In March 2023, Boots No7 released its ground-breaking Future Renew skincare line, which targets visible signs of cumulative damage. The product is backed by 15 years of collaborative scientific research between No7 and The University of Manchester (UoM). Professor Mike Sherratt, who is part of the Division of Cell Matrix Biology and Regenerative Medicine at UoM, and Dr Mike Bell, Head of Science Research at No7, led the project.
The research strengths within the interdisciplinary division at UoM span many areas of bioscience and its applications, including but not limited to:
- cell-matrix biology
- stem cells
- tissue engineering and regenerative medicine
- wound healing
Brand-new, novel ‘super peptides’
Dubbed as a ‘super peptide’ blend and a world-first, the line is No7’s biggest cosmetic science innovation ever. These are brand-new, novel peptides that have never been used in a skincare product. The ‘peptide discovery pipeline’ uses machine learning, combined with subsequent testing in cultured cells and on the skin of volunteers, to predict and characterise novel peptides. The pipeline is ground-breaking and could benefit other areas of bioscience and health, including age-related diseases.
Long-term Walgreens Boots Alliance funding, since 2009, has enabled the development of Future Renew’s technology, from basic scientific understanding to in vitro and in vivo testing and then to commercialisation.
The innovation follows on from over a decade of collective knowledge on skin and the extracellular matrix. It is generated by research across numerous tissues and supported by multiple funders, including the Biotechnology and Biological Sciences Research Council (BBSRC).
Peptides and proteins; what’s the difference?
Peptides are short chains of two to 50 amino acids. Longer chains of over 50 amino acids are called polypeptides. Proteins are larger molecular structures made up of one or more polypeptides.
Being smaller doesn’t make peptides any less important than their larger molecular siblings. They play an essential role in many biological processes and are critical for our medical health. For example, oxytocin, one of our ‘happiness hormones’, is a naturally produced peptide in mammals.
Peptides have been a mainstay in the cosmetics industry for years, commonly used in serums and moisturisers. Despite their established nature, there has been no fundamental principle for the discovery of new peptides. Traditionally, peptides are used for an array of effects, including:
- increasing collagen production for smoother, thicker, and firmer skin
- preventing the breakdown of collagen
- decreasing muscle activity for wrinkle reduction
- supporting metabolic processes, such as the breakdown of free radicals that cause skin ageing
- improving the skin barrier for better water retention resulting in plumper-looking skin
Twenty years ago, the peptide Matrixyl®, a string of five amino acids, started being used in skincare products. It was after this scientific breakthrough that the collaboration between the teams started. The deep bioscience expertise within the UoM team in the North West was a strong draw for the No7 team, with its close proximity to the Boots base in the East Midlands.
From here, their quest to discover new peptides that could prompt skin repair began. This successfully resulted in brand-new synthetic tetrapeptides (each made up of just four amino acids) called pal-GPKG and pal-LSVD.
Why does skin age?
Our skin is the largest organ in the human body and is made of three layers:
- the epidermis is the outermost layer that is continually regenerated to maintain a protective layer
- the dermis is the thickest layer of skin, comprising connective tissue, capillaries, sweat glands, hair follicles, sebaceous glands, and nerve endings
- the hypodermis is the deepest layer of skin and includes fat for insulation and connective tissue
It is the dermis that is particularly relevant for Future Renew. Like in many tissues, the cells in the dermis are held together by a complex and intricate network of molecules called the extracellular matrix (ECM). Many of the macromolecules in this matrix will be familiar to skincare fans, such as collagens and elastins. Collagen is a protein that makes skin strong and resilient. Another protein, elastin, keeps skin flexible.
Many skin components change over time due to environmental or lifestyle-related damage and the natural ageing of cells. For example, collagen and elastin content in the dermis decreases and becomes disorganised. The skin becomes thinner and less elastic and is more vulnerable to injury. The boundary between the epidermis and dermis also thins and weakens. Accumulatively, this causes wrinkles.
A lesser-known protein found within the ECM is fibrillin, which forms part of elastic fibres and was a focus of the Boots and UoM collaboration. Fibrillin binds to elastin and provides a sort of scaffold for development, making it integral to not only the elasticity of skin but also other important structures. For example, fibrillin reduction impacts the stiffness of our arteries, impacting cardiovascular health.
Research led by Professor Rachel Watson at UoM, who is now part-funded by BBSRC, found that fibrillin was a great marker for ultraviolet (UV) damage. Successive PhD student research at UoM, led by Professor Sherratt, then found that fibrillin has plenty of amino acids that interact with UV. This makes it particularly susceptible to UV damage and causes it to break down into peptide fragments.
This then led to UoM work, characterising which 700 proteins exist in the skin (the skin proteome), which led to later key peptide research. This skin ageing research work continues with a recent £720,000 award from BBSRC, led by Professor Anna Nicolaou and with Professor Watson as co-investigator, in partnership with Boots.
Extensive BBSRC funding has supported numerous other projects at UoM, spanning skin, the dermis layer, the ECM, and various skin components, including:
The nature of this research spans skin health but also wound healing and regenerative biology. It’s led to an improved fundamental understanding of fibrillin microfibril structure, its role in elastin and elastic microfibres, and how it interacts with other ECM proteins.
Professor Clair Baldock was a key recipient of some of this funding. She leads the division at UoM, with one award involving Professor Sherratt as a co-investigator. The division has received long-term investment from numerous funders, including:
- Medical Research Council
- Wellcome Trust
- British Heart Foundation
This investment has created a basis of knowledge on fibrillin, which enabled the later research that led to Future Renew’s creation.
Dr Mike Bell says:
The BBSRC-funded work [on the skin] has been a bit of a magnet for us.
That’s really great work, really great expertise, and we would like to build off that and do something more.
It’s important that, as a business, we’re always also committing investment to run alongside the discovery.
So how does Future Renew work, and why is it exciting?
Pal-GPKG and pal-LSVD are peptides, meaning they are small molecules that are good at penetrating the skin barrier. This gives them a definite advantage over larger molecules, such as proteins or growth factors. They are synthetically produced and mimic naturally occurring peptides, working together as a ‘super peptide blend’. Toxicology testing showed Future Renew would be suitable for human skin, including sensitive skin.
The product boosts the skin’s natural self-repair function. Initial in vitro testing on cells shows that the peptides promote ECM proteins that are involved in matrix organisation and function, including fibrillin. Subsequent work with human volunteers demonstrated that, in living skin, the peptide combination promoted the expression of not only ECM genes but also genes which play a vital role in epidermal health.
One of the peptides is found in collagen, and the other is found in elastic fibre proteins, basement membrane proteins, and laminins.
Professor Mike Sherratt says:
Often, it’s the structure of the matrix that’s really important for function, not how much of those molecules you have.
In vivo, the two peptides in combination are switching on lots of pathways that we know are important for continued skin health.
When you do put them together, you find there is a synergy.
Collaboration is key
Synergy across the teams has been a crucial component to the success of this discovery too. As Dr Mike Bell continues:
The other aspect which has been really important is network building.
We’ve got partners that act almost like a hub-and-spokes model, where our Manchester collaboration is at the centre of our skin research.
But we have satellite partners that work together synergistically.
We can identify opportunities to link up, where different experts can come together to solve a problem in different ways.
It’s really important to me that we have research partnerships that don’t work in isolation.
That’s the power of it.
A hotpot of interdisciplinary research
The super peptide discovery and Future Renew’s success would not have been possible without combining several scientific disciplines through interdisciplinary collaboration.
Dr Mike Bell says:
Skin is so complex it has to have interdisciplinary research, and that’s the only way in which we can really understand the different elements of it.
For fibrillin, we first looked at it from a histological viewpoint, then you go into biomechanics, and suddenly you’re into the physics of skin at the atomic level.
Then thinking about skin penetration and trying to detect where these peptides are going, and that requires chemistry.
And we go even beyond that because we’re interested in ethnography, sociology, and anthropology.
How do consumers behave? How are they going to think about ageing?
All the cultural elements that will impact their behaviours and their lifestyle choices.
What impacts on their skin will change over time and through a life course.
A new formula for success
Machine learning and omics were also critical in identifying and narrowing down which peptides would be a good bet.
Before settling on the two peptides, pal-GPKG and pal-LSVD, the project used an algorithm called Prosper, developed by Monash University. The algorithm was used to predict cleavage sites for proteins, meaning where skin proteins could be cut to make useful peptides. Then, using bespoke computer code written in Manchester, the team used the cleavage site positions to predict an initial list of 1,000s of potential peptides. This was the first time that protease cleavage site prediction had been used in such a manner, so this ‘peptide discovery pipeline’ is a new way of predicting peptides from protein collections.
The team then narrowed their focus to just the tetrapeptides due to how they could easily penetrate the skin and be easily made from many natural proteins or molecules. Eventually, eight peptides were chosen for lab testing due to:
- their high solubility
- their high potential for bonding and interacting with receptors
- how easily it would be to mass manufacture them
Robotic technology at the University of Liverpool and mathematical modelling were also used to formulate the product. This combination of cutting-edge bioscience, artificial intelligence technology, omics, mathematics, and cosmetic science enabled the super peptide discovery.
There are currently 11 ongoing patents between Boots and UoM for the various discoveries that led to Future Renew, including the novel peptide technology and the peptide pipeline method.
Boots and UoM will be renewing their contract for another five years and will be expanding the current research into new areas.
Professor Mike Sherratt says:
The most amazing thing to me is that all eight of the peptides that we chose to test affect cells.
So, cells are sensitive to small fragments of matrix proteins in their environment, and they respond differentially.
For me, this is an immensely exciting part of it because this gives us a potential way to tune cell behaviour.
We’re not at the point yet where we can predict what a particular peptide will do to cells.
So that’s part of the next step.
Screen enough peptides so that we can make those predictions.
Dr Mike Bell says:
We want to work on skin diversity and explore the skin across the pigmentary spectrum.
The peptide work has established a technology platform for us.
There are still so many things to find out about the peptides.
And we’ve got a pipeline of peptides that we still want to look at and other applications maybe beyond skin care.
This includes two BBSRC-funded Industrial Partnership Awards for UoM-Boots collaborative research:
- Professor Catherine O’Neill is leading a project into how our skin microbiome affects the skin’s sunburn response, as well as investigating and identifying a bacterial molecule known to cause cell death in response to UV. This has a protective effect by preventing the multiplication of UV-damaged cells, and the project aims to find if other bacterial species can protect us from UV-caused DNA damage
- Professor Anna Nicolaou is leading a project on:
- how the lipid content in the epidermis changes as we age
- which molecular mechanisms cause these changes in lipid content
- how we might combat these changes and their associated decreases in skin strength and resilience
Growing the next generation of scientists, then and now
Professor Sherratt started his career at UoM as a PhD student in Professor Cay Kielty’s lab, with this experience sparking his first interest in this exciting field of research. Looking to the future, he is keen to support the career progression of early career researchers now. He says:
I’ve seen the struggles that young scientists go through with career progression and identifying careers.
I think we lose a lot of a lot of very good people early on.
What could be done to simplify or strengthen those pathways by which people can go from a PhD through to those academic positions?
If we could address that, it would be really worthwhile.
For the first time, Boots are leading a new BBSRC Collaborative Training Partnership (CTP), with UoM as a partner, building on the existing successful relationship. The CTP’s focus is skin health and ageing research, supporting the development of new therapeutic interventions, and addressing the lack of diversity within skin and cosmetics research. The first cohort of students will start the new programme in September 2022.
BBSRC’s CTP scheme highlights the importance of academic and industry collaboration, interdisciplinary and multidisciplinary research, and transferable skills. The four-year studentships will be delivered over the period 2022 to 2028 with £22.5 million of funding from BBSRC, and more than £14 million cash and in-kind co-investment from industry partners.
Dr Mike Bell says:
This sort of science is really attractive because it is interdisciplinary.
There are some really big challenges we’ve got to answer.
You can make a difference.
Hopefully, what we are doing is making a lot of people very happy and more confident in their skin and in themselves.
So, I think STEM is really important.
We need to attract more people into the sciences, and I think we need to attract more people and more scientists into our industry.
Find out more
Top image: Future Renew product line. Credit: Walgreens Boots Alliance