Healthy games

Cartilage repair

Finding impurities

Healthy games

Science

Galactic romanticism

To boldly go where no man has gone before is probably not the most distinctive description of what scientists are doing. But the inspirational meaning of this well-known Star Trek phrase – a space-walking transliteration of the Latin expression terra incognita – is what best captures the adventurous nature of science. The following collaborative science projects all aspire to this galactic romanticism.

Stories by K.E.D. Coan, Michael Mildner, Ege Huesemoglu and Goran Mijuk, Photos by Adriano A. Biondo and Bjoern Myhre

Healthy games

Table of contents

Healthy games

Cartilage repair

Finding impurities

Published on 30/09/2022

Playing video games to improve cognitive health has the potential to help people train their minds in an enjoyable, convenient, and more effective way. Cognitive decline affects most people as they age, as well as being a common symptom of traumatic brain injury and diseases such as Alzheimer’s and Parkinson’s. There are no cures for these conditions, but cognitively stimulating games can help slow the decline. Through such games, physicians – who usually only see patients once or twice a year – could also have a more continuous and unbiased picture of their patients’ progress. Despite these potential benefits, no clinically validated games have made it to the market yet. This is because developing effective games and proving their benefit have been significant challenges for this field – challenges which Prabitha Urwyler aimed to meet with her recent FreeNovation Award.

At the time Urwyler received this award in 2018, she was leading cognitive training research at the University of Bern, ARTORG Center for Biomedical Engineering Research, Gerontechnology & Rehabilitation. Through collaborations with the neighboring memory clinic, her project first held focus groups to confirm which types of games participants enjoyed most (puzzles and strategy games). From there, Urwyler’s team custom-designed two games to train specific cognitive skills – a matching game for visual search and a maze game for spatial navigation. To make sure that the games adapted and continuously challenged the players, the team incorporated AI algorithms as well. Removing bias from the results being another priority, Urwyler ensured that these games were language-free so that native speakers of any language could still readily understand and play the game. When the time finally arrived to test the games in a clinical setting, the project faced the unforeseen challenges of the COVID-19 pandemic. But with some further adjustments, such as mailing gaming tablets and giving instructions over the phone, Urwyler still completed a small proof-of-concept study. The results were successful enough for the project to be now discussing the next steps. A revised feasibility study and a large international clinical trial are now planned with new engagement features in a broader product suite by startup Neurometry with its clinical and research partners.

Boosting blockchain

Blockchain technology – which offers the hope of making digital systems extremely safe – may still be an arcane field for most. But a cross-functional Novartis team is convinced this digital tool has the power to transform the pharmaceutical industry and make drug delivery safer and engagement with patients more direct and personal, among many other things.

This was the idea when Marco Cuomo and Daniel Fritz embarked on a pan-European research project in 2018, which four years down the road is bearing the first fruits and could turn into a bigger, industry-wide association next year.

“When we looked into the possibility of leveraging blockchain technology, we quickly realized that we can only do this with both strong internal support and external partners – blockchain is a team sport,” says Cuomo. “That’s when we contacted Gwenaelle Nicolas, who helped us set up a project with the European Union’s Innovative Medicines Initiative.

The project, known as PharmaLedger, attracted a lot of industry interest early on. Today, it includes nearly 30 organizations, among them 12 pharmaceutical companies. It is a network of some 200 people, who have since been working flat out to lay the groundwork for introducing the technology.

With strong support from Novartis Technical Operations, the team has paved the way for the introduction of electronic product information, which could eventually replace the paper package leaflet that accompanies every pack, not only saving money but also reducing waste and our carbon footprint. Pilots are planned for 2023.

“The key challenge of blockchain technology is to prove the value for the industry to adopt it more broadly,” says Cuomo. “It takes a lot of convincing.”

The team believes that their efforts are worthwhile, and that the collaboration will pay off in the years to come. For this reason, they have set up a non-profit, Switzerland-based association, which will continue the IMI project into the future. Now they are working to attract partners to the association.

“There are many things for which blockchain could be a game changer,” Fritz says. “Once the electronic product information is a reality, it will be possible to update it real-time or provide patients with recall or other information such as how to dispose of the product. We are also working on solutions to tackle counterfeiting, among many other things.”

Precision medicine

While a cure for cystic fibrosis (CF) is not yet available, there are several drugs on the market that help keep potentially life-threatening conditions associated with CF at bay, thereby allowing patients – who are particularly prone to bacterial lung infections – to lead longer and healthier lives. With a range of therapeutic agents in development targeting the disease’s underlying molecular defects, medical care for CF is likely to improve even further.

One major obstacle in treating CF has been the vast variability of the mutations that affect the gene encoding the CF transmembrane conductance regulator (CFTR) protein. So far, over 2000 CFTR mutations have been identified, which result in distinct clinical phenotypes. As such, there is a need for an accurate and rapid diagnostic tool to help clinicians determine which drug works best for the patient.

To alleviate this problem and help clinicians provide individually tailored treatments to people with CF, Nathalie Brandenberg, a researcher at École Polytechnique Fédérale de Lausanne (EPFL) who was awarded a FreeNovation grant in 2017, is currently working on a bioengineered rectal organoid system designed to serve as a surrogate readout in assessing therapeutic effectiveness.

Rectal organoids are in vitro primary stem cell cultures. Brandenberg and her team generate them from patients with CF to study individual responses to authorized CFTR-modulating drugs.

“In other words, depending on the organoids’ response, targeted treatment regimens can be offered to patients,” says Brandenberg, who is in charge of the project based at EPFL. Her team first successfully derived intestinal epithelial organoids from mice, before moving on to human trials.

“Our research lies within the domain of translational medicine, as we strive to connect basic research with medical practice,” Brandenberg says. Reflecting on her work from a clinical vantage point, she adds: “Organoids, which serve as models, enable us to pinpoint and tailor the most effective therapeutic approach – especially for those patients with rare CFTR mutations who lack therapy options.”

Once the trials are complete, Brandenberg and her team aim to take their in vitro diagnostic test to a commercial scale, which would allow CF patients to gain better access to innovative treatments – in a minimally invasive and cost-effective way.

Cartilage repair

Whether due to age or disease, cartilage degeneration is a painful condition that affects many of us. But a collaboration between the Friedrich Miescher Institute for Biomedical Research (FMI) and the Department of Biomedicine at the University Hospital of Basel is developing a new approach to regenerating lost cartilage, beginning with a leading cause of low back pain: intervertebral disc disease, such as disc herniation and sciatica. Professor Ivan Martin’s group, at the University Hospital, recently discovered that cartilage cells from patients’ noses have the ability to reform cartilage elsewhere, for example to treat osteoarthritis in the knee. This was a thrilling preliminary result, but to develop this approach further, they needed the molecular expertise of Professor Filippo Rijli’s group at the FMI. Rijli is a specialist in how gene expression is regulated during the development of neurons and the cells that make cartilage in the face. By understanding and controlling the molecular mechanisms underlying the regenerative capacity of cartilage cells of the nose, the aim is to broaden Martin’s work to repairing cartilage in the spine as well. The two groups are excited to be breaking down the walls that typically exist between the clinic and fundamental developmental research, and this ambitious and interdisciplinary collaboration was awarded funding through the highly competitive European Research Council Synergy Grant.

DNA rules

Our DNA encodes the proteins that make all the difference between health and illness. But understanding how our cells orchestrate which proteins are produced, and when, is still a riddle. Each of the cells in our bodies holds about two meters of DNA and, to fit in all of this genetic material, DNA is tightly wrapped around specialized protein clusters for storage. When bound up like this, DNA is effectively unreadable. But when the right time arrives to access a gene, dedicated helper proteins – so-called transcription factors – come to release just enough DNA to reveal the information needed. Humans have over 1500 different transcription factors. Discovering how they enable DNA readout is the aim of Nicolas Thomä's group at the Friedrich Miescher Institute for Biomedical Research in Basel. In 2021, Thomä received one of the prestigious European Research Council (ERC) grants. These grants support top researchers in their exploration of ambitious, “high risk, high reward” ideas. One of the starting points for Thomä work is an innovative tool, developed by his group, which allows the research team to quickly learn exactly how these transcription factors interact with DNA. This knowledge may present new opportunities for drug targets, and the insights gained from this research could provide a foundation for developing better drugs for a wide range of diseases.

Restoring vision

Many types of blindness are caused by the degeneration of the light-sensing cells, called photoreceptors, in the eye. These cells can be dysfunctional from the outset – as in genetic diseases like retinitis pigmentosa – or this can result from age or injury. But what if advances in gene editing therapies could help regain this lost ability? Recently, a technology called optogenetics has shown some of the first clinical evidence of restoring limited vision in patients. Optogenetics involves adding the genetic code for a light-sensitive protein to cells that otherwise wouldn’t have this function. This technique has existed for many years as a tool in basic biology, but its use in the clinic is still in the early phases of development. As such, there are many aspects that need optimization and, in particular, optogenetics could potentially be much safer and more effective if successfully combined with one of the best gene editing technologies to date – CRISPR/Cas. These molecular scissors have transformed gene editing and medicine by making it possible to insert new gene sequences at specific locations in the genome. But combining optogenetics with CRISPR/Cas was an ambitious and very exploratory idea that had yet to be tried – until Dr. Sonja Kleinlogel’s FreeNovation project.

Kleinlogel leads a translational optogenetics lab at the University of Bern in Switzerland and she received a FreeNovation grant in 2019. Her idea to combine the CRISPR/Cas technology with optogenetics was based on her previous successful work restoring vision by adding a designer optogenetic protein to retinal cells. Using CRISPR/Cas, the expression of an existing light-sensitive protein could be simply “switched” on without the need to incorporate an additional optogenetic protein. Importantly, with CRISPR/Cas, the production of the light-sensitive protein could be put under the control of the native protein production machinery of the retinal cell –which meant that not too little (which would not restore vision), or too much (which could be toxic) would be produced. During the FreeNovation project, Kleinlogel’s lab used the new approach to successfully reverse blindness in a mouse model, proving that the idea could work in principle. The technique is far from reaching clinics anytime soon, but the group is now looking into whether it will work in human donor tissue. If all goes well, this could provide the groundwork to treat a wide range of diseases that cause blindness in an estimated 2 million people worldwide.

Finding impurities

Drug recalls due to the presence of so-called nitrosamines – organic compounds with cancerogenic properties – have unfortunately appeared time and again in the recent past.

Most recently, a large US drug producer issued two recalls due to elevated nitrosamine levels. Likewise, Sandoz was forced to execute a voluntary recall of certain lots of a pain relief drug, spotlighting the need for more sensitive detection methods.

To optimize impurity screening effectiveness and thus remedy this potential health hazard, a Genesis Labs team from Sandoz Slovenia is working on a new analytical method to allow for the systemic and high-sensitivity evaluation of nitrosamine residue. By developing a novel metalloporphyrin-based chemosensor, the team also aims to make conventional, time-consuming approaches such as paper-based evaluation a thing of the past.

“Both chemically synthesized and biologically active substances can be contaminated with nitrosamines during the production process,” notes Zdenko Časar, Genesis Labs coach and project leader based in Slovenia. Contrary to standard methods that can only detect up to 10 different nitrosamines, the new test method being developed by the team is geared toward identifying all different kinds of nitrosamines that can form during the drug manufacturing process.

“Using UV spectroscopy and by leveraging the photophysical properties of metalloporphyrins, we offer a screening method simple enough to be operated on a daily basis by technicians, with a view to ensuring that our patients have continuous access to innovative treatments,” Časar highlights. The team consisting of three chemists from Sandoz Slovenia, alongside three associates from the Novartis Institutes for Biomedical Research and Global Drug Development in Basel, cooperates closely with the University of Ljubljana and the University of Technology and Architecture in Fribourg, capitalizing on academic and industrial know-how across different borders.

Currently, the team is busy optimizing the metalloporphyrin-based compound and further developing the screening method, which, if successfully scaled up for industrial use, would prove a game changer in detecting nitrosamine residues, taking the company one step further in its efforts to secure patient access to innovative therapies and treatments at all times.

Microbiome health

The composition of the microbiome in people’s guts correlates with their health. However, given the biochemical complexity of the gut microbiota, it remains a challenge for scientists to determine the exact causal relationship between the gut microbiota and various diseases.

In a bid to address this gap in knowledge, Emma Slack, Professor at the Institute of Food, Nutrition and Health at ETH Zurich and winner of the FreeNovation grant in 2017, has developed a novel methodology for functional microbiome research in mice. Mice models have been the gold standard in microbiota studies, and Slack’s team has gone to great lengths to set up a system amenable to complex measurements and interventions in ultrasterile environments that allow microbiota control.

To achieve this, Slack’s team installed a commercial metabolic cage system inside germ-free “bubble” isolators with a view to preventing any contamination from the environment. This allowed the team to quantify a range of vitality parameters over time and compare animals with zero microbiome or animals colonized with one or a few microbes to those with a complete microbiome with thousands of species. “It took us around 18 months to get everything up and running,” said Slack, hinting at the complexity of the task on hand.

The system, she said, “helped us gain unique insights into how gut microbiota modulates metabolic response. For instance, we could confirm the known fact that mice lacking microbiome eat significantly more, but could additionally demonstrate that this increased food intake results in these animals extracting around the same number of calories from their food per day as other mice,” added Slack, pointing to the appetite control function of gut microbiota-released calories.

Slack’s results not only expand our mechanistic understanding of microbiota-host interactions but pave the way for new therapies. Currently, Slack and her team are participating in the consortium Zurich Exhalomics, which consists of 14 multidisciplinary research teams across different universities and aims to build a noninvasive measurement system to diagnose diseases using biomarkers in patients’ breath. “A major fraction of our volatile metabolome is microbe-derived and, by integrating this analysis into our study of selectively colonized mice, we have the potential to understand the mechanisms linking breath biomarkers to disease,” Slack noted.

Slack is optimistic about the prospects of their research translating into tangible results for patients: “Analyzing a patient’s microbiome via exhaled molecules opens up completely new possibilities for disease treatment and prevention. Building on our research with mice, we aim to harness the bacterial activity to develop therapeutic interventions tailored to the recipient’s microbial individuality, thereby taking a stride toward precision medicine.”

Deep learning

From their offices on the fourth floor of the Biozentrum, Erik van Nimwegen and Thomas Julou can see the Novartis Campus as well as the Roche Towers. However, despite the high density of top pharmaceutical companies and expertise in this city, there are no new antibiotics in sight. And this alarming outlook is not limited to Basel.

“One of the reasons for this situation is that current methods of antimicrobial research are unable to identify compounds that specifically target cells in slow- or nongrowing states,” explains Erik van Nimwegen, a theoretical physicist by training, professor at the Biozentrum and research group leader. “And this methodical failure is a key obstacle for the development of new antibiotics,” adds Thomas Julou, who is supervising the experimental lab of the group. Both van Nimwegen and Julou believe that it is crucial to characterize the action of antibiotics at the single-cell level, and that this has the potential to identify compounds that are active against pathogens which are refractory to antibiotic treatments.

Their research is supported by a grant from FreeNovation, the funding program of the Novartis Research Foundation, which aims to promote offbeat project proposals and pioneering spirit.

While current image analysis tools to identify bacteria cells still rely on manual curation for segmentation and tracking, throughput remains highly constrained. “To solve this limitation was a key focus of our FreeNovation project, and to do so, we took advantage of artificial intelligence,” says Julou. The automated segmentation and classification of complex objects in images by convolutional neural networks is often referred to as “deep learning.”

FreeNovation started in 2016 with the aim to promote offbeat project proposals that are hard to fund by conventional programs.

Van Nimwegen decided to completely redesign the image analysis software in order to take advantage of deep-learning tools. He says that “as a result, the precise probability maps obtained now allow us much more accurate cell tracking, which in turn dramatically reduces the need for manual curation by the user. Our high-throughput setup captures the diversity of responses to treatments, including rare events where bacteria cells survive prolonged exposure.”

Taking this diversity of cell appearance and morphology into account for image analysis will be the next challenge for this research group to put their vision into practice.

Health disruptors

Our Commitment to Patients and Caregivers stands high on the agenda of Novartis, which is in the process of propping up its patient engagement teams across the globe under the leadership of Marc Boutin. Efforts to include patients more intensively in the drug development process has been on the company’s mind for many years. But to become a truly patient-centric organization takes time, not least because there needs to be a mindset change across the entire industry, including regulators, payers as well as the entire pharmaceutical value chain.

Thomas Hach, a Novartis veteran who has been working in different drug development and research roles, knows how hard it is to bring about this change since these groups are extremely diverse, making communication and interest alignment difficult. Hence, as part of the company’s continued push to strengthen the Novartis Commitment to Patients and Caregivers, the team launched the international patient platform Invisible Nation together with the Global Heart Hub, a non-profit alliance of heart patient groups worldwide.

“Invisible Nation is an attempt to bring together and raise awareness for the more than 300 million people worldwide who suffer from atherosclerotic cardiovascular diseases,” says Thomas Hach. “But the key thing is really to leverage this big community and effect necessary changes across the value chain.”

One key element in the attempt of Novartis is to help patients share their voice early when it comes to the setup of clinical trials, regulatory input, reimbursement modalities and other elements that are part of drug development. However, since there are so many players in the field, Hach says that Invisible Nation ultimately wants to “influence the influencers” and thus drive change at the policy level.

“Only when policy makers really have an understanding of the underlying challenges faced by heart disease patients, can we expect to see change on a regulatory level, which benefits all,” Hach says, adding that there are many more hurdles to overcome in the years ahead but that together we can take up this challenge.

Still, Invisible Nation has already made some progress since it was launched last year. The group has not only attracted new patient organizations, it also made inroads on the political scene when Neil Johnson from the Global Heart Hub held a speech at the Irish Parliament, urging for a new strategy for cardiovascular health, which “must involve patients as key stakeholders.”

For Johnson as well as the Novartis team, patients are the biggest disruptors in the healthcare arena since their insights can help improve medical development and outcomes. “And this is the ultimate goal of all our efforts,” Hach says, underlining that “such an effort can only be achieved in collaboration with all stakeholders, from patients to payers.”

You may also be interested in the following:

Back to the main page

02.10.2022

Pilar and the Petri dishes

The fabulous world of fungi.

18.09.2022

Measuring mobility

The long road to new clinical endpoints.

Galactic romanticism

Your privacy is important for us.

Strictly necessary cookies

Performance cookies