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Working around the Body Clock: A Cancer Researcher and her Start-Up

A professor, mother, start-up CEO, and karate enthusiast – there are many sides to Angela Moreira Borralho Relógio. Her career has taken her from Lisbon to Hamburg with stops in Heidelberg and at Charité – Universitätsmedizin Berlin along the way. All this has made her a thoroughly interdisciplinary European researcher. She has a real focus on the practical application of her research and this motivates her to keep going further and thinking bigger. It was a pleasure to spend an afternoon together at Stiftung Charité’s new offices in Berlin-Mitte, from where you can see the iconic high-rise Charité hospital building. After many years in Berlin, Relógio and her working group completed their move to Hamburg in summer 2023. We invited her back for a FACES interview to tell us about her experience on our Inventors for Health pilot program from 2019 to 2021, among other things.

The biological clock is central to Angela Relógio’s research, teaching, and entrepreneurship. It ticks in virtually every cell of the body and plays a crucial role in human health. It is also known as the circadian clock because it roughly covers a 24-hour period. “Circadian” comes from the Latin circa (about) and dies (a day). Disruption to the circadian rhythm can negatively impact a person’s physical and cognitive abilities and is associated with an increased risk of sleep disorders, depression, diabetes, neurodegenerative disease, obesity, and cancer. But it is impossible to generalize – everyone’s “internal clock” ticks differently. 

When we sit down to talk, I mention digging out Relógio’s 2019 Inventors for Health funding application in our archives in preparation for our meeting. “The memories!” she laughs. A lot has happened since then. The TimeTeller project has led Relógio and her team to develop a non-invasive way to profile your individual circadian rhythm, and they have also created a testing kit that can be delivered all over the world. This year, following intensive preparations, they founded a start-up under the same name which will enable them to scale up and commercialize the TimeTeller kit and associated laboratory analysis.

I ask if Prof. Relógio can remember the beginnings of her research career. She answers without hesitation. She has always been interested in cancer research and even wrote her final dissertation on radiotherapy during her first degree in physics engineering. After studying in Portugal, she joined the European Molecular Biology Laboratory (EMBL) in Heidelberg: “I wanted to research cancer and combine what I had already done with the latest techniques that I hoped to learn in the lab.” The team in Heidelberg was very interdisciplinary and welcomed her academic background with open arms. She had never even held a pipette but all that would soon change. 

In Heidelberg, she built up a deep understanding and respect for the gradual discoveries and progress inherent to laboratory research and basic science. In 2007, she then moved to Charité – Universitätsmedizin Berlin in search of a more direct clinical approach.

Angela Moreira Borralho Relógio

Funding program
Inventors for Health (pilot)

Funding period
2019 to 2021

Circadian Medicine and Systems Biology

Project title
TimeTeller: A non-invasive method for the molecular and computational characterization of the internal biological clock in humans 

Former Institution
Charité – Universitätsmedizin Berlin


Founded TimeTeller GmbH

2020 – present
Professor of Systems Medicine and Biostatistics, MSH Medical School Hamburg 

Joined the BIH Digital Health Accelerator

Habilitation in Molecular Biology and Bioinformatics, Charité – Universitätsmedizin Berlin

From then on, Relógio made the circadian rhythm – “basically oscillators and waves!” – her focus. It was an area where she could apply her expertise in both physics and biology using computer-based analysis. Some significant achievements have included a Rahel Hirsch scholarship at the Charité which gave her a certain degree of academic independence and enabled her to work on her habilitation, followed by a BMBF grant in connection with the e:Bio systems biology innovation competition which enabled Relógio to establish a five-person team to work on the effect of the circadian rhythm on cancer cells. Winning the BSIO Female Independence Award was very motivating too. “The award also helped me to buy the equipment I really needed back then,” she says.

It became increasingly clear to Relógio that there was a lack of clinical studies on the circadian rhythm within the field of cancer research. She sought out clinicians who might provide samples from cancer patients and include her and her team in their studies. She was driven by the belief – cemented by the few scientific studies she could find on the subject – that the time of day that a patient receives their chemotherapy treatment may make a difference. She soon realized why there were so few systematic studies: there was no standardized and easily applicable method that researchers could use to measure this biological rhythm accurately.

“Let’s develop one ourselves!” was the logical conclusion. By this point, the team had already established their own way of measuring the rhythm of cells in a petri dish and it worked well. Together, they embarked on “a kind of pioneer work”, Relógio recalls with pride. They demonstrated how the “clock” in cancer cells ticks differently to the one in normal cells.

This led them to identify a new goal: to minimize the side effects of chemotherapy by sparing and saving healthy cells as much as possible while stopping the growth of cancerous ones, ideally eliminating them. That is the persistent paradox of established cancer treatments. A deadly illness is fought with a poisonous cocktail of chemicals which can cure the cancer but harm the body. “It is a big problem in drug development. Around 90 per cent of the substances tested are eliminated. In the case of around 30 per cent of these, it is not that they would be ineffective, but they are just too toxic.”

So began a new phase involving a suspicious amount of hair. And not just hair. Relógio and her team also took their own blood and saliva samples for experimental purposes. The memory makes her smile. The circadian rhythm can be measured in all three sample types. The researchers’ blood, sweat, and tears were almost literally worth it. Later they would focus on saliva: “you only need to spit”. But this still presented potential difficulties. What if cancer patients are unable to do so? They may no longer be able to produce spit reliably, or they might have an infection or a dry mouth. Further studies were needed – and helped overcome these concerns. Saliva samples were the way to go.

In conversations with external stakeholders, the question of patenting the method for measuring the circadian rhythm and taking a more commercial approach in future arose. Relógio carried this question around for a while before coming across Stiftung Charité’s call for the Inventors for Health pilot program. She was surprised at the outcome of her application, not just because it successful (as one of three projects selected for the innovation funding program), but also because the jury was genuinely excited about TimeTeller’s potential. She had thus far not received that kind of feedback within scientific circles.

Over the next few years, her knowledge and self-confidence as an entrepreneur grew. She invested her own money in TimeTeller and filed two patents. All this would have been unimaginable without Inventors for Health – or “I4H” for short, as Relógio calls it in our conversation – and the mentors and network she was able to access through the program. Significant support came from people like Marvin Stolz (Head of Innovation, Stiftung Charité) and Craig Garner (Professor of Neuroscience and translational research expert as well as cofounder of SPARK-BIH). The flexibility of the funding also enabled Relógio to hire another employee and buy a robot which meant her team could suddenly analyze twelve samples at once instead of just one. “It feels like nothing from where we are now, but it was an amazing leap forward at the time,” she says. “We have since developed a very professional TimeTeller kit. But back then in the I4H bootcamp, we were just making boxes out of paper, adding pieces of sponge and plastic and going, this is how it might look one day!” Relógio has to laugh at those initial attempts at product design. She learned that a good kit is one that can be used correctly by people who have never seen it before, so that samples they take can be successfully analyzed in the lab. Relógio and her team thus asked people to test the kits to find out what worked. The results and feedback from these people fed into various different versions of the TimeTeller kit – with or without an ice pack, gloves, or image-based user instructions, for example – until they finally arrived at the version used today. 

At the same time, more and more questions were emerging on the research side. The team needed to work out how to extract the most RNA possible from a test person’s saliva and validate the rhythm measurements: “Does this really work for everyone or not?” And the ultimate goal was still a long way off: “Our vision was to be able to tell cancer patients the best time to undergo their individual treatment.” Notwithstanding their expertise in mathematical modeling, they slowly realized that it was not possible to generalize. “You can’t just specify a treatment time regardless of what the treatment itself involves. The disease is actually less relevant than the medicine – whether you take aspirin or ibuprofen makes a difference. These medicines impact your body differently, so the optimal time to take them also varies.”

The next logical step was for Relógio and her lab group to focus on the medication Irinotecan which has a wide range of applications. It is used to treat various types of cancer including bowel and ovarian cancer. Relógio explains that the biological clock – which is itself determined by genes – regulates at least 50 per cent of a person’s genome, including the cell cycle and metabolism. The immune system and the ability of cells to repair themselves are also governed by the circadian rhythm. Once the right medication for a person has been identified, the researchers could synchronize a person’s biological clock and metabolism with the metabolism of the medication. They could also identify a curve indicating the toxicity of the drug for that individual. This curve would then show the least and most toxic time to take the medicine.

The process outlined above worked very well in the lab. But clinical studies were needed to investigate the extent to which it would be feasible in practice. So far everything indicated that it would work. Relógio emphasizes that all the scientific results and mathematical models up until then had been published because she did not want processes like patenting to slow down scientific advances. She shows that being a researcher and an entrepreneur does not have to be a contradiction in terms, an important message for others in the medical field. “It is a decision you have to make,” Relógio says. “There are plenty of companies out there that keep things to themselves. But I did not want to keep things secret, I wanted to help people!” Relógio is pleased that fellow researchers can use the results from her lab to further their own work.

Im Rahmen der Inventors for Health-Förderung lernt Relógio Anne-Mette Jensen kennen, eine der Mentorinnen des Pilotprogramms. Jensen kennt sich aus mit The Inventors for Health scheme brought Relógio into contact with Anne-Mette Jensen, one of the mentors on the pilot program. Jensen was familiar with the process of founding companies in the MedTech field, as well as aspects like product design. She also had a good network and knew who could code or design good apps. And she was just “a great person”. When Dorothée Döpfer, the program manager at BIH for the Digital Health Accelerator (DHA), saw Relógio present at the I4H bootcamp, she encouraged her to apply for DHA funding too. “I’m so grateful,” Relógio says, “because otherwise I might not have done so.” She wrote the application together with Jensen, drawing on everything she had learned and developed at I4H. 

While working on the application, it became clear to her that they would need the support of doctors too. Relógio toyed with the idea of collaborating with those researching leukemia because blood samples from such a systemic type of cancer would work well. She approached Professor Angelika Eggert, the renowned childhood cancer specialist and Director of the Department of Pediatric Oncology and Hematology at the Charité, who was open to the idea. Eggert’s lab became a clinical TimeTeller partner, and Relógio could start a study on leukemia and the circadian rhythm with Eggert’s group. Relógio joined the Digital Health Accelerator with this project. She then successfully took part in stage two, learning more and more about regulations, market authorizations, simply put: business. At the same time, she continued her research work, taking part in a large gynecological oncology study at the Charité led by Professor Jalid Sehouli and Professor Elena Ioana Braicu involving patients from over twenty hospitals in Germany. At this stage, she could not yet advise individual patients on the optimal time to take their medication for ethical and legal reasons. That was hard for Relógio as this was what she really wanted to do. But she could generate valuable data with which to evaluate whether the TimeTeller prognoses aligned with the eventual outcomes of the participants in the study regarding the progression of the disease and side effects. 

Relógio managed to recruit healthy participants for a control group from her sports club at the time in Berlin. Almost 200 people were prepared to have their sports performance analyzed at different times of day and linked to their biological clock. The results were incredibly accurate, “a huge success!” Word began to spread. A Portuguese hospital got in touch with Relógio. Researchers there were working on Parkinson’s, a disease which responds very well to sport and movement therapy. Often the progression of the disease can be slowed in this way. The Parkinson’s project, which Relógio then designed with the team there, is still running today. Overall, TimeTeller is now involved in numerous studies across a diverse range of potential applications, including a recent study on brain tumors and another in women’s health. There are so many more possibilities.

It is hardly surprising that MSH Medical School Hamburg, a private university, began to take an interest in Relógio’s ingenuity and passion for research. At the time of her negotiations with MSH, Relógio had completed her habilitation and was leading a research group at the Charité. “At some point you want to get to the next level and become a professor,” she explains. And MSH would ultimately make her a convincing offer. She not only got to move with her working group and continue work on TimeTeller, but was also able to found a new institute, the Institute for Systems Medicine. These days, she is on first-name terms with Ilona Renken-Olthoff, the Director of MSH. Relógio praises her openness and approachability and sees her as a real role model for career women. She is also grateful for the support that she received in Hamburg at the Medical School and beyond. At first, Relógio had to commute between Berlin and Hamburg. But a start-up grant from InnoRampUp made the move north complete. Indeed, moving was a condition of the grant from IFB Hamburg. It made complete sense to Relógio that the funding should benefit the region and so her family made the move too. The timing was important to her as a mother, and it worked well for both her son and daughter. 

What next? “Now is the time to stay realistic!” Relógio says. Her caution might seem strange given her successful track record, with patents filed in the USA and Europe and a network that has gone from strength to strength, but she points out that the start-up still needs to prove itself financially viable. Now her children are older, she has plenty of energy for research, teaching, and entrepreneurship. She even teaches me a little Portuguese during our interview: relógio in fact means “clock”. Maybe it was all meant to be.

Dr. Nina Schmidt
August/September 2023