The legacy of liposomes: how fundamental research keeps on giving

Tue, 17/10/2023 - 10:30

The legacy of liposomes: how fundamental research keeps on giving

The legacy of liposomes: how fundamental research keeps on giving

The Babraham Institute is a centre for expertise in cellular and molecular biology. Supported by cutting-edge scientific facilities and technical experts, the Institute’s research teams delve into the intricacies of how our bodies function, right from the moment of conception, with one united aim: to sustain health throughout the life course and reduce the physical decline and disease vulnerability of our bodies seen with age. Today’s discoveries will provide the foundation for health gains in the future.

A discovery made at the Babraham Institute (then known as the Institute of Animal Physiology) in the 1960s played a part in the 2020-2021 COVID-19 vaccination development efforts, and continues to enable innovation in cancer treatment. This 50-year journey provides an example of how a strong foundation of fundamental research secures our ability to respond to urgent challenges facing humanity.

A field founded on a serendipitous observation

Electron microscope
The microscope gifted to the Institute by the Wellcome Trust

Of the three COVID-19 vaccines used in the UK during 2020 and 2021, two — the Moderna and Pfizer/BioNTech — are mRNA vaccines. Often described as ‘plug and play’ due to the potential for the mRNA template to be tweaked as required, the critical element of these vaccines is a lipid vesicle coat that is essential for the template mRNA to be safely transferred into cells. The discovery of how to create membrane vesicles goes back over 50 years when a new field of scientific discovery was founded that would eventually give rise to the lipid vesicles used in COVID-19 vaccines.

In 1961, the Babraham Institute received a gift from the Wellcome Trust of an electron microscope. Among the first in the queue to test it out was Alec Bangham, a researcher and former physician, and his colleague Robert Horne. Bangham was investigating the properties of red blood cells, in particular why they don’t stick to each other. During his experiments, Bangham began to model the cell surface using lipids. Scientists had already shown that lipids formed different structures when immersed in water but, because they exist on a nanoscale, their exact shape was difficult to image directly. After the arrival of the electron microscope, Bangham and his colleague Robert ‘Bob’ Horne took the opportunity to put liposomes under the lens and for the first time were able to image the double layer vesicles formed by lipids using a negative stain technique developed by Bob Horne and Sydney Brenner. Bangham and Horne submitted their paper, ‘Negative staining of phospholipids and their structural modification by surface-active agents as observed in the electron microscope’ to the Journal of Molecular Biology on 11th December 1963.

Alec Bangham, a black and white protrait
Alec Bangham in 1972

Branded ‘liposomes’ by Bangham’s collaborator Gerald Weissmann, these molecular vesicles had a surprisingly useful property: they are able to fuse with the surface of cells, releasing their contents inside. In research terms, Bangham and Weissmann were pleased to have found a good model for cells, creating a system for studying cellular membranes. In impact terms, the recognition that liposomes could be used as a drug-delivery mechanism opened the door to a huge range of therapeutic opportunities.

Developing liposomes for drug delivery

The key step forward in the journey to drug delivery came in 1970, with the work of Gregory Gregoriadis, a colleague of Bangham’s, and Brenda Ryman at the Royal Free Hospital School of Medicine. Gregoriadis and his team confirmed the prospect of using liposomes as a potential immunological adjuvant for vaccines for the purpose of generating an enhanced immune response. Liposomes consequently became a key interest for pharmaceutical companies, but before drugs could be packaged into liposomes, more research was needed to show that liposomes would be safe inside the body.

Research into liposomes expanded over the subsequent decades with major developments coming in the form of modifications to the membranes surrounding the cargo for delivery. In the early 2000s, several drugs for rare diseases were produced using liposomes but they remained difficult to manufacture. Eventually, researchers refined the structure of the lipid vesicles, creating the great-grandchild of the liposome — the lipid nanoparticle.

Building a new type of vaccine

In parallel to the development of lipid nanoparticles, mRNA technology was breaking new ground by providing a way to give instructions to cells that would help treat diseases. The two worlds would unite in 2020, when Pfizer/BioNTech and Moderna received approval for their mRNA lipid nanoparticle vaccines against the SARS‑CoV‑2 virus.

“There is a lot to learn from the story of liposomes, including the importance of close collaborations with industry to make life-changing interventions possible and accessible.”

The speed of development of the mRNA vaccines was only possible because of the foundation of work that enabled this sprint start, such as that of Alec Bangham at the Institute, and the subsequent development of his invention by academic scientists, funders and life science and pharmaceutical companies who recognised the field as having potential. Also vital was the longstanding investment in basic research that led to the two technologies coinciding. The global success of the COVID-19 vaccines has shown the power of lipid-based drug delivery and the approval of lipid nanoparticle vaccines for COVID-19 is laying the groundwork for the treatment of other diseases.

The importance of the ‘knowledge arsenal’

Dr Simon Cook, Director of the Babraham Institute, commented: “The trajectory of Alec Bangham’s work is certainly inspiring for researchers whose focus is to understand the fundamental workings of cells. There is a lot to learn from the story of liposomes, including the importance of close collaborations with industry to make life-changing interventions possible and accessible.”

Sir Brian Heap, friend of the late Alec Bangham and former Director of the Babraham Institute added: “The Wellcome Trust’s gift to the Institute of its first electron microscope and ancillary equipment in the 1960s proved a crucial step for liposome research. The Babraham Institute has developed a history of investment in cutting-edge facilities that continues to this day, encouraging scientists to pursue questions that can provide the critical foundation of future breakthroughs. The work in the ‘60s and the pace of the COVID-19 vaccine development in recent years point to the value of strong investment in fundamental research to create the knowledge arsenal needed to address future challenges.”

Immunology expertise improving vaccine response

Immune cells in a mouse spleen from an aged mouse
Immune cells in the spleen of an aged mouse

The predecessor to the Babraham Institute was focused on animal physiology in the 1960s whereas since 1993 the Institute has focused wholly on human health. The story comes full circle with Institute immunologist Dr Michelle Linterman and her lab playing an important role in 2020 in pre-clinical studies to assess the effect of age on the immune response to the Oxford–AstraZeneca COVID-19 vaccine.

“The pandemic highlighted how much of a health imbalance is caused by the immune system decline seen with age,” explained Michelle. “I thought the most useful thing was for us to offer something that nobody else could contribute quickly — and that was our ability to use aged mice as a pre-clinical test of how this vaccine is likely to work in an ageing immune system.”

The research indicated that two doses of the vaccine would give good protection against infection in all adults. Ongoing work in the Linterman lab continues to identify why immune response after vaccination declines with age and how vaccines or vaccination strategies may be altered to ensure a robust response, and thereby strong protection, in older people.

Today’s discovery for healthcare innovation

Fundamental research continues to provide the launchpad for innovation. Running through the Institute’s timeline is a dedication to discovery-led research, collecting pieces of the picture to create knowledge that can be used to improve lives.

Our future scientific and intellectual capital depends on this feedstock of fundamental research, generating invaluable understanding across the range of specialisms. Which of the discoveries made today will build our ability to meet the challenges of tomorrow?


Image description: Phosphatidylcholine liposomes stained with acridine orange. Credit: Arkhipov Sergey, Wikimedia CommonsCC BY-SA 4.0 DEED

Authors: Honor Pollard, Communications Officer, and Louisa Wood, Head of Communications