When I heard the news, I laughed.
Dr. Deborah Levy, the director of McLean Hospital’s Psychology Research Laboratory, called to tell me there was a mouse scampering around in a laboratory that had been designed to replicate genes found inside Calen and me.
I am not only living in my Mouse House, I have also helped create a Close family mouse!
The story of how my family got our own genetically engineered mouse begins when Calen first arrived at McLean Hospital in 2002 and agreed to donate blood as part of a research project. During a genetic analysis of his blood years later, doctors discovered that one of his genes had an intriguing mutation. Instead of having two copies of certain genes, which was what most people had, Calen had four copies. More important, one of the genes with four copies was not just any gene. It was one that scientists suspected could play a role in mental disorders.
Dr. Levy had spent much of her career searching for genetic links that could help explain the origins of schizophrenia. Energetic and brilliant, she is not only a researcher but also an associate professor at Harvard Medical School. She called Calen and asked whether he would undergo more tests and whether he would give her his permission to contact other members of the Close family about donating a blood sample for her research. She was especially interested in my blood because I also had been diagnosed with a mental illness.
Everyone agreed to participate: my children, my siblings, Tom (Calen’s father), and my parents (Dad was still alive at the time). When the genetic results were analyzed, they revealed two things. First, I was definitely the daughter of Bill and Bettine Close, which automatically disqualified me from appearing on one of those awful “guess who’s the father” tabloid television shows.
Dr. Levy and her research team also discovered that Tom and eight members of the Close family had the correct number of genes, but Calen and I did not. We had the exact same mutation, which meant that I had passed it to him.
Dr. Levy said this discovery was important because one of the mutated genes is the gene that codes for an enzyme called glycine decarboxylase, or GLDC, which breaks down glycine. Having extra copies of this gene could cause glycine to break down faster than it does in other people’s brains. Without enough glycine, an important brain receptor known as the NMDA receptor won’t function normally. Neuroscientists believe that a malfunctioning NMDA receptor is associated with psychosis, especially schizophrenia.
Dr. Levy and her team assured me that our mutated gene could be a “smoking gun” when it comes to figuring out the underlying causes of our mental illnesses. This is because no one really understands the genetic underpinnings of serious mental illnesses. Doctors rely on clinical assessments of the symptoms they observe and have to decide if an individual has schizophrenia, a mood disorder such as bipolar disorder, a smattering of both—as in schizoaffective disorder—or severe depression.
Finding an intriguing errant gene could be the first step in understanding the biology of mental illness and, many researchers hope, eventually finding a cure.
Dr. Levy asked whether Calen and I would be willing to undergo additional tests if she could get funding for research from the National Institute of Mental Health. We said yes, and after several years and endless paperwork, Dr. Levy finally got the green light. Ten years after Calen first donated his blood at McLean, we were about to become guinea pigs.
Mattie and I were the first to go to McLean for a full week of tests, including brain-imaging scans (MRIs)—which I hated because of my claustrophobia—various cognitive tests, brain-wave tests (EEGs), clinical interviews, and movement disorder assessments. Both of us also had a plug of skin removed from our derrieres.
Dr. Levy sent a sample of our DNA to the laboratory of Dr. James Lupski at the Department of Molecular and Human Genetics at Baylor College of Medicine in Houston to be “sequenced.” The skin cells from our butts were converted into neurons by Dr. Kristen Brennand, a stem cell biologist at the Icahn School of Medicine at New York’s Mount Sinai Hospital, who is an expert at developing in vitro models of schizophrenia.
But of the many scientists working on Dr. Levy’s research project, it was Dr. Uwe Rudolph, the director of the Laboratory of Genetic Neuropharmacology at McLean, who got the best assignment. He genetically engineered a mouse with the same gene mutations that had been found in Calen and me!
I call that mouse the Close family mouse.
After Mattie and I finished at McLean, Calen and Sander arrived for a week of tests at the hospital and went through the same procedures, including having skin samples taken from their butts. The reason Mattie and Sander were included was that we are all in the same family, yet Mattie and Sander didn’t have our mutated genes.
After the doctors collected all the data from the four of us, we moved to the next stage of research. Every two weeks big boxes were mailed to Calen and me containing doses of liquid medicine prepared by McLean Hospital pharmacist Laura Godfrey. We were supposed to drink one dose after each meal at specific intervals for a total of six months. Some of the doses contained glycine powder with lemon flavoring. The other doses were a look-alike, taste-alike placebo. We didn’t know which doses contained glycine and which were the placebos, but the first time we took glycine, Calen and I both became nauseated and vomited. This meant that we were getting too much glycine, so the amount was cut back until we had no side effects. Because this was a “blind” study, we weren’t supposed to be able to tell the difference—but trust me: after you have vomited because of something you drank, you don’t forget. Calen and I could both tell which drink contained the glycine, because it was the only time we had any side effects; that did not happen on the placebo, no matter how high the dose got. To be fair, we both got a lot better on glycine, and once the dose was adjusted we had no side effects. That made it worth it. The amazing thing is that we persevered. That is something we are very proud of. It turned out to be a good thing, because we got so much better on glycine. It was particularly hard for me, because I got glycine first, then I had to get through thirteen weeks waiting for the time when I knew I would get glycine again.
I was proud that both of us completed the first twelve weeks. After that came the six-week “open label” phase, during which the study was no longer blind and we were told that we were getting glycine. Dr. Levy and her team began increasing our glycine intake while giving us periodic blood tests and checking our weights. The results showed that our symptoms improved when we took glycine, but not when we took the placebo. Dr. Levy said this was significant because it demonstrated that our mutation was “medically actionable,” which meant the deficiency caused by the mutant gene could be at least partially corrected by taking glycine.
Dr. Levy and other researchers have found mutated genes in individuals with mental illnesses, including those with schizophrenia, bipolar disorder, autism, epilepsy, attention-deficit/hyperactivity disorder, and intellectual disability. Sadly, she and others still have a long way to go before they understand the mysteries of our brains. This is just one reason it is so important to support biomedical research. There are so many individuals and families who would benefit from such an investment.
Although the clinical tests are finished, Calen and I are still being studied. With the support of NIMH, we are continuing to take glycine to see if it will enable us to cut down on the pharmacopoeia of meds that both of us are now taking. If it does, glycine (or something like it) in pill form may become available for others with similar mutations.
I’m really proud that my family has played a key role in helping scientists pinpoint a possible cause for severe mental illnesses, but I’m also happy that Dr. Levy got us involved for several reasons. The fact that my children, siblings, parents, and Tom immediately agreed to donate their blood and be tested says a lot about their characters. I’ve been frank in this book about my family’s disputes and our different personalities. But when it came to helping Calen and me, and possibly others, they were “all in.”
There’s another personal reason why these tests mattered. When you have a mental illness and people are talking behind your back about how you are “crazy,” when everything in the media suggests that persons with mental illnesses are dangerous and scary, and when you realize that sometimes you can’t trust your own brain to interpret reality for you, you often feel as if it is all your fault, that somehow you are to blame and that you are responsible for your wild mood swings or for seeing things that aren’t there or hearing sounds that no one else hears.
I’ve made mistakes in my life, and I am not trying to avoid taking responsibility for many of the foolish decisions I’ve made, but what Dr. Levy’s research documents is that it isn’t just all me. I have mutated genes that affect my brain, just as some people are born with a physical challenge. And despite our illnesses, Calen and I were able to make a unique contribution to medical science. If we had decided not to participate, no one would ever have known that our mutation was actionable and we would not have experienced the benefits of glycine.
Why some individuals develop a mental disorder and others don’t remains a mystery. Uncle Seymour had one, so do I, and so does Calen. Other illnesses have been mysteries to us, but scientists have solved them. I hope someday we will not only find ways to help those of us who do have one but also find a cure. I hope that day comes soon.