gene activation and repression, but the main orchestration of gene expression occurs by virtue of these master-regulatory proteins.
IV. Some viruses still carry their genes in the form of RNA.
PART SIX
* * *
POST-GENOME
The Genetics of Fate and Future
(2015– . . .)
Those who promise us paradise on earth never produced anything but a hell.
—Karl Popper
It’s only we humans who want to own the future, too.
—Tom Stoppard, The Coast of Utopia
The Future of the Future
Probably no DNA science is at once as hopeful, controversial, hyped, and even as potentially dangerous as the discipline known as gene therapy.
—Gina Smith, The Genomics Age
Clear the air! Clean the sky! Wash the wind! Take the stone from the stone, take the skin from the arm, take the muscle from the bone, and wash them. Wash the stone, wash the bone, wash the brain, wash the soul, wash them wash them!
—T. S. Eliot, Murder in the Cathedral
Let us return, for a moment, to a conversation on the ramparts of a fort. It is the late summer of 1972. We are in Sicily, at a scientific conference on genetics. It is late at night, and Paul Berg and a group of students have clambered up a hill overlooking the lights of a city. Berg’s news—of the possibility of combining two pieces of DNA to create “recombinant DNA”—has sent tremors of wonder and anxiety through the meeting. At the conference, the students are concerned about the dangers of such novel DNA fragments: if the wrong gene is introduced into the wrong organism, the experiment might unleash a biological or ecological catastrophe. But Berg’s interlocutors aren’t only worried about pathogens. They have gone, as students often do, to the heart of the matter: they want to know about the prospects of human genetic engineering—of new genes being introduced permanently into the human genome. What about predicting the future from genes—and then altering that destiny through genetic manipulation? “They were already thinking several steps ahead,” Berg later told me. “I was worried about the future, but they were worried about the future of the future.”
For a while, the “future of the future” seemed biologically intractable. In 1974, barely three years after the invention of recombinant DNA technology, a gene-modified SV40 virus was used to infect early mouse embryonic cells. The plan was audacious. The virus-infected embryonic cells were mixed with the cells of a normal embryo to create a composite of cells, an embryological “chimera.” These composite embryos were implanted into mice. All the organs and cells of the embryo emanated from that mix of cells—blood, brain, guts, heart, muscles, and, most crucially, the sperm and the eggs. If the virally infected embryonic cells formed some of the sperm and the egg cells of the newborn mice, then the viral genes would be transmitted from mouse to mouse vertically across generations, like any other gene. The virus, like a Trojan horse, might thus smuggle genes permanently into an animal’s genome across multiple generations resulting in the first genetically modified higher organism.
The experiment worked at first—but it was stymied by two unexpected effects. First, although cells carrying viral genes clearly emerged in the blood, muscle, brain, and nerves of the mouse, the delivery of the viral genes into sperm and eggs was extremely inefficient. Try as they might, scientists could not achieve efficient “vertical” transmission of the genes across generations. And second, even though viral genes were present in the mouse cells, the expression of the genes was firmly shut down, resulting in an inert gene that did not make RNA or protein. Years later, scientists would discover that epigenetic marks had been placed on viral genes to silence them. We now know that cells have ancient detectors that recognize viral genes and stamp them with chemical marks, like cancellation signs, to prevent their activation.
The genome had, it seemed, already anticipated attempts to alter it. It was a perfect stalemate. There’s an old proverb among magicians that it’s essential to learn to make things reappear before one learns to make things disappear. Gene therapists were relearning that lesson. It was easy to slip a gene invisibly into a cell and into an embryo. The real challenge was to make it visible again.
Thwarted by these original studies, the field of gene therapy stagnated for another decade or so, until biologists stumbled on a critical discovery: embryonic stem cells, or ES cells. To understand the future of gene therapy in humans, we need to reckon with ES cells. Consider an organ such as the brain,