Accelerating skin disease research

Dr. ClarkHarvard Medical School houses the state of the art Partners Healthcare Biobank, containing human pathology specimens and information about living consented patients - all records searchable by diagnoses - as well as access to cutting edge human analytic techniques. Now, thanks to a new National Institutes of Health- (NIH-) funded center, these resources are available to anyone interested in carrying out translational skin disease research on human cells and tissues.

In mid-2016, researchers at Brigham and Women’s Hospital and Harvard Medical School received a five-year $4.35 million NIH grant to establish the Human Skin Disease Resource Center (www.humanskin.org).

“The purpose of our center is to accelerate human skin disease research. We provide human samples and cutting edge human analytic techniques to anyone at any institution who wants to carry out human skin disease research,” Rachael A. Clark, M.D., Ph.D., a dermatologist at Brigham and Women’s Hospital, Harvard Medical School, and director of the Human Skin Disease Resource Center, tells Dermatology Times. “The reason I wanted to establish this Center is that there are many unrecognized differences between mice and humans. If you read, for example, Nature Medicine, most of the work presented is carried out in mice. But between 90 and 95% of the cancer therapies that work in mice don’t work in humans.”

Dr. Clark, who presented on the Center and other research topics at the March 2017 American Academy of Dermatology (AAD) Annual Meeting in Orlando, Fla., says the need to transition skin research from animals to humans is paramount.

“For example, all the therapies designed in mouse models to combat methicillin-resistant Staphylococcus aureus (MRSA) infection have failed in human trials,” Dr. Clark says.

Human tissue for the taking

Human skin disease research has evolved in big ways, she says.

“It used to be that there weren’t a lot of great techniques to study human cells and tissues, but that has really changed over the last five years,” Dr. Clark says.

Not only have techniques evolved, but so has the availability of biobanks to provide disease-specific tissue samples.

“The whole point of our center is to give these resources to anyone, anywhere, who wants to do this type of research, with the goal of making observations we know will work in our patients,” she says.

Dermatologists and other researchers interested in a skin disease - any skin disease - can tap into two separate biobanks at the Center - one containing 5 million FFPE-preserved human tissue samples and one with 22,000 characterized and fully consented living patients. The Center has serum, blood DNA and gene variant chip profiling from those patients and are able to call the patients in for further study.

“Let’s say you are interested in psoriasis and want to know if a particular gene variant is overexpressed. Around 12,000 living patients are genotyped, and we have over a thousand psoriasis patients. You could access these patients and healthy controls without psoriasis to see if that gene variant is shared. Then, you could have them come in and give blood, to see how that gene variant changes the way the immune cells behave,” Dr. Clark explains.

The Center also can provide researchers with human engrafted mice. These immunodeficient mice, grafted with human skin grafts and injected with blood from a second donor, develop an inflammatory dermatitis. This model is ideal for studying skin inflammation and testing novel topical and systemic therapies on human skin and immune cells in an accessible animal model.

“One the goals of our Center is to bring more dermatologists into translational skin disease research,” Dr. Clark says. “We can help you design the experiments and even carry them out for you.”

NEXT: Access to testing

Access to testing

If a dermatologist, for example, has a cohort of patients with a particular disease and is not sure how to go about studying the mechanism of that disease, the Human Skin Disease Resource Center can help.

Among the cutting edge analytic services available, there are new tissue imaging techniques that evaluate proteins and cells using multicolor immunofluorescence. The Center has an automated microscope with sophisticated software that images sections and counts how many of each cell type there are, and how much of the stained protein is expressed.

“That sample can also be used for gene expression analysis, using NanoString [NanoString Technologies] based arrays,” Dr. Clark says. “NanoString profiling gives you a picture of up to 800 genes in one test, and it works beautifully on formalin fixed paraffin embedded (FFPE) samples, which are the type in most dermatology tissue archives. So with a single patient sample, you can do gene profiling to figure out what genes and pathways are activated. Then, by immunostaining sections from that same sample, you can look and see what cells express those genes and more. You can carry out a whole research project built around your own samples.

Two of the Center services are focused on immuno-analysis because many skin diseases are immune mediated. Center’s researchers can help design and analyze T-cell receptor, or TCR, sequencing studies, a one-step test that measures the number, diversity and TCR sequences of all T cells in a sample. It can be used to track particular T cell clones across many tissues and across time. For example, TCR sequencing is allowing rapid diagnosis of cutaneous T- cell lymphoma and measuring the number of malignant T- cells in skin and blood over time.

There’s more. The Center offers CyTOF, or cytometry by time-of-flight, analyses, a technique that allows researchers to take a small number of cells and study up to 64 markers at one time.

“CyTOF is one of those things that’s available at only the larger medical centers but we can do it for anyone that wants to run their samples,” Dr. Clark says.

The Center funds others’ research

The Human Skin Disease Resource Center also has money allotted to fund grants. Visiting scholar grants fund a researcher to visit the Center in order to learn how to work with human tissue and how to use new techniques. “Translation Accelerator” grants provide start up money for a researcher who wants to ask a particular question using human cells and tissues. The Center is particularly interested in supporting new investigators, investigators new to human skin research, and investigators who have only worked previously in mouse models.

Some of this is free

The Center is designed to provide a great deal of help, including resources, protocols and experimental design and approaches, for free. But researchers who carry out testing through the Center usually fund these studies from their own grants or other support, according to Dr. Clark.

“Part of the fun of this is having people reach out to us with research questions,” Dr. Clark says. “The more clinically relevant the question is, the more excited we are about it.”

For more information, visit www.humanskin.org or email humanskin@bwh.harvard.edu.

Disclosure: Dr. Clark reports no relevant disclosures.