Mapping the Human Proteome: A Conversation With Dr Lydie Lane

This year, science celebrates mapping 90% of the human proteome, an endeavor that has been achieved by the Human Proteome Project (HPP). Technology Networks explored the journey to this successful feat by speaking with Dr Lydie Lane.

Lane has been co-directing the CALIPHO group at the University of Geneva and the SIB Swiss Institute of Bioinformatics with Professor Amos Bairoch since 2009, where the researchers' main mission is the evelopment of neXtProt. She is also the co-chair of the C-HPP component of the HPP.  

Molly Campbell (MC): Why is it important that we map the human proteome, in addition to the human genome?

Lydie Lane (LL): Mapping the genome was very important because the genome contains all the instructions to build the components of a living cell or a living organism. But the true actors of life are proteins. They act as little machines that are responsible for all our biological functions (nutrition, reproduction, respiration etc). “Mapping the proteome”, i.e. observing these proteins in biological samples, allows us to understand in which quantity they are produced and when, how they work, where they are located, how they interact together and how they are modified or broken in certain conditions, etc. This information is key to understanding how the human body works.

MC: Your research lab's main mission is the development of neXtProt. For our readers that are unfamiliar, please can you tell us about neXtProt?

LL: neXtProt is a freely accessible “one-stop-shop” on human proteins. We select high quality information on human proteins from a variety of online resources, standardize this information and redistribute it through our intuitive web interface and dedicated viewers. We have developed unique query tools that allow researchers to mine this huge quantity of information and answer very specific questions. 

MC: The HPP is divided into the C-HPP and the B/D-HPP. As the co-chair of the C-HPP executive committee, can you please explain why the project is divided in this way?

LL: One of the very first tasks of the HPP was to get convincing experimental evidence for the existence of each of the ~20’000 proteins predicted by the analysis of the human genome. Since the genes encoding these ~20’000 proteins are distributed on the 24 human chromosomes, it was natural to divide the work chromosome per chromosome. As the HPP is an international project, each participating country initially chose one chromosome and became responsible for monitoring the validation status of all predicted proteins on this chromosome.

The 24 human chromosomes can be seen as books containing the instructions to produce all the human proteins. However, once the proteins are produced, the function they perform in the body is independent from the chromosome that originally encoded them. In order to study their role or their involvement in disease it is important to study proteins in their global context. The B/D HPP project tackles this challenge by focusing on broad biological or medical questions and applying more systemic approaches.

The C-HPP and B/D HPP are complementary projects to understand the human proteome in all its complexity. The first one ensures that all proteins are covered by the project, and the second one puts all pieces together.

MC: Please can you discuss your lab's contribution to the HPP and the typical research methods you adopt in this space?

LL: As the reference knowledgebase of the HPP, neXtProt integrates and standardizes all the data generated by the teams participating in the project and produces annual metrics to monitor its progress. This is done in close collaboration with the other key resources involved in HPP, such as the Human Protein Atlas and PeptideAtlas.

For about 10% of the human proteins, we have no clue on their possible biological function, as they don’t look like any other characterized protein in other species. This represents the “dark matter” of the human proteome. Our team uses a combination of approaches to propose functional hypotheses for them, hoping to stimulate laboratories to work on these potentially very important actors of human biology.

MC: What challenges have you encountered in the HPP? How did you work to overcome them?  

LL: The HPP is a large consortium with very skilled and enthusiastic teams who strive to understand the complexity of the human proteome. This is a daunting task and it is sometimes difficult to prioritize the actions. The annual HUPO meetings and the intermediary HPP meetings have proven very important to share the results and define common standards.

One of the biggest challenges is that there is no dedicated funding for the HPP project, in contrast to the former Human Genome Project. Nearly all the teams (including ours) participate in the global HPP effort on a voluntary basis, which undoubtedly slows down the whole project.

MC: What has been a major highlight for you throughout your involvement in the HPP?

LL: Ten years after the official launch of the HPP, we were very happy to announce this year that more than 90 % of the human proteome is now validated with high stringency. This provides the community with a solid ground for functional studies.

In the past eight years, we have also contributed to the functional validation of several “dark proteins” with potential involvement in diseases. 

MC: What are your next steps in this research space?

LL: Validating the existence of proteins is good, but understanding what they do is better! We hope that the knowledge and tools we integrate in neXtProt will continue to facilitate and speed up the generation of functional hypotheses for all the understudied proteins.

We also need to better represent the inter-individual variability of the human proteome in neXtProt. Indeed, understanding the impact of genetic variations on proteins’ structure and function is key to understand disease mechanisms and susceptibility.

Finally, we will continue to improve the interoperability of neXtProt with resources focusing on clinical and pharmacological data in order to better answer the needs of the medical community.

Dr Lydie Lane was speaking to Molly Campbell, Science Writer, Technology Networks.