In Denmark, we primarily transplant hearts, lungs, livers and kidneys, plus a few corneas and very few pancreases.

If doctors are to develop transplant procedures for more organs, they need to understand what the organs look like in a healthy body; both at cellular and molecular level. This knowledge is the first step in removing the organ correctly and in keeping it alive during transfer and once it is in the new body. We have lacked this knowledge for virtually all organs.

Until now.

At Stanford Health Care in Northern California, 15 deceased people made a major and important contribution to research in 2020 and 2021. The patients had agreed to being organ donors and thereby saved several lives. However, after each organ transplant, the staff stayed in the operating theatre and took biopsies of the remaining organs in the deceased donor’s bodies.

The biopsies were sent to a laboratory where Antoine de Morree, an associate professor at Aarhus University, and others were ready to analyse the material.

"Normally, we don't receive such large pieces of vital organs. And certainly not healthy tissue, because we usually only take a biopsy when there is suspicion that something is wrong," he says.

The researchers analysed the healthy organs and created a so-called cell atlas. The atlas is a molecular characterisation of the cell types and provides completely new insight into the organ physiology.

The project is called Tabula Sapiens and forms a basis for comparison with healthy organs that has not existed until now. The new cell atlas is a frame of reference – a benchmark of what organs should look like at cell and gene level.

"We’ve long known what the organs look like anatomically, but we haven’t known what healthy organs look like at molecular and cellular level. For many of the organs, this is the first time we’ve examined healthy tissue. This means that, for the first time, we can determine the appearance of a healthy organ at this level. The cell atlas is therefore an invaluable benchmark for developing new transplant procedures that can be used by researchers all over the world," explains Antoine de Morree from the Department of Biomedicine at Aarhus University.

Each organ has its own team

The study was conducted in the US by a large international consortium with more than 160 researchers. They have analysed 24 different tissues or organs from 15 healthy donors: Bladder, blood, bone marrow, diaphragm/skeletal muscle, eye, fat, heart, kidney, large intestine, liver, lung, lymph node, mammary, pancreas, prostate, salivary gland, skin, small intestine, spleen, thymus, tongue, trachea, uterus and vasculature.

For many of the organs, doctors have not known the healthy cellular and molecular composition until now. However, the new cell atlas comprises almost 500,000 cells and provides molecular characterisations of 475 cell types, their distribution across tissues, and tissue-specific variation in gene expression.

The atlas can be used in research into how we can transplant more types of organs and tissues – and as a benchmark for each individual operation:

"When you remove an organ, you want to know whether it's healthy or different; you need a benchmark. If, for example, there are many more immune cells than there should be, there may be an infection that means it’s less likely the organ will survive," explains Antoine de Morree.

Each organ in the study was treated by a specialist team who already knew the specific tissue. Antoine de Morree’s speciality is muscle stem cells, and in the study he was responsible for analysing the muscle tissue from the abdominal cavity and the diaphragm.

"Some organs are very difficult to get from healthy, living people. I’m very interested in the diaphragm, but if we take biopsies of the diaphragm, the patient can’t breathe. So the study was an opportunity to get access to this material, and get enough of it to conduct many experiments," he says.

He is thrilled about getting so much tissue from several different healthy donors. This makes it possible to compare organs across ethnicity, age and gender.

Important to understand health

However, he is just as excited that the study includes many organs from the same donor. One of the deceased donors gave the study biopsies from 17 different organs.

"What’s so good is that we can compare cell types across different organs in a single individual. We know that there are blood vessels in each organ, but are they the same? And are the immune cells patrolling the lung different from the immune cells patrolling the kidney? The study shows very interesting differences between the organs. This is new knowledge within basic biology," says Antoine de Morree.

The project data will be available to everyone.

"We haven’t just released the raw data, we’ve also developed a browser tool, so that researchers who are unsure about precisely what they want can still navigate the data," he says.

"The result is important, because we researchers generally focus on disease and on understanding what happens when things don’t work. However, it may be just as important to understand what’s happening when things are healthy. Now, for the first time, we have a frame of reference that shows what a healthy organ should look like. This is the first step in transplanting more types of organs," says Antoine de Morree.

The research results - more information

• Facts about the type of study: Cellular and molecular analyses of human organ biopsies. The organ donors in the study were selected on the basis of comprehensive health reports and they had all given their permission. After the organs for transplant had been removed and sent to a recipient, biopsies were taken of up to 24 other organs in the donors' bodies and distributed to specialist laboratories.
  Partners: Stanford University, the University of California San Francisco and the University of California Berkeley. Antoine de Morree was employed at Stanford University before he came to Aarhus University.
  The study was conducted in collaboration with the NGO Donor Network West in California, and the biopsies were taken at Stanford Health Care, a transplant hospital. This was where the first successful heart transplant in the US took place, and the world’s first combined heart-lung transplant.
• External funding: CZ Biohub and Chan-Zuckerberg Foundation
• Read more: Tabula Sapiens is the world’s largest cell atlas, with several tissues from the same human donors. This is the first atlas to include histological images of tissue and details of the intestinal microbiome. Read the scientific article here: www.science.org/doi/10.1126/science.abl4896

Contact

Tenure-track Assistant Professor Antoine de Morree
Aarhus University, Department of Biomedicine
Mobile: +45 60 79 07 22
Email: demorree@biomed.au.dk