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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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