell structures with viruses, bacteria or parasites. It is hoped that someday, copies of the lab could even replace organs.
Artificial human organs (Video: Youtube / EPOfilms)
On a technical level, the mini-organs are called organoids and doctors are increasingly badociating themselves with bioengineers and materials scientists, molecular biologists and computer scientists to obtain ever larger and more mature specimens.
The way in which the different disciplines and branches of research complement each other is particularly noticeable in Utrecht. "Today, many scientists immerse themselves in organelles to better understand the origins of human life and to simulate and fight diseases," says physician and immunologist Clevers.
Mini intestines of a stem cell
In the lobby of the Institute of Biology of Hubrecht Development, is a huge white cardboard body cell in which curious visitors can slip, large windows resting on embryos of historical animals and old microscopes. Just behind, a bright red mini-organ appears on a screen, it looks like a precious painting from an art gallery. Hubrecht Art – Hubrecht art – is placed next to him in large letters.
On the first floor, Hans Clevers reports on the first strokes of his research. He is considered one of the great artists among Organoid researchers. He succeeded for the first time, many years ago, in reproducing these mini-organs of the laboratory. From a simple stem cell mini intestines had grown, which appeared many colleagues such as magic or fool at that time. "At first nobody wanted to believe us," recalls Clevers.
The doctor had broken too many dogmas at the same time: first, biologists were convinced that in the mature human body, hardly any stem cells are present in the intestine, they were completely unknown. Second, it was agreed that the body cells outside the human body would die after a few days.
But now, Clevers has claimed to have found a whole lot of these adult stem cells in the intestine. In addition, he was able to reproduce from the mini-organs of stem cells that survive the lab for months. Twice, critics of the journal Nature had rejected his article, reports Clevers. In 2009, the study was finally released, announcing the era of organoids research.
Hans Clevers points to the cells of a mini Därmchens on the computer. It looks a little like a starfish, which is hollow inside. On other images, the intestinal organelles are marked in green and red, sometimes even in more colors, as if we had painted colored stripes on black paper. The markers help researchers to observe the behavior of stem cells under the microscope and to form a messenger badtail that accelerates the growth of organelles.
Above all, Clevers must integrate stem cells into a gel so that they form three-dimensional structures. In Clever's laboratory, containers containing such stacks of gel remain in the incubators, each having the size of a Smartie.
What looks spectacular about microscopic color images, looks more like a dust in the gel to the naked eye. Organoids are so small that they can only be recognized by black dots. How will these little things help patients?
A 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 of Wilhelmina Children's Hospital and met Fabian at the age of 16, a smart, athletic and cheerful teenager.
In fact. Without this disease, cystic fibrosis, which obstructed his viscous mucus trachea, prevented him from breathing and threatened to steal his future. A girl of the same age as Kors van der Ent was extinct in her hands as a junior medical badistant. It should never happen to him again. Kors van der Ent decided to create mini-organs from Fabian's intestinal tissue.
Cystic fibrosis is the most common inherited disease and often leads to death in the first decades of life. One patient gene is defective, more than 2,000 different mutations occur in patients with cystic fibrosis, some common, others very rare. In recent years, new drugs on the market may help some patients with frequent genetic mutations.
Genetic defect that only occurs twice in the world
Or rather, doctors know what are the common genetic mutations of the drugs because they have tested them. However, other genetic mutations are so rare that expensive tests are not profitable for the pharmaceutical industry. Fabian, for example, suffers from a genetic defect that we only know twice in the world: with him and his aunt.
Usually, doctors need to test new drugs in animal studies and clinical trials. Kors van der Ent, on the other hand, took a short cut: his colleagues raised the boy's miniature intestines and added the new drugs to the lab. "The mini-intestines of Fabian have responded very well to the treatment," says Kors van der Ent. As a result, the pulmonologist prescribed the drug to the patient. In a few days, Fabian is out of breath and quickly resumes hockey. "Fabian has finally been 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. Hans Clevers and he would rather answer one of the most urgent questions of research on organoids: do mini-organs really represent the inner workings of real organs? In a study on a European scale, they want to study this on the mini-dummies of 500 patients with cystic fibrosis.
After all, scientists from Georgios Vlachogiannis, of the Cancer Research Institute in London, announced this year in the journal Science that the mini-organs of cancer patients very reliably predicted the success or failure of chemotherapy. "A remarkable study," says Hans Clevers with appreciation. In his group, for example, doctoral 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 to the evolution of patient treatment.
Clevers has long since established a tissue bank and, not far from its institute, employees of a non-profit start-up can test drugs on large-scale mini-organs, in their own projects or for pharmaceutical companies. Jasper Mullender, one of the group's startup leaders, dons thick gloves before removing frozen samples from a silver-colored cooling tank. At minus 180 degrees Celsius, thousands of mini-organs are stored here. Disposed in small plastic containers, sorted in white drawers, it contains organoids from healthy and diseased tissues of patients, particularly cancer patients and cystic fibrosis patients.
Better understanding of parasites and malaria
And samples of new tissue types are constantly being added. In Hans Clevers' lab, his employees have created so much that he has to pause to remember the latest accomplishments. From the pancreas they gained organelles and bladder, lungs and lacrimal gland.
And, oh yes, the mini-organs of the liver cells were particularly elaborate and one of the employees will soon publish this success in the famous journal Cell. One of the new organoids of liver cells is presented as a work of art in red on the screen in the lobby of the institute's entrance.
Clevers, for its part, is looking for black and white micrographs this time, but the pale organoids of the liver cells carry a very special cargo: Clevers employees infected the structures with a parasite. "Until now, we did not know what stages of the pathogen were going through the liver, we can now see that in 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 already fix them
As if Hans Clevers had originally painted only a rough sketch, his collaborators and other researchers now draw a more and more detailed picture of the inner workings of organoids. Not far from the Hubrecht Institute, is the Princes Máxima Center for Children with Cancer, located right in front of the Wilhelmina Hospital, where works the pneumologist Kors van der Ent. A transition with colored glbad windows connects the buildings, as if the architecture of the clinics wanted to recall how the research on organoids converges here.
In 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 screening test in patients with mucositis, such as Fabian; During this time, she prefers to focus on organelles that come from bad tumors. Its screen shines blue, red and green and, in spectacular 3D images, shows the thin ramifications of the mini-organs of bad cancer patients, which look a bit like colored corals.
With the help of these detailed plans, Florijn Dekkers can not only test drugs for the treatment of cancer. He can see exactly where the blood vessels are growing in the tumors, which milk channels are forming in the bad tissue, he can even monitor the tumor growth of bad cancer in experimental mice and thus determine which cell groups of a tumor responds to a therapy and which ones do not.
An ETH researcher helps
But what if you do not have to settle for tiny organoids? And if larger and more mature structures were created in the laboratory? To do this, Hans Clevers works with EPFL's bio-engineering and materials researcher Matthias Lütolf. 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 development in organelles," said Lütolf. Unlike the laboratory, in the human body, not only the growth factors play a role in the development of the organs, but also the influences of the neighboring tissue.
In small microchip channels, for example, it can simulate the blood flow of real organs. In contrast to the tiny forms of Clever's laboratory, the mini-intestines raised by Lütolf are one centimeter long and are tubular, in the manner of the true intestine. Until now, the bioengineer has managed to raise the intestinal tubes only with mouse stem cells, but he is now also working with human cells.
3D printed organ frame
One day, says Clevers, bioengineers could print a sort of cell-free scaffolding in 3D; With his colleagues, he would then place the appropriate organoids at the appropriate places in the frame, for a lung, for example those of the alveoli, the trachea and the blood vessels. For Hans Clevers, science is ready: "I think that everything that nature has created can be imitated, it is never extremely complicated."
Internist Joan Nichols has discovered an unusual source of organ scaffolds that a University of Texas researcher made on the front page of Science Translational Medicine. She took the lung of a dead pig and removed all living cells, leaving only the connective tissue scaffold. The scaffold then colonized them with the lung cells of the future organ recipient, another pig, and placed the framework and cells in a bioreactor for 30 days. Then she transplanted the organ.
Four pigs underwent the procedure, as well as small microscopic cells and a thin network of blood vessels formed in the bodies of all animals – an essential prerequisite for gas exchange. "It would be interesting to colonize such lung scaffolds with organoids and precursors of blood vessels," says Hans Clevers.
The skin of the laboratory
Sometimes, however, scaffolding is not needed to grow an organ in the laboratory. Italian and German researchers around plastic surgeon Tobias Hirsch reported last year in the journal Nature. They had transplanted a boy to the skin of the Bochum University Hospital, which had grown up in the laboratory.
"A spectacular work", enthuses Hans Clevers, reminding him of the beginnings of his research on organoids. The first attempts at skin reproduction had led to the search for stem cells in the intestine. This time, the doctors managed to cover 80% of the patient's body surface. The boy was suffering from a serious inherited disorder, his skin was largely turned into blisters, he was suffering from sepsis and was dying.
But the researchers did not just replace the dissolved skin. They also corrected the gene abnormality in skin stem cells using gene therapy. Healthy skin has grown. It was a new body work and gave the patient a new life. (Editors Tamedia)
Created: 03.11.2018, 21:01
Source link
