Your body is unknown territory

Your body is unknown territory

The body contains thousands of cell types unknown to scientists. New technology has revealed gaps in our knowledge of the body, and findings may lead to new treatment methods for everything from cancer to cystic fibrosis.

84 percent of the body's cells are red blood cells, but they make up only four percent of the body weight.

Gene therapy targeting new lung cells

A map of the lung cells has revealed a new cell type, the ionocyte, which plays an essential role in the incurable cystic fibrosis disease. The researchers now hope that gene therapy directed at ionocytes will revolutionize the treatment of the disease.

Nanoparticles detect lung cells. Gene therapy for cystic fibrosis could include the CRISPR gene tool, which is inserted into nanoparticles (green) that the patient breathes. The particles end up in the mucus of the lung (white layer), where they have access to ionocytes (orange). The particles can be provided with antibodies that ensure close contact with the ionocytes.

Gene scissors remove the diseased gene. CRISPR comprises an RNA strand that tracks the diseased CFTR gene in the cell nucleus and an enzyme that cuts off the gene (green). The cell tries to glue the ends together, but instead inserts the healthy variant of the gene into the hole (orange). Thus, the cell has only a healthy CFTR gene.

Cells with barcodes

The new, pioneering technology of single-cell RNA sequencing allows researchers to read active genes in hundreds of thousands of cells simultaneously. Special DNA barcodes also make it possible to trace each active gene back to a cell.

Cells get a gem each

The researchers dissolve a tissue sample and insert the cells (pink) through a tube. There they are first mixed with small beads (blue, yellow, and green), after which oil is added. The oil causes small water droplets to form, each containing a cell and a pearl.

DNA captures active genes

The cell (pink) releases its RNA molecules (white), which reflect the active genes. Rna binds to small DNA fragments that the researchers have placed on the bead (blue). All contain a specific DNA bar code that is only found on the current bead.

The barcodes are traced

The cell's RNA is translated into DNA sequences using the barcode (blue). The researchers sequenced DNA from all water droplets simultaneously, but thanks to the barcodes, they can trace each sequence back to a particular bead and cell.

With surprise, neuroscientist Ed Lein studies the results of the analysis of brain cells in the outermost layer of the cortex.

Together with his colleagues at the Allen Institute in Seattle, USA, he has just examined the brains of two deceased persons and identified all known types of brain cells.

The researchers have also come across an unusual cell type with which they have never been acquainted.

Eager to see the unknown cell with his own eyes, the scientists produce the microscope. They see a cell with a characteristic shape: A round cell body with a sea of thin outlets.

Because the shape reminds them of a rosehip from a rose bush, the cell gets the name rosehip cell, rosehip cell.

The discovery, made in collaboration with other research groups in the US and Europe, is one of the first in the new global project Human Cell Atlas.

The project aims to map all cells in the human body and thus revolutionize our knowledge of the activities of the cells.

At present, about 1,500 researchers from 62 countries are participating in the project, and they have already found many hitherto unknown cell types and drawn detailed maps of several of our bodies.

The breakthroughs have shown, among other things, which cells are behind the incurable cystic fibrosis disease and how cancer cells counteract an otherwise hopeless immune therapy.

The project is paving the way for new forms of treatment that benefit from the inherent weaknesses of the disease.

Each cell has its pattern

The body has a huge variety of cells that perform many different tasks and look completely different.

Red blood cells are full of the protein hemoglobin, as they are supposed to carry around oxygen in the blood.

Nerve cells have long nerve strands and close connections with their neighbors, ensuring fast and efficient communication.

Because fat cells store fat, which is used as energy reserves, they can be over 200 times larger than red blood cells.

The variety of cell types in the body is no less astounding by the fact that they all have the exact same DNA.

However, the cells express DNA in different ways, thereby putting different proteins into play. For example, a brain cell expresses genes responsible for the formation of neurotransmitters such as dopamine and serotonin.

These genes are useless for the immune cells, which instead need genes for the formation of substances that contribute to the defense against infections.

Therefore, each cell type has a pattern of active and inactive genes that give it its unique shape and function.

For the past 150 years, researchers have identified cell types based on, among other things, their shape and location in the body, which has resulted in the discovery of approximately 200 different cell types.

In recent decades, however, new technology has made it possible to see precisely which genes the cells express, and much indicates that the body’s cells can be divided into significantly more, perhaps thousands, types.

Even with the advanced genetic engineering methods of our time, it is only recently that scientists have been capable of getting an overview of the body’s myriad of cells.

They had to settle for either examining a few cells at a time or seeing which genes are active in an organ without knowing which cells in the organ are doing what.

However, new technology has changed. Today, researchers can analyze the gene activity of each cell in a sample containing hundreds of thousands of cells.

Algorithm reveals new cell types

One of the cornerstones of the Human Cell Atlas project is the single-cell RNA sequencing technology.

In the past ten years, the technology has become so advanced that researchers can measure the gene activity of each cell in a tissue sample at the same time.

This is exactly what makes the technology so well suited for mapping the human body.

If the cells had only had two to three genes, it would have been easy to categorize the cells based on the activity of the genes. Still, with over 20,000 genes, there are so many combining possibilities that researchers are forced to rely on newly developed algorithms that can manage the massive amounts of data.

Based on the data entered, the algorithm places each cell in a kind of coordinate system with over 20,000 dimensions (one dimension for each gene), and depending on the activity level of the genes, the cell gets its place in the coordinate system.

Cells that are close to each other in the system have similar patterns of gene activity and can be said to belong to the same category.

The algorithm identifies delimited categories of cells in the coordinate system and thus gives the researchers an overview of what cell types the tissue contains.

This led to the development of a large number of new cell types and subgroups of previously known cell types.

New cells can lead to cures

Ed Lein’s new cell phone was one of Human Cell Atlas’s first discoveries. It is a nerve cell, but unlike many other nerve cells, it inhibits electrical signals rather than transmitting them.

In doing so, it helps to control what information arrives – an important function that prevents the brain from drowning in unnecessary signals.

Nypon cells are not the only new cell type that Human Cell Atlas has revealed, and probably not the most important.

However, it could be the so-called ionocytes in the lungs. The ionocytes express higher levels of the CFTR gene than any other cells in the body.

CFTR plays a leading role in the genetic disease of cystic fibrosis, affecting more than 70,000 people around the world.

The gene encodes a protein that transports water and chloride ions into and out of cells. It is involved in secreting mucus into the lungs.

People with a mutation in the gene form a thicker mucus layer in the lungs than normal and suffer from a variety of life-threatening respiratory problems.

Despite decades of intensive research on the disease, there is still no cure, but the discovery of the ionocytes provides increased hope for the future.

The researchers have long believed that the production of the CFTR protein has been distributed over several of the well-known airway cells. Still, the discovery shows that most of the CFTR is expressed in the ionocytes, which make up only about one percent of the airway cells.

It opens up entirely new types of cystic fibrosis treatment methods, where researchers can target the ionocytes in their efforts to achieve regular CFTR activity in people born with cystic fibrosis.

Map solves the mystery of pregnancy

Human Cell Atlas is more than just finding new types of cells.

One of the most important aims of the project is to create detailed maps of the cells in the body’s various organs and tissues and to find out how the cells work together.

In one of the project’s studies, the researchers focused on the tissue that connects the mother and the fetus during the first weeks of pregnancy.

Then the fetus’s placenta is attached to the uterus via decidua, a mucous membrane that is formed in the uterus. So far, our knowledge of decidua has been limited.

The researchers knew that cells from the fetus communicate and mingle with the mother’s cells in the decidua and that the mucosa is extremely important in the early stages of pregnancy.

Exactly how the mother and fetal cells interact, however, has been a mystery.

Typically, the immune system attacks foreign cells, but during pregnancy, the mother’s immune system does not respond to another human being ingesting her body.

After the Human Cell Atlas survey of decidua, the researchers have gained an insight into how the mother and fetal cells interact.

The researchers mapped about 70,000 cells from decidua, and the analyzes showed both new types of cells and provided insights into a previously unknown interaction between the cells.

The researchers discovered, among other things, three types of immune cells that differ from corresponding immune cells in the blood. In particular, one of the new cell types appears to have a close relationship with the fetus.

It forms proteins that recognize fetal cells and, at the same time, releases substances that suppress other immune cells.

Taken together, the map of decidua has revealed an environment optimized to inhibit the immune system’s response to the invasion of fetal cells.

This new knowledge could help women who have difficulty getting pregnant because their immune cells tend to repel the fetus.

Projects reveal cancer genes

The researchers are also in the process of examining the liver, one of the body’s most essential organs. Some of the liver’s tasks are to disarm toxins, purify the blood, and adjust metabolism.

The liver is also the only organ that can regenerate itself, even after being down to 25 percent of its original size.

Even though the liver has been thoroughly explored for over a hundred years, some of its cells have been hidden from science – until the researchers in the Human Cell Atlas project recently mapped the cells in nine donor liver tissues.

The researchers analyzed over 10,000 cells and found mainly already known cell types. However, they also revealed subgroups of liver cells that science has never encountered before.

Among other things, they discovered a new type of cell in the bile ducts of the liver, a network of ducts that lead bile fluid from the liver to the gallbladder.

The cell acts as a stem cell and can develop into both healthy liver and bile duct cells.

In addition to healthy livers, the researchers examined cancer-affected livers, and by comparing them, they discovered a number of genes associated with the conversion of healthy liver cells into cancer cells.

Therefore, it is now possible to develop extremely targeted treatment methods to stop the early stages of liver cancer.

Atlas provides new treatment methods

Most diseases can be attributed to harmful changes at the cellular level. A comprehensive atlas of all cells in the body will provide the researchers with optimal conditions for making accurate diagnoses and developing new treatment methods.

Already, the Human Cell Atlas project researchers are well on their way to finding more effective treatment methods for both cystic fibrosis, inflammatory diseases, and cancer.

With their new knowledge about the ionocytes in the lungs and their central role in cystic fibrosis, researchers can develop gene therapies that specifically target the ionocytes, and that correct their mutated CFTR gene.

Unlike cystic fibrosis, inflammatory diseases can include hundreds of genes, all of which contribute to the disease.

Many of these genes are still unknown to the researchers, who know neither what they do nor in which cells they are most active. It is changing the atlas.

For example, researchers have mapped cells in intestinal tissue from healthy individuals and people with inflammatory bowel disease.

By comparing the cells, the researchers discovered a handful of cells in the diseased tissue that was not present in healthy tissue.

They could also see that the activity of more well-known cells changed in the diseased tissue.

Thus, researchers now have the tools needed to develop treatment methods that either remove diseased cells or correct their gene activity.

Current knowledge of cancer cell gene activity has given researchers a reliable card.

So-called immunotherapy, which helps the immune system fight cancer, has proven to be a jump-inducing treatment method.

However, it does not work for everyone, and in many cases, it only works for a limited period before the cancer cells become resistant.

A survey of the cancerous tissue has shown that cancer cells that build up resistance to immunotherapy activate a specific genetic program that protects them from treatment.

The researchers have now come up with a way to deceive cancer by combining immunotherapy with a drug that shuts down the cancer cell protection program.

Particles release gene scissors

When the antibodies on the nanoparticle bind to the ionocyte surface, the particle fuses with the cell so that the content of the particle falls into the cell. The content consists of CRISPR (light green) and a healthy version of the cell's diseased CFTR gene (orange).

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