Researchers bet on mini laboratory organs

Technologies that emulate human organs should bring about changes in the two most ethically complicated stages of drug research, the so-called pre-clinical (animal tests) and clinical (human tests) phases. In addition to the obvious advantage of saving living beings from risks, these methods can generate results closer to those observed in humans.

One of the biggest difficulties in the development of new drugs is that the results of studies conducted in the animal model are not always confirmed in tests with patients.

The outcome can be dramatic: the drug fialuridine, for the treatment of hepatitis B, which had passed the animal phase, was discontinued after causing the death of five patients from a group of 15.

After that, the American biotechnology company Emulate found the high degree of toxicity of the drug when redoing the studies using the so-called organ-on-chips, a kind of computer chip with a microenvironment adapted to develop human cells.

Emulate works with the FDA (US regulatory agency equivalent to Anvisa) on Covid-19 and Alzheimer’s vaccine studies.

Jim Corbett, president of the company, is an advocate of alternative methods to reduce the use of animals in research and is in favor of passing the proposal to modernize the FDA’s criteria, presented this year in the US Congress.

Another technology that points in the same direction is that of mini-organs — organoids created in the laboratory from induced pluripotent stem cells (iPS). In this process, adult cells are induced to regress to an embryonic stage and fed the same proteins that command the diversification of embryonic cells into different organs of the human body.

“This is the beauty of development, cells have a kind of internal program and, when they receive the right signals, they know what to do”, says Aitor Aguirre, professor of biomedical engineering at the University
de Michigan.

Aguirre’s group developed a miniheart with complexity equivalent to that of a first-trimester fetus. With about a millimeter, the organoid manages to form the layers of the heart wall, chambers and functional blood vessels and even beat, enabling studies of infeasible congenital heart diseases in an animal model.

Brazilian researchers have also used organoids to demonstrate a causal relationship between Zika virus and microcephaly. As animals are not easily infected and develop less severe conditions, scientists chose to create a mini-brain from iPS; infected with the virus, it got smaller, just like children’s brains.

“Mini-brains revolutionized neuroscience because they recapitulate a human brain in the early stages of embryonic development”, says Patrícia Garcez, a researcher at the Institute of Biomedical Sciences at UFRJ. The study is being carried out in partnership with the Instituto D’Or de Pesquisa e Ensino.

“It is very beautiful to see the process happening in vitro, because it is a rare and inaccessible material.”

The mini-organs can also be three-dimensional, produced in 3D printers with a gel bioink created from the fusion of reprogrammed cells and a matrix that simulates tissue-supporting proteins. In the end, a chemical reaction guarantees a less gelatinous consistency to the organoids.

Bioprinting allows scientists to mix cells from different tissues and create complex structures, such as blood vessels or the mini-livers cultivated at USP’s Center for the Study of Human Genome and Stem Cells.

“First we differentiate the cells into several types because, in general, a tissue is not formed by just one type. Then we mix and apply 3D bioprinting”, explains professor and researcher Ernesto Goulart.

At UFRJ, professor Leandra Baptista joined Inmetro and is currently developing a three-dimensional lung tissue for Covid-19’s viral infection tests.

The tissue does not yet produce mucus or contract as in breathing, but the reproduction of certain functional characteristics of the lung, such as structure and cellular composition of the tissue, provides more relevant answers, says Baptista, who is also the founder of the tissue bioengineering startup Gcell.

The products are regulated by Anvisa in the area of ​​regenerative medicine to recover the normal functions of organs and cells. The group is also completing studies of bone formation from adipose tissue stem cells to cover critically defected skull areas.

For Leandra Baptista, tissue bioengineering can help to abolish the use of animals in tests, as happened in the cosmetic industry. Since the appearance of skins reconstructed in the laboratory, the model has been abandoned by most of the large companies in the sector.

But exchanges are not always possible, says Patrícia Garcez, also from UFRJ, whose group is trying to discover the factors that increase the possibility of transmitting the Zika virus from pregnant women to fetuses. “A study like this is only viable in complete organisms, so the animal model has its turn”, says the scientist.

The restrictions push the eradication of human or animal testing into a future whose arrival is still difficult to predict — but it is already on the horizon.