I'm currently reading "A Crack in Creation" by Jennifer Doudna in order to deepen my knowledge of the gene editing space and will be sharing my cliff notes in memos.
Chapter 1, Second Half - Cliff Notes
Researchers have been dreaming of DNA-based cures for disease for as long as they've known about genetic disease. But repairing a defective gene is like finding a needle in a haystack and then removing that needle without disturbing a single strand of hay in the process.
The question is: "How could you insert replacement genes into damaged cells?"
The answer? Viruses.
It sounds scary, but viruses have the uncanny ability to splice new genetic information into the DNA of cells. And researches realized they could use viruses to deliver therapeutic genes to humans.
The approach of using viruses as gene-delivery vehicles is referred to as "viral vectors" and it is still one of the most effective ways we know to insert genes into a cell's genome, and thus, alter the genetic code of living organisms.
A few specific traits make viruses effective as 'vectors.' For starters, viruses have evolved to be incredibly efficient at infiltrating cells of any type. For as long as life has existed, organisms from all kingdoms - bacteria, plants, animals, and so on- have had to contend with parasitic viruses, whose sole goal is to hijack cells, insert their own DNA into them, and trick the cells into creating more copies of the virus.
Over the eons, viruses have leaned how to exploit practically every weak spot in a cell's defense system, and they have perfected strategies of dumping their genetic payload into the interior of the cell. As a tool, viral vectors are astoundingly reliable; researchers working with viral vectors can get genes into target cells with nearly 100 percent efficiency. For the scientists who pioneered their therapeutic use, viral vectors were the ultimate Trojan horse.
To give you an idea of just how good viruses are at splicing their genetic material into the genome of infected cells, get this: A full 8 percent of the human genome- over 250 million letters of DNA- is a remnant of ancient retroviruses that infected ancestors of our species millennia ago.
Scientists in the 1970s and 1980s developed ways to cut and paste segments of DNA into genomes and isolate specific gene sequences. This enabled them to insert therapeutic genes into viruses and remove dangerous genes so that the viruses would no longer harm infected cells.
Scientists had essentially turned these viruses into benign missiles, engineered to deliver their genetic payload to the desired target, and nothing else.
The budding field of cancer immunotherapy makes use of this. Tumor fighting cells are loaded with genes that target molecules specific to tumors. This has been hailed as one of the most promising breakthroughs for cancer treatment and proof that gene therapy still has much to contribute to the field of medicine.
But despite the hype, gene therapy hasn't been the panacea that scientists and physicians had hoped it would be; in fact, at times it seems to have done more harm than good. The field received a shock in 1999 when a patient died after suffering a massive immune response to a high does of viral vector.
In the early 2000s, five patients in a gene therapy trial for X-linked SCID developed leukemia- a cancer of the bone marrow. The cancers resulted from the retrovirus's errant activation of a cancer causing gene which caused the cells to proliferate uncontrollably. This incident underscored the inherent risks of giving patients large quantities of a foreign agent and randomly jamming a few thousand letters of DNA into their genomes.
Gene therapy, by its very nature, is also ineffective for a wider range of genetic conditions that aren't caused by missing or deficient genes. Such conditions can't be fixed by simply delivering new genes into cells. Take Huntington's disease, in which the altered gene produces an abnormal protein that completely overrides the effect of the second, healthy copy of the gene. Since the mutated gene dominates the non-mutated gene, gene therapy (the addition of another normal copy of the gene using a retooled virus) would have no effect on Huntington's or other dominant conditions.
For these and many other hard-to-treat genetic disease, what doctors really need was a way to repair problematic genes, not just supplant them. If they could fix the defective code that caused the issue, they could target recessive and dominant diseases alike without ever having to worry about the consequences of splicing a gene into the wrong place.