Photo: EMBL

What holds the innermost together

By PETER SPORK

Photo: EMBL

March 16, 2023 · For five years, scientists have been measuring individual cells of the body. This has resulted in an atlas that makes it possible to understand the mechanisms behind disease and health.

At the beginning of the corona pandemic, there was a race between science and the virus. Where and how do the pathogens penetrate human cells and tissues? Could this be where potential antidotes come in? Are there prevention options that prevent the virus from entering? And surprisingly quickly there were answers.

This was due to a unique public database that researchers from all over the world could access: the Human Cell Atlas. It has been collecting information on human cells, sorted by cell type and tissue, for five years. And there was also information about cells of the nasal mucosa, which explained why the coronavirus can penetrate there particularly easily and effectively. Thus, a target structure was found to fight the virus.

It was not only in this case that the potential of the Human Cell Atlas became apparent. Later, with his help, it was also possible to detect organs and cells that SARS-CoV-2 affects in the further course of the disease. New information about individual infected cells in the lungs, heart, liver, kidneys or brain helped.

Pulmonary epithelium: The electron microscope image shows a single, stained cell sitting on the surface of the lung tract. In this case, it is a cell infected with Sars-CoV-2 pathogens (pink), from which the nucleus (white), mitochondria (yellow) and the endoplasmic reticulum (cyan) can be seen. Images: EMBL


It is only in the last ten years or so that science has been able to investigate body cells in isolation from each other and thus get to the bottom of the miracle of this smallest unit of life. Each of us humans consists of about 37 trillion cells. They all descend from the same ancestor, a single fertilized egg. But they have very different histories of origin, form large groups of similar design as tissues, form complicated organs. Together, the cells form a gigantic, incomprehensibly complex networked, maximally individual ecosystem. Only this system defines our uniqueness, our tendency to some diseases, but also our individual way of resilience and our health and life expectancy in general.


It is therefore an old dream of biology to completely decode the individual cell – to know how it works, to be able to explain what distinguishes the estimated three hundred human cell types from each other and how they communicate with each other. Whoever understands the cell to its innermost being understands life.

Connective tissue cell in embryonic state: In the two skin fibroblasts "reconstructed" from stem cells, the cytoskeleton (green) and the cell nucleus (orange) with the stained DNA are made visible. Images: Tischer & Corallino/EMBL


The biology behind disease, health and prevention

Humanity is currently coming a huge step closer to this dream. In initial approaches, it is becoming apparent that researchers are increasingly understanding complex diseases because they are discovering their causes at the cellular level. Consequently, this is why the research branch of single-cell biology has emerged. The idea: When we measure individual cells, we read what happens there as long as we stay healthy. In addition, we recognize at the earliest possible time how and whether diseases are in the offing. And we record the contribution that the networking of several cells makes to human life. In the foreseeable future, the science of more and more ailments will know these mechanistic backgrounds. This also means that medicine can specifically prevent more and more diseases or treat them individually and effectively.

"In order to understand the development of diseases and develop new treatments against them, we need to understand cells, their internal circuits and their interactions in health and disease," write molecular biologists Aviv Regev and Sarah Teichmann and their team in an article for the journal Nature Medicine. The two researchers have significantly shaped single-cell biology. Both led working groups at world-renowned institutes – one at the Broad Institute in Cambridge, USA, the other at the Wellcome Sanger Institute in Cambridge, UK – when in 2016 they gathered about a hundred researchers from all over the world to make a dream come true: to create a database that collects as much information as possible about the most diverse types of human cells possible and makes it available to science around the world. should. A little later, work began on this atlas of human cells, or HCA for short.

Retinal cells of the eye: As in many tissues, the star-shaped astrocytes (light blue) are one of many cell types, each of which is cross-linked and has different functions. On the microscope image of these cultured cells, the cell nuclei (magenta) of glial cells can also be seen. Images: EMBL


In the meantime, there are data on healthy and diseased cells at various stages of development and from almost all organs. Whether a scientist is researching asthma, influenza, cystic fibrosis, morbid obesity, cardiovascular disease, blood cancer, Alzheimer's disease, psoriasis or anything else: he or she will find what he or she is looking for in the cell atlas.

On the website of the consortium behind the atlas, access to the databases of the most important participating institutes can be found. There, for example, you can search for publications or for known short molecular biological sequences of DNA or RNA molecules as well as epigenetic labels. Researchers can enter their own data and receive information on which cells these could be typical.

Most impressive is the journey through the data of the Human Bio Molecular Atlas Program, HuBMAP: There, researchers can go on a journey in the virtual human body. They zoom in on individual organs, tissues or cells and pick out a wide variety of data by clicking and scrolling. Whoever wants, you can create a guest access and start with some practice. Without basic knowledge, however, the data can usually not be understood.

Skin cells in optical perfection: Making the individual cell components – including defects – visible under the confocal light microscope is often only possible if the staining techniques are varied. Here, the cytoskeleton is marked with an antibody that brings a green glowing molecule into the target cell. The DNA is stained blue separately. Images: Julia Hansen/EMBL


Regev and Teichmann stress that the corona pandemic was, in a sense, a practical test of "that single-cell analyses have the potential to provide information for drug discovery as well as for diagnosis and treatment in clinical practice." But there are other examples.

For example, people suffering from Crohn's disease often have unique communities of different cell types in the small intestine. When researchers compared the data of healthy and sick people, it was shown that those patients in whom this special cell community exists do not respond to therapy with so-called TNF-alpha inhibitors such as infliximab or adalimumab. Now it is possible to see which drug works before the therapy – a great step forward for those affected.

A certain type of cell, which is particularly important for the genetic lung disease cystic fibrosis, was even discovered only thanks to the human cell atlas. The cell type in which the disease-causing protein is formed is so rare that previous analyses had been too crude for them.

The use of single-cell biology is also important for the understanding of cancer. Only recently have targeted analyses of cells from different parts of a tumor as well as immune, nerve or tissue cells from its environment become possible. As a result, researchers are gaining a better understanding of how the malignant disease develops, what makes it insensitive to conventional treatments and how it can be combated even more effectively in the future.

Last but not least, the deep look into individual cells will also solve the great mystery that different patients sometimes have the same symptoms without a common cause being found. Only thanks to new data from the cell level can it be recognized when different changes in different types of cells have the same effect. This happens whenever both cells are active in a common network of numerous cells and bring it out of balance in a similar way.

Blood cell with defensive function. Of this neutrophil immune cell, one of the many different white blood cells, only the membrane on the surface and thus the shape of the cell can be recognized. Among other things, information about vitality and metabolic status can be derived from the cell form. Images: Ronchi & Diz-Muñoz/EMBL


Watching the cell at work

Today, more than 2300 researchers from 83 countries make their data available to the HCA consortium. They evaluated millions of cells from thousands of people. They provide high-resolution images of individual human cells and their spatial location in tissues. And they combine their images with tangible information about the biological processes in precisely defined individual cells, cell types and tissues.

This includes information on which genes are currently active in the respective cells. The technique behind it is called transcription analysis or transcriptomics. The researchers measure so-called gene expression profiles. They record which genes are read in the cell and which are not. Or to put it bluntly: They watch the cell at work. Of course, this work is always a direct response to signals from other cells or to stimuli from the environment.


In addition, there is single-cell epigenomics, i.e. the collection of data on the epigenetics of as many individual cells as possible. This involves structures that sit on or next to the genes and determine which of their genes this cell can use at all and which cannot. This "additional" or "minor" genetics determines the program of each cell and defines its identity, for example as a skin, liver or nerve cell. In addition, epigenetic structures also react to environmental influences and signals from other cells. They give the cells a kind of memory.

In the meantime, the biologists even measure which proteins occur in a cell at a certain point in time. This so-called proteomics is the supreme discipline of the many different "omics", i.e. the modern disciplines of a scientific measurement of life.

Ultimately, all these methods are about learning as much as possible about the ecosystem that the cells of entire organs, tissues and organisms form together. This system is a complex network from which our health and many other of our personal characteristics can be explained.

Fat cells such as those from the liver are found almost everywhere in the body. As a crucial energy store, it is especially interesting. to determine the storage vesicles - lipid sicles - which are labelled on this image with a yellow fluorescent dye around the nucleus. Images: Schultz Group/EMBL


Previously, it was impossible to analyze the individual elements of this system. For a long time, cell biologists had to be content with looking through the microscope. They captured the shape, location and appearance of the smallest unit of life. Thanks to molecular biology and genetics, much more detailed information about structure and function was later added. It was possible to distinguish and type the cells using the "omics".


About ten years ago, however, these techniques were limited to the characterization of large sections of tissue. The data reflected a mishmash of information from millions to billions of individual cells. A large part of the information was lost, because individual cells are of course often different. In the jumble of data, it was impossible to detect the specific response of a single cell to a particular stimulus.

It was like trying to research the properties of apples, but only having a multi-fruit juice available. It was impossible to determine exactly what the properties of individual cells are and how several cells "talk to each other".

Single-cell biology leads out of this dilemma. Because she finally misses life on a level that is high enough resolution to better understand it with the help of modern technology. Systems biologists feed their computers with the new, precise and detailed data from the HCA's bank.

Brain cells as a model for the treatment of Parkinson's, Alzheimer's or ALS: On the multi-color image, different cells and cell components are each marked with their own colors. The green-colored network are microtubules in nerve cells, the pink spots are glial cells that mainly "feed" the neurons in the brain. Images: Mikael Marttinen/EMBL


With the help of artificial intelligence, more precisely with the method of machine learning, also known as deep learning, they identify important properties of individual cells and analyze how they interact as a network. This ultimately enables the vision of a systems biological calculation of complex life processes and thus the calculation of reliable forecasts about the future of individuals.


Now it is even conceivable that the therapy and prevention of complex diseases will become a highly precise, individualized matter in which each person receives his own recipes. Diseases could occur much less frequently than today. The healthcare system could become fairer and cheaper. Scientists today are able to "identify and understand cell types in unprecedented detail, resolution, and breadth," according to the HCA web pages. "We believe that the work of the HCA is of great benefit to all of humanity."

The pioneers Regev and Teichmann describe their mission as follows: It is about "a reliable basis for a deep understanding of human health as well as the diagnosis, monitoring and treatment of diseases". That sounds very optimistic. But for a long time it also seemed unthinkable to find out what was going on inside the many individual cells. So perhaps it is not utopian to decipher the secret of health after all.

Where the fight against cancer may be decided

Cell therapy hui, hair replacement pfui: Heidelberg cancer researcher Jan Korbel on the possibilities and ethical limits of the new precision medicine.

Cancer researcher Jan Korbel Photo: EMBL

For a long time it was said that the genome in the cell nucleus was already the sesame open for high-tech medicine, now it is the decoding of the cell that is praised as the ultimate step into so-called precision medicine. Is progress really that crucial?
In any case, it is a very important step in this direction. As a result, precision medicine is much further along than was thought possible eight or ten years ago, especially in cancer medicine. The genome is a crucial factor. With single-cell analysis, however, we can now see much more clearly how heterogeneous tumors are composed and how cancer cells interact with each other and with healthy tissue. The analyses still have some weaknesses, but they are an important source of information.

They work on tumors themselves. How do you use single-cell analyses?
We can perform mutation analyses. This makes it possible to visualize the strong changes in chromosomes in individual cells that occur in cancer cells.

What is medically gained if we know the condition of each cell?
First of all, we have the opportunity to catalog each cell and find out what state it is in in the healthy body. And we can then also use this to understand the condition in the sick person. The vast majority of diseases are caused by a complex interaction of cells. We are dealing here with ecosystems of cells. Cancer cells "talk" to neighboring fibroblasts, which support them in proliferation. On the other hand, there are immune cells that fight the cancer. The cell atlas helps us to understand such interactions, which in turn advances the development or optimization of therapies. We follow the evolution of tumors in real time.

... which is very dynamic, as many cancer patients unfortunately have to experience first-hand.
Yes, many tumors are extremely plastic, they change their properties, often only individual cells in the tumor. Many can thus resist the therapies that have been initiated.

Are such detailed analyses already routine in modern cancer centers?
More and more often. In Germany, there are two major initiatives in the course of the Decade of Cancer. Our group works on colorectal cancer, breast cancer and pancreatic cancer. That's still research. However, genome studies in cancer patients, which are currently being carried out in specialized centers for subsequent therapy planning, are already well on the way to clinical routine.

Will every patient be transparent, i.e. cellularly measured from head to toe, every tumor cell and metastasis recorded in real time before the therapy is decided?
I see this as the way, at least for cancer. We simply need to see the tumor much more strongly as something dynamic that cannot be treated statically. If we look at the tumor only statically, we may not see at the moment we take the sample whether the tumor has the potential to develop rapidly or slowly. We now have data suggesting that tumors that develop rapidly are particularly often fatal.

"In that case, I would refer to wigs"

JAN KORBEL

Such precise methods also open up completely different possibilities. The cells become more malleable, easier to manipulate. "Body modification" is such a trend, a designed body, cells as desired. As an ethics officer at your institute, how do you evaluate such concepts?
When it comes to optimizing people, I'm skeptical. But the older you get, the more many wonder if you can't regenerate tissues or organs to be more vital. Hair loss or adult-onset diabetes are candidates that can theoretically be addressed with cell therapies. One can ask oneself: Do you really need this? But what about Alzheimer's or other age-associated diseases? Tailor-made stem cells could help at some point, but clinically such a thing is not yet carried out seriously for good reason. The exception is blood diseases such as sickle cell anemia or leukemia, in which stem cells are used because those affected would otherwise die.

Do other scientists see it the same way as you do, rather cautiously?
We discuss this very openly. There are cautious and rather progressive views. In any case, I am skeptical about body optimization. In the case of serious, potentially fatal diseases, however, one must ask: How high is the level of suffering? Ethics are on the side of progressives in such cases, if the user protocols are well and carefully drawn up.

What about the safety of the interventions? Cells can degenerate.

Yes, this risk is not always great, but it is not zero either. At least in the case of fatal diseases, physicians are more willing to inform patients about the possibilities, and they are prepared to accept the risk, for example, of possible carcinogenesis.

Once such radical interventions are socially acceptable, the need to refresh the cells as early as possible could quickly increase. The step to expensive wellness medicine is then not far away, fresh hair from retreaded cells, for example?
Sure, but I'm skeptical about approval. To put it bluntly, I would refer to wigs in this case. But of course, there are grey areas, and with many signs of aging, we are right in the middle of the hard-to-decide cases. I see ethics as particularly challenged here. I hope she will have a great deal to say in the future.

The interview was conducted by Joachim Müller-Jung.