Using microbes as factories

Joleen Masschelein's journey in microbiology

Joleen Masschelein started as a group leader at the VIB-KU Leuven Center for Microbiology in 2020. Her Laboratory for Biomolecular Discovery & Engineering is passionate about exploring the vast and untapped microbial world to uncover new compounds with therapeutic potential.

We talked to Joleen about her journey into microbiology, the major challenges, and the exciting discoveries made and yet to come.

Hi Joleen, how did you start in the field of microbiology?

"I have always been fascinated by the microscopic world of living cells and microbes. It, therefore, felt like a natural choice for me to study Bioscience Engineering at KU Leuven and specialize in Cell and Gene Technology. During this time, I discovered that microorganisms have excellent chemistry skills and can produce highly complex molecules with valuable properties for humankind, such as antibiotics, immunosuppressants, insecticides, and anticancer agents. All around us, bacteria produce these molecules to fight other bacteria, fungi, and insects for food. As scientists, we can use these microbial weapons for drug development. In fact, the majority of our clinical drugs today are derived from microbial sources. Inspired by the possibility of discovering new medicines from bacteria, I performed my PhD research at the Laboratory for Gene Technology at KU Leuven. During my PhD, I found that bacteria isolated from our local student restaurant produce a new family of broad-spectrum antibiotics. I purified these antibiotics, elucidated their structures and mode of action, and found that they were constructed by a highly unusual enzymatic assembly line within the bacteria.

After my PhD, I received a Marie-Skłodowska Curie individual fellowship to join the group of Prof. Greg Challis at the University of Warwick in the UK. There, I looked closer into the enzymatic assembly lines that make pharmaceutically-important natural products in bacteria. I also developed strategies to engineer these assembly lines so that they produce new antibiotics with improved activity against multidrug-resistant pathogens. We showed that bacteria could create those valuable drugs much faster, more sustainable, and cheaper than synthetic chemists. In 2017, I returned to Belgium to continue my career as a postdoc at the Rega Institute for Medical Research at KU Leuven, supported by a fellowship from the Research Foundation - Flanders. There, I started developing my independent research by leading a team of PhD and Master students working on the mode of action of a new anti-MRSA (a dangerous multi-resistant bacteria)antibiotic. In 2020, I started my lab as a junior group leader at VIB and assistant professor at the Department of Biology at KU Leuven."

Your goal is to engineer and use microbes to produce complex molecules. What are the major challenges you encounter?

"We are currently working with bacteria that naturally live closely with humans, plants, and animals. These bacteria can be difficult to isolate and cultivate in a lab environment. The majority of bacteria have actually yet to be grown outside of their natural host! Because they are so tricky to isolate, they have received very little attention from researchers. As a result, there are limited tools available for genetic manipulation. It can also be challenging to make bacteria produce these complex molecules. Their production is often triggered by stress signals from their host or the natural environment. The key is then to figure out what these signals are and to 'fool' them into producing our molecules of interest. Luckily, synthetic biology is advancing fast and offering solutions to circumvent many of these issues."

You're also interested in making beneficial human-associated bacteria for in vivo biotherapeutic applications. Does this mean we might soon be ingesting microbe factories to treat certain diseases?

"Yes, although there is still a long road ahead! In the last decades, the beneficial health effects of the human microbiota have been exploited through the development of probiotics. In that sense, probiotics are the first generation of microbiome therapeutics. With the recent explosion in microbiome and synthetic biology research, a new field in human disease treatment is emerging that aims to unlock the next generation of microbiome therapeutics by engineering beneficial intestinal microorganisms for drug production and delivery. A small but growing number of examples have shown that healthy gut bacteria can be engineered to detect and respond to diseases by delivering therapeutic proteins.

Such microbiota-based cell therapy systems offer several significant advantages compared to conventional drug treatment. For example, beneficial bacteria can be easily administered as probiotics and do not elicit an immune response. They are also capable of efficiently colonizing specific parts of our body and can therefore be used to deliver drugs to remote sites in the human body that are otherwise difficult to reach. In addition, they can be engineered to produce multiple medicines simultaneously and release them in adequate local concentrations, thereby avoiding side effects in other parts of the body.

Advances in synthetic biology are rapidly expanding our ability to generate bacteria with new and complex functions. Several bacteria are already in (pre-)clinical trials for treating intestinal diseases. However, the current set of therapeutic bacteria has two crucial limitations. The first is that they are rapidly eliminated from the body. This makes them ineffective against chronic intestinal disorders, such as colorectal cancer, a major public health concern affecting over four million people in Europe alone. To be able to treat such long-term diseases, we are engineering more stable and abundant gut bacteria. Secondly, current bacteria have so far only been engineered for the production of therapeutic proteins. To improve the range of available treatment options, we are trying to engineer them so that they can also produce structurally complex small-molecule drugs."

After our interview, Joleen received an ERC starting grant to genetically engineer beneficial Clostridium bacteria from the human gut so that they can be used for monitoring and treating chronic intestinal diseases.

Your research led to the discovery and improvement of enacyloxin, an antibiotic against one of the most dangerous multi-resistant bacteria in hospitals. Do you have any other exciting discoveries in the pipeline?

"Yes, our research on natural product biosynthesis in microbes has led to the discovery of new enzymes that can perform complex and unusual chemical reactions. We are exploring the possibility of developing these enzymes as biocatalytic tools for green chemistry. My team has also identified new antibiotics against Acinetobacter baumannii and Klebsiella pneumonia, two of the most high-priority multidrug-resistant pathogens designated by the World Health Organization. Furthermore, we have uncovered novel anticancer agents and found a way to engineer bacteria to produce a structurally simplified variant that maintains its anticancer activity. This variant provides a promising starting point for developing anticancer drugs with enhanced selectivity and reduced toxicity. Finally, we are establishing an efficient platform for producing large libraries of structurally diverse cyclic peptide drugs in bacteria and evaluating them through screening in micro-droplets."

How do you see your research field evolving in the following years?

"I think synthetic biology will play a major role in creating a more sustainable future, with engineered microorganisms as a key component. Synthetic biology will become a biodesign platform that can predictably create cells or microbes that can produce a wide range of novel molecules and materials for various industrial applications. Currently, only a fraction of the available microbes in nature is used for the production of synthetic biological materials. In the next decade, the focus will be identifying and domesticating non-model species with metabolic networks more suitable for hosting particular chemical reactions. I also see the field moving towards developing engineered communities of bacteria that work together to build structures and synthesize molecules for different applications. Scalability will improve, and the use of high-throughput data collection and machine learning will optimize the design of synthetic biological products, allowing us to move away from a random trial-and-error approach."

In the future, I think engineered microorganisms will play a significant role in agriculture, food and fuel production, medicine, and even space exploration.

Finally, what's your favorite microorganism?

"The Pseudomonas bacteria. They are found in many different environments, and some species can produce bright green, blue, or even bright red pigments, making them quite eye-catching! Beyond their visual appeal, they are also an incredibly rich source of antibiotics and other natural products with medicinal properties. They often use new chemistry and unique biosynthetic pathways to assemble these molecules. And, unlike some bacteria, they don't mind too much that we manipulate their DNA, making them easy to engineer."

Pseudomonas bacteria
Pseudomonas bacteria

Want to know more about Joleen's research? Visit her website and listen to her podcast on EOS below (in Dutch).

Website preview
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Antibiotica dienen eenvoudig gezegd om bacteriën te doden. De medicijnen zijn tegelijk ook (minstens voor een deel) door bacteriën of schimmels gemaakt. Hoe ...
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Joleen Masschelein

Joleen Masschelein

Principal Investigator, VIB-KU Leuven Center for Microbiology

India Jane Wise

India Jane Wise

Science Communications Expert, VIB


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