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22 April, 2022 - 12:30 By Tony Quested

Cambridge irons out the wrinkles in anti-ageing science arena

Cambridge is playing a lead role in developing technology designed to rejuvenate skin cells and arrest the march of age-related diseases.

The science has huge implications for regenerative medicine, including wound treatment, and holds out the prospect of halting the progression of some neurodegenerative diseases such as Alzheimer’s.

The Cambridge BioMedTech cluster has what looks like a winning hand rammed with aces:-

  • Shift Bioscience at the Babraham Research Campus has funding in place to advance the technology, leveraging Machine Learning and deep biological insight.
  • Amazon founder and chairman Jeff Bezos, armed with a $3 billion war chest, recently unveiled a new Cambridge-California company Altos Labs with a similar vision to Shift.
  • Research from the Babraham Institute has developed a method to ‘time jump’ human skin cells by 30 years, turning back the ageing clock for cells without losing their specialised function. 
  • Professor Wolf Reik has a synergistic role at the heart of the core science, having been an inspirational figure in the Babraham research and acting as an adviser to both Shift and Altos.

This latter factor should help engender a synergistic approach to future research collaboration across leading players and accelerate progress. A competitive, commercial-centric footrace could prove counter-productive based on research soundings taken by Business Weekly. 

As Daniel Ives, co-founder and CEO of Shift Bioscience remarks: “You can’t cut corners when you are dealing with human lives. The side effects of getting it wrong might not be just nausea – they could be cancer.”

Ives (pictured below), whose company is backed by serial Cambridge entrepreneur Dr Jonathan Milner, said the potential rewards to humanity are too significant to compromise.

Minds and imaginations started racing when Babraham Institute recently revealed that its research had mined a new technique for rejuvenating skin cells. 

This technique has allowed researchers to rewind the cellular biological clock by around 30 years according to molecular measures – significantly longer than previous reprogramming methods.

The partially rejuvenated cells showed signs of behaving more like youthful cells in experiments simulating a skin wound. This research, although in early stages, could eventually have implications for regenerative medicine, especially if it can be replicated in other cell types.

Research from the Babraham Institute has developed a method to ‘time jump’ human skin cells by 30 years, turning back the ageing clock for cells without losing their specialised function. 

Work by researchers in the Institute’s Epigenetics research programme has been able to partly restore the function of older cells, as well as rejuvenating the molecular measures of biological age. 

The new method, based on the Nobel Prize winning technique scientists use to make stem cells, is said to overcome the problem of entirely erasing cell identity by halting reprogramming part of the way through the process. This allowed researchers to find the precise balance between reprogramming cells, making them biologically younger, while still being able to regain their specialised cell function.

In 2007, Shinya Yamanaka was the first scientist to turn normal cells, which have a specific function, into stem cells which have the special ability to develop into any cell type. 

The full process of stem cell reprogramming takes around 50 days using four key molecules called the Yamanaka factors. The new method, called ‘maturation phase transient reprogramming’, exposes cells to Yamanaka factors for just 13 days. 

At this point, age-related changes are removed and the cells have temporarily lost their identity. The partly reprogrammed cells were given time to grow under normal conditions, to observe whether their specific skin cell function returned. 

Genome analysis showed that cells had regained markers characteristic of skin cells (fibroblasts), and this was confirmed by observing collagen production in the reprogrammed cells. To show that the cells had been rejuvenated, the researchers looked for changes in the hallmarks of ageing. 

As explained by Dr Diljeet Gill, a postdoc in Wolf Reik’s lab at the Institute who conducted the work as a PhD student: “Our understanding of ageing on a molecular level has progressed over the last decade, giving rise to techniques that allow researchers to measure age-related biological changes in human cells. We were able to apply this to our experiment to determine the extent of reprogramming our new method achieved.”

Researchers looked at multiple measures of cellular age. The first is the epigenetic clock, where chemical tags present throughout the genome indicate age. 

The second is the transcriptome, all the gene readouts produced by the cell. By these two measures, the reprogrammed cells matched the profile of cells that were 30 years younger compared to reference data sets.

The potential applications of this technique are dependent on the cells not only appearing younger but also functioning like young cells. Fibroblasts produce collagen, a molecule found in bones, skin tendons and ligaments, helping provide structure to tissues and heal wounds. The rejuvenated fibroblasts produced more collagen proteins compared to control cells that did not undergo the reprogramming process. Fibroblasts also move into areas that need repairing. 

Researchers tested the partially rejuvenated cells by creating an artificial cut in a layer of cells in a dish. They found that their treated fibroblasts moved into the gap faster than older cells. This is a promising sign that one day this research could eventually be used to create cells that are better at healing wounds.

In the future, this research may also open up other therapeutic possibilities; the researchers observed that their method also had an effect on other genes linked to age-related diseases and symptoms. 

The APBA2 gene, associated with Alzheimer’s disease, and the MAF gene with a role in the development of cataracts, both showed changes towards youthful levels of transcription. 

Babraham said the mechanism behind the successful transient reprogramming was not yet fully understood and was the next piece of the puzzle to explore. The researchers speculate that key areas of the genome involved in shaping cell identity might escape the reprogramming process. 

Professor Reik, a group leader in the Epigenetics research programme until his recent move to lead the Bezos-inspired Altos Labs Cambridge Institute in the UK, said: “This work has very exciting implications. Eventually, we may be able to identify genes that rejuvenate without reprogramming, and specifically target those to reduce the effects of ageing. This approach holds promise for valuable discoveries that could open up an amazing therapeutic horizon.”Professor Wolf Reik

Professor Reik (above) was a key New Year hire for Altos which was officially launched in California: He now leads The Altos Cambridge (UK) Institute of Science and is a leader in epigenetic reprogramming of mammalian cells, honorary professor of Epigenetics at the University of Cambridge, and served most recently as director of the Babraham Institute in Cambridge. 

Also an adviser to Shift Bioscience, Professor Reik received the Wellcome Prize in Physiology and is a member of the European Molecular Biology Organisation and the Academia Europaea, a Fellow of the Academy of Medical Sciences and of the Royal Society.

Shift Bioscience is ideally positioned to help take the anti-ageing research to a fresh plateau. The company’s machine learning technology enables a clear route to drugs that safely reset cells and tissues to a youthful state. The word ‘safely’ is key here, Daniel Ives believes.

He says: “Cell reprogramming offers a path to comprehensive rejuvenation but has a ‘Goldilocks’ problem. Too little and you have no rejuvenation, too much and you risk cancer. 

“To fulfil its potential, cell-reprogramming must be made safe. Based on a novel application of machine learning, we have the opportunity to tame cell reprogramming and safely reset cells and tissues back to a youthful state.”
Shift is currently validating gene causality and weeding out unsafe genes – the final step before interventions.

Ives says: “There is still so much we don’t know about the safe rejuvenation of cells. Validating findings is a painstaking process and we have maintained our stance that this area is an exciting opportunity but that there are no instant solutions. 

“We believe we are in a very good position and can see the finishing line although it remains some way in the distance. We are on a voyage of discovery and  hope and believe that there will be collaboration between scientists in this area of research and that the race will not turn into a great drama spurred by commercial interests.

“When competition is too high, contestants can resort to zero-sum tactics that harm progress and we can’t let this happen here because the stakes for humanity are too great. 

“We benefit from a strong scientific support team of advisers that share this view, with Jonathan Milner providing the most longstanding source of inspiration and support.”

Milner is excited by the prospects for Shift and the science and has reiterated his backing for the venture in the most enthusiastic terms. He told me: “It’s a super-hot space with a real prospect of addressing diseases of ageing in the next few years.”

Cynics will no doubt cite the potentially high cost to the NHS and global health provider equivalents of having more people living well into what is considered old age. But the Shift team is well aware of the need to see people live longer – not die longer.

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