The course of biomedical research and the practice of modern medicine
have crossed into a new frontier—that of molecular genetics.
The sequencing of the human genome will forever change the way that
we view disease, and, in many cases, will point the way toward cures
for diseases that we have not yet characterized. The disciplines
of musculoskeletal research and clinical orthopaedics are part of
this revolution. The following discussion highlights some of the
recent advances in molecular and genetic biology, describes their
possible application to the care of orthopaedic patients, and presents
some of the social and ethical issues associated with the use of gene-altering
therapy in humans.
The elucidation of the human genome is perhaps the single most
meaningful project ever undertaken in biomedical research. The final
outcome of this project will be the foundation from which new paradigms
of curing disease will emerge.
The Human Genome Project was officially begun in 1990 through
a coordinated effort of the United States Department of Energy and
the National Institutes of Health. The project was slated to last
for fifteen years but has been essentially completed in approximately
ten years. A working database of DNA sequences is available now
and, by 2003, the entire project should be complete. The stated
goals of the project were (1) to identify all of the approximately
30,000 genes in the human genome, (2) to store the information in
a form that would facilitate data analysis, (3) to develop more
sophisticated sequencing methods, and (4) to address the ethical, legal,
and societal issues that may arise from use of the information.
Knowledge of the human genome will impact every area of medicine
and will revolutionize our field. We will gain a much more sophisticated
understanding of the genetic determinants of disease, including
an individual’s propensity for the development of diseases
such as cancer, heart disease, and arthritis. Table I lists some
of the diseases for which genetic testing has already commenced,
and our ability to predict the likelihood of disease will continue
to expand. Knowledge of the genome will aid in the development of
powerful and specific pharmacologic agents and will increase our
capacity to treat human disease. Drug design will be enhanced by
the identification of specific gene targets, and pharmacologic agents
will be synthesized to target the activity of a specific gene or
protein. Gene therapy will become a reality in the future, and while
it will undoubtedly be used for the treatment of diseases arising from
genetic mutation, it will also probably be used for the treatment
of developmental, degenerative, and traumatic conditions as well
as cancer.
With the advent of the era of molecular medicine, important issues
will confront orthopaedic surgeons, who will need to be conversant
with the new technologies. There are moral, ethical, and medical
considerations regarding genetic testing. Positive results of genetic
tests that identify a predilection for cancer or other serious disorders
only indicate the probability that the disease will develop. We
know that many individuals who test positive will never have the
disease and that individuals who show no predilection can still
be affected. Compounded with the seriousness of the implications
of a positive finding, errors in testing may have profound economic
and/or social effects. Furthermore, the design of new drugs
will raise issues regarding both safety and cost.
A genome is a compilation of genes that defines an organism or
an individual. A gene is a sequence of nucleotides that contains
a promoter region and a coding region (Fig. 1). The promoter region of a gene
determines whether the gene will be expressed, and the coding region
defines the sequence of amino acids in the resulting protein.
The orthopaedic genome is a constellation of
thousands of genes that are directly involved in the genesis and
maintenance of the musculoskeletal system. The orthopaedic genome
includes gene families coding for connective-tissue matrix molecules
(including both the biosynthetic and degradative aspects of their
metabolism), the factors controlling skeletal development, bone
and cartilage metabolism, and the intracellular and extracellular
signaling pathways involved in the autocrine, paracrine, and endocrine
control of skeletal function and repair. Notable discoveries in
the study of the orthopaedic genome during the last decade have
included the identification of parathyroid hormone-related protein
(PTHrP)1, the bone morphogenetic
proteins (BMPs)2, and the hedgehog
family of molecules3 and the elucidation
of their roles in skeletal development and fracture-healing. The
identification of these primordial regulators of skeletogenesis
has resulted in new approaches to clinical problems. For example,
it soon may be possible to recapitulate the formation of skeletal
tissues such as articular cartilage. Regeneration of new matrices
rather than incomplete repair of existing cartilage should allow
for better long-term results in the treatment of arthritis.
In the study of osteoclastogenesis, four proteins (receptor activator
of nuclear factor-kappaB [RANK]; osteoprotegerin; osteoclast
differentiation factor; and tumor necrosis factor-related activation-induced
cytokine [TRANCE]) that regulate osteoclast formation
and activity have recently been discovered4-7.
RANK binds to a receptor on osteoclast precursor cells and effects
their final differentiation into osteoclasts. Osteoprotegerin is
a soluble decoy receptor that resembles RANK and inhibits osteoclast
function8. Characterization of
these molecules has provided alternative approaches for the control
of bone resorption, which should lead to useful therapies for blocking
bone loss in patients with osteoporosis, inflammation-mediated osteolysis,
cancer, and other skeletal disorders.
Anabolic regulators of bone formation, including core binding factor
alpha 1 (Cbfa1) and its gene (Cbfa1)9,10, have also been discovered. This
gene codes for the transcription factor Cbfa1, which is both necessary
and sufficient for the differentiation of cells into the osteoblast
lineage and also enhances the differentiation of chondrocytes during
endochondral bone formation. Thus, Cbfa1 is involved in osteoblast and
chondrocyte differentiation and appears to play a key role in controlling
the activity of these cells. Animals or humans deficient in Cbfa1
have arrested bone development, which leads to developmental abnormalities
such as cleidocranial dysplasia.
Human DNA is comprised of forty-six chromosomes, which contain
approximately 30,000 unique genes. Gene structure is highly conserved
throughout nature, and the paradigm described in Fig. 1 holds not only
for the animal kingdom but also for viruses, bacteria, and plants.
Each individual gene is comprised of several characteristic elements,
including a promoter, or regulatory region, and a transcriptional
element, or coding region. Genes are important because they dictate
cell and tissue function. Genes encode a sequence from which messenger
RNA is transcribed, which, in turn, serves as a template for protein synthesis.
Since the expression and function of specific proteins determine
the character of cells, and ultimately tissues, the genetic sequence
regulates both cell and tissue function.
Gene activation is dependent upon and regulated by the activation
of transcription factors. In most cases, only a small portion of
each gene directly codes for the protein sequence. The vast majority
of the gene is comprised of sequences involved in the regulation
of gene expression or of spacing sequences (introns). The promoter
is the region of the gene that is directly involved in regulation.
The promoter, typically up to 1000 bases in length, contains short
DNA sequences that can bind to regulatory proteins called transcription
factors. There are a large number of transcription factors; these
factors recognize unique sequences of DNA, ranging from six to twelve
bases in length, with high specificity. Transcription factors are
able to recruit enzymes and other proteins necessary for messenger
RNA synthesis. Each gene is regulated by multiple transcription
factors that work both independently and in concert to regulate
gene expression.
The portion of the gene that is responsible for coding messenger
RNA contains both introns and exons. The exon sequences directly
code for RNA, and the interval sequences between exons are referred
to as introns. Intron sequences are enzymatically removed from newly
transcribed RNA by a splicing mechanism that rejoins the exonic
mRNA at specific sites. The mRNA is then translated on the ribosome
to form specific proteins.
The binding of specific transcription factors to the promoter region
of various genes controls the expression of these genes. Thus, the
expression of a specific gene is dependent upon (1) the promoter
sequence of that gene (i.e., the presence or absence of short sequences
composed of six to twelve bases that permit specific transcription
factors to bind to DNA) and (2) the presence of specific transcription
factors within the cell. Some genes are necessary for basal function
and are expressed in all cells. These genes are sometimes referred
to as constitutively active genes, and their promoter region contains
regulatory sites that bind to ubiquitously expressed transcription
factors. Other genes are expressed in a much more restricted manner.
The transcription factors that regulate these genes are similarly
often selectively expressed. Thus, the Sox-9 gene,
which induces type-II collagen, is expressed in mesenchymal cells
undergoing chondrogenesis, and the Cbfa1 gene,
which is necessary for bone formation and induces osteocalcin, is
expressed exclusively in osteoblasts.
In many cases, transcription factors are present in cells but
are in an inactive state. Many transcription factors are activated through
the phosphorylation of serine or threonine amino acids located on
these proteins. For some transcription factors, phosphorylation
results in translocation from the cytoplasm to the nucleus, where
they can bind to the promoter region of specific genes, leading
to activation.
Transcription factor activation is the culmination of a series
of phosphorylation events that comprise what is called a signaling
pathway. Signaling pathways are composed of a series of sequentially
activated kinases (Fig. 2), which are enzymes that add phosphate
groups to target proteins. A paradigm that has emerged suggests
that binding of a growth factor or other ligand to a cell membrane
receptor leads to autophosphorylation and activation of the receptor. The
activated receptor is then capable of phosphorylating a target kinase.
A series of such events occurs until there is activation of a kinase
that leads directly to transcription. Multiple, separate signaling
pathways have been defined, including the protein kinase A, protein
kinase C, Akt or protein kinase B, mitogen-activated kinase, and
JAK/STAT (Janus Activated Kinase/signal transducer
and activator of transcription proteins) signaling pathways.
During the last ten years, the production of large quantities
of recombinant growth factors has had a great impact on the treatment
of human diseases. An increasing number of recombinant growth factors
have been approved for clinical use, and some of these factors have
a role in the treatment of orthopaedic patients. For example, growth
hormone and insulin-like growth factor-1 increase the longitudinal
growth of bone in children deficient in these proteins11. Erythropoietin increases hematopoietic
precursors and has been shown to decrease the need for perioperative
transfusions in orthopaedic patients12.
Bone morphogenetic proteins 2 and 7 are currently in phase-III clinical
trials, and it is hoped that delivery of these growth factors to
local sites will enhance reparative bone formation.
In spite of the successful clinical use of recombinant growth factors,
there has been a shift away from such factors and toward signaling
molecules as molecular therapeutic targets. This shift is due, in
part, to the realization that the binding of growth factors to a
membrane receptor is a complex event that usually activates several
signaling pathways simultaneously. For example, the binding of BMPs
to a specific receptor simultaneously activates three separate signaling
pathways. Thus, activation of the Smad signaling pathway, which
is responsible for BMP-signaling, is accompanied by activation of
the mitogen-activated protein kinase (MAPK) and protein kinase-C
signaling pathways13. As a consequence,
BMP receptor-binding stimulates gene expression mediated by several
separate transcription factors, including Smad, ATF-2 (activating
transcription factor-2), and AP-1 (activating protein-1) transcription
factors.
Therefore, recombinant growth factors, through receptor-mediated
interactions, typically produce a large and heterogeneous response
due to simultaneous activation of multiple signaling pathways and
transcription factors. In some cases, these separate transcription
factors can have disparate effects on target cells: one transcription
factor may stimulate a desired cellular response (through activation
of a specific set of genes), while another transcription factor
may actually partially antagonize the response. Therefore, in theory,
more exquisite control of cellular processes can occur with regulation
at the level of intracellular signaling molecules. This is resulting
in a conceptual shift from the use of recombinant growth factors
toward the use of molecules targeting intracellular signaling pathways,
a shift that will be accelerated by further progress in methods
of gene delivery.
There are several strategies for targeting signaling pathways. One
is the development of chemicals that inhibit or activate specific
kinases or other enzymes. This strategy depends on knowledge of
the three-dimensional structure of the protein. An example is the
recent development and clinical use of a class of new molecules
designed to inhibit the cyclooxygenase-2 enzyme. Another method
is the direct delivery of genes that, once inside the cell, can
use the intracellular apparatus to result in expression of an activated
signaling protein. In contrast, there is the potential to genetically
engineer genes that give rise to mutated proteins that can block
specific signaling pathways. Other, more creative strategies being
developed and investigated include the use of small RNAs or peptides
that can inhibit the synthesis of specific proteins.
Methods of gene delivery have steadily improved, and the delivery
of specific genes to cells in vitro has become
relatively routine. The expression of genes is dependent upon the
promoter that is used in a genetically engineered construct. Thus,
a promoter that restricts expression to specific cell populations
could be used. For example, when the type-X collagen promoter is
used to drive expression, the target gene would be expressed only
in hypertrophic chondrocytes and not in other cells. Alternatively,
a promoter that includes a high level of expression in a large number
of cells, such as the promoter for the viral large T antigen, could be
used. Thus, introduced genes can have generalized or restricted
patterns of expression. Furthermore, expression can be limited to
specific cells at particular stages of differentiation, depending
on the specificity of the promoter used in combination with the
target gene.
The most challenging aspect of regulating gene expression has
been the method used to deliver genetic material into the cell.
DNA is highly charged and does not readily cross the cellular membrane;
thus, several methods have been developed to insert DNA into the
cell. The most common method in clinical trials has been the use
of attenuated viruses that lack genes critical for viral replication.
Thus, adenovirus-based gene therapy involves use of a replication-incompetent virus
containing a target gene that encodes (expresses) a particular protein
and is driven by a specific promoter.
Several strategies are being investigated to circumvent the immune
response to adenovirus-based gene therapy. One method is the development
of viral gene delivery methods in which there is no expression of
viral proteins, and thus, no immune response. The adeno-associated
viral vector, in particular, appears to have potential in this regard.
However, this virus is much more difficult to produce and its ability
to express target genes is less reliable than that of other viral delivery
systems.
Yet another route for the introduction of specific proteins into cells
takes advantage of a short twelve-amino-acid protein sequence (the
so-called TAT protein), derived from the HIV genome. This peptide
permits efficient intracellular uptake of recombinant proteins.
The use of the TAT protein is a strategy for direct delivery of
signaling proteins into cells, permitting modulation of intracellular
signals that will alter the expression of those cells. Thus, recombinant
proteins that contain this small TAT sequence can be delivered to
cells in vitro or in vivo following
local or systemic injection.
Successful tissue development and repair require the sequential
expression of genes that modulate a complex set of events, including
differentiation from primitive mesenchymal precursors, progressive
maturation of cells, apoptosis or programmed cell death, and secretion
of a specific and highly organized extracellular matrix. As the
particular genes of the orthopaedic genome and the signals that
regulate their temporal expression are elucidated, potential points
of therapeutic intervention will become defined. These manipulations
will affect a large number of orthopaedic conditions, including both
reparative and degenerative conditions.
Thus, in the post-genomic era, when the sequences of all genes
are known, the goal will be to find the subset of genes that are
causative of or are directly related to a disease process. Knowing
the sequence of genes alone is not the complete story; more important
is their functional role. Functional genomics involves the knowledge
of a specific gene’s role in both normal and pathological
cell processes.
The key step, then, is to identify the small number of genes that
are involved in a disease process from among the 30,000 genes that
comprise the human genome. Efficient identification of important
genes is facilitated by screening methods that permit the simultaneous
analysis of a large number of genes. In one such method, called
gene array, a large number of genes—as many as 10,000 to
20,000—are placed onto a small chip. The relative expression
of the arrayed genes in different populations of cells can then
be compared. This technology has led to breakthroughs in our understanding
of some diseases. For example, the genes involved in the metastasis
of malignant melanoma were recently defined14.
This methodology has potential applications in the study of musculoskeletal
disease. One important target, in which the molecular events remain
elusive, is osteoarthritis. This is among the most prevalent diseases
in our society, affecting more than half of the individuals over
the age of sixty-five and resulting in enormous health-care costs.
Gene arrays that compare the patterns of gene expression in normal
and osteoarthritic articular cartilage could lead to improved understanding
of specific treatments for this disease.
There is a growing appreciation that the likelihood of human disease
is dependent upon an individual’s genetic background. Different
individuals can have diverse responses to the same stimulus, depending
on the genetic determinants involved. For example, patients’ response
to interleukin-1 (IL-1) correlates with their response to Helicobacter
pylori infection15. In
those with an extensive inflammatory reaction, the bacteria are
eliminated but the gastric mucosa are damaged, leading to achlorhydria
and an increased risk of gastric cancer. In contrast, in those who
have a limited inflammatory reaction, the bacteria are not eliminated
and gastric ulcers tend to develop. The basis of this finding lies
in a single base difference in the promoter region of the IL-1 gene.
Thus, while the region coding the IL-1 protein is the same in all
individuals (i.e., all of our IL-1 protein sequences are identical),
single base differences in the regulatory region result in differential
levels of gene expression among different individuals, depending
upon the sequences that they inherited. These important single base differences
occur in nearly all genes and influence our propensity for disease.
These differences are called single nucleotide polymorphisms, or
SNPs.
It is likely that inflammatory conditions that affect the musculoskeletal
system also depend upon specific patterns of gene expression. This
has already been established for certain forms of inflammatory arthritis.
Similarly, implant loosening, an inflammatory condition leading
to osteolysis and failure, is also more likely in individuals with
certain genetic backgrounds. Thus, a differential response to wear
debris may explain why some prostheses loosen and others do not,
and this genetic information may target future therapies toward patients
at high risk for this complication.
Gene arrays permit exquisite molecular subtyping of diseases, such
as cancer, that are heterogeneous in genetic expression but indistinguishable
in clinical manifestation. The use of gene arrays potentially permits
the widespread collection of genetic information on an individual
basis. Just as each individual has a unique fingerprint, a unique
genetic blueprint for each individual is possible and is likely
to be defined in the future. With the growth of functional genomics,
this information will provide important insight into the risk of
a multitude of human diseases, including those of the musculoskeletal system.
This development will markedly improve future medical care but has
obvious ethical implications.
The following case study, a hypothetical assessment of a patient
considering a total hip arthroplasty in the year 2010, is an adaptation
of the "Shattuck Lecture—Medical and Societal Consequences
of the Human Genome Project" by F.S. Collins16.
Assume that a sixty-year-old man with osteoarthritis of the left
hip comes into your office. He has complete loss of the joint space
and marked limitation of activity. He also has mild hypertension
but is otherwise in good health. In addition to performing a complete
history and physical examination, you scan the microchip on his
insurance identification card and find that a "Genetic
Index" screening for important diseases in men indicates
that his relative risks for common cancers, heart disease, and osteoarthritis
are 0.76, 0.53, and 4.20, respectively.
None of these genetic factors would predispose him to complications
associated with a hip arthroplasty, so a further workup is performed.
You order an "Arthroplasty Loosening Index" that
examines the risk of implant loosening on the basis of the differential
expression of genes known to be involved in prosthetic loosening.
The relative risks associated with each of the five genes known
to influence bone resorption around a prosthesis are depicted in Table II.
Considering all of the genes together results in an Overall Composite
Loosening Index of 15.3. This means that the patient’s
risk for the development of prosthetic loosening, based on his genetic
background, is 15.3 times greater than that of the average person.
After the patient’s age, weight, and activity level have
been factored in, the Overall Composite Loosening Index indicates
that he has a relative risk of 23.4. That is, he is 23.4 times more
likely to undergo revision surgery for loosening of the implant
within ten years than a low-risk patient is. Do you proceed with
the operation?
Given the favorable Genetic Index score for important diseases
and the relatively long life span expected for the patient, you
proceed with the surgery. However, after the procedure you refer
the patient to the Orthopaedic Molecular Therapy Unit for
prophylaxis against prosthetic loosening.
Does this scenario represent fiction or reality? By the year 2010,
it is likely to be a reality.
There are a number of ethical issues that require public debate,
but we have chosen to focus on four areas of concern that influence
both the field of medicine and society and that are particularly
relevant to the care of patients with musculoskeletal problems.
These ethical dilemmas include the following: (1) How will this
new information regarding the human genome be used? (2) How will
patient safety be maintained in an era in which we race to achieve
new cutting-edge medical treatments that will benefit our patients
but also will have the potential to provide huge profits for industry?
(3) What safeguards need to be developed as partnerships between
academia and industry continue to expand? and (4) Should advances
in genetic medicine only be used to treat disease and genetic problems
or should genetic enhancement of individuals be considered?
Our purpose is not to provide answers for these ethical dilemmas
but to use this forum to stimulate public debate and to heighten
awareness of the ethical challenges associated with this era of
technological advancement.
Ethical Issues and the Human Genome
The identification of the human genome has received public attention
worldwide. Scientists will use this information to identify the
genes that are associated with particular diseases and inherited
medical conditions and also to identify the signal transduction
pathways that lead to various pathological conditions in order to
develop effective treatment strategies. This information should
enhance the efficacy of preventive medicine. There has been considerable
interest in genetic testing over the past few years as genes associated
with different cancers (e.g., breast and colon cancer) and other
conditions have been identified. As our knowledge of the human genome increases
and further links with various diseases are established, the demand
for genetic testing will increase. At the present time, patients
can undergo periodic screening examinations to diagnose a disease
at an early stage, can change their lifestyle or diet in an attempt
to delay the development of a disease or to limit its manifestations,
and can even consider enrolling in experimental clinical trials.
It is possible to envision a future scenario in which genetic information
is used to develop gene therapies to treat a variety of diseases.
However, we will clearly need to develop strategies to handle this
new information, given the obvious concerns about the improper use
of such information by employers, health-care providers, and insurance
companies. Will screening for the development of certain medical
conditions become a routine part of pre-employment and pre-insurance
testing? Should screening for genetic diseases be a routine aspect
of a health-care evaluation? How should health-care professionals
handle this information, particularly when the patient has a gene
for a fatal disease for which there presently is no treatment? Does the
physician have an obligation to inform other relatives, such as
siblings and children, that they are at risk for the development
of a fatal or seriously debilitating disease? What type of burden
would this place on teenagers and young children if this information
were revealed to them? Clearly, the potential for expanding the
efficacy of preventive medicine is great, but these ethical dilemmas
will have to be resolved by policymakers, clinicians, and, probably,
the courts over time.
Patient Safety
Recent advances in genetic research will enable scientists to use
gene transfer to treat diseases associated with genetic mutations
(e.g., osteogenesis imperfecta) and a variety of other musculoskeletal
problems, including rheumatoid arthritis; bone loss associated with
fracture, nonunion, or revision total joint arthroplasty; and cartilage
injury. This type of genetic manipulation is called somatic cell
gene therapy17,18. Although investigators
in this field are enthusiastic about the potential of using gene
therapy to treat difficult clinical problems, the tragic death of
Jessie Gelsinger, in an experimental gene-transfer trial at the
University of Pennsylvania, demonstrates the inherent risk associated
with the development of new treatment regimens. The association
of this case with a general lack of protection for human subjects
and the question of a financial conflict of interest highlights
the potential ethical problems associated with the use of new technology19. Furthermore, the investigation
of this death led to the identification of hundreds of unreported
adverse events that have occurred among volunteers enrolled in different
gene-transfer experiments. Interestingly, the involved researchers
were in compliance with the requirements of the Food and Drug Administration
even though the adverse events were not reported to the National
Institutes of Health19. This tragedy
has led to the development of an extensive educational effort regarding
the importance of the protection of human research subjects and
to the development of new regulations designed to limit adverse
events in the future. Any clinical trial that is performed to test
the efficacy of new drugs must provide maximum patient protection
and informed consent. In addition, investigators must be wary of
patients’ unrealistic expectations about the efficacy of
new therapeutic regimens. This is of primary importance when treating patients
with musculoskeletal conditions, many of whom are young and otherwise
healthy. In most cases, the proposed therapy will not be life-saving
and the goal will be to improve quality of life. Safety is more
important than efficacy.
There is clear support for the development of new treatment strategies
that employ either recombinant proteins, cytokines, or somatic cell
gene therapy. However, the development of germ-line gene therapy
is more controversial. This gene-transfer strategy would result
in alteration of the genetic makeup of the sperm and ova, which
would be passed on to succeeding generations18.
A debate on the moral implications of germ cell gene transfer is
beyond the scope of our discussion, but, as scientific breakthroughs
occur, difficult ethical questions will arise and physicians should
be ready to actively engage in debating these issues with policymakers
and researchers.
Academia and Industry
Many of the most important advances in medicine that have been
made in the past few decades have been the result of partnerships
between academic institutions and industry. Such research collaborations
can be extremely productive as long as academic freedom is maintained
and maximum patient protection is ensured19,20.
The potential for conflicts of interest is inherent in the practice
of medicine, but it is magnified by the important role of pharmaceutical
and biotechnology companies in the development of treatment modalities
involving molecular medicine, particularly gene therapy. In addition,
academic institutions have encouraged their faculty to develop biotechnology
companies in which the institution has a substantial financial interest.
Furthermore, the testing that is necessary in order to bring recombinant
proteins or various gene-therapy strategies to market usually requires
academic investigators to develop collaborations with industry because
of the expense associated with clinical trials20.
This may lead to a conflict of interest for the investigator because
of the potential for huge profits associated with the successful
development of these agents, particularly if the investigator owns
stock in the company.
The potential for conflict of interest in these situations must be
recognized. A study of pulmonologists showed not only that physicians’ prescribing
patterns were affected by incentives offered by pharmaceutical companies
but that clinicians were often unaware of the effect that such enticements
had on their own behavior21. If
physician behavior can be influenced by such small gifts as a pen
or a free lunch, there is significant potential for a conflict of
interest if more substantial financial gain is at stake. Investigators
may overstate the potential efficacy of a particular treatment regimen
to potential patients, and a truly objective analysis of the data
might not be possible.
It is expected that an investigator would declare his financial interest
during the informed-consent process. However, even the disclosure
of potential conflict of interest to patients does not relieve the
physician of the responsibility of making choices that are in the
patient’s best interests. Patients may not fully understand
the implications of a physician’s receiving financial compensation
if the results of a particular trial are successful. Most patients
enter the physician-patient relationship under the assumption that
the physician will do what is in the patient’s best interest
and may not suspect that financial remuneration may affect an important
treatment decision22. Therefore,
in these situations, disclosure of a potential conflict of interest
to patients is probably not sufficient to safeguard the integrity
of a clinical trial. Investigators with a direct financial interest
in the outcome of the clinical trial should not be involved in the
direction of the study, patient selection, or the informed-consent
process20. Furthermore, medical
journals should consider developing new policies so that potential
conflicts of interest related to economic interests are scrutinized
more closely.
Genetic Enhancement
Advances in molecular medicine have clearly captured the attention
of all elements of our society. A recent article in Sports
Illustrated entitled "Unnatural Selection" discussed
the potential role of genetic engineering in producing a new breed
of athlete who would exceed the present limits of human performance23. There is a general consensus that
the development of gene-transfer strategies to treat medical diseases
is acceptable but the use of such strategies for genetic enhancement
is questionable. For example, the use of recombinant proteins or
gene therapy to heal fractures, treat nonunions, and repair cartilage in
order to enhance patients’ quality of life and to allow
athletes to continue their activities seems quite reasonable. However,
is it appropriate to use these techniques to enhance athletic performance
by increasing muscle strength, oxygen transport, or overall body
size? Evidently, athletes are already interested in using insulin-like
growth factor to enhance muscle strength on the basis of findings
in animal studies23. If our experience
with anabolic steroids and erythropoietin provides any guidance,
the abuse of growth factors to enhance athletic performance will
become a reality if safeguards are not provided. In addition, physicians
and the public need to be educated about the importance of using
these growth factors in the correct way. It is well known that various
growth factors can cause either cell proliferation or inhibition
depending on the dosage used. In addition, growth factors may have
different effects depending on the type of administration and the anatomical
delivery site. Serious adverse events can be expected if these factors
are used in the wrong way.
Will we eventually have a class of human beings who have been
genetically altered to enhance athletic performance? Clearly, with
the substantial potential for financial gain, this fantasy could
become a reality. Public education strategies need to be developed,
and governing bodies of various athletic organizations need to formulate
policies defining both the proper and the illegal use of this new
technology.
The "Principles of Medical Ethics" adopted
by the American Academy of Orthopaedic Surgeons assert that the
orthopaedic profession exists for the primary purpose of caring
for the patient24. This requires
that decision-making related to clinical care be focused on what
is best for the patient and not what is best for the surgeon or
a corporate sponsor24. As we enter
this age of molecular medicine, we need to maintain our focus on
patient protection and patient care. Orthopaedic surgeons need to
participate in public education and public debate concerning the
use of new molecular agents in order to enhance the care of our
patients and to ensure that the appropriate safeguards are in place
to protect them.
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