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Statement by Anton-Lewis Usala, M.D.
Clinical Professor of Pediatric Endocrinology
Brody School of Medicine, East Carolina University
Founder, Encelle Inc.

TISSUE REGENERATION, NOT TRANSPLANTATION, TO CURE HUMAN DISEASE

Chronic disease states such as Type 1 Diabetes, Parkinson’s Disease, and Spinal Cord Injury result from the destruction of specific cells. Replacement of these tissues may provide immense relief, and possibly cure, of the disease.

One approach to replace these tissues is to find acceptable transplantation sources and implant donor cells into a patient. If these cells are derived from a source other than the patient, there will be problems with rejecting the “foreign” transplant material. Cloned patient cells (cells that are induced to replicate with the same DNA template as the patient) do not have foreign markers and theoretically would not be rejected. However, cloning by the transfer of somatic nuclei into unfertilized eggs requires a dramatic remodeling of chromosomal architecture. Many proteins are specifically lost from nuclei and others are taken up from the egg cytoplasm. These proteins determine which DNA genes are promoted and expressed, and which DNA genes are repressed.

Since cellular transplant material obtained from developing embryos must overcome the problem of appropriate integration into the transplant site in order to replace the function of the destroyed tissue, scientifically it may make more sense to induce the patient’s own tissues to replicate at the desired site as the communication and integration networks are mostly in place. Embryonic stem cell transplantation has repeatedly been shown to be ineffective in large animal models largely because they are not capable of integrating into mature host structures. Even if the stem cells are obtained from cloned embryos, and subsequently are not rejected on the basis of immunologic compatibility, the transplanted stem cells still are not capable of forming the complex integrative network that many structures require.

The developing embryo is surrounded by unique proteins and environmental factors. Once the embryo reaches a more mature fetal stage, the cells are surrounded by more mature proteins and growth factors, leading to more highly differentiated cell functions. Throughout this process, the DNA template that codes for the expression of all cell functions remains the same. One hypothesis states that if the correct embryonic environment could be duplicated, a patient’s cells may be able to be induced to regenerate in a given site, as they rapidly did earlier in the patient’s life during embryogenesis. This would result in totally compatible, integrated, replacement tissue for the disease being treated.

I would like to share with the committee the preliminary results of a product I developed to induce regeneration of a specific kind of tissue in animal and human patients. My hypothesis was that exposing cells derived from the mesodermal embryonic germ layer to an embryonic scaffolding structure, the patient cells originally derived from this germ layer would be induced to behave as they did during embryogenesis. Mesodermally derived cells give rise to such differentiated structures as blood vessels, deep skin structures, bone and cartilage. The artificial embryonic scaffolding was made from long chain naturally occurring biopolymers that I modified to inject into patients wounds to induce explosive regeneration of skin, blood vessels, and supporting structures. This embryonic scaffolding contained no cells, only structures for the patient’s cells to bind to.

The results I am about to show have been presented at several scientific meetings, but have not yet been published in full manuscript form. Shown is an example of the rapid wound healing induced in a dog that had naturally occurring diabetes and developed multiple full thickness skin ulcers. The dog had undergone multiple courses of antibiotics and surgical closure procedures, but the ulcers would not heal because of the chronic destruction of blood vessels commonly seen with long standing diabetes. After a one-time injection of the embryonic scaffolding, the dog’s wound’s healed with regenerated tissue. The new tissue resulting from exposure to the embryonic like matrix was determined to be structurally identical to non-wounded areas, without the usual scarring that is normally seen with healing lesions. Further large and small animal studies confirmed our finding, and a six patient feasibility study was approved by the Food and Drug Administration to examine the effect of a one-time injection in patients with chronic diabetic foot ulcers refractory to conventional therapy.

Within days of a one-time injection, all the patients experienced rapid diminution of ulcer size, with apparent regeneration of skin, blood vessels, and surrounding structures. Since the new tissue derived from the patients’ own tissue, there was seamless integration with no evidence of rejection. Further study is required to determine if this particular product is safe and effective, but clearly the large animal and human patient studies suggest cellular transplantation is not necessarily required to replace damaged tissue.

Destroying a human embryo to obtain cellular material does in fact destroy a human life, not a potential human life. Shortly after conception, a human being has a unique DNA template from which ALL other cells are generated. The process by which cells become specialized is called differentiation. A differentiated heart cell has the same DNA template as a differentiated skin cell, and they both have the same DNA template as the undifferentiated cells early in embryogenesis.

The mass of cells that begins this replication and differentiation, either shortly after conception or induction through nuclear transfer, defines the beginning of any mammal’s life. This differentiation process continues until death. The continuum of human life thus starts at the beginning of the complex, explosive process of cellular DNA differentiation during embryogenesis and ends at death. One cannot stop the continuum at any one point and say it is not human life because it lacks the ability to do certain functions. When the mass of cells has feelings or reason is subject to debate. When it begins as human life is a biologic fact.

All laws are based on precedent. The difference between a just and an unjust society is the precedent the society accepts to base its jurisprudence upon. In my view, the United States is a uniquely just society because it is the first government in the history of humankind in which the right of the individual supersedes the perceived right of the state, thus defining the individual as society’s most valued entity. The first ten amendments to our constitution explicitly prevents government, even if so desired by the majority, from violating these individual rights. As a developing embryo, whether cloned or naturally obtain, is scientifically a human being, the United States must not set the precedent of allowing individuals to be sacrificed for the illusion of a greater good.

Transplantation strategies, whether derived from foreign donors or cloned cells from the patient themselves, are clearly not the only approach to replace damaged tissues. Other avenues are further along in clinical trials, and should be considered as a first approach for study. Indeed, the patient’s existing cells provide the most rationale source for fully integrating replacement tissues, as occurred during embryogenesis.

REFERENCES

Usala AL. Methods for increasing vascularization and promoting wound healing. US Patent #6,261,387; issued July 17, 2001.

Hansen M, Kurinczuk JJ, Bower C, and Webb S: The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med. 2002 Mar 7;346(10):725-30.

Hill RS, Klann RC, Lloyd WH, Lacy SA, Pitts JD, Penland SL, Dudek R, Marston W, Usala AL: Improved wound healing of diabetic foot ulcers following treatment with a novel biopolymer. Abstract submitted to the ADA Annual Meeting, 2002.

Kikyo N, Wade PA, Gushin D, Ge H, and Wolffe AP: Active remodeling of somatic nuclei in egg cytoplasm by the nucleosomal ATPase ISWI.
Science. 2000 Sep 29;289(5488):2360-2.

Usala AL, Klann R, Bradfield J, Ray S et al: Rapid Induction of Vasculogenesis and Wound Healing Using a Novel Injectable Connective Tissue Matrix. Diabetes 49 (Supplement 1): Abstract 1664 PO, 2000.

Usala AL, Dudek R, Lacy S, Olson J, Penland S, Sutton J, Ziats NP, Hill RS: Induction of Fetal-Like Wound Repair Mechanisms In Vivo with a Novel Matrix Scaffolding. Diabetes 50:(Supplement 2)A488, #2048-PO, 2001.

Usala AL. On the Horizon: Current Research into Advanced Therapies for the Diabetic Foot Ulcer. Wound Management Symposium 2000, UNC Chapel Hill School of Medicine, Chapel Hill, NC, September 22, 2000.

Usala AL. Current Research and Future Products. Wound Management Symposium 2001, UNC Chapel Hill School of Medicine, Chapel Hill, NC, September 29, 2001.