The Most Detailed Protein Map of Human Cells to Date Generated

Researchers from the Sinai Institute of Health have published a study that conducted ultra-detailed studies on the organization of living human cells, providing a new tool that can help scientists around the world better understand what happens during a disease.

The new research, published in the Nature, was conducted in the laboratory of Dr. Anne-Claude Gingras, a professor in the Department of Molecular Genetics at the University of Toronto and a senior researcher at the Lunenfeld-Tanenbaum Institute (LTRI).

Co-first author Christopher Go and Dr. James Knight studied the human cell landscape using 192 protein markers known to be present in specific organelles that can "mark" adjacent proteins in the same compartment.

Go said: “The human cell atlas can predict the location of 4000 proteins in all compartments of living cells. We sampled all the major organelles of human cells and used innovative analysis to create the highest resolution map to date. Many unmapped proteins have high accuracy in the new positioning.”

The human body consists of trillions of cells, each of which is subdivided into different compartments with different functions, just as there are different rooms in the house for sleeping or cooking. These chambers are called organelles, and each contains different proteins that perform specific activities associated with the chamber. Mitochondria, known as the power source of cells, are an example of organelles.

Scientists say understanding which proteins reside in which organelles is an important first step in understanding the role of each cellular protein. The early approach was usually to kill the cells first and then try to separate the organelles from each other.

“Previously, it was like dismantling houses and isolating each individual room,” Go said. “These methods can only provide a rough view of the cellular organization.”

The Gingras laboratory has developed tools to detect proteins using mass spectrometers. In the new study, they purified proteins that were "labeled" by organelle markers and identified each by mass spectrometry. The team then used computer tools to reconstruct human cells.

Dr. Knight, a bioinformatician at the LTRI Gold Glass Laboratory, said: “Through our study, we have shown that we can pinpoint thousands of proteins at one time with relatively few efforts. Previous approaches to localizing proteins require separate studies for each protein, or require limited focus.”

Considering the vast nature of the human cell map, the team also created an analytical portal that enables researchers around the world to study the data in greater depth. Users can scan 192 markers in detail and compare their own protein localization data with the predicted data in the human cell graph.

While this work provides a better understanding of the internal organization of human cells, it can also be used to better understand what happens during disease, Knight says.

“Human diseases are typically characterized by the fact that, at the molecular level, proteins have abnormal behavior that leads to cells behaving in a pathological manner. In these cases, proteins often change their location in the cell,” Dr. Knight said. “Our study is the first step to address the challenge in normal cells, and we can use it to compare with altered cellular states, such as disease conditions, to identify proteins with unexpected localization, which may help us better understand diseased cells.”

The team stated that this map will be used in various projects to help further elucidate protein localization in human cells. Future efforts will include the use of chemical, viral, and disease conditions to better characterize how cells are structurally adapted to these stressors. This could inform future research efforts, mechanistic understanding of disease states and the development of future therapies.