Background
on (GermLine) gene therapy
In 1995, W. French
Anderson, "The Father of Gene Therapy", wrote in Scientific
American that we live in the fourth revolution
of medicine. The first was public health measures like
sanitation to prevent rapid, widespreading disease. The
second, surgery with anesthesia to help doctors actually
cure illness. The third, antibiotics to fight infections
and vaccines to eliminate viruses. And the fourth, gene
therapy, with its potential to deliver genes into a patient's
individual cells, to cure diseases otherwise considered
incurable.
There are approximately 100 trillion cells in
our bodies. The human body has two basic types of cells: "somatic" cells
and "germline" cells.
Somatic cells are nonreproductive cells, like those in your
muscles, skin, lungs, liver, and heart. Germline (a.k.a. "germ
line" or "germ-line") cells are reproductive cells: sperms
or eggs.
In the heart of nearly all cells (except red blood cells),
is the nucleus which
contains a complete set of blueprints that are written on
23 pairs of threadlike- double-helix structures
which we call chromosomes .
Each pair of chromosomes is made up of gigantic pairs of
molecules--- DNA (deoxyribonucleic
acid) ---each containing some 60 million to 250 million
chemical bases. Each DNA strand is connected to a complementary
DNA strand by base pairs that
form "rungs on the DNA ladder". These bases are all built
by just four chemicals: adenine
(A) , thymine (T), guanine
(G), and cytosine (C) . A-T-G-C ,
a four-letter alphabet the encodes the more than 30,000 information
packets on chromosomes---called genes ---that
define human beings to the smallest detail. (And also virtually
every other known form of life on Earth, except for some
viruses [such as RNA viruses and "prions" [that are based
on proteins].)
Genes can be translated by the cell's machinery into proteins .
DNA designs life; proteins express it. Everything from brain
cells to skin cells are all ultimately built from proteins
specified in the DNA blueprint (using a RNA intermediary).
And although DNA is correctly translated into the proper
proteins 99.999% of the time, just one wrong chemical base
in one gene of one chromosome can lead to a life-long, debilitating
genetic disease.
Gene therapy may
be defined as "evolving medical techniques used to treat
inherited diseases by replacing, manipulating, or supplementing genes
that are not functioning with healthy ones". For many diseases,
this may be the only true long-term cure.
Creating replacement genes that can supplement, replace,
or usurp malfunctioning ones is just the first step. Inserting
these replacement genes into the proper place on a human
chromosome is quite another. The daunting challenge is to
find a vehicle, a way to carry replacement gene(s) into the
nucleus, the heart of the cell, and insert those genes where
they belong. We call vehicles that carry genes into the cell
nucleus "vectors" .
Researchers have piggybacked human replacement genes onto
inactive, non-disease-causing viral vectors. Like retroviruses .
Or lentiviruses, similar to inactivated AIDS virus. Or adenoviruses ,
like those causing common colds. Or adeno-associated viruses
that help other viruses. Or inactivated herpes viruses. Some
vectors have been known to cause mutations. Some work only
on growing, dividing cells. Some are very inefficient. All
existing viral vectors can only carry a few very small genes---a
few thousand base pairs. ( Click
here for highlights on viral vectors .)
There are also nonviral vectors
that are based on synthetic chemicals. A few have reasonably
good rates of carrying replacement genes into human cells,
a process called "transfection".
Few consistently carry their gene payload into the cell nucleus.
You can describe two basic "types" of
gene therapy: somatic gene therapy and germline gene therapy
(which is also called "human inheritable genetic modification").
But it's actually a lot more complicated than that! With
somatic gene therapy, if you could fix the "somatic" cells
(such as brain cells, heart cells, muscle cells, nerve cells,
etc), you could theoretically cure the patient. But that
patient would still carry that same genetic abnormality in
the genes of their germline cells (sperm or egg cells). But
unfortunately, the patient's child may still inherit that
genetic disease.
In theory, with germline gene therapy,
one could technically cure the child before it is born,
and that child's descendants by "fixing" the problem genes in germline cells. (This is
also known as "human inheritable genetic modification").
In theory, there are at least several options for germline
gene therapy. One is to modify a patient's sperm or egg cells
so that the genetic defect is not passed on to the next generation.
Another is to modify the genes of a fertilized egg (or early
embryo) and then place that back in a mother's womb. Both
methods could cure a child before it is born, as well as
that child's descendants. These methods could technically
work for planned pregnancies, such as in vitro fertilization.
But for 99.99% of the world's pregnancies, if/when doctors
discover that an unborn child is carrying a genetic disease,
it's too late. In that case, in theory, one day---sooner
that you might think---it may be possible to perform germline
gene therapy for developing fetuses while they are still
in their mothers' wombs. It is a radical approach, but
it holds the potential to stamp out many genetic diseases
forever.
It also has the potential to be used/misused in ways we
only think we can imagine.
Today the only type of gene therapy performed in the United
States is somatic gene therapy. At present, although germline
gene therapy is not illegal, there are no sanctioned clinical
trials of germline gene therapy in human beings. (Click
here for a recent statement about the science and ethics
of germline gene therapy from NHGRI [National Human Genome
Research Institute].) In some nations it is illegal,
but in many, it is an issue that has yet to be addressed.
It is a technology moving at a dizzying pace. In the last
60 years, we've come a long, long way: 1942: The discovery
of DNA 1953: DNA's structure is defined 1970s: Genes are
first spliced 1977: Techniques are developed for rapid sequencing
of DNA 1990: The first patient undergoes gene therapy 1997:
The first human artificial chromosome (HAC) is created 2000:
The human genome (basic description of genes on DNA) is described.
Germline gene therapy is an issue we are going to have to
face.
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