Genes work like this, too. Once we know what a particular gene does under normal circumstances, it becomes easy to set a benchmark and see when it’s not performing as expected, and vice versa. So, in the case of SOX18, people with HLTS help to highlight the important work the gene normally does in helping the body develop the right lymphatic mechanisms to pull back any excess fluid that leaks out into and between the crevices of our tissue.
That’s incredibly useful information. But, of course, it still didn’t help us to understand why Nicholas was suffering from kidney failure.
Could HLTS and his renal failure have been just a coincidence? Certainly. There are, after all, people all around the world who suffer from two or more similar medical problems that aren’t at all connected genetically. Maybe Nicholas was simply unlucky in this same sort of way. That didn’t sit well with me. I felt a persistent pull to continue exploring how his particular SOX18 mutation and renal failure might be related, especially given the lack of any explanation. And so, with Nicholas as our guide, we embarked on another genetic adventure.
***
When we come across a patient in whom we’ve been able to identify a specific mutation, it’s helpful—and can even be vital—to know whether it’s original or inherited. Therefore, one of the first things we do is check the DNA of the patient’s parents, to see which parent the mutation was inherited from. If the parents do not have the same mutation in their genes, it might be a new genetic change, one that we call de novo. We can’t immediately assume we’re looking at an original difference because we also have to account for a common human foible—infidelity.
And that, as you might imagine, can lead down a potentially prickly and perilous path of parental altercations, particularly if the genetic condition we’ve observed is one that others should be alerted to as a matter of life and death.
In Nicholas’ case, we couldn’t find the mutated gene in either of his parents’ DNA, even after we confirmed paternity. So, according to what I just told you, that would mean we were looking at a new or de novo mutation.
Except for one tragic thing. The year after Nicholas was born, his mother, Jen, became pregnant with another boy. Seven months into the pregnancy, Jen became very sick. An investigation into her condition revealed that her baby was in crisis. Which prompted an emergency in utero surgery that failed to save the child. An evaluation of the lost child’s DNA showed that he had the same SOX18 variation as his brother. Nicholas was not alone.
Did both of the boys somehow develop exactly the same new mutation? That’s incredibly unlikely. Rather, I suspect that one of Nicholas’ parents might be carrying a mutation in cells within their reproductive organs. When we see this type of inheritance pattern—parents without a mutation who have more than one child with the same genetic mutation—we call it gonadal mosaicism.
Now that it was established how Nicholas might have inherited his SOX18 mutation, I was ready to dig deeper. And when I did, one thing continued to really stand out: The few other known individuals with his condition were homozygous for the SOX18 mutation, meaning they carried two copies of the mutated gene. Nicholas, though, inherited only one copy of a misbehaving SOX18 gene, not two, which meant that he was heterozygous for that mutation. Unlike Nicholas, these other “carrier” parents did not have HLTS. Even though they were all heterozygous and had only one mutation in their SOX18 gene just like Nicholas had. Which means that if we understood the genetics correctly, Nicholas should not have had HLTS.
Many times in genetics, trying to answer one question leads to five new ones. What we’d hoped for Nicholas was that all these questions would bring us closer to the reason for his kidney failure. As I stepped back to reassess his case I began to wonder if Nicholas’ striking kidney failure could be caused by another condition, one that was genetically similar but distinct from HLTS.
Theories are one thing. Attempting to prove or disprove them is of course a completely different story. To do that, we would need to find another genetic needle in a haystack made up of seven billion individuals. Practically speaking, the chances that we would find another person with the exact same genetic mutation and the exact same symptoms as Nicholas were next to none. With those kinds of odds I couldn’t help but fail. Which meant it was definitely worth trying.
And so I did what any good geneticist who’s looking for answers does: I went on tour. While on the road presenting Nicholas’ case at as many medical conferences as possible, I kept on hoping that someone would show up who had seen a patient with symptoms similar to those experienced by Nicholas.
Looking back, I’m not sure exactly what I was naively thinking, given that the odds of this actually happening were staggeringly not in my favor. But knowing that it might just help Nicholas as well as provide an immense amount of valuable new medical knowledge, it was at least worth a shot.
As we’ve seen over and over, understanding rare cases like Nicholas’ has the power to impact and change our lives as well. Thankfully, there’s an entire world of genetic researchers and physicians who are dedicated to getting to the bottom of these very complicated medical mysteries. And unbeknownst to me at the time, on a completely different continent, there was a team of devoted physicians and researchers who happened to be asking the very same questions about a patient remarkably similar to Nicholas. Against incredible odds, this patient of theirs, Thomas also happened to have HLTS.
Just like Nicholas, and unlike the other few people with HLTS who had inherited two mutations, Thomas was found to be carrying only one copy of a SOX18 mutation. Crucially, and to my complete and utter surprise, he also had suffered renal failure, leading to a kidney transplant.
Most importantly—here’s the part we still can’t fathom—Thomas not only shared the same clinical features as Nicholas, incredibly he shared the exact same mutation of one of his SOX18 genes.
When I finally saw a photograph of Thomas, the experience was absolutely surreal. There, on my computer screen, staring back at me late one night when I was alone in my office, was a man who could have been—no, I might have sworn he was—the 38-year-old version of 14-year-old Nicholas.
Both of them had the same regal, nearly hairless heads, the same almond-shaped eyes, the same full, red, and deeply bowed lips, and, most of all, the same kind and wise look—as though they’d been carved from the same material substance.
Given the incredibly difficult journey they’d both been on, perhaps in a way they had.
For the moment, there’s still no answer to the mystery of how these two individuals, separated by age and some 4,000 miles, came to exhibit such a strikingly similar genetic condition, physical appearance, and medical course, which included kidney failure, that apparently no one else on the planet has.
That similarity, added to all the others, left us with only one conclusion: We were looking at an entirely new condition.
Now, the benefits for the next person to come along with HLTRS (the extra R is for “renal”) are pretty obvious. Nicholas has received his new kidney, an amazing gift from his father, Joe, and he’s recovered quite well from the surgery. He’s also been getting good marks on his report cards. No small feat for a young man who has missed so much school due to medical appointments and hospital visits. He’s also recently been opening up socially in a way that he hadn’t in the past. Notwithstanding the fact that he’s an incredible kid with an impressively supportive and loving family, those very real quality-of-life improvements can also be attributed to the close medical supervision and the multidisciplinary and specialized expert care he’s received since his condition has been more precisely identified. And what has worked for Nicholas and Thomas will be the first thing tried the next time around. Not to mention that the next patient will know much sooner that he or she is not alone in the world.
Of course, what we’re talking about here could be a one-in-a-billion sort of situation—if that. The next time around could be a long, long time away.
So what does that have
to do with the rest of us?
Well, quite a bit, actually.
***
Today, there are more than 6,000 known rare disorders. When they are all grouped together, we find that these conditions affect as many as 30 million Americans.1 That’s roughly one in 10 people living in the United States, or more than the entire population of Nepal.
A good way to visualize this is to picture a football stadium in which almost everyone is wearing a white shirt, save for every single person in every tenth row—those people are all wearing red. Look around the stadium. What do you see? A sea of red.
Now imagine that everyone wearing a red shirt is also holding an envelope. And imagine that in every envelope there is a piece of paper with a sentence on it. And imagine that all of those sentences, put together, tell a story about everyone else in the stadium.
That’s how genetic research into rare diseases works. We’ve already talked about how just a small number of people who carry a mutation in the SOX18 gene can help us better understand the way it works to help the body build its lymphatic system.
And here’s where Nicholas and Thomas can help the rest of us: Many cancers hijack the lymphatic system for their own benefit and spread. Mapping out how SOX18 is involved in this process will offer a new and much needed target for treating certain types of cancer. It’s also certainly possible that Nicholas and Thomas might help us better understand the role of SOX18 in supporting healthy kidneys.
Which is why, above all else, we are indebted to Nicholas, Thomas, and the multitude of others with genetic conditions who assist us in our work. They’re far more likely, given the history of medical discoveries, to be providing potential health benefits to others than to be reaping benefits from it themselves.
This certainly isn’t a new concept, and it far precedes our modern understanding of genetic medicine. Way back in 1882—two years before Gregor Mendel’s death—a physician by the name of James Paget, now considered to be one of the founding fathers of medical pathology, noted in the British medical journal The Lancet that it would be shameful to set aside those who are impacted by rare diseases “with idle thoughts or idle words about ‘curiosities’ or ‘chances’.”
“Not one of them is without meaning,” Paget continued. “Not one that might not become the beginning of excellent knowledge, if only we could answer the questions—why is it rare? Or being rare, why did it in this instance happen?”
What was Paget talking about? Well, just consider the story of one of the most successful drugs in medical history to see how clearly the rare can inform the common.
***
We need fat. When we don’t eat enough of it, life can become quite unpleasant—not just from a gastronomical perspective but from a physiological one as well. Ultralow-fat diets can lead to poor absorption of fat-soluble vitamins such as A, D, and E, and have even been linked in some people to depression and suicide.2
But, like many things in life, it’s not very hard to get too much of a bad thing. And the trade-off for a high-fat diet, for many people, is too much low-density lipoprotein or LDL. Having too much LDL cholesterol in your blood can lead to atherosclerosis, a term that comes from the ancient Greek words athero, meaning “paste,” and skleros meaning “hard.” “Hard paste” is a really good way to describe the plaques that can build up along some of our arterial walls. As that happens, these vital passageways become narrowed and less flexible—a deadly combination predisposing often-unsuspecting victims to heart attacks and strokes.
And this, unfortunately, is not a rare condition. Cardiovascular disease, or CVD, affects about 80 million Americans and is the number one cause of death in the United States, claiming the lives of some half a million people a year.3
But we might not understand much at all about CVD if not for a very rare genetic condition called familial hypercholesterolemia, or FH.
In the late 1930s, a Norwegian physician named Carl Müller began looking into this disease, which is essentially an inherited form of very high cholesterol. What Müller learned was that people who are born with FH don’t build up a high level of LDL—they start their lives with it.
Now, we all need some cholesterol to function—it’s the starting material our bodies use to create many hormones and even vitamin D—but if we have too much of it floating through our bloodstream we run the risk of dying from complications related to heart disease. For people with FH, that fate can come really early in life because they can’t easily shift the LDL out of their blood and into their liver, like most of us do. The result is extremely high levels of cholesterol that becomes trapped within the circulatory system.
Under normal circumstances, our bodies use LDLR, one of the genes implicated in FH, to make a receptor that the liver uses to mop up LDL. Normally, that helps keep this type of cholesterol from building up in your blood, oxidizing, and harming your heart. But if you carry a copy of the LDLR gene that has a mutation that leads to FH, then the normal movement of cholesterol doesn’t function, and all that fat is left in your cardiovascular piping to potentially run amok.
It’s not uncommon for men who carry two copies of these mutations to die from a heart attack in their 30s, or even earlier. This can happen even if they’re running marathons and following the healthiest diet imaginable.
What Müller could not have imagined back then was that he was helping set the conceptual stage for the development of one of the biggest blockbuster drugs in pharmaceutical history.
We’ve long known that high LDL levels in most people can be addressed with diet and exercise. But since that’s not enough for people with FH, those following in Müller’s footsteps were seeking another way to knock down the high levels of LDL associated with this rare condition. What they came up with was a drug targeting an enzyme called HMG-CoA reductase. This enzyme is normally involved in helping our bodies make more cholesterol while we sleep at night. Blocking this enzyme with a corresponding drug, it was hoped, might result in lower levels of LDL in the blood. You may have even heard of this class of drugs or are taking one of them right now.
Atorvastatin,* more commonly known by the brand name Lipitor, is one of the most popular drugs of the group known as statins. It became a blockbuster drug and is currently prescribed to millions of people around the world. Unfortunately for some of the people who inherited mutations that led to FH and played such a key role in advancing our basic medical understanding, Lipitor isn’t as effective. A few promising new orphan drugs are now being approved for use in people with FH. Yet for some of them, the only real way to bring their LDL levels under good control is a liver transplant.
For many millions of others, though, Lipitor has been a literal lifesaver, helping people with elevated cholesterol avoid an early demise from coronary artery disease, even if their health problems are not just solely related to genetics but rather to an indulgent lifestyle.
When it comes to medicine, the people who need it most—and deserve it most—often don’t get it first. And sometimes they don’t get it at all.
But as we’re about to see, that’s not always the case.
***
Sometimes, the distance between an initial genetic discovery and an important treatment innovation can take decades. That, as we discussed earlier, was the case in the quest to find a cure for PKU, starting with Asbjørn Følling’s discoveries in the mid-1930s and culminating with Robert Guthrie’s work in making tests for the disease accessible to nearly everyone.
Sometimes, though—increasingly and excitingly—things happen a lot more quickly. That’s the story of argininosuccinic aciduria, or ASA, a metabolic disorder that affects the urea cycle in which the body struggles to get rid of normal amounts of ammonia.
Does that sound familiar? Yes, ASA is very similar to OTC, the condition shared by Cindy and Richard. Much as in the case of OTC, people with ASA have trouble converting ammonia through the cycle of steps it takes to end up with urea.
People with ASA also often suffer from cogn
itive delays. At first, it was assumed that these neurological effects were the result of the higher levels of ammonia in their systems, as in Richard’s case. But doctors soon realized that, in people with ASA, the developmental issues remained at play and seemed to worsen over time, even when consistently lower levels of ammonia were maintained.
Recently, though, researchers at the Baylor College of Medicine began to home in on another symptom that some people with ASA suffer from: an unexplained increase in blood pressure. They knew that a simple molecule called nitric oxide was incredibly important for keeping blood pressure down. They also knew that the enzyme responsible for causing ASA is a prime route in the pathway for the production of nitric oxide in the body.
With that in mind, the Baylor team set aside some of the issues related to ammonia and focused directly on giving ASA patients drugs that act as nitric oxide donors. Lo and behold, the patients showed some promising improvements in memory and problem solving. And, as an added benefit, their blood pressure normalized, too.4
That’s very far from a cure, but rather than decades, this vital link took just a few years to establish and is already being used by some doctors to try to treat some of the long-term symptoms of ASA. It’s also helping inform the quest to address the involvement of nitric oxide depletion, which might be occurring in a variety of other much more common conditions such as Alzheimer’s disease, another reminder of how the rare can help shed light on a condition that in one way or another affects us all.
Often, the ways in which people with rare diseases might be able to help the rest of us seem quite obvious. As we saw previously, by starting with people who have a rare genetic condition like FH that causes high cholesterol and heart attacks and eventually working toward a drug treatment like Lipitor, physicians can now help millions.
Inheritance: How Our Genes Change Our Lives--and Our Lives Change Our Genes Page 21