We’d
like to thank The Genetics and Public Policy Center and The Pew
Charitable Trusts for giving us permission to excerpt from their
comprehensive report “Human Germline Genetic Modification: Issues and
Options for Policy Makers.” For additional information on genetic
technology issues, we encourage you to visit their website www.dnapolicy.org.
What is HGGM?
What is HGGM?
Human Germline Genetic Modification (HGGM) refers to techniques that
would attempt to create a permanent inheritable (i.e. passed from one
generation to the next) genetic change in offspring and future
descendants by altering the genetic makeup of the human germline;
meaning eggs, sperm, the cells that give rise to eggs and sperm, or
early human embryos.
Is it Fact, or Fiction?
For many decades, the technical barriers to HGGM have seemed
insurmountable. Thus, discussions of HGGM have focused on the
correctness of the ends associated with HGGM rather than the
feasibility of the means. Some have viewed HGGM as having the potential
for species perfection, while others have condemned the concept as an
attempt to usurp God by making “man his own self creator.”
Two recent advances in stem cell research suggest that the
technological barriers may soon be overcome. Scientists recently have
created genetically modified mice by genetically modifying the cells
that give rise to sperm, and using these resulting sperm for
fertilization. In addition, scientists have genetically modified human
embryonic stem cells. These techniques overcome what were long regarded
as impenetrable technical barriers, bringing the possibility of HGGM
much closer. Therefore, the time is right for a new public discussion
about whether, when, and how HGGM research should proceed.
Scenarios for HGGM—Feasibility and Demand
Given current scientific knowledge, HGGM is widely viewed as
unsafe to attempt in humans. Yet recent scientific developments suggest
that HGGM may become more technically feasible in the future. The
question remains whether and for what purpose HGGM would occur.
Scientists’ willingness to invest the time and research to develop the technology may be limited by the many existing alternatives to HGGM (including PGD—prenatal genetic testing—followed by termination, adoption, embryo or gamete donation, and somatic therapy.) On the other hand, several factors may create consumer demand. Prospective parents, those with sick children or genetic disease in the family, and patients themselves may create a demand for HGGM. For some patients, any possibility of treatment or cures is worth pursuing. The fame and fortune HGGM could bring to scientific and medical pioneers and the companies that back them may spur interest in the technology. And although there may be alternatives to “therapeutic” uses, the potential to “enhance” a future child, rather than prevent a heritable disease may create its own consumer demand.
Scientists’ willingness to invest the time and research to develop the technology may be limited by the many existing alternatives to HGGM (including PGD—prenatal genetic testing—followed by termination, adoption, embryo or gamete donation, and somatic therapy.) On the other hand, several factors may create consumer demand. Prospective parents, those with sick children or genetic disease in the family, and patients themselves may create a demand for HGGM. For some patients, any possibility of treatment or cures is worth pursuing. The fame and fortune HGGM could bring to scientific and medical pioneers and the companies that back them may spur interest in the technology. And although there may be alternatives to “therapeutic” uses, the potential to “enhance” a future child, rather than prevent a heritable disease may create its own consumer demand.
Understanding the possible technical approaches to HGGM requires an understanding of some basic
genetic concepts. The categories listed below take you step by step—escalating in extremity—through these concepts.
• Genetics
• Genes and Disease
• Genetics and Reproductive Technologies
• Germline Genetic Modification
• Cloning—Extreme Genetic Modification
Genetics
Understanding the possible technical
approaches to human germline
genetic modification (HGGM) requires an understanding of some basic
genetic concepts. An individual’s genetic makeup, known as his or her
genome, is the complete set of genes that are spelled out in DNA. The
human genome contains 20,000-25,000 genes. Most of the human genome is
contained in a structure within the cell called the nucleus, and is
referred to as nuclear DNA. Nuclear DNA is packaged into 46
chromosomes, 23 of which came from the mother’s egg, and 23 from the
father’s sperm. When egg and sperm join upon fertilization, the
resulting cell, known as the zygote, contains the full complement of 46
chromosomes. The single cell zygote divides repeatedly, becoming first
an embryo, then a fetus. Every time a cell divides, the entire
genome—all 46 chromosomes—is copied so that the same information is
contained in the resulting cells. Nearly all cells in the body—also
known as somatic cells—contain 46 chromosomes. Eggs and sperm, which
are called germline cells, contain only 23 chromosomes.
In addition to the nuclear DNA, a small portion of the human genome is found in structures within the cell called mitochondria. Mitochondrial DNA or mtDNA contains only a few genes. Unlike nuclear DNA, almost all of a person’s mitochondria—and the mtDNA—comes from the mother’s egg.
In addition to the nuclear DNA, a small portion of the human genome is found in structures within the cell called mitochondria. Mitochondrial DNA or mtDNA contains only a few genes. Unlike nuclear DNA, almost all of a person’s mitochondria—and the mtDNA—comes from the mother’s egg.
Genes and Disease
The genomes of any two people are 99.9 percent identical. The 0.1 percent difference in DNA sequence between individuals makes each person genetically unique. These differences in DNA sequence often are referred to as genetic variations. Most genetic variations carry no harmful effects. Some variations, however, can cause disease or increase one’s risk of developing disease. A variation as small as one nucleotide in the DNA sequence can disrupt a gene severely; these deleterious alterations in DNA sequence are called genetic mutations. Genetic conditions such as Huntington Disease, cystic fibrosis, or sickle cell disease are caused by mutations in single genes.Not all genetic conditions result from mutations in single genes. Some genetic conditions result from chromosomal abnormalities, where a person carries too many or too few chromosomes, or chromosomes that are missing or carry extra segments of DNA. For example, an extra copy of chromosome 21 causes Down Syndrome. Many chromosomal abnormalities result in pregnancy loss or stillbirth, whereas others cause birth defects, developmental delays, or mental retardation.
Genetics and Reproductive Technologies
New reproductive technologies have developed alongside an increased understanding of the roles genes play in disease. Preimplantation Genetic Diagnosis (PGD) combines genetic testing and in vitro fertilization (IVF). IVF involves collecting eggs from a woman, fertilizing the eggs with sperm in a petri dish, and transferring the resulting embryo(s) to a woman’s uterus. PGD typically involves removing one or two cells from an embryo two to four days after fertilization, extracting DNA from these cells and testing the DNA for a specific genetic alteration or chromosome abnormality. Embryos free of the genetic disease being tested for or possessing desired genetic characteristics are selected for transfer into the woman’s uterus.Germline Genetic Modification
If and when it occurs, human germline genetic modification would
involve introducing a new genetic sequence into a person’s germline
cells that could be passed to future generations. The techniques that
might be used in humans draw from successful germline genetic
modification studies in animals, human stem cell research, and human
somatic gene therapy techniques where non-heritable genetic changes are
made in an attempt to cure or treat disease.
In theory, there are several ways to modify a person’s genome. An entire gene or part of a gene could be inserted somewhere into the genome. This inserted DNA sequence, sometimes called a transgene, could be a normal copy of a resident gene. Introducing a normal copy of that gene could compensate for the nonfunctioning or malfunctioning resident gene. Instead of introducing a whole gene, a transgene could be a segment of DNA that affects the function of a resident gene to turn it on or off. Alternatively, the transgene could introduce a whole new, and previously non-existent gene function into the genome. An example would be the gene for green fluorescent protein that has been introduced into a number of laboratory animals to make them glow.
All cells in an adult animal’s body develop from the zygote, the fertilized egg. Because germline genetic modification seeks to modify all of the cells in the adult body, the genetic modification must be introduced into the eggs and sperm, the precursor cells that give rise to eggs and sperm or very soon after fertilization in a zygote or very early embryo.
There are a variety of theoretical uses of human germline genetic modification. “Therapeutic,” or health-related modifications of the genome would seek to cure or ameliorate a disease in future generations. “Enhancement,” or non-health related, uses would be aimed at adding or augmenting characteristics or traits not related to disease, such as muscle mass or height. Some uses, however, are not easily categorized as either therapy or enhancement. For example, germline genetic modification conceivably could be performed to confer resistance to disease, which might be considered both therapeutic and enhancement. Such a use may best be termed "preventative."
In theory, successful HGGM could eradicate a genetic disease in a family by permanently replacing a gene containing a mutation with a normal copy of that gene. Single gene disorders such as cystic fibrosis or Huntington disease would be the most straightforward targets for HGGM because replacing the mutated gene should prevent the disease. Using HGGM for multifactorial diseases or to enhance complex traits such as intelligence are much less feasible because they involve many genes and many environmental factors, and the genetic contributors remain largely unknown.
In theory, there are several ways to modify a person’s genome. An entire gene or part of a gene could be inserted somewhere into the genome. This inserted DNA sequence, sometimes called a transgene, could be a normal copy of a resident gene. Introducing a normal copy of that gene could compensate for the nonfunctioning or malfunctioning resident gene. Instead of introducing a whole gene, a transgene could be a segment of DNA that affects the function of a resident gene to turn it on or off. Alternatively, the transgene could introduce a whole new, and previously non-existent gene function into the genome. An example would be the gene for green fluorescent protein that has been introduced into a number of laboratory animals to make them glow.
All cells in an adult animal’s body develop from the zygote, the fertilized egg. Because germline genetic modification seeks to modify all of the cells in the adult body, the genetic modification must be introduced into the eggs and sperm, the precursor cells that give rise to eggs and sperm or very soon after fertilization in a zygote or very early embryo.
There are a variety of theoretical uses of human germline genetic modification. “Therapeutic,” or health-related modifications of the genome would seek to cure or ameliorate a disease in future generations. “Enhancement,” or non-health related, uses would be aimed at adding or augmenting characteristics or traits not related to disease, such as muscle mass or height. Some uses, however, are not easily categorized as either therapy or enhancement. For example, germline genetic modification conceivably could be performed to confer resistance to disease, which might be considered both therapeutic and enhancement. Such a use may best be termed "preventative."
In theory, successful HGGM could eradicate a genetic disease in a family by permanently replacing a gene containing a mutation with a normal copy of that gene. Single gene disorders such as cystic fibrosis or Huntington disease would be the most straightforward targets for HGGM because replacing the mutated gene should prevent the disease. Using HGGM for multifactorial diseases or to enhance complex traits such as intelligence are much less feasible because they involve many genes and many environmental factors, and the genetic contributors remain largely unknown.
Cloning—Extreme Genetic Modification
Another technique that genetically modifies
the germline is Somatic Cell Nuclear Transfer (SCNT). SCNT involves the
transfer of the
nucleus of an adult somatic cell into an egg from which the nucleus has
been removed. The resulting zygote could be allowed to develop into an
embryo that is genetically identical to the adult who donated the
somatic nucleus. Although technically the resulting embryo is
genetically modified in the sense that its genome has been changed,
this wholesale genome replacement is considered to be cloning.
Excerpted from Human Germline Genetic Modification: Issues and Options for Policy Makers
with permission from The Genetics and Public Policy Center and The Pew Charitable Trusts.
with permission from The Genetics and Public Policy Center and The Pew Charitable Trusts.
