How do blood-forming stem cells know how to migrate to the marrow? How can a malignant T cell slip out of the blood and into the skin? Glycobiology may hold the answers.

As a second-year medical student, Robert Sackstein, MD, PhD, had the opportunity to observe a bone marrow transplant in a young man who was suffering from primary marrow failure.

Sackstein, now a member of the Brigham Departments of Dermatology and Division of Hematology recalls sitting at the bedside as filtered marrow cells were infused into the patient’s bloodstream. Sackstein remembers that within weeks, the patient began producing new blood cells, indicating that the infused blood-forming stem cells had migrated to the marrow and begun proliferating. But when Sackstein asked the patient’s treating physician to explain how the cells navigate to this location, the only explanation he received was that “the cells just know to go to the marrow.”

Sackstein was left unsatisfied by this answer.

Decades later, John O’Malley, MD, PhD, of the Department of Dermatology, found himself treating a patient who had walked into his clinic with bright red skin. O’Malley, who sees patients with cutaneous lymphomas, knew that this was a telltale sign that his patient’s T cells had slipped out of the blood and into the skin, leaving his patient with a poor prognosis. It also left O’Malley with questions: Why is it that, in some patients, malignant T cells can so easily escape into the skin and cause devastation? What drives the progression of their disease? What could he do to help this patient and others like him?

Both O’Malley and Sackstein’s quests to find answers would lead them into an important field: translational glycobiology, the study of how glycans (sugar molecules that can attach to a wide variety of biological molecules) can influence health and disease.

But while Sackstein forged his own path without mentorship from glycoscientists or training in chemistry, enzymology or structural biology, today, thanks to funding secured by the Department of Dermatology, the next generation of physician-scientists like O’Malley can receive more formal mentorship and training at the Brigham and continue a legacy of leadership in this emerging field.

The Fourth Macromolecule
In the world of biological macromolecules – the complex molecules made up of unions of thousands of atoms or more – the nucleic acids, proteins, and the lipids are usually the focus of attention. But a fourth class of biological macromolecule – the glycans – play a critical, yet underappreciated, roles in a wide variety of biologic processes in both health and disease, including inflammatory diseases, cancers and degenerative diseases.

“There is a pressing need to expand our knowledge into how glycans affect human well-being, but there are very few biomedical scientists that possess the needed education and skills for performing research into how glycans control human biology,” said Sackstein. “The key to bridging this translational chasm is to support the development of translational glycobiologists.”

Charles Dimitroff, PhD, of the Department of Dermatology, runs a laboratory focused on the glyco-pathological basis of immunity, inflammation and cancer. He notes that for decades, basic glyco-scientists have appreciated the critical (and often elusive) impact of carbohydrate chains displayed by proteins, such as antibodies, growth factor receptors, receptor tyrosine phosphatases and integrins. But bringing that knowledge to bear on clinical outcomes for patients requires deeper integration with clinicians.

“In the emerging age of biological therapeutics in which proteins are common entities, clinical scientists need to appreciate how carbohydrate modifications on proteins can alter their functionality, which ultimately translates to the successful treatment of patients,” said Dimitroff.

Uncovering Connections
Sackstein’s work on human bone marrow cells led him to the discovery of a previously unrecognized  glycoprotein, now known as Hematopoietic Cell E-/L-selectin Ligand (HCELL). Sackstein uncovered that HCELL directs the migration of stem cells to the marrow. His lab continues to study the role of HCELL in a variety of disease contexts, including graft versus host disease and blood cancers.

“As clinicians, our research is often inspired by the person who cannot get well,” said Sackstein. “For certain problems that affect our patients, we cannot undertake the needed research to engender a solution without an understanding of the basic science of carbohydrates.”

O’Malley too has begun to see connections between his patients and a critical glycoprotein. The subset of patients he treats with red skin and a poor prognosis tend to produce a large amount of cutaneous lymphoma antigen (CLA) – an E-selectin ligand that helps recruit T cells into the skin from the blood stream.

“CLA allows cells to interact with the endothelium almost like Velcro,” explains O’Malley. “CLA sits at the terminal end of a sugar and is present either on a protein or lipid. It’s the Velcro component that recognizes E-selectin on the endothelial cells, allowing T cells to stick and then enter the tissue.”

Interestingly, the BWH Department of Dermatology has a legacy of discovery when it comes to CLA. In 1997, a team from the Brigham published the structure of CLA in Nature, showing that it was a uniquely glycosylated form of a known protein, PSGL-1.

O’Malley is interested in finding out if these ligands are playing a malignant role in helping drive cutaneous T cell lymphoma.

“As a dermatologist, I find glycobiology very interesting,” said O’Malley. “The sugars found on the surface of cells can dictate whether that cell can get into the skin or not. And we don’t have a great understanding of how these sugars are mediating inflammation. Since the skin is accessible, it’s a great field through which to be able to understand human glycobiology in inflammatory skin diseases.”

Funding to Train Translational Glycobiology’s Proteges
The Brigham Dermatology of Department received very sweet news earlier this year: The National Heart, Lung, and Blood Institute, part of the National Institutes of Health, selected to fund its career development program in translational glycobiology at Harvard. A joint venture between the BWH Dermatology Department and the Department of Surgery at Beth-Israel Deaconess Medical Center, the program represents something truly unique in the Harvard University ecosystem and in the field.

“In the history of the field of glycosciences, it is unprecedented that hospitals have served as the academic thrust for this discipline,” said Sackstein. “The fact that two clinical departments from two different hospitals converged to lead in creation of this Harvard University-wide effort serves as a signal that glycoscience is already embedded in clinical medicine, and that the Harvard wellspring for glycoscience research and education is hospital-based faculty.”

Funding from the NHLBI will make possible the “Harvard Program in Translational Glycobiology Career Development” (Harvard ProTG), a training program for clinicians and basic scientists who are interested in the field.  The program is open to all current post-doctoral fellows and clinical trainees, and also to early-stage faculty.  Salary support for the Harvard ProTG Scholars (trainees), for up to three years at their relevant professional level, is made possible through the award. Scholars will immerse themselves in glycoscience-based laboratory inquiry, focusing on the glycobiology of conditions related to the mission of the NHLBI (heart, blood, lung and sleep disorders).

“Glycobiology and the glycosciences are finally getting the recognition they deserve,” said Thomas Kupper, MD, chair of the Department of Dermatology. “I am pleased and proud that the Department of Dermatology and Brigham and Women’s Hospital, through Dr. Sackstein’s efforts, are playing a leadership role in this field, both nationally and internationally. The implications of new discoveries directly related to better care for patients are enormous.”