In the 1980s, when George Murphy, MD, was just beginning his career at the Brigham, he had the opportunity to assist Brigham reconstructive plastic surgeon Dennis Orgill, MD, PhD, and MIT materials scientist Ioannis Yannas, PhD, on the development of a biodegradable membrane they hoped would act as an artificial skin and facilitate wound healing. Made from bovine collagen and a jelly-like substance derived from sharks (glycosaminoglycan), the membrane had the capacity to thwart the formation of dysfunctional scar tissue and promote true regenerative skin healing. (Known as Integra, the membrane is used all over the world today for wound healing.) The investigators didn’t realize it at the time, but they had stumbled upon the healing power of skin stem cells—several decades before skin stem cells had been discovered.
In the years ahead, seminal discoveries and experiments by Brigham investigators including Murphy, who is now the director of Dermatopathology, and his colleague and collaborator Christine Lian, MD, would build a compelling case for why skin stem cells may be at the root of two seemingly unrelated phenomena: skin regeneration and the development of cancer.
Rare but Powerful
In 2004, Murphy began his second foray into the world of skin stem cells by working intensively with Natasha Frank, MD, of the Division of Genetics; Markus Frank, MD, of the Renal Division; and Tobias Schatton, PhD, of the Department of Dermatology. In 2007, the team pioneered a discovery that made the cover of the journal Nature: the first identification of stem cells responsible for malignant melanoma, a potentially deadly yet poorly understood form of skin cancer.
“Like queen bees in a hive of hundreds of workers, relatively rare malignant skin stem cells are crucial to the genesis and maintenance of an entire tumor,” said Murphy. “Stem cells tend to be covert and there is a scarcity of biomarkers with which to detect them. The molecule that was discovered—ABCB5—could identify stem cells in normal skin and identified a cell in malignant melanoma that, although only a small component of melanoma, appeared to drive the tumor.”
These insights have led to a clear and concise goal in cancer therapeutics: target and eliminate malignant stem cells. But Murphy and colleagues want to take this goal one step further by targeting precursor cancer skin stem cells before melanoma poses danger.
“Melanoma is curable when it’s very early. But when it gets to be the volume of something potentially no larger than a lentil, it can metastasize and kill you,” said Murphy. “This switch—from a curable stage to a deadly stage—is critical to study.”
In contrast to stem cells that have gone awry, normal skin stem cells are essential to the health and well-being of mature, functional skin. The ability to manipulate the fate of normal skin stem cells could also hold the secret to regenerative wound healing. How to control stem cell behavior and destiny, therefore, became the burning question.
Hidden in the Epigenome
Murphy and Lian credit the origins of their collaborative partnership to “strategic adjacency” (being in the same building) and luck.
“It was both science and serendipity that brought us together,” said Lian. “Now that the potential problems can be seen more clearly, our goal is to home in on the stem cell epigenome in ways that will lead to new and effective therapies for our patients. Together, we are aggressively pursuing this goal.”
By 2011, Lian had joined the Program in Dermatopathology, bringing with her a fundamental insight into the role of the “epigenome,” the external coating that envelops the DNA molecule and regulates its behavior (or misbehavior, in the case of a malignancy).
Lian had joined the Brigham in 2004 as a postdoc, where she worked on the second floor of 221 Longwood Ave., striving to bring insights from epigenomics to bear on clinical work. Lian was especially interested in melanoma, in part because of the tremendous socioeconomic impact of the disease. She soon heard about Murphy—who was working just two floors above. Their proximity helped bring about a new collaboration.
That collaboration led to the creation of the Dermatopathology Stem Cell/Epigenomics Laboratory. In 2012, they published a paper together in the journal Cell, exploring the role of a critical epigenetic mark—a chemical punctuation mark that tells a cell how genes should be read—in melanoma skin stem cells. The team found that the loss of this key epigenetic mark was a hallmark of melanoma, with both diagnostic and prognostic implications, and could be identified in precursor cells. This landmark discovery suggested that the skin stem cell epigenome may be a key to both controlling melanoma and skin regeneration.
“The epigenome controls the way DNA behaves, just like a mutation. But unlike a mutation, changes to the epigenome are reversible,” said Lian. “This opens up exciting therapeutic possibilities and avenues to pursue.”
More Questions to Explore
Lian, Murphy and their colleagues are intent on identifying novel ways to target and destroy skin cancer stem cells as well as to control and regulate skin stem cells capable of regenerative healing through therapeutic modulation of the epigenome.
In addition, they are pursuing questions related to aging and transplant rejection through collaboration with multidisciplinary experts and by leveraging diverse, cutting-edge technologies, including next-generation-epigenetic sequencing, three-dimensional bioprinting, and highly multiplexed image capture to simultaneously visualize critical stem cell molecules. The lab works closely with the Harvard Stem Cell Institute, and major collaborative proposals are planned and underway in areas including regenerative wound healing, cancer prevention and epigenomic therapeutics.
“We’ve assembled a multidisciplinary team interested in the conjunctiva of the eye, the dental cavity, the regenerative properties of salamanders and more,” said Murphy. “We have found investigators across the Boston area who share their interest in the role of skin stem cells but have expertise and interests in far-ranging areas.”
Lian and Murphy are optimistic that this team, with its wide-ranging expertise, will take the steps needed to understand and control those rare cells that both drive cancers and hold the key to tissue regeneration.