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Mathias Uhlén: Discovering the Building Blocks of Man

Researcher Mathias Uhlén, Ph.D., opens the human proteome for all researchers to explore. He then leads the journey into what makes us healthy, how disease starts, when the aging process begins and how to apply that knowledge to life sciences discovery and technology to improve the human condition.

“These proteins are necessary for everything in the human body, and many are targets for pharmaceutical drugs,” says Uhlén, a professor of microbiology and biotechnology at the KTH Royal Institute of Technology (KTH; Stockholm, Sweden). He adds that all cells need proteins to maintain housekeeping functions such as cell growth, energy generation and basic metabolism, “and when you take a pill that affects a specific protein target, you affect every cell in the human body.”

Uhlén reveals another surprise he encountered: the highest number of unique proteins is found in the testes, followed by the brain and the liver. “That bit of research created a lot of stir in the media when we published it two years ago,” Uhlén says. “I always thought, and I think many researchers still believe, that a lot of the unique protein building blocks in humans are found in the brain, but that is not true.”

His research became The Human Protein Atlas (HPA), a map of human proteins in cells, tissues and organs throughout the body, unveiled using antibodies and various omics technologies that include mass spectrometry-based proteomics, transcriptomics and systems biology. His group launched an open-source interactive website in 2005 with this research that features protein expression data based on approximately 700 antibodies and hosts more than 200,000 visitors every month. Uhlén also reports that many visitors are pharmaceutical companies. “I think the data are surprising for the pharma companies and they are checking for the presence of their targets in the human body,” he says.

In the process of researching proteins, Uhlén’s group at KTH first described a number of innovations in science, including engineered protein A and protein G for purification of antibodies; affinity tags for purification of recombinant fusion proteins; solid phase methods based on magnetic beads for DNA handling using the biotin-streptavidin system; pyrosequencing leading to the first next-generation DNA sequencing instrument; and affibodies, protein binders aimed for therapeutic applications.

Uhlén’s group also published 480 papers that resulted in 50,000 citations, making Uhlén the highest cited Swedish scientist in medicine under the age of 65. Patented innovations emerged as well, achieving more than €1 billion in sales and helping Uhlén start 14 companies, four of which are now publicly traded.

“We want to understand the human building blocks of life to map the biomolecular parts list of humans,” says Uhlén. “We hope that it leads to a better understanding of human biology and also better diagnostics and treatments for patients.”

Opening the Proteome

In the 1990s, Uhlén worked on The Genome Project with genomics pioneer J. Craig Venter, Ph.D., who he counts as an inspiration for his research today. Sequencing the human genome gave new insights into human biology and disease and led Uhlén to desire an understanding of the dynamic expression of each of the approximately 20,000 protein-coding genes and the function of each protein.

He began to build the HPA, which represents the joint efforts of KTH, Uppsala University and Uppsala Akademiska University Hospital (both located in Uppsala, Sweden) as well as collaborations with 14 other countries. More recently, the group received added support from the Science for Life Laboratory (SciLifeLab, based in both Uppsala and Stockholm), a national center for molecular biosciences with a focus on health and environmental research.

Three separate parts compose the HPA and each focuses on a particular aspect of the genome-wide analysis of the human proteins. The Tissue Atlas exhibits the distribution of the proteins across all major tissues and organs in the human body. The Cell Atlas shows the subcellular localization of proteins in single cells. Finally, the Pathology Atlas reveals the impact of protein levels on the survival of patients with cancer. What most gives Uhlén a sense of satisfaction are three published articles that capture the heart of this research.

Uhlén’s 12-year development of the HPA is featured in the 2015 article “Tissue-Based Map of the Human Proteome,” which charts the human tissue proteome using quantitative transcriptomics on a tissue and organ level combined with protein profiling using microarray-based immunohistochemistry to achieve spatial localization of proteins down to the single-cell level. In this article, Uhlén's team provides a global analysis of the secreted and membrane proteins, as well as an analysis of the expression profiles for all proteins targeted by pharmaceutical drugs and proteins implicated in cancer. According to his article, analysis of the 618 proteins targeted by clinically approved drugs unexpectedly shows that 30 percent are expressed in all analyzed tissues. An analysis of metabolic activity based on genome-scale metabolic models reveals the liver as the most metabolically active tissue, followed by adipose tissue and skeletal muscle.

In 2017, Uhlén’s team unveiled two articles that expand the searchable data of the original HPA. A Subcellular Map of the Human Proteome” reveals that because proteins function in the context of their environment, an understanding of cellular processes requires knowledge of protein localization. In this report, the team uses immunofluorescence microscopy to map 12,003 human proteins at a single-cell level into 30 cellular compartments and substructures. They validate their results by mass spectroscopy and use them to model and refine protein-protein interaction networks. The team demonstrates that the cellular proteome is highly spatiotemporally regulated. Many proteins localize to multiple compartments, and many show cell-to-cell variation in their expression patterns.

The second article published in 2017, “A Pathology Atlas of the Human Cancer Transcriptome,” is a study of genome-wide transcriptomics data and clinical metadata of almost 8,000 patients that analyzes the proteome of 17 major cancer types. The research provides more than 900,000 patient survival profiles that include data for tumors of colon, prostate, lung and breast origin. This interactive data set can also be used to generate personalized patient models to predict how metabolic changes can influence tumor growth.

Together, the three articles have been cited more than 2,000 times already, Uhlén reports. “Some of the resulting innovations from our research are not clear cut, but we have now initiated several clinical trials and more than 200 patients have been treated in clinical trials with molecules that have come out of the work of our group,” he says, adding that 95 percent of all the therapeutic antibodies being sold commercially today have been purified using innovations from his research group. “It is of course extremely rewarding that our inventions have contributed to millions of cancer patients being treated with antibodies.”

Diving into Life and Research

Not content to relax in a chair, Uhlén’s life outside of his work is as vigorous as his time in the lab. He likes to explore the world through travel adventures, which he captures in short video movies that he enjoys producing. “As I work rather a lot, it’s nice to take time away with my family,” he says.

He and his wife recently escaped to the unique and pristine ecosystem of the Okavango Delta (Botswana, Africa), a 9,300-square-mile wilderness sanctuary comprising water channels, lagoons and islands. More recently, Uhlén and his three daughters snorkeled their way through Mauritius in the Indian Ocean. Ages 26, 24 and 22, the older two daughters followed their father into medicine, one working as a medical doctor, the other as a nurse. The third daughter moved into Uhlén’s business footsteps.

"While I never intended to do research and always thought of going into industry, I got hooked early on," says Uhlén. “The path into science was very much serendipity.” Being the top scholar in chemistry at KTH when he earned his Ph.D. in biotechnology in the 1980s merited Uhlén a research stipend to study anything he wanted.

"I had the money to do research, but I didn’t know what to do," he comments. Advice from his KTH mentors, including Hans Wigzell, Ph.D., a former president of the Karolinska Institute, pointed him toward molecular biology. "So I used the money to do medical genetics research in Uppsala for Lennart Philipson, Ph.D., and then did post-doctoral studies at The European Molecular Biology Laboratory (EMBL; Heidelberg, Germany). Then I came back to KTH with knowledge and technology and started my own group," says Uhlén, who became a professor in microbiology at KTH in 1988. “It started small, but now more than 100 graduate students have got their Ph.D. as part of our team. It’s been a nice journey.”

He celebrates the diversity of his research career. In the 1980s, he worked in protein production and purification. This led to an opportunity to do research into tree biology and forestry in the 1990s. At this time, he also became involved with laboratory automation and genomics before spending the 2000s pursuing the HPA.

“These were very different fields. It’s quite fun to move into new ones,” he says, noting that he spent a significant amount of time in industry, holding board positions for a couple of companies and serving in various leadership roles for scientific endeavors, including being the founding director of the SciLifeLab. “It’s always a bumpy road to start a new enterprise, but I enjoy doing that work and it’s interesting.”

Keynote Presentation at SLAS Europe Conference

Uhlén’s next step is to direct his career toward precision medicine and using new tools of technology for analyzing human body fluids in diagnostics. This is the topic of his keynote presentation on June 27 at the inaugural 2018 SLAS Europe Conference and Exhibition in Brussels, Belgium.

"We take two methods already established in hospitals today–classical diagnostics and modern medical imaging–and combine that with new omics technologies, which use massive big data analysis,” says Uhlén. “What results is the world's most comprehensive analysis of healthy people to create a database.” The database includes samples gathered from research subjects every three months over the course of years to analyze health changes such as infections and aging.

“We determined the biomarkers for disease, aging and health and will now move into using that as a precision medicine platform. I have some unpublished results I plan to share with the SLAS Europe community at the conference," says Uhlén. “The ultimate aim is to help the doctor diagnose patients, find disease early and decide about and follow treatment plans.”

He joins other keynote speakers, including futurist Peter Hinssen of nexxworks (Ghent, Belgium), and policy maker Max Lemke, representing Components and Systems of the European Commission (Brussels, Belgium), at the conference. In addition to the keynote speakers, the scientific program includes 50 presentations addressing emerging and hot topics in investigative biology, life sciences technology and life sciences discovery. Event participants also can explore the latest products, technology and services of more than 70 companies in the innovative exhibition.

Uhlén is excited about participating in the SLAS Europe Conference. "This community is interesting to me," he says, noting that like SLAS, his career thrives at the intersection of life sciences discovery and technology. "In the 90s I was working a lot with automation and started a company called Magnetic Biosolutions (later acquired by Nordiag AS) that did robotics for labwork. We sold more than 500 of these laboratory automation systems to different researchers. My presentation before this scientific community brings my career full circle."

May 7, 2018