Redesigning medicine with synthetic biology

Inspired by nature, Synthetic Biology offers exciting opportunities to change the future of medicine.

The field of synthetic biology brings together engineers, physicists, and molecular biologists and uses engineering principles to model, design, and build synthetic gene circuits and other molecular components that do not exist in the natural world. Researchers can then piece these biological pieces together to rewire and reprogram living cells — or build cell-free systems — with novel functions for a variety of applications.

“For me, the most exciting thing about synthetic biology is finding unique ways or seeing how living organisms can solve a problem,” says David Riglar, Sir Henry Dale Research Fellow at Imperial College London. “This gives us opportunities to do things that would otherwise be impossible with inanimate alternatives.”

Scientists are harnessing the power of synthetic biology to develop a wide variety of medical applications, from powerful drug production platforms to advanced therapeutics and novel diagnostics.

“By approaching biology as an engineering discipline, we are now beginning to develop programmable drugs and diagnostic tools that can sense information in our bodies and respond to it dynamically,” said Jim Collins, Termeer Professor of Medical Engineering and Science at the Massachusetts Institute of Medicine Technology (MIT).

These novel drugs could be equipped with synthetic elements that can control the localization, timing and dosage of their activities. This offers significant advantages over traditional therapeutics in terms of flexibility, specificity and predictability – and opens up exciting possibilities for precision medicine.

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A tool kit for synthetic biology

In recent years, the cost of DNA sequencing and synthesis has fallen rapidly – and the development of gene editing technologies, such as CRISPR-Cas9 – have enabled researchers to engineer biological systems with unique and increasingly complex functions.

“The combination of these tools has given us unprecedented opportunities to apply synthetic biology to study living systems and understand how they function,” says Riglar.

The underlying premise of synthetic biology is that living systems can be broken down into a library of individual components. Engineering principles are then used to design these biological parts and engineer into new systems for a variety of industrial, agricultural, pharmaceutical and environmental applications. In practice, however, these biotechnological approaches are not always easy.

“There are two major challenges – the first is that we still don’t have comprehensive design principles for biology – and that means that their complexity can still get in the way of our best design plans,” explains Collins. “Second, we still have a fairly anemic library of biological parts — on the order of a few dozen that have been reused and repurposed over the last two decades. We need to dramatically expand this toolkit through synthesis and biomining efforts.”

To drive future advances, synthetic biologists are beginning to take advantage of machine learning approaches – which can help inform design, e.g. B. by generating new components or suggesting the best experiments to perform.

gut biosensors

In recent years there has been a spate of studies showing that the trillions of microbes that live in and on our bodies play a crucial role in maintaining good health. These have been used extensively Next-generation sequencing approaches to provide a snapshot of species species and abundance in these microbial communities that establish relationships between healthy and diseased states. The results have links between disorders of the human intestinal flora and many different diseases – including inflammatory bowel disease, cancer and neurodevelopmental disorders. However, other experimental approaches are needed to understand the underlying mechanisms of how interactions between the gut microbiota and the host affect human health and disease.

“One of the biggest challenges in examining the gut is that it’s quite inaccessible,” says Riglar. “Therefore, there is currently only a very limited understanding of what happens in these back-and-forth interactions between the host and the microbiota.”

Advances in synthetic biology are allowing researchers to engineer engineered probiotic bacteria that can detect, record, and report on changes in the gut. Using this approach, Riglar’s team has developed biosensors that can act as live diagnostics of inflammation – or can be used to measure bacterial dynamics in response to inflammation and underlying microbiota changes in the mouse gut.

In the short term, these living biosensors will help researchers better understand disease processes to uncover pathways that might be targeted with traditional therapeutic approaches. However, the longer-term goal is the development of engineered bacteria for clinical applications – for example, to monitor for changes in the gut that can indicate the presence of disease. For example, the Collins group recently demonstrated the potential of using a genetically engineered strain of Lactococcus lactisa bacterium commonly found in fermented foods as a live diagnostic agent that could help improve disease surveillance in populations at risk of cholera outbreaks.

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Advanced Therapeutics

Researchers are also applying synthetic biology to engineer living cells and acellular systems that can sense and dynamically respond to information in our bodies – ushering us into an era of programmable drugs.

Antibiotics not only target bacteria that cause infection, but can also alter the gut microbiota — which can cause diarrhea and contribute to the development of antibiotic resistance and the development of many chronic diseases. To overcome these problems, Collins’ team developed a strain of L.lactis which can break down a class of widely used antibiotics in the gut. When given to mice in combination with antibiotics, it helped protect the gut microbiota while circulating antibiotic levels remained unchanged.

“By applying synthetic biology, we have developed a living therapeutic that has the potential to counteract the potential adverse effects of antibiotic use,” says Collins.

Further on the path to clinical development is a live therapeutic for a rare genetic disease called phenylketonuria (PKU). Children born with this condition are unable to break down phenylalanine, which can build up in their bodies and cause brain damage. As an alternative to a low-protein diet, researchers have developed bacteria that can break down this amino acid in the gut. Positive top-line results from a Phase 2 study led by biotechnology company Synlogic showed that this living therapeutic can successfully lower circulating blood levels of phenylalanine – suggesting it has the potential to become a transformative treatment for patients with PKU .

Researchers are also using synthetic biology to develop novel therapeutics without the use of living cells. Many RNA-based therapeutics are messenger RNAs (mRNAs) that encode a therapeutic protein—but targeting gene expression only to cells that cause or are affected by disease is proving to be a major hurdle. To address this challenge, Collins’ group developed eToeholds, small programmable switches that can be engineered into an RNA sequence to target protein production to specific cell types or states – such as virus-infected cells.

“This system offers unprecedented programmability and flexibility – it opens up a wealth of possibilities for the development of RNA therapeutics that are only activated in cells where they are needed, thereby reducing the risk of unwanted side effects,” says Collins.

Solving global challenges

At the interface of biology and technology, synthetic biology is becoming one of the dominant medical technologies of this century.

“It’s an exciting time to be working in this space,” says Collins. “I hope that within the next decade we will see new classes of therapeutics and diagnostics that will have a broad impact on the lives of people around the world.”

However, the potential of synthetic biology goes far beyond improving human health – because the application of these technologies could also help researchers tackle some of the world’s most pressing environmental and sustainability problems.

“I think the idea of ​​applying engineering principles to living systems that have evolved over billions of years can give humanity a real advantage in addressing some of the existential challenges we face,” says Collins.

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