Fate Loses another Round to Science

We often use ‘genes’ as a kind of synonym for ‘fate.’ He smoked and weighed 300 pounds, but he lived to 90—‘he just had good genes.’ ‘No matter what genes you have, exercise will help you live longer.’ ‘We don’t know why he turned out that way, it may just have been genetic.’

Fate versus choice. Of course, we’ve heard of ‘gene’ therapy for years, but, as a New York Times report put it back in December, 2011, gene therapy is “a technique with a 20-year record of almost unbroken failure.”

A report this month in the New England Journal of Medicine, among the world’s most prestigious venues for reporting research results, changes all that—decisively. Score: Science-1, Fate-0.

Scientists at St. Jude’s Children’s Research Hospital, in Memphis, Tennessee, reported that they had essentially cured hemophilia B by inserting new genetic material into the bodies of patients—and the gene change is still doing its job after more than three years, with no significant side effects.

It is the first major disease to be successfully treated by gene therapy. Or, to put it more technically, the first “documented long-term expression of a therapeutic transgene.”

Gene therapy always had as its first target so-called ‘one-gene disorders,’ where the presence or absence of a single gene is decisive. There are dozens of such diseases, most rare, but for those afflicted, it is indeed ‘fate’—you are born with the gene, you get the disease, suck it up.

One in 25,000 men born in the world each year inherit hemophilia B (rarer than hemophilia A). With this disorder, their bodies do not produce blood-clotting factor and so the slightest injury can be serious or fatal. Their entire lives are circumscribed by the need to avoid any injury whatsoever. The blood-clotting protein that they are missing, factor IX, can be injected every two or three days, lifelong, at a cost of about $250,000 per year. One young man in the St. Jude’s treatment study recalled that his father took him on overnight fishing trips, but always brought along the needle and the serum in the picnic cooler.

Hemophilia B is a one-gene disease inherited almost exclusively by males because the genes for blood-clotting factor are on the X chromosome; males have no backup copy of that chromosome, but females do.

The treatment protocol reported this month, bringing up to date a smaller preliminary study in 2011, overcame the acute problems that face gene therapy. The required new genetic material must be inserted into the patient’s cells, where it can take hold and begin to produce the needed protein—in this case, blood-clotting factor—that is missing. But how to deliver it there?

The method, initially shocking but now well known, is to infect the patient with a virus. A virus goes to the cells, sneaks in, and begins to reproduce itself. But a virus can be modified, in a sense tricked, to carry the genetic material into the cells. That technique is well known, well refined, but there are two problems: how to ensure that the virus itself, once in the cells, does no damage, and how to prevent the body’s immune system from doing its job by killing off the virus.

For the hemophilia B treatment, the genetic material must go to cells in the liver, where blood-clotting factor is created. To deliver it, the treatment team used a harmless virus that would not reproduce in the cells (the solution to problem one) and a virus to which patients had never been exposed—and so had built up no immunity (the solution to problem two).

It worked, lodging genetic material in the cells, which then began producing the clotting factor and has kept producing it for more than three years. Interestingly, the new genetic material produces only about five percent of the blood-clotting factor that normal bodies produce—but that is enough to make all the difference. The patients treated at St. Jude’s now lead normal lives, without fear of a suddenly minor mishap that could mean hospitalization and even death. Call them treated or call them cured, depending on your definition, but their bodies no longer manifest the disorder called hemophilia B. The question, unlike for normal individuals, is how long the genetic material will keep working.

The convention, now, in publishing studies in prestigious journals, is to credit not only the scientists who design and lead the study, but as many assistants and helpers as possible, so the New England Journal of Medicine lists dozens of ‘authors.’ In fact, St. Jude’s hematologist, Arthur Nienhuis, M.D., has devoted three long decades to the search for ways to deliver healthy genes into the body; this is the culmination and triumph of his life’s work.

With his step, the way seems open—the potential—to deliver genes to treat virtually any disease or disorder with a genetic component—and that includes everything from heart disease, stroke, and cancer; to depression, schizophrenia, and dementia; to allergies, hair loss, and myopia.

Of course, all those are multi-gene disorders, some with complex interactions with ‘environmental’ factors such as eating habits, exercise habits, prenatal developments, and carcinogens. That is why gene therapy began with one-gene disorders, which are difficult enough as 20 years of failures, and now one resounding success, demonstrate.

The dozens of one-gene disorders could succumb to treatment in fairly short order, now. But effective—perhaps soon ‘routine’—ways to deliver genes into the cells means that in experiments with animals, scientists, who suspect a gene of taking a key role in, say, breast cancer, now have a potentially decisive way to test their hypothesis: change the gene and watch the effect in an animal model of the disease.

Looking ahead and, perhaps, day dreaming, we know that working inside the cells, in the cellular machinery—working on the ‘nano’ scale—is virtually new in medical history. All previous interventions, as heroic and complex as they were, manipulated the cells themselves. Working inside the cell, including in its genetic mechanisms—and the ability to target repairs—puts scientists where all of life’s most profound processes, and mysteries, occur.

Among those processes, certainly, is the secret to why we age—and why we die.  No ‘fate,’ after all, ‘intended’ us to die. But the evolution that created our species works precisely by focusing on perfecting bodies for the job of reproducing—surviving until we have offspring and so pass along our genes to the next generation. Anything that advances that goal is ‘selected’ and strengthened. And anything that happens after that, well, scientists joke that evolution ‘doesn’t give a shit about you’ after your reproductive years. There is truth to that.

But evolution’s purposes, which once were synonymous with our biological fate, are expressed, above all, inside our cells, in our chromosomes, our genes, and how the proteins they produce do all of life’s jobs.

The lives of men born with hemophilia B have been transformed by deliberate, carefully targeted intervention inside the cells. And so, one day, may be man’s fate.

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About the Author: Walter Donway

Walter Donway contributes to Savvy Street on political economy, science, and trends in fiction, film, and culture. Walter Donway’s most recent book is Donald Trump and His Enemies: How the Media Put Trump in Office (Romantic Revolution Books: New York, September 2017). His Amazon profile can be found here