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Disease and treatment

In the future, we will use living medicine

Microorganisms do not always make us ill. The correct composition of bacteria in our intestines can make us healthier and even heal illness. Scientists will now programme bacteria in our intestines to produce medicines that can make us healthy when we are sick. If this succeeds, it will enable bacteria to be used to combat most diseases and replace traditional pill-based treatments.

Ever since penicillin was discovered in 1928, humanity has used the arsenal of microorganisms to combat other microorganisms that cause disease. Researchers have screened fungi and bacteria for substances that kill or inhibit the growth of pathogenic bacteria and then extract them and use them as effective antibiotics. With current medicine, dosing is a big challenge in effectively defeating infection. A major Danish research initiative aims to solve this problem.

“People typically take one or a few doses a day, so the concentration of medicine in the body varies greatly over time. Instead of this traditional treatment, we will use specially engineered bacteria that can produce the pharmaceutically active molecules on demand. We hope that this living medicine can lead to more effectively treating people with disease in general,” explains Morten Sommer, Professor, Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark.

Bacteria react as the human body would

The new technology, advanced microbiome therapeutics, works by modifying the genome of bacteria so they secrete specific molecules that can influence other bacteria or the body’s mechanisms. Traditionally, medicine has been given orally, intravenously or topically. However, the body’s systems often eliminate the medicines rapidly. Regular dosing is therefore necessary to maintain treatment.

“Advanced microbiome therapeutics provides a unique opportunity to change this model. When bacteria colonize the intestines, they create a stable version of the therapeutic compound, and the aim is to get them to respond to their surroundings so they can secrete the required compound on demand. We will thus be able to treat diseases in a precise and targeted manner.”

Nevertheless, the idea of getting microorganisms to combat other microorganisms in the body is far from new. For years, research on the human microbiome has focused on the importance of having healthy intestinal flora. In the quest to create healthier intestinal flora, researchers have previously experimented with probiotics in milk products or, in more extreme cases, transplanting intestinal tissue from donors with healthy intestinal flora.

“The idea behind living medicine is to treat a disease in the same way as the body would do it. If the body would respond to a disease, such as diabetes, it would produce insulin in response to certain signals in the body, and that would lower the blood sugar. We can achieve a similar thing with bacteria because we can engineer them to respond to the same signals and produce those same molecules as the body.”

Communication is the most difficult

Living medicine can therefore potentially treat a variety of diseases. By modifying the bacteria, the researchers can even tailor them to solve the health challenges of individual people. The researchers can also ensure that the bacteria persist only in one individual’s intestines and cannot spread to other people.

“Ensuring that cell-based medicine cannot spread in an uncontrolled way between people is central to the project. Over the past years, we have learned how to engineer very sophisticated control systems in bacteria, and that allows us in a variety of different ways to ensure that a bacterium persists only in the patient who is treated and only for the time period that we would like them to persist for.”

However, the greatest challenge in developing living medicines lies elsewhere: in how the many complex bacterial communities interact in our body.

“Currently, there is relatively little information about how engineered bacteria will interact with a bigger community of bacteria in our intestinal system. That is going to be a major thing we will study in this project. We will aim to develop strategies that allow us to override some of these interactions to ensure that the living medicine has an opportunity to establish itself.”

Of course, the researchers dream of developing new treatments for specific life-threatening diseases.

“A successful outcome of this project would be developing, in 6 years, a framework for how we can engineer living medicine, how we can control the bacteria and how we can use bacterial therapy to treat people.”

In 2018, the Novo Nordisk Foundation awarded a Challenge Programme grant to Morten Sommer, Professor, Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, for the project Design and Engineering of Biological Molecules and Systems. The project will be carried out in collaboration with Fredrik Bäckhed, Professor, University of Gothenburg; Max Last Nieuwdorp, Professor, University of Amsterdam; and Tine Rask Licht, Professor, Technical University of Denmark.

Morten Otto Alexander Sommer
Professor
Our work is broadly aimed towards understanding how biological systems establish, organize and evolve. We use cutting edge technology and aim to translate our basic research findings into entities, policies and education that provide long term benefits to society. Antibiotic resistance Evolution is rendering our medicines against many infections useless threatening to bring us back to the pre-antibiotic era. In many cases resistance to a particular antibiotic did not evolve within the resistant human pathogen, but rather was acquired by lateral gene transfer from other resistant bacteria. These resistant donor bacteria need not be pathogenic, yet they contribute to the evolution of antibiotic resistance in human pathogens by serving as an accessible reservoir of resistance genes. We are using a variety of culture-dependent and culture-independent methods to characterize how these reservoirs are interacting, with the ultimate goal of creating quantitative models for how antibiotic resistance genes arise in human pathogens. We study the adaptive mechanisms of drug resistance and collateral sensitivity using a combination of laboratory evolution and sampling of clinical isolates, with the goal of developing novel treatment strategies for countering resistance development. Synthetic biology for sustainable generation of value chemicals Increasing concerns related to climate change caused by our reliance on fossil fuels for many processes in our society prompt the need to look for alternatives. Biological systems can be engineered to perform conversions of renewable input substrates to value added products using much less energy than conventional methods. We use a variety of metagenomic and culture based techniques for harnessing biological diversity useful for generation of biofuels and other value chemicals. We build synthetic selection networks that sense and respond to specific metabolites inside the cell. We deploy these tools for pathway discovery, strain optimization for specific metabolic engineering targets. We use synthetic selection systems for multiplexed interrogation of biological phenotypes enhancing our understanding of cellular metabolism and regulation. Human microbiome and engineered microbiome therapeutics The human microbiome is to an increasing extent being implicated in a wide range of disease and health states. We study the human microbiome during interventions, with a particular focus on antibiotic treatment and resulting microbiome modulation. We design and build new interventions for modulating the microbiome to promote specific community compositions or functionality. We also design and build interventions that can amend the functionality encoded in the gut microbiome.