Today we meet with Dr. Cecilia Lindskog, group leader at Uppsala University in Sweden, and the site director of the Tissue Atlas part of the Human Protein Atlas (HPA). Her research is focused on protein science, understanding the biology and functions of human proteins expressed in different organs, and the underlying mechanisms leading to cancer and other diseases.

We asked her 10 questions about the past, the present, and the future of the Tissue Atlas.

Photo: Dr. Cecilia Lindskog, group leader at Uppsala University in Sweden, and the site director of the Tissue Atlas part of the Human Protein Atlas (HPA).

Q1: Cecilia, could you explain the Tissue Atlas in simple words?

The Tissue Atlas is an open-source tissue-based interactive map of the human proteome launched in November 2014. It is part of a multinational research project, the Human Protein Atlas (HPA), which aims to map all the proteins in the human body.

The Tissue Atlas is a collection of hundreds of immunohistochemical microscopic images corresponding to tissues from most parts of the human body, showing where all human proteins are localized.

The Tissue Atlas is based on quantitative transcriptomics on a tissue and organ level combined with protein profiling using tissue microarray-based immunohistochemistry to achieve spatial localization of proteins down to the single-cell level. By navigating the Tissue Atlas, you can explore the human secretome, the membrane proteome, the druggable proteome, the cancer proteome, and the metabolic functions of proteins in 32 different tissues and organs. 
 

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

Since we are using intact tissue samples and microscopic sections, we can localize exactly where the proteins are found, both wherein the tissue and inside the cells and see it with our own eyes. The spatial information of each protein gives important clues on the function of the protein itself. In many cases, only certain cell types or a subset of the cells express a certain protein.

Q3: What is the translational application, if any?
To understand the underlying biology of diseases, the molecular repertoire under normal circumstances is very important. Our data provides a thorough overview of the localization of every protein in normal (healthy) tissues. It is also possible to compare the expression with cancer samples from the Pathology Atlas.

The information on the Tissue Atlas can be used for the identification of potential diagnostic or prognostic markers applicable to clinical pathology, but also for exploring potential drug targets. In drug development, it is very important to know exactly where the drug target is expressed, to understand how the drug may work and which potential side effects that may arise when using the drug.

Q4: Could you share a turning point or defining moment in the Tissue Atlas history?
As I mentioned before, the Tissue Atlas is a part of the HPA project. When RNA expression data was added to it in 2013, a whole new era started, as the integrated omics approach allows us to comprehensively categorize all human genes according to expression levels.

The Tissue Atlas and the whole HPA database are like a living organism growing and expanding as bits of knowledge and new technologies come along. Every year new antibodies and new tissue samples are added. In 2017, for example, the Tissue Atlas was expanded with extended tissue profiling of the caudate nucleus of the brain, with the addition of the thymus and a refined annotation of over 500 genes elevated in the testis.

Q5: How prevalent is the use of the Tissue Atlas today compared to similar databases?
Well, this is a difficult question. There isn’t much data to compare it with.  The Tissue Atlas is the only atlas based on immunohistochemistry across all major normal organs where researchers have open access to 10 million immunohistochemistry images corresponding to 87% of all human protein-coding genes. The database has >100.000 unique visitors per month and is one of the top databases related to omics data.

The primary antibodies use to generate the immunohistochemical staining for the images in the Tissue Atlas, are commercially available as Triple A Polyclonals from Atlas Antibodies.

Q6: Is there any barrier to the wider adoption of the Tissue Atlas?
A large proportion of the proteins have an unknown function, and, at the RNA level, the corresponding genes seem to be expressed in most tissues, although at different levels. Using immunohistochemistry, it is a challenge to interpret such results, as there is no “ground truth” if the differences in expression levels also are expected to be seen on the protein level.

However, I am sure that the integration of several datasets and the continue collaborating with research groups from different disciplines using different methods will help us to increase our understanding of these unknown proteins.

Q7: Neuroscience and cancer research: how does the Tissue Atlas enhance the understanding of diseases?
The data organized into the Tissue Atlas is fundamental to understanding how the protein behaves under normal circumstances (i.e. in healthy tissues). We can then compare this knowledge with the data obtained by using, for example, human cancerous tissues – this comparison can apply to any disease. The ultimate goal is to collect information that will help to develop new therapeutic targets.

Q8: What questions were you addressing when you started using the Tissue Atlas?
Which tissue expresses the most proteins? What kind of proteins are expressed in different tissues?  How does a disease such as cancer alter the distribution of proteins in a certain tissue? We were looking for answers.

Today, our aim is to provide a thorough and comprehensive overview of all human protein-coding genes and show where these proteins are localized within the tissue, by screening all major organs and tissue types in healthy and cancerous human tissues.

Q9: What happens next in the process of the Tissue Atlas and discovery?
Even with multiple breakthroughs in the past several years, there remain elusive discoveries that are still out of our reach, but they could be addressed with the involvement of experts in various fields. For now, we can look more into details in the already existing images available, add and validate more antibodies and analyze extended samples, such as samples from rare tissues.

Q10: If you could offer readers one key piece of advice about the Tissue Atlas, what would it be?
Don’t forget to look at the images! The deeper you navigate the Tissue Atlas, the more you discover. The spatial localization of proteins in the tissue is a unique piece of information. The immunohistochemistry images can be seen in high resolution by clicking on the various tissues. Just by clicking on the primary data section, you are directed to the stained images from 44 normal human tissues, including 76 distinct cell types.

The actual images contain much more information than cannot be summarized with bar charts and numbers only. The Tissue Atlas is so rich and detailed that you might be surprised to find unique information about your protein of interest.

Readings

Uhlén M, et al. Tissue-based map of the human proteome.  Science 2015 347(6220):1260419.

Uhlén M, et al. A human protein atlas for normal and cancer tissues based on antibody proteomics. Mol Cell Proteomics. 2005 4(12):1920-32.