inherited immune deficiencies. These diseases
regulator), is embedded in the membranes of
were chosen because the mutant gene causing the
several cell types in the body, where it serves
disease was known and there was evidence that
as a channel, transporting chloride ions out
even a few corrected cells could restore complete
of the cells. In CF patients, depending on the
immune function. Since 2000, 37 children
particular mutation the individual carries, the
with either X-linked severe combined immune
CFTR protein may be reduced or missing from
deficiency (X-SCID, the “Bubble Boy Disease”) or
the cell membrane or it may be present but
ADA-SCID (deficiency of the adenosine deaminase
not functioning properly. In some mutations,
enzyme that prevents the correct development
synthesis of CFTR protein is interrupted, and the
and functioning of T-lymphocytes) have been
cells produce no CFTR molecules at all.
treated with this approach. Bone marrow cells
from these patients were exposed to a virus
Although all the mutations associated with CF
containing a normal copy of the mutant gene and
impair chloride transport, the consequences
were then transplanted back into the patients.
for patients with different mutations vary. For
To date, 33 of these 37 patients (89 percent) have
example, patients with mutations causing absent
been cured. Two patients had very low rates of
or markedly reduced CFTR protein levels may
gene transfer, one patient failed the bone marrow
have more severe disease than patients with
transplant, and one patient died of an adverse
mutations in which CFTR is present but has
event related to the gene therapy. In comparison,
altered function. The different mutations also
the best conventional therapy for SCID is bone
suggest different treatment strategies. For example,
marrow transplantation from a compatible donor.
the most common CF-related mutation (called delta
If compatible bone marrow donors had been
F508) leads to the production of protein molecules
available for these patients, only 65 percent
(called delta F508 CFTR) that are misprocessed
would be expected to survive, so gene therapy
and degraded prematurely, before they reach the
is the treatment of choice for these diseases.
cell membrane. This finding suggests that drug
treatments that would enhance transport of the
Cancer presents a complicated problem for any
CFTR protein to the cell membrane or prevent
treatment because the exact mutation causing
its degradation could yield important benefits
the disease is not usually known and therapies
for patients with delta F508 CFTR. Such drug
can injure the healthy cells surrounding the
strategies have been vigorously pursued by the
tumor. Gene therapy is being used to treat a
Cystic Fibrosis Foundation, leading to clinical
variety of cancers, however. One successful
trials of compounds that both assist protein
strategy is to use gene therapy to modify the
processing and encourage proper functioning of
body’s white blood cells so that they become
CFTR once it reaches the membrane.
efficient killers of tumor cells. In one study,
26
patients with malignant lymphomas that had
inception of the HGP, required more than eight
been resistant to all other therapies were treated
years and $50 million. In contrast, now that the
with gene-modified white blood cells. More
HGP is completed, finding a gene associated with
than three-quarters of the patients responded to
a Mendelian disorder can be accomplished in just
the treatment, and 41 percent were completely
weeks at a cost of less than $10,000.
cured of the disease. In another study, genetic
modifications were able to direct white blood
Over the past few years, research into human
cells to another type of cancer: neuroblastoma,
genetic variation has made the dramatic transition
a common childhood cancer with no effective
from focusing primarily on genes associated with
treatment. The neuroblastoma tumors shrank or
single-gene disorders, which are relatively rare
disappeared in half the patients. Because of the
in the human population, to focusing on genes
specificity of these anticancer cells, there were
associated with common multifactorial diseases.
no significant side effects. All told, more than
Because these diseases are not rare, we can expect
1,000 patients have participated in cancer gene
that this work will affect many more people.
therapy studies, and none of them has died as
Understanding the genetic and environmental
a consequence of the gene therapy. Because of
bases for these multifactorial diseases will also
the success of these studies, gene therapy is now
lead to increased testing and the development
being used earlier in the treatment of cancer,
of new interventions that will likely have an
when the prospects for a cure are better.
enormous effect on the practice of medicine
in the next century.
Gene therapy is being developed for many other
diseases as well. Dogs have been cured of all
Genetics, Ethics, and Society
these diseases by gene therapy:
What are the implications of using our growing
• hemophilia,
knowledge of human genetic variation to improve
• several enzyme deficiencies that slowly kill
personal and public health? As noted earlier, the
brain and muscle cells because they store
rapid pace of the discovery of genetic factors in
toxic substances,
disease has improved our ability to predict the
• a third immune-deficiency disease, and
risk of disease in asymptomatic individuals. We
• hereditary blindness.
have learned how to prevent the manifestations
of some of these diseases, and we are developing
The success of these animal studies has allowed
the capacity to treat others.
the therapies to be developed for humans with
the same diseases. A recent study of gene
Yet, much remains unknown about the benefits
therapy for hereditary blindness has shown
and risks of building an understanding of
vast improvement in the vision of the treated
human genetic variation at the molecular level.
patients, and it is hoped that this result will
While this information would have the potential
lead to effective gene therapy for other sight
to dramatically improve human health, the
disorders such as glaucoma.
architects of the HGP realized that it would also
raise a number of complex ethical, legal, and
As Figure 6 indicates, the Human Genome
social issues. To anticipate and address these
Project (HGP) has significantly accelerated the
issues, they established in 1990 the Ethical,
pace of both the discovery of human genes and
Legal, and Social Implications (ELSI) program.
the development of new healthcare strategies
This program, perhaps more than any other, has
based on knowledge of a gene’s structure and
focused public attention, as well as the attention
function. The new knowledge and technologies
of educators, on the increasing importance of
that emerged from HGP-related research have
preparing citizens to understand and contribute
also reduced the cost of finding human genes. For
to the ongoing public dialogue related to
example, the search for the gene associated with
advances in genetics.
cystic fibrosis, which ended in 1989, before the
27
Understanding Human Genetic Variation
Human Genetic Variation
Ethics is the study of right and wrong, good and
Second, ethics requires a solid foundation of
bad. It has to do with the actions and character of
information and rigorous interpretation of that
individuals, families, communities, institutions,
information. For example, one must have a solid
and societies. During the past two and one-half
understanding of biology to evaluate the recent
millennia, Western philosophy has developed a
decision by the Icelandic government to create a
variety of powerful methods and a reliable set of
database that will contain extensive genetic and
concepts and technical terms for studying and
medical information about the country’s citizens.
talking about the ethical life. Generally speaking,
Knowledge of science is also needed to discuss
we apply the terms “right” and “good” to those
the ethics of genetic screening or of germ line
actions and qualities that foster the interests of
gene therapy. Ethics is not strictly a theoretical
individuals, families, communities, institutions,
discipline but is concerned in vital ways with
and society. Here, an “interest” refers to a
practical matters.
participant’s share or participation in a situation.
The terms “wrong” or “bad” apply to those
Third, discussions of ethical issues often lead
actions and qualities that impair interests.
to the identification of very different answers
to questions about what is right and wrong
Ethical considerations are complex and
and good and bad. This is especially true in a
multifaceted, and they raise many questions.
society such as our own, which is characterized
Often, there are competing, well-reasoned
by diverse perspectives and values. Consider,
answers to questions about what is right and
for example, the question of whether adolescents
wrong, and good and bad, about an individual’s
should be tested for late-onset genetic conditions.
or a group’s conduct or actions. Typically, these
Genetic-testing centers routinely withhold
answers all involve appeals to values. A value
genetic tests for Huntington disease (HD) from
is something that has significance or worth in
asymptomatic patients under the age of 18. The
a given situation. One of the exciting aspects
rationale is that the condition expresses itself
of any ethics discussion is the variety of ways
later in life and, at present, there is no treatment
the individuals involved assign values to things,
for it. There is not necessarily an immediate,
persons, and states of affairs. Examples of values
physical health benefit for a minor from a specific
that students may appeal to in a discussion
diagnosis based on genetic testing. In addition,
about ethics include autonomy, freedom, privacy,
there is concern about the psychological effects
sanctity of life, religion, protecting another
of knowing that later in life one will get a
from harm, promoting another’s good, justice,
debilitating, life-threatening condition. Teenagers
fairness, relationships, scientific knowledge,
can wait until they are adults to decide what
and technological progress.
and when they would like to know. On the
other hand, some argue that many adolescents
Acknowledging the complex, multifaceted
and young children do have sufficient autonomy
nature of ethical discussions is not to suggest
in consent and decision making and may wish
that “anything goes.” Experts generally agree
to know their future. Others argue that parents
on the following features of ethics. First, ethics
should have the right to have their children
is a process of rational inquiry. It involves
tested because parents make many other
posing clearly formulated questions and seeking
medical decisions on behalf of their children.
well-reasoned answers to those questions.
This example illustrates how the tools of ethics
For example, we can ask questions about an
can bring clarity and rigor to discussions
individual’s right to privacy regarding personal
involving values.
genetic information; we can also ask questions
about the appropriateness of particular uses of
One of the goals of this module is to help
gene therapy. Well-reasoned answers to such
students see how understanding science can
questions constitute arguments. Ethical analysis
help individuals and society make reasoned
and argument, then, result from successful
decisions about issues related to genetics and
ethical inquiry.
health. Lesson 5, Making Decisions in the Face
28
of Uncertainty, presents students with the case of
dysfunction. Ethics provides a framework for
a woman who is concerned that she may carry
identifying and clarifying values and the choices
an altered gene that predisposes her to breast
that flow from these values. But the relationships
and ovarian cancer. The woman is faced with
between scientific information and human
numerous decisions, which students also consider.
choices, and between choices and behaviors,
Thus, the focus of Lesson 5 is prudential decision
are not straightforward. In other words, human
making, which involves the ability to avoid
choice allows individuals to choose against sound
unnecessary risk when it is uncertain whether
knowledge, and choice does not require action.
an event will actually occur. By completing the
lesson, students understand that uncertainty is
Nevertheless, it is increasingly difficult to
often a feature of questions related to genetics
deny the claims of science. We are continually
and health, because our knowledge of genetics is
presented with great amounts of relevant publicly
incomplete and constantly changing. In addition,
accessible scientific and medical knowledge. As a
students see that making decisions about an
consequence, we can think about the relationships
uncertain future is complex. In simple terms,
among knowledge, choice, behavior, and human
students have to ask themselves, “How bad is the
health in the following ways:
outcome and how likely is it to occur?” When
the issues are weighed, different outcomes are
Knowledge (what is known and not known)
possible, depending on one’s estimate of the
+ Choice = Power
incidence of the occurrence and how much
burden one attaches to the risk.
Power + Behavior = Enhanced Human Health
(that is, personal and public health)
Clearly, science and ethics both play important
roles in helping individuals make choices about
One of the goals of this module is to encourage
individual and public health. Science provides
students to think in terms of these relationships,
evidence that can help us understand and
now and as they grow older.
treat human disease, illness, deformity, and
29
Understanding Human Genetic Variation
References
American Society of Human Genetics, American
Geier, R., Blumenfeld, P.C., Marx, R.W., Krajcik,
College of Medical Genetics. 1995. Points to
J.S., Fishman, B., Soloway, E., et al. 2008.
consider: Ethical, legal, and psychological
Standardized test outcomes for students
implications of genetic testing in children and
engaged in inquiry-based science curricula
adolescents. Journal of Human Genetics, 57:
in the context of urban reform. Journal of
1233–1241.
Research in Science Teaching, 45: 922–939.
Biological Sciences Curriculum Study. 1999.
Green, E.D., Guyer, M.S., and the National Human
Teaching Tools. Dubuque, IA: Kendall/Hunt
Genome Research Institute. 2011. Charting a
Publishing Company.
course for genomic medicine from base pairs
to bedside. Nature, 470: 204–213.
Bonwell, C.C., and Eison, J.A. 1991. Active
Learning: Creating Excitement in the
Harrison, G.A., Tanner, J.M., Pilbeam, D.R.,
Classroom. (ASHE-ERIC Higher Education
and Baker, P.T. 1988. Human Biology: An
Report No. 1). Washington, DC: The George
Introduction to Human Evolution, Variation,
Washington University: School of Education
Growth, and Adaptability. New York: Oxford
and Human Development.
University Press.
Brody, C.M. 1995. Collaborative or cooperative
Hickey, D.T., Kindfeld, A.C.H., Horwitz, P., and
learning? Complementary practices for
Christie, M.A. 1999. Advancing educational
instructional reform. The Journal of Staff,
theory by enhancing practice in a technology
Program, and Organizational Development,
supported genetics learning environment.
12(3): 134–143.
Journal of Education, 181: 25–55.
Collins, F.S., Patrinos, A., Jordan, E., Chakravarti,
Knapp, M.S., Shields, P.M., and Turnbull, B.J.
A., Gesteland, R., and Walters, L. 1998. New
1995. Academic challenge in high-poverty
goals for the U.S. Human Genome Project:
classrooms. Phi Delta Kappan, 76(10):
1998–2003. Science, 282(5389): 682–689.
770–776.
Collins, G.S., and Barker, A.D. 2007. Mapping
Lander, E.S. 1999, January. Array of hope.
the cancer genome. Scientific American,
Supplement to Nature Genetics, 21.
296: 50–57.
Lazarou, J., Pomeranz, B.H., and Corey, P.N. 1998,
Corrigan, P., Watson, A., Otey, E., Westbrook,
April 15. Incidence of adverse drug reactions
A., Gardner, A., Lamb, T., et al. 2007. How
in hospitalized patients. Journal of the
do children stigmatize people with mental
American Medical Association, 279: 1200–1205.
illness? Journal of Applied Social Psychology,
37(7): 1405–1417.
Lynch, S., Kuipers, J., Pyke, C., and Szesze, M.
2005. Examining the effects of a highly rated
Feero, W.G., Guttmacher, A.E., and Collins, F.S.
science curriculum unit on diverse students:
2010. Genomic medicine—an updated
Results from a planning grant. Journal of
primer. New England Journal of Medicine,
Research in Science Teaching, 42: 921–946.
362: 2001–2011.
31
Human Genetic Variation
Mange, E.J., and Mange, A.P. 1999. Basic Human
Rennie, J., and Rusting, R. 1996, September.
Genetics, 2nd ed. Sunderland, MA: Sinauer
Making headway against cancer. Scientific
Associates, Inc.
American, 275(3): 56.
Martinez, F.D., Graves, P.E., Baldini, M., Solomon,
Roblyer, M.D., Edwards, J., and Havriluk, M.A.
S., and Erickson, R. 1997, December.
1997. Integrating Educational Technology
Association between genetic polymorphisms
into Teaching. Upper Saddle River, NJ:
of the 2-adrenoceptor and response to
Prentice-Hall, Inc.
albuterol in children with and without a
history of wheezing. Journal for Clinical
Saltus, R. 1998, April 20. Tailor-made drugs.
Investigation, 100(12): 3184–3188.
The Boston Globe.
Minner, D.D., Jurist Levy, A., and Jeanne Century,
Saunders, W.L. 1992. The constructivist
J. 2009. Inquiry-based science instruction—
perspective: Implications and teaching
What is it and does it matter? Results from
strategies for science. School Science and
a research synthesis years 1984 to 2002.
Mathematics, 92(3): 136–141.
Journal of Research in Science Teaching,
published online at Wiley InterScience
Sizer, T.R. 1992. Horace’s School: Redesigning
( www.interscience.wiley.com).
the American High School. New York:
Houghton Mifflin Co.
Moore, J.A. 1993. Science as a Way of Knowing:
Vogel, F., and Motulsky, A.G. 1997. Human
The Foundations of Modern Biology. Cambridge,
Genetics: Problems and Approaches, 3rd ed.
MA: Harvard University Press.
New York: Springer.
National Human Genome Research Institute
Watson, A.C., Otey, E., Westbrook, A.L., Gardner,
Web site. http://www.nhgri.nih.gov.
A.L., Lamb, T.A., Corrigan, P.W., et al.
2004. Changing middle schoolers’ attitudes
National Institutes of Health. 1996. Congressional
about mental illness through education.
Justification. Bethesda, MD.
Schizophrenia Bulletin, 30(3): 563–572.
National Research Council. 1996. National
Weiss, I.R., Pasley, J.D., Smith, P.S., Banilower,
Science Education Standards. Washington, DC:
E.R., and Heck, D.J. 2003. Looking Inside the
National Academy Press.
Classroom: A Study of K–12 Mathematics and
Science Education in the U.S. Chapel Hill, NC:
Perkins, D. 1992. Smart Schools: Better Thinking
Horizon Research.
and Learning for Every Child. New York:
The Free Press.
Wilson, C.D., Taylor, J.A., Kowalski, S.M., and
Carlson, J. 2010. The relative effects and
Project Kaleidoscope. 1991. What Works:
equity of inquiry-based and commonplace
Building Natural Science Communities,
science teaching on students’ knowledge,
Volume 1. Washington, DC: Stamats
reasoning, and argumentation. Journal of
Communications, Inc.
Research in Science Teaching, 47(3), 276–301.
32
Additional Resources
for Teachers
Online Genetics Education Resources
Ge