But what if that game is life, and cruel, impersonal genetics is the dealer? There is no luxury of folding your hand and waiting for the next one. People with genetic diseases need to find a way to play the hand that they’re dealt. Fortunately, new scientific research is helping explain the rules of the game, especially for the genetic disease called Huntington’s Disease (HD).
HD is different from most other genetic diseases – it is not immediately fatal and doesn’t strike small children. But that’s where HD is especially cruel. Symptoms don’t show up until the patient is in their 30’s or 40’s, when they’ve already had children and have unwittingly given their kids a chance at inheriting the disease. And Huntington’s may not carry away its victims quickly, but the slow loss of mental and physical function is even more painful.
Unfortunately, it’s not only HD that’s the problem. There are at least 17 other genetic diseases like HD that have the same underlying biological problem. It is this problem that researchers are tackling with renewed vigor. Scientists have already managed to overturn some conventional wisdom in this area. Finding out the rules of the game, and how to play the game advantageously, is what this research is all about. Like all good poker players, scientists are ultimately trying to get a royal flush.
However, before they can help HD patients play the game successfully, researchers need to find out what all the rules are. For HD, the rules involve a deceptively simple and fundamental biological process in all of our bodies. Countless times a day, our cells grow and divide to produce new cells. In order to do this, each cell must copy its DNA in order to give a copy to the new cell. DNA are the letters in the instruction manual for life, specifically C’s, G’s, A’s and T’s. But letters mean nothing without words (genes). Genes prevent the book of life from dissolving into a jumble of meaningless letters. In addition, genes produce proteins, which are the delivery vans carrying the copies of the book of life. They are the business end of DNA. Without proteins, genetic instructions would never be “read” or seen by anyone. These delivery trucks provide the link between the book of life and its readers. Without this infrastructure, the cell could not perform any of the instructions in its precious book. Of course, when something goes wrong in this entire publication process, as it does in Huntington’s Disease, the results can be catastrophic.
HD happens because sometimes cells copy their DNA incorrectly. Some parts of our DNA consist of nothing more than the same letters repeated over and over again. Like a book with the same letters printed over and over on each page. When the book is copied, it becomes very easy for extra letters to be inserted. This is exactly what happens in HD. The HD gene has a bunch of clustered repeats of three letters – CAG. When the cell copies this stretch of CAG’s, it sometimes slips up and puts in extra copies without noticing. Too many CAG sections, and the HD gene produces a deformed protein, the cause of Huntington’s. For many years, scientists speculated that the cell’s proofreading system, or DNA repair, was somehow not doing its job properly. They thought that the repair machinery allowed these extra CAG’s to pass through because the machinery was defective or because it didn’t notice the extra copies.
But there were problems with this theory. There are many areas of repetitive DNA in our genomes, and not all of them are prone to this type of expansion. Furthermore, diseases like HD are only seen in humans, and only in specific genes. In fact, HD patients rarely have problems with repetitive DNA in their other genes. Translation: it was unlikely that there was something fundamentally wrong with DNA repair, or with the copying machinery.
In 1995, researcher Cynthia McMurray had a breakthrough. She found that CAG sections could spontaneously bind to one another, forming unusual DNA segments called “hairpins”. These hairpins were enormously stable. Other three-letter sequences didn’t form hairpins, or formed them much less efficiently. Presumably, for these sections, our DNA repair machinery was much better at removing them. But the CAG repeats survived, and every copy error was faithfully integrated into the cell’s DNA.
Recent research by McMurray’s laboratory group at the Mayo Clinic has shed some more light on the exact problem with CAG repeats. She and her fellow researchers zeroed in on the question of why DNA repair was unable to remove the hairpins. What they found was surprising. Even in cells with absolutely perfect DNA repair, CAG hairpins effectively hijacked the repair machinery and disabled it. Two important cogs in the repair mechanism, proteins named Msh2 and Msh3, did recognize the hairpins. But when they tried to bind the hairpins in order to remove them, they became stuck. With two important proteins essentially glued to the problem area, the repair machinery didn’t know what to do. As a result, the CAG repeats never got fixed. In order to prove that Msh2 and Msh3 were key contributors to the underlying problem of HD, McMurray and her co-workers removed the Msh2 and Msh3 genes from laboratory mice. Even when these mice were given dozens of CAG repeats – enough to give a human the disease – they did not become ill. This suggested that DNA repair can work well enough without Msh2 and Msh3 to prevent the repeats from being a problem.
McMurray’s discovery had shocking implications. It suggested that Huntington’s Disease is basically a fluke of nature. Simply because CAG repeats (and not some other three-letter sequence) exist in the HD gene, hairpins form. Once this happens, even effective DNA repair becomes disabled and ineffective. The hairpins resemble an aggressively bluffing opponent at the poker table. Poker players need to know how to combat this problem, or else they too will become stuck.
This aggressive bluffer has been seen by other scientists besides McMurray. They have also seen how the cell unsuccessfully attempts to counter the bluff with Msh2 and Msh3. Many of these researchers have independently verified that the removal of Msh2 and Msh3 eliminates any CAG expansion. This solution has also been successfully tested in the lab for at least one other HD-related disease that has this three-letter expansion problem. That disease, myotonic dystrophy, features a CTG repeat instead of CAG. Even with a slightly different repeat sequence, Msh2 and Msh3 were important in propagating expansion. Ironically, the two proteins that should prevent these kinds of problems end up making the problem worse.
However, removing such important proteins in humans is obviously not the right solution. The key is to play the game intelligently, not drastically. But researchers hope that all their new knowledge on HD can indeed help patients grab that elusive royal flush.
Thankfully, some progress has already been made in this area. One new avenue of research involves cutting off the extra CAG sequences after they become a part of the deformed HD protein. This would theoretically halt any continuation of the disease and might even reverse it. Another similar idea is to prevent the mutant HD protein from improperly interacting with other proteins. This theory rests on the idea that extra CAG sequences can sometimes bind to other proteins that do not normally interact with a normal HD protein. Disrupting these rogue interactions could also be beneficial to patients. Scientists have even observed that people with HD are often afflicted with metabolic problems – they don’t turn food into energy in quite the proper way. A third line of potential treatment would involve fixing these metabolic side effects by increasing metabolism.
On a more fundamental level, researchers are also focusing on specific pathways in the cell that target mutant proteins for destruction. If these pathways can be stimulated, more of the mutant HD protein may be “caught” and destroyed. In parallel, chemicals are being studied to help stabilize any “good” versions of HD protein in patients. Making the normal versions stronger may very well impair the rise of the mutated HD proteins.
Finally, the most ambitious potential treatment is gene therapy. It would be ideal if scientists could find a way to target the mutant HD gene and replace it with a normal HD gene. Or even change the mutant back to its original form without replacement. But the most powerful potential solution is also the most difficult. The challenge for researchers is to find a way to target only the mutant HD gene and not any other genes in the body. For that matter, they must avoid potentially normal HD genes as well. Also, any mutant silencing mechanism must be delivered safely and effectively.
However, one thing about HD research is clear. Thanks to the work of Cynthia McMurray and others, more critical information about this disease has been uncovered than ever before. Only a deeper understanding of the “why” of a disease can lead to solutions on how to fix it. By illuminating the perils of CAG repeats, hairpins, and disabled DNA repair, researchers have taken one giant step forward towards helping those who have been dealt a bad hand in the poker game of life. The goals are the same – to play well, and to stay in the game for as long as possible.
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