Interview with a scientist: Cell Atlas - past, present and future challenges

The Cell Atlas, part of the Human Protein Atlas project, is the most comprehensive database for subcellular protein localization. Read on to learn more about it!

Today we meet with Dr. Peter Thul, group leader at the Human Protein Atlas (HPA) project, Stockholm, Sweden. Peter is one of the scientists behind the Cell Atlas: a database that provides high-resolution insights into the expression and Spatio-temporal distribution of proteins within human cells.

We asked Peter 10 questions about the past, the present, and the future of the Cell Atlas.

Q1: Peter, could you explain the Cell Atlas in simple words?

As part of the Human Protein Atlas (HPA) project, the Cell Atlas focuses on a particular aspect of the humane proteome. Here, we want to know how proteins are distributed within single cells. To answer this question, we are using fluorescent immunocytochemistry, which allows us to systematically assess the protein's location in various cell lines and assign them to fine subcellular structures such as organelles.

Our images are publicly available on the HPA website and can be explored along with interactive educational sections about organelle proteomes or protein expression during the cell cycle.


Photo: Peter Thul, Ph.D. Group leader, Human Protein Atlas, Stockholm, Sweden.

Q2: What does it deliver in terms of biological insights?

Subcellular distribution is an essential step in protein characterization, as it is often directly linked to the protein's function, its regulation, and the availability of possible interaction partners. Thus, on a cellular level, the knowledge of a complete organellar proteome helps to understand its role in revealing novel functions.


Q3: What is the translational application, if any?

One possible application could be the discovery of novel biomarkers for cancer. For example, suppose we identify a gene that shows variations in the expression levels in single cells and that is correlated with the cell cycle. In that case, we can search for that gene in the HPA database (specifically in the Pathology Atlas) to understand whether it is highly expressed in a specific tumor cell line and if this correlates to shorter patient survival.


Q4: Could you share a turning point or defining moment in the Cell Atlas creation history?

I would say that one of the defining moments was our major release in 2016, along with the publication of our paper in the AAAS/Science journal. For this release, we increased the number of mapped proteins to over 12,000, added more subcellular structures, included custom assays, thus providing data beyond our normal standards.

There was so much information, so we had to re-design the educational pages because we wanted them to be more informative and intuitive for the users.

On a cellular level, the knowledge of a complete organellar proteome helps to understand its role in revealing novel functions.


Q5: How prevalent is the use of the Cell Atlas today compared to other resources?

The Cell Atlas is still the most comprehensive database for subcellular protein localization, and we are constantly adding new data and features. The increasing number of visitors on the HPA website and the positive feedback we constantly receive clearly indicate how many researchers and educators like it.

In recent years other initiatives have been launched with a similar goal. This might be seen as competition to us. However, in my opinion, such initiatives generate more attention towards protein mapping and atlases in general. Furthermore, each initiative has a different approach, so we are complementing each other, providing altogether a more holistic view of the human biology.


Q6: What do you see as a limit of the Cell Atlas, if any?

I mainly see technical limitations. For example, when working with immunofluorescence (ICC-IF), you need a super-resolution microscope to distinguish small structures of less than 200 nm. Unfortunately, at the moment, we cannot pass this limit.

The fixation of the cells for the antibody-staining is another technical disadvantage because it makes it hard to follow dynamic cellular processes over time.


Q7: How does the Cell Atlas enhance the understanding of human diseases?

The Cell Atlas is a helpful resource for the identification of a mislocalized protein causing a disease. In fact, proteins have to be present and active in the right place at the right time in order to function correctly. The mislocalization of proteins characterizes many diseases to other parts of the cells. For many proteins, there is still no available data about their subcellular location besides the information that we provide on the Cell Atlas.


Q8: What questions were you addressing when you started working on the Cell Atlas?

One of the most intriguing observations of the Cell Atlas is that approximately half of the proteins localize to more than one organelle simultaneously. These so-called "multilocalizing proteins" play a significant role in increasing the proteome's functionality and the cell's complexity from a systems perspective. Therefore, I was interested in multilocalizing proteins detected in both the Golgi apparatus and the nucleus, which are non-neighboring organelles and have distinct functions. Interestingly, these multilocalizing proteins link both organelles (Golgi apparatus and nucleus) by yet to unravel connections.  


Q9: What happens next in the process of cell biology discovery?

We live in a time where the amount of available image data is massively increasing, where the quality of image analysis and modeling is making immense progress thanks also, to novel approaches such as the Convolutional Neural Networks (CNN). I think that in the next future, CNNs will not only enable and speed up the work with big data but will also unveil new information in the existing datasets missed before. With the CNNs approach, it is also possible to make models of canonical cells, accurately predicting the outcome of an assay without experimenting in the wet lab.


Q10: If you could offer readers interested in cell biology one key piece of advice, what would it be?

Seeing is believing. The visualization of biological processes by microscopy is a powerful tool to understand and explain cellular events. So always have a look at our images in the Cell Atlas!


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Read more about the Human Protein Atlas!