“Today we are learning the language in which God created life.”
That's a quote from US President Bill Clinton on June 26, 2000 when a rough draft of the human genome was announced to widespread, international fanfare. Clinton was certainly not the only one to make big claims about the Human Genome Project (HGP). Journalists and politicians throughout the developed world heralded that the results would lead to “the end of disease.” Of course, things are never that simple.
Little did the community know at the time that the project would only uncover a small portion of what's really going on in our genes. They were only scratching the surface. What the architects of that project once dismissed literally as junk surrounding our genes is proving far more vital than anyone ever expected—in fact, it may hold the very keys to understanding evolution itself.
When scientists began the HGP, they were expecting to find approximately 100,000 protein-coding genes to account for the complexity of our species. What they found instead was that humans only have about 25,000, about the same number as fish and mice. In fact, according to biologist Dr. Michael Skinner, “the human genome is probably not as complex and doesn't have as many genes as plants do.”
That's sort of a problem, because if we humans are supposed to be the complex species we hold ourselves out to be, then why don't we have as many genes as an oak tree? Maybe because genes are only part of the story.
Clinical geneticist Marcus Pembrey thought so… and long before the genome was ever mapped.
Back in the early 1980s, Pembrey headed the clinical genetics department at Great Ormond Street Hospital for Children in London, where he treated families with unusual genetic conditions.
According to Pembrey, “We were constantly coming across families which didn't fit the rules and didn't fit any of the patterns that genetics were supposed to fit.”
The most tantalizing example was the paradox shown by two incredibly rare and separate genetic disorders: Angelman syndrome, and Prader-Willi syndrome. These two completely different diseases were eventually chased down to their genetic roots. Astonishingly, they were both caused by the same genetic defect, a certain sequence of DNA that was deleted from chromosome 15.
How could this be? How could the same deletion, the same genetic abnormality, cause two completely different diseases?
When Pembrey dug into the inheritance pattern for the conditions, he came across something remarkable. It was the origin of the mutation, not the change alone, that determined which disease would manifest itself.
We all receive a set of chromosomes from each of our parents. If the deletion was on the chromosome 15 that the child inherited from the father, then he or she would be born with Prader-Willi syndrome. If, however, the deletion was on the chromosome 15 that the child inherited from the mother, he or she would be born with Angelman syndrome. It's as if the chromosome 15 knows where it came from.
This might not sound profound. But what Pembrey stumbled upon showed for the first time in humans that there is more to inheritance than simply the coded sequence of DNA, and that something other than genes was being passed between generations.
Discoveries like Pembrey's helped spawn a budding area of science—epigenetics—that aims to answer just how much of “us” comes from outside our genes.
Epigenetics could help explain how a complex human, capable of language and mathematics and philosophy, can be created with only 25,000 genes. It could help us better understand what causes disease and provide us with a wealth of new opportunities for drug discovery and development in areas such as cancer, diabetes, and neurodegenerative disorders.
The best way to begin to explain epigenetics, which literally means “on or above genetics, is with an analogy. Think of your genome—your DNA—as like the hardware of a computer. Your epigenome is much like the software, which tells the hardware what to do. It's the epigenome that tells our cells what sort of cells they should be – a skin cell, a heart cell, etc. All these cells have the same genes, but your epigenome decides how much or whether some genes are expressed in different cells in your body.
Here's a very simplified explanation of how this works:
The human body contains billions (if not trillions) of cells. Each of these cells (apart from red blood cells and reproductive cells) contains your DNA, the blueprint of your genetic code. But just because the cells have the DNA doesn't mean that they know what to do with it. So they receive outside instructions from organic compounds called methyl groups. The methyl groups bind to the DNA in different ways and tell it things like “don't express this gene” or “do express this gene.” They also bind differently to a skin cell versus a heart cell, for example; that's one of the ways that a skin cell knows it's a skin cell and a heart cell knows it's a heart cell.
In addition to methyl groups, epigenetics is also controlled by histones, proteins that function basically like spools that the DNA wraps itself around. These histones can change how tightly or loosely the DNA is wound around them. The more tightly wound, the less the gene can express, and vice versa. In other words, methyl groups act like gene switches, turning them on and off, while the histones are more like a dial that controls the volume (i.e., the degree to which the gene is expressed).
Distinct methylation and histone patterns exist in every cell to tell it what to do, which constitutes a sort of second genome that we call the epigenome.
What's particularly interesting about the epigenome is that, unlike the genome, it's dynamic. While epigenetic instructions do pass on as cells divide, they can change throughout your life based on environmental factors, what we eat, and how we live—and these changes can apparently (though not conclusively proven yet) be passed on to our children and our children's children.
Since these epigenetic tags decide what genes get expressed and to what degree, the implications of a dynamic epigenome are profound.
As geneticist Randy Jirtle puts it:
“We've got to get people thinking more about what they do. They have a responsibility for their epigenome. Their genome they inherit. But their epigenome, they potentially can alter, and particularly that of their children. And that brings in responsibility, but it also brings in hope. You're not necessarily stuck with this. You can alter this.”
At the end of the day, epigenetics might sound like sort of a buzzkill because if the current thinking is right, it would make it tough to ever enjoy another guilt-free French fry, cocktail, or fine cigar. But with the bad comes the good.
For example, mounting evidence suggests that certain types of cancer and other diseases are caused by misplaced or missing epigenetic tags; scientists are hard at work developing drugs to silence some of those “bad” genes that were supposed to be turned off in the first place.
We're already seeing the archaic days of genetic modification give way to much more subtle and precise forms of genetic medicine, like the temporary genetic suppression available in the first generation of RNAi therapies just now coming to market—a trend we have followed to great profitability in Casey Extraordinary Technology. Now, we can only hope that epigenetics follows the same amazing curve of advancement that the HGP unleashed for genetics. If it does, the possibilities are extraordinary.