CLAIRE AND WNT PROTEINS

A principal character not introduced until the second chapter is the heroine of FRACTURED, Claire Hodgson, a vivacious stem cell biologist whose intellect, creative curiosity and professional ambition have propelled her into the ranks of the preeminent scientists in her field. Born and raised in Sydney she left Australia to continue her education and training. After completing a Ph.D. in cell biology and two post-doctoral fellowships Claire is now the director of the Stem Cell and Regenerative Medicine Laboratory at the academic medical center where she is employed. She is beautiful and brilliant, and she’s made a remarkable discovery—she can make bones.

Her process uses three-dimensional printers that use biologic fluids and cells rather than plastics or metal. The result is a living tissue not an inanimate object. In Claire’s system the 3-D bioprinter builds the complex structure of bone while also incorporating stem cells and cell-signaling proteins into the biologic matrix. This process results in living, genetically matched, bone tissue that can be grafted into a patient to repair defects caused by trauma or induced by surgery. The story’s protagonist, orthopedic surgeon Mark Thurman, who works at the same institution, although at different facilities, found out about her research and they began collaborating in an effort to develop methods to repair bone injuries in trauma patients. As the story begins they have completed a three-year struggle, climbing a mountain of obstacles and bureaucratic red tape, and are ready to begin treating actual human patients.

A 3-D Bioprinter at WFIRM

Claire became fascinated with 3-D printers at an early age when her father, an engineer, showed her one. This interest evolved into printing complex biological tissues and led her to study at the Wake Forest Institute for Regenerative Medicine in Winston-Salem, North Carolina. WFIRM is not fictional. It is one of the leading centers for 3-D biological tissue printing. Dr. Anthony Atala is the director of the institute and graciously invited me to tour the facilities last year.

The Author Visiting WFIRM with Tour Host, Dr. John Jackson

Claire’s process is revolutionary. She has designed and built a 3-D printer that produces bone tissue with stem cells incorporated into the rigid calcium phosphate structure. A simple analogy is an egg. If a 3-D printer were to be programmed to make an egg it would build the shell and deposit the liquid egg white and yolk as the shell was built. As the print head moved back and forth over the egg it would deposit calcium for the shell or fluid and cells for the center and gradually create the structure. This is the same for bone but on a much more complex level and at much finer resolution. The printer creates microscopic areas for bone cells, called lacuanae, then deposits stem cells and a biologic fluid into them as the bone is being printed, like millions of microscopic eggs. In this manner the architecture of bone is created using a 3-D printer (see my second blog post, FRACTURED BONES, for more information on the anatomic structure of bone). Recall that a stem cell is a pluripotential cell. This means it has the capacity to develop into any type of cell in the body once it receives the correct signal. The printing process has been designed so that cell-signaling proteins are incorporated into the fluid bathing the stem cells. Some of these proteins are from a family called Wnt proteins.

Diagram of the Noncanonical Wnt Signaling Pathway

Claire has figured out how these Wnt proteins stimulate a stem cell to change into a bone-producing cell, called an osteoblast. The stem cells used to print the bone specimen are obtained from patient biopsies then cultured in her laboratory until needed for the 3-D printing. Once the bone graft is produced, with the stem cells contained in the lacunae, it’s ready to be surgically implanted into the patient. Claire and Mark hope that once the graft is in the patient the Wnt proteins will signal the beginning of a cascade of intracellular events resulting in the stem cells differentiating into osteoblasts. The osteoblasts then begin producing new bone stimulating very rapid fracture healing uniting the printed bone into the patient’s skeleton. There is considerable scientific evidence this actually could occur. Philipp Leucht, MD and Jill Helms, DDS, PhD, recently published a research paper where they state: “There is now a substantial literature supporting a role of Wnt signaling in skeletogenesis and a growing appreciation for the functions of Wnt proteins in regulating stem cell and skeletal cell behavior.” (Wnt Signaling: An Emerging Target for Bone Regeneration, J Am Acad Orthop Surg 2015;23: 67-68)

I hope this brief overview convinces you the work Claire and Mark are doing isn’t the stuff of science fiction, it’s actual cutting edge research that I expect to be available for patients in the not-too-distant future.