Tissue Engineering, Regenerative Medicine
Stem Cell Research: Benefits and Controversies

by Michael Rozen, MD; Michael D. McDonald, Dr. P.H; Thomas C. Jepsen

At a 1988 workshop, the National Science Foundation (NSF) defined tissue engineering as “the application of principles and methods of engineering and life sciences toward fundamental understanding …and development of biological substitutes to restore, maintain and improve tissue functions.” According to the NSF, this definition is “intended to include procedures where the biological substitutes are cells or combinations of different cells that may be implanted on a scaffold, such as natural collagen, or as synthetic, biocompatible polymers to form a tissue.”

Since NSF issued that definition, research has demonstrated that engineering biological tissues may provide therapeutic alternatives for improving health and the quality of life. Two tissue engineering inventions are now in use: skin replacement for ulcerations, and a scaffold that allows the slow release of an anticancer agent to combat a form of brain cancer.

Tissue engineering’s full scientific potential continues to be constrained by ethical debate, research restrictions, a lack of research funding, migration abroad of tissue engineering experts, and the absence of a clear strategic plan. These constraints have contributed to a loss of jobs for U.S. scientists, engineers and physicians, as well as to a loss of leadership in this important field of health care discovery. What is stem cell research? What is tissue engineering technology? And what potential does each possess in regenerative medicine?

Stem Cell Science

Stem cells, the precursors of all human tissue, are not defined by their appearance but rather by their versatility. While stem cells are found in both adult and embryonic tissue, it is in the latter that they appear to have their greatest potential to differentiate into other cells and tissues.

Adult stem cells are cell types found in the developed human body. They are capable of differentiating into a limited variety of cell types; one type is the hematopoietic stem cell found in bone marrow. On the other hand, embryonic stem cells (ES) are taken from a human ovum, or egg that has either been fertilized or stimulated into growth with chemicals or electrical stimulation in a culture medium outside the body. The egg then develops into several hundred cells (called a blastocyst), and undifferentiated ES are removed from its center. These cells have the greatest potential to grow into specific cell types for regenerative medicine.

Other stem cells sources include umbilical cord blood (which has erroneously been called “fetal stem cells") and true "fetal cells," which enter a pregnant woman's bloodstream from her fetus and remain in her system for years, and which seem to have the remarkable ability to regenerate her tissue when needed.

The therapeutic implications of the different biologic properties of the various types of stem cells are not yet clear. Stem cells derived from umbilical cord blood, although limited in amount of material, are non-invasive and are non-destructive to embryos. They are also “naïve,” meaning that they can be used for many purposes. Umbilical cord blood stem cells are significantly less likely to being rejected than the stem cells coming from bone marrow. However, in addition to being limited in amount, these stem cells are limited in versatility, compared to embryonic stem cells. This limitation means that they may be used more as a substitute for bone morrow stem cells, but are unlikely to substitute for embryonic stem cells.

A Presidential Directive

On 9 August 2001, President Bush issued a Presidential Directive authorizing federal funding for 78 then-existing embryonic stem cell lineages that had previously been derived from excess embryos created for in vitro fertilization. Unfortunately, this directive barred expenditure of federal funds on any other lines of embryonic stem cell research. Of the original 78 eligible stem cell lines, only 21 remain available today. Of these, a few have shown chromosomal abnormalities and all have spent time growing in various containers and on various medias, raising the potential for contamination and alteration of capability. Further, the limited source does not provide adequate genetic diversity for our population or disease conditions.

The Anticipated Benefits

Stem cells show promise for treating certain diseases, including Parkinson's Disease, diabetes and Alzheimer’s. Stem cells are also useful in immunological and pharmacological research, as well as in cancer research. ES are able to influence the complex chemical choreography that tells other growing cells what to become. A recent study published in the October 2004 Science demonstrated that researchers were able to rescue mice that would have died prior to birth from a genetic heart defect. Instead of replacing defective cells, embryonic stem cells were able to release chemical signals that caused the defective heart tissue to grow properly.

The Controversies

Ethical issues surrounding stem cell research promote controversy. Embryonic stem cell production requires the destruction of fertilized human ova, a requirement that those who believe life begins at conception find objectionable. In a recent study, researchers at the University of Pennsylvania and Rutgers University surveyed how 217 in vitro fertilization clinics across the country disposed of unused frozen clusters of cells. They found variation in the disposal method, but a feeling of respect. “I don’t think anyone who deals with these frozen embryos considers them to be persons, said Arthur Caplan, bioethicist at the University of Pennsylvania. “But I think that they feel they are deserving of respect.”

Using stem cells from other sources, such as adult stem cells or stem cells from umbilical cord blood, are less controversial. Techniques for producing stem cells that do not require fertilized human ova (e.g. somatic cell nucleus transfer, parthogenesis) are being developed.

Another ethical dilemma is that techniques used to produce stem cells for healthcare research ("therapeutic cloning") may also be able to be used to produce clones of human beings ("reproductive cloning"). Most legitimate scientists reject the use of stem cell research for this purpose.

We Need a National Strategy

The lack of a cohesive national strategy for regulating stem cell research has created an oversight void. While U.S. regulations limit publicly funded research to just a few stem cell lines, private research remains essentially unregulated. With private funding, research can be carried out on any type of stem cell, including embryonic stem cells not covered by the Presidential Directive. Many universities are quietly building "firewalls" between their publicly funded and privately funded research labs. The University of Minnesota, for example, has developed policies and board oversight to permit using private funds for embryonic stem cell research.

At least 40 states now target biotechnology as a top development goal. Several states, including California and Rhode Island, see the economic and health potential, and have propositions pending for providing public funding. California’s Proposition 71 asks state voters to approve $3 billion in bonds over 10 years to fund stem cell research. But California’s approach contrasts sharply with Louisiana’s, which would ban all cloning research, including that designed to treat disease.

To address this issue, the United Kingdom created the Human Fertilisation and Embryology Authority (HFEA, www.hfea.gov.uk), which grants licenses to all agencies doing embryonic research, including fertility clinics and those doing therapeutic cloning. Any person creating or using an embryo outside the body (IVF) in the UK requires a license from HFEA. Instead of trying to regulate stem cell research by legal fiat, HFEA issues or denies licenses on a case-by-case basis.

The Technical Limitations

Stem cell research is itself nascent. We need basic research to identify and understand key intracellular and intercellular communication, algorithms and processes that signal stem cell differentiation, suppress developmental abnormalities and control cell maturation. We need to overcome hurdles associated with “signaling” for differentiating the proper cell type to use stem cells for regenerative medicine. Having stem cells differentiate into individual cell types (e.g., skin cells) may be far less difficult than having them differentiate into fully functioning hearts or kidneys. We also lack research on the aging of tissue differentiated from stem cells and their susceptibility to genetic defects. Attempts to use animals in transgenic research to provide human replacement organs have achieved mixed results. And finally, it is still not clear just how many stem cell lines are necessary to provide immunological and pharmacological matches for the wide spectrum of the human population and disease conditions.

Why Is This Important to Engineers?

Engineers are deeply involved in tissue engineering, regenerative medicine and stem cell research. Biomedical engineers are exploring ways to use stem cells to create tissue and to heal disease. Computer scientists using advanced modeling techniques and sophisticated databases are using bioinformatics to solve the genetic and genomic problems associated with stem cell research. Engineers and scientists are now using neural networks to determine the relative weighting of genetic characteristics for predicting disease outcome and to identify possible "gene repair" scenarios. Biomedical engineers are also using communications technology techniques to understand cell signaling.

Engineers must understand the issues surrounding stem cell research and express their opinions to lawmakers for the United States to maintain its leadership position in healthcare research. A majority of U.S. senators and members of Congress have already sent letters to the President espousing the benefits of and supporting broader public funding for stem cell research. To gain support for stem cell research, congressional and executive branch leaders must encourage “tissue engineering” experts to remain in the United States by promoting a favorable research environment, providing significant unfettered public research funding, promoting honest ethical debate, and establishing a cohesive national strategy encompassing all stem cell research.

Michael Rozen, MD; Michael D. McDonald, Dr. P.H; Thomas C. Jepsen are members of IEEE-USA’s Medical Technology Policy Committee. Views expressed in this article are the authors' and do not necessarily reflect those of IEEE-USA. Comments may be submitted to todaysengineer@ieee.org.