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Skin in the game: Procter & Gamble scientists identify and target a novel pathway involved in hyperpigmented skin spots in vitro.

Procter & Gamble scientists discover novel pathway
causing skin hyperpigmentation

Every day, people around the world look in a mirror and notice a new speckle, dot, or properties: In the human epidermis, one dendritic melanocyte interacts with PHOTO: COURTESY OF PROCTER AND GAMBLE
splotch on their skin. Spots caused by hyperpigmentation—where an area of skin is about 36 keratinocytes (another type of skin cell) and supplies them with melanin.
darkened—affect all ethnicities, skin tones, genders, and ages, and can be a point of We know that the presence of hyperpigmented spots is influenced by multiple
pride, frustration, or perplexity for the owner. For decades, scientists at The Procter & intrinsic and extrinsic factors, such as ultraviolet B (UVB) exposure, hormone
Gamble (P&G) Company, which owns several of the world’s leading skincare brands imbalance, inflammatory status, and aging; there has also been abundant research
including OLAY, have been trying to unravel the mystery of how hyperpigmented spots on the factors influencing melanin pathways, which include melanin synthesis,
form and grow. Now they are closer to cracking a new code, thanks in part to the melanogenic cytokines, and melanosome transfer. However, the precise mechanism
creativity of one scientist and a supporting cast of thousands of other scientists underlying melanocyte dendricity, or branching, has not been clear—until now.
and engineers.
The P&G team discovered a novel correlation between the presence of spots
Tomohiro Hakozaki, a research fellow in P&G’s Beauty Technology Division, has and an increase in the dendricity of
been singularly focused on skin pigmentation for almost his entire career. With melanocytes through comparing spot
a Ph.D. in dermatological science, Hakozaki has worked in various areas of skin area versus nonspot area in multiple
biology and biometrics as he has sought to better comprehend the mechanism types of facial spots, including melasma,
within skin cells that causes hyperpigmentation. “You might remember when you solar lentigo, and postinflammatory
first see the spot on your face, and you react ‘what’s this?’” he says. “When we do hyperpigmentation (PIH)/acne marks. The
consumer research, spots always pop up as a number one or two skincare concern. findings, which indicate that “increasing
This is what motivates my life’s work. My dream is to develop the technology to fade the export network of melanosomes
and ultimately remove unwanted spots.” may be a key common mechanism for
increased pigmentation in spots,” were
To find a solution to stop the spots, P&G scientists leveraged their knowledge reported in their groundbreaking paper
about skin and pigmentation. While human skin color has several components, the for the Journal of the European Academy of
biggest driver is melanin, and when it is localized in some areas, it appears as a Dermatology and Venereology. In essence, Tomohiro Hakozaki
spot. Melanin is produced in melanocytes, very specialized skin cells with dendritic

Produced by the Science

the greater the dendricity, the more example, P&G has been adding SDL

channels there are for melanin to niacinamide (a.k.a. vitamin B3),

to be deposited on the surface of an invention that has recently been

the skin. And the team uncovered granted a U.S. patent.

another fascinating correlation: a It makes sense that P&G

PHOTO: ADAPTED FROM J. WANG ET AL. THE COMBINATION OF SUCROSE DILAURATE AND SUCROSE LAURATE SUPPRESSES HMGB1: AN ENHANCER OF MELANOCYTE DENDRICITY AND MELANOSOME TRANSFER TO KERATINOCYTES. JEADV , SUPPL. , 11. link between the proinflammatory scientists would be the ones who

protein high mobility group box 1 unraveled the science behind

(HMGB1) and “skin pigmentation spots. The company has always

machinery.” Indeed, this pesky invested heavily in R&D and has

protein is a key contributor pursued a science-first approach in

to stimulating formation of improving people’s lives.

melanocyte dendricity. There are still abundant

With this discovery, the P&G opportunities to explore. “A spot is a

team aimed to examine what very small place on your skin, but it

compound could potentially involves very complex biology and

suppress the development of this pathways. What we have achieved

dendricity in vitro. In collaboration is discovering a new intervention

with a supplier, they identified a pathway in vitro,” says Hakozaki.

special ratio of sucrose dilaurate “But there is more to discover

(SD) and sucrose laurate (SL) in that can help the whole skincare

combination, called SDL; these two industry in scientific research.”

compounds have been used for He continues to be engaged and

years as emulsifiers, dispersants, energized by this research. “I love

or stabilizers in cosmetics, my job,” he says. “There is a saying

foods, and pharmaceuticals, that ‘the only way to do great

with no safety issues. However, work is to love what you do.’ If you

the team demonstrated that the haven’t found it, keep looking.

SDL combination produced a Don’t settle. As with all matters of

“stabilizing” effect—a marked the heart, you’ll know it when you

reduction of HMGB1 release, and a find it. This is exactly what I have

significant decrease in melanocyte [found] here. It is really exciting to

dendricity formation and a be working on cutting-edge science

reduction of dendrites already with thousands of talented people

formed. “SDL can effectively Immunofluorescence and cell culture studies from Procter & Gamble scientists show that increased in specialties such as biology
stabilize the melanocyte from melanocyte dendricity is linked to hyperpigmented skin spots and that a combination of sucrose dilaurate and beyond.” Clearly, P&G values
the root, which is a breakthrough and sucrose laurate suppresses melanocyte dendricity in vitro. Hakozaki, because as he says, “the

in vitro science discovery in the industry regarding the spot-fading mechanism,” company has allowed me to stay focused in this field for more than a decade.” And

Hakozaki notes. Moreover, SDL also reduces the melanosome transportation for an innately curious scientist, dedicated to improving the lives of people around

machinery protein Rab27a through the dendrite tips within melanocytes in a the world, that hits the spot.

coordinated manner, inhibiting melanin production and transfer and lowering the

total melanin amount in the epidermis. Sponsored by
“To prove this, we did a lot of sequential in vitro experiments,” Hakozaki says.

“There are many ways to reduce melanin production. Most of them relate to

melanin synthesis. This is the only one we found so far to modulate the melanocyte

dendricity effectively. So [for me] it was a ‘holy cow’ moment as a team member!”

This advancement has the potential to create whole new branches of technology.

”Human biology is so complex,” Hakozaki says. “We believed there should be much

more, some other mechanism involved here.” And now that they know what that

mechanism is, scientists can develop new technology for targeting spots. For

























































































RESEARCH

◥ disruptive detection technologies that can
very sensitively and specifically identify early
REVIEW SUMMARY biological changes, whether in tissue struc-
ture, biochemistry, or function. Powerful mo-
CANCER lecular analytical technologies and advanced
imaging and histopathological methods are
Early detection of cancer increasing the ability to sensitively find earlier
tumors, while the use of synthetic markers
David Crosby*, Sangeeta Bhatia, Kevin M. Brindle, Lisa M. Coussens, Caroline Dive, may help to amplify their signal.
Mark Emberton, Sadik Esener, Rebecca C. Fitzgerald, Sanjiv S. Gambhir, Peter Kuhn,
Timothy R. Rebbeck, Shankar Balasubramanian* The fifth challenge is how to appropriately
evaluate early detection approaches. Transla-
BACKGROUND: When cancer is detected at the The second challenge is determining the tion of biological insights into new diagnostic
earliest stages, treatment is more effective and risk of developing cancer. How can we use technologies and execution of clinical trials
survival drastically improves. Yet ~50% of can- germline genomic susceptibility, family his- to validate those advances require substantial
cers are still only detected at an advanced stage. tory, exposures, demographic, and behavioral time and money. We discuss ways in which
Improved earlier detection of cancer could sub- data to build nuanced risk models to identify that process might be improved.
stantially increase survival rates. Although re- who should be tested for cancer and how test
cent advances in early detection have saved results should be interpreted and followed OUTLOOK: For early detection to deliver trans-
lives, further innovations and development of up? Progress is being made to address this formative progress in cancer survival, wider
early cancer detection approaches are needed. challenge through improved understanding skill sets beyond cancer biology are essential,
The field is evolving rapidly, owing to advances of the genomics of cancer risk, integration including engineers, chemists, physicists, tech-
in biological understanding and an increasing of that insight with other risk factors, and nology developers, and behavioral and com-
pace of technological progress. the development of large-scale population puter scientists. Integrated, interdisciplinary
cohorts where risk models can be developed collaboration is key to bringing new ideas to
ADVANCES: We highlight five challenges facing and validated. address the challenges of early cancer detec-
the field, current work in those areas, and where tion. We believe that early detection of cancer
more research is needed to make early detec- The third challenge is finding and validat- is approaching a tipping point, as biological
tion a reality. The first challenge is to build a ing biomarkers of early cancer. There is con- insight and technological capacity are increas-
greater understanding of the biology and siderable difficulty in finding accurate signals ing at an unprecedented rate and as public
behavior of early disease. This will help iden- of early cancer (which usually exist in very and private funders of research are increas-
tify ways to distinguish between consequen- small amounts) amid the noise of normal hu- ingly willing to invest. This Review discusses
tial, aggressive lesions and inconsequential man physiology. Although progress has his- the current state of the field and suggests con-
lesions that will not cause harm. Such in- torically been slow, many promising early structive ways forward that build on current
sight will be crucial to realizing the potential detection markers are emerging, including cir-
for early detection to inform treatment deci- culating tumor DNA, circulating tumor cells, ▪progress to deliver effective earlier detection of
sions and improve survival, while minimizing proteins, exosomes, and cancer metabolites.
the risk of overtreatment. Alongside studies in Advances in data analysis methodologies (such cancer and appropriate intervention.
human samples, better models of disease are as machine learning) and integration across
enabling identification of early signals of tu- marker types in multimodal tests are also ac- The list of author affiliations is available in the full article online.
morigenesis and clarifying the contributions celerating progress. *Corresponding author. Email: [email protected]
of the immune system and microenvironment (D.C.); [email protected] (S.Ba.)
to tumor development. The fourth challenge is technological. It in- Cite this article as D. Crosby et al., Science 375, eaay9040
volves both the iterative improvement of ex- (2022). DOI: 10.1126/science.aay9040
isting approaches and the development of
READ THE FULL ARTICLE AT
https://doi.org/10.1126/science.aay9040

Challenge 1 ?? ? Challenge 3 •New technology to Challenge 5
Understanding the Finding and validating amplify signal Evaluating early
biology and prognosis •Identify risk factors cancer detection detection
of early cancer •Develop integrated risk biomarkers •Minimize invasiveness approaches
of test
•Develop new models models •Understand markers in •Appropriate,
•Explore the •Use risk to target biological context •Continuous monitoring progressive trial design
(surrogate end points?)
microenvironment screening •Validate in appropriate Challenge 4 •Understand results in
•Determine consequentiality populations Developing accurate real-world context
technologies for early
of changes •Analyze and integrate with detection
appropriate methods

Challenge 2
Determining the risk
of developing cancer

The early detection of cancerÑchallenges and ways forward. This figure summarizes challenges that impede the early detection of cancer and the areas of
current research that are helping to overcome them.

1244 18 MARCH 2022 ¥ VOL 375 ISSUE 6586 science.org SCIENCE