Four months after I walked into a lab at Harvard University and gave a vial of blood to have my genome sequenced, my search to understand my DNA led me to Mark Sanders, a former Indiana firefighter.
It took a little while to explain why I was calling and then he told me his story:
Sanders was hard at work one day in 2009 in Hammond when he felt so tired that he had to sit down and take a break, even as his captain glared down at him out of a burning building. Sanders soon learned that his exhaustion was the result of primary myelofibrosis, a disease he’d never heard of. He was fatigued because his bone marrow had “quit making blood,” as he put it. He was 53 at the time, the same age as I am.
A weightlifter who had four times won the bench press championship at the World Police and Fire Games, Sanders soon needed monthly and then weekly transfusions to stay alive. He and his wife, Diane, desperately sought a bone marrow transplant. Searches of a national bone marrow registry, and a rally that brought in 500 volunteers, turned up no matched donors.
“I was basically just at home, dying,” Sanders recalled.
Sanders finally found a match and received a transplant in October 2010 at the Mayo Clinic in Rochester, Minnesota. He spent three months recuperating at a nearby apartment, accompanied by Diane and their two cats. His immune system weakened during recovery, he became infected with Legionnaire’s disease and almost died.
After recovering, Sanders retired from firefighting to garden and play the fiddle. He knows other myelofibrosis patients who haven’t fared as well.
“I had been so physically fit all my life,” he said. “There’s no reason or rhyme to why I have it or got it, and there’s not a lot of people around you can talk to who have it.”
I hung up the phone and took a deep breath. DNA in his blood cells carried the same rare genetic variant that my sequencing had revealed.
The variant is linked to a group of blood disorders, of which primary myelofibrosis is the most serious. Doctors don’t know whether this gene variant itself causes disease, yet it is seen so often in three blood disorders that its presence is used to confirm their diagnosis. I had to consider that my future might hold a fate similar to Sanders’s.
My path to Sanders began on Monday, Jan. 2, when I was sitting alone in my office in downtown Boston. Just after 4 p.m., I got an e-mail message from Madeleine Ball, a Harvard University researcher, telling me that the results of my genome sequencing were ready. The procedure is gaining use in cancer clinics and children’s hospitals, and will become increasingly common as the cost drops to $1,000, no more than that of many diagnostic procedures, such as MRI or colonoscopy, manufacturers and researchers say.
Before even a minute had gone by, the lengthy report was there for me to view.
“Here it is,” I thought, clicking on my inbox. “Mortality in an e-mail.”
Even as my DNA was chopped up, labeled, photographed and decoded by machines in California, the speed and power of sequencing was exploding. Life Technologies Corp. said Jan. 10 that its new Ion Proton machine will be able to sequence an entire genome in a day, for $1,000. Last month, Roche Holding AG made a $5.7 billion hostile bid for Illumina Inc., which said it will also soon have machines that can provide 24-hour genome sequencing. Google Inc. and Amazon.com Inc. were investing in technologies to manage the tidal wave of information coming from these machines.
Now my own deciphered genome, the chemical instructions for making all the cells and tissues of my body, was complete. That evening marked the start of a medical and personal struggle to understand the report’s findings. The genome rules our bodies in ways that remain enigmatic. Many of the diseases and medical conditions I thought would emerge in the analysis, didn’t. At the same time, there were unpleasant surprises that cast a shadow on my future and now confront me and my family with tough medical decisions.
Before my sample was taken, I met with Denise Lautenbach, a genetic counselor who works in research programs at Harvard Medical School. We’d discussed the possible revelations that might come. My father, grandfather and some uncles have suffered from a shaking disorder called essential tremor. I worried about other conditions that run in my family, such as thyroid disease, diabetes and depression. While dementia isn’t a theme, I was curious about whether I have the APOE4 gene variant that raises the risk of Alzheimer’s disease.
Breast Cancer Risk
I also prepared by speaking with others who have had their genomes sequenced. Greg Lucier, chief executive officer of sequencer maker Life Technologies, discovered he has a gene that might raise the risk of breast cancer in himself and his daughter. Would I find out the same thing? What about far rarer conditions, such as amyotrophic lateral sclerosis and Huntington’s disease, both of which can be predicted by sequencing?
My mind raced as I scanned the results that late Monday afternoon, looking for familiar words and phrases that might be connected to other conditions that run in my family.
It appeared to be a good report. I saw a genetic variant linked to slightly higher-than-normal risk of an age-related eye disease called macular degeneration. No surprise; about 10 percent of the U.S. develops this condition, and my mother has it. There was a variant linked to higher schizophrenia risk; again, not a huge boost in odds of a disease that affects about 1 percent of the population (and which I’m probably too old to develop). There were gene variants linked to liver and bowel disease, neither of which I suffer from.
Then my eyes were drawn back to the top of the report and a variant called JAK2-V617F. I realized then that the list was ranked in order of medical importance. Clicking on an entry brought me to a few pages of medical information, and those pages were linked to published scientific and medical studies. I began reading about JAK2 more closely.
This wasn’t good. The report classified the JAK2 variant’s clinical importance as “high,” and its impact as “well-established pathogenic,” meaning harmful. It’s seen frequently in people with rare “cancer-like” blood diseases. Indeed, as the report said, doctors test for the JAK2 variant to confirm cases of these diseases, called myeloproliferative disorders.
Did that mean that I already had a rare disease? My eyes widened. I read on.
Researchers currently see the variant as “one of an accumulation of changes that leads to the development of these cancer-like diseases,” the report said. “It is unclear how to view the presence of the variant in people who don’t have symptoms of the disease.”
After about 40 minutes of reading and thinking, I remained mystified. The report said “cancer-like.” I kept staring at the word “cancer,” while the companion “like” seemed to disappear. I’ve written about other people’s illnesses for years. What had started out as a cutting-edge science story was beginning to feel more like an unsettling visit to the doctor’s office with its confusion, struggles to understand, and shivers of dread.
Puzzling Medical News
“How worried should I be?” I kept thinking. Anticipation had been building inside me for months. Now my results were here and I barely knew what to make of the most important one.
I picked up the phone and called my wife, Judi, who’s a nurse. After 21 years of marriage, we’re accustomed to regular discussions of medical issues, in part because Judi has type 1 diabetes, which requires daily monitoring and insulin. Still, this was some of the most serious and puzzling medical news I’d ever received. I was careful to keep from sounding frightened.
“I got my results,” I said when she picked up the phone. I poured out the details, focusing on the JAK2 variant.
Judi’s voice was calm. I didn’t have any of the symptoms of diseases associated with the gene, she said. I’m usually energetic and active; that meant it wasn’t clear what the variant meant in my case.
“At least if there is a problem, we’ll find it earlier if you’re evaluated yearly,” she said.
“They told me that none of these results should be used to make medical decisions,” I said. “I’ll meet with the researchers later this week to talk about everything.”
We agreed that, overall, the report was good news. I didn’t realize there was more news to come.
I left the office and got on my bike, which I had ridden to work that day. I pedaled carefully to make it home safely through the streets of Boston, which is never guaranteed, genes or no genes.
Three days after getting my results, I took a seat in the office of George Church, the Harvard scientist who started the Personal Genome Project that arranged my sequencing. Joe Thakuria, the clinical geneticist and project medical director who took my blood sample in this same office in September, was there to lead the discussion of my results. The team had been through meetings like this before, having analyzed and released the genomes of 10 people, including Church, in 2008. I was already feeling a stomach full of emotions: was this about to be a new chapter in my life? And if so, how long would that chapter be?
Thakuria asked if I had any questions before we began. I told them how thrilled I was that I hadn’t seen certain genes that I expected given my family’s medical history, such as the variant for essential tremor. I’d seen nothing in my report about Alzheimer’s risk, which I considered a good sign.
Not Bad News
The researchers stopped me. The technology used to sequence my DNA has difficulty penetrating certain portions of the genome. One such region contains the gene that makes a blood fat called apolipoprotein E. Consequently, my results might not show whether I have the version of a gene, called APOE4, which raises the risk of Alzheimer’s disease.
Never mind, I thought. I can live without that knowledge.
The absence of the gene for benign tremor, the condition my father and grandfather had, wasn’t necessarily such good news, the team explained. As-yet unknown genes might cause the same condition. No news wasn’t always good news; it just wasn’t bad news.
With the three of us, along with Ball and Alexander Zaranek, another project researcher, crowded around the table in Church’s office, the team then turned to the JAK2 variant. The appearance of the gene in my blood had surprised even the Harvard scientists.
“This is probably the most serious variant that we’ve actually seen to date in the study,” Thakuria said. “It’s very rare.”
The JAK2 gene contains the DNA code for making a protein used to send signals through cells. About two out of 1,000 people have the V617F variant, which was discovered in 2005 and appears to encourage blood cells to grow and divide.
Many scientists believe it’s an acquired gene variant, meaning that I wasn’t born with it and my children and other blood relatives probably don’t have it. While JAK2 may have arisen in response to my own habits, at this point, it’s unclear what may have led to the mutation.
The JAK2 variant is found in about 90 percent of people with polycythemia vera, an oversupply of red blood cells. This disease is usually treated with drugs or phlebotomy, the draining of some blood from the system. It’s also frequently found in patients with essential thrombocytosis, an overproduction of platelets that usually requires no treatment and can be addressed with blood-thinners when patients have symptoms. It’s also used to diagnose primary myelofibrosis, the condition Sanders, the former firefighter, had. About 10 percent of these cases can develop into dangerous leukemias.
That’s three conditions linked to one gene. One of the three has a possibility of becoming cancerous, Thakuria said.
“I don’t want you to fret about this,” he said. It was the first of several times I would hear him say it.
At that point, Thakuria opened up a link to a 2010 study attached to the report. Scientists have been conducting studies of individual genes for years. The team had found a study of 10,507 people in Copenhagen who gave blood samples and then were followed for as long as 18 years. The Copenhagen researchers went back and analyzed the blood samples; 18 had the JAK2 variant.
‘Very Scary Figure’
What it showed was that 14 of the 18 people with the variant developed cancer in their lifetimes. All of the 18 died within the study period.
“That’s a very scary figure,” Thakuria said.
Information was starting to wash over me without really penetrating. I struggled to keep thinking of good questions for the team. Instead, I started asking myself questions: “What am I doing here? What are these people telling me?” I searched the faces arrayed around me, trying to see whether any of the researchers looked as panicked as I felt.
I tried to listen closely as Thakuria explained what the variant and the study might mean. There were a number of shortcomings in the Copenhagen study that made it difficult to interpret, he said. For example, he said, the authors had been liberal in their use of the word “cancer.” Some of the disorders developed by patients with the JAK2 variant were of the milder variety such as polycythemia vera, which isn’t typically classified as a cancer.
Issue of Deaths
Then there was the issue of deaths. It wasn’t clear whether people with the variant had died of the conditions they had been diagnosed with, or other causes, Thakuria said. Half of them had died in their 80s, and seven had died in their 70s. This is not far from average life expectancy, he pointed out.
“Half of them could have died of bicycle accidents,” he said, smiling.
There were other reasons not to fret, Thakuria said. Although the JAK2 variant often shows up in these conditions, no one knows precisely what role it plays. It may be a cause of the disorders, or an effect of changes elsewhere in the genome. The JAK2 variant was unlikely to be the only cause of these diseases; several things -- things that remain unknown to us -- would probably have to go wrong before any disease would arise. In this context, the gene wasn’t quite so scary, Thakuria said.
Black and White
I thought about a conversation I’d had with Ball just a few days earlier, while my genome were still being analyzed. I had called to see when the results were coming. She said they were “interesting,” but didn’t want to discuss them until a clinical geneticist had a chance to review them. Her voice sounded like she didn’t want to reveal everything she knew.
“I wish everything were black and white,” she said. “Unfortunately, things just don’t turn out that way very often.”
The researchers said I now needed to confirm that the sequencing was correct with another round of testing using a different technique. I would give another blood sample. If the variant was there, we’d talk more about what steps to take.
The meeting lasted almost two hours, and I left Church’s office with Thakuria. We walked to a restaurant about halfway between Harvard Medical School and Fenway Park to sit and have a drink. I continued to quiz him on the relationship between the JAK2 variant and the diseases we’d been talking about.
Sitting on a barstool next to Thakuria and listening to him discuss the JAK2 variant, I felt reassured. It occurred to me that this wasn’t how most people would receive the news of their results. As a reporter working on a story about genomics, I had access to experts that many people wouldn’t. What will happen as more people get results from broad genome sequencing?
I spoke about this during a meeting with Harold Varmus, director of the U.S. National Cancer Institute, and a co-winner of a Nobel Prize in 1989 for his work to find genes that promote the growth of cancer cells. I mentioned I had just received my results.
“How do you feel?” he asked.
“It’s been an interesting process,” I said. “It’s still playing out.”
Varmus nodded. Gathering genetic data from thousands of people can help researchers understand health by correlating gene variations with diseases, he said. He was concerned, however, that companies may not always ensure that people who have undergone sequencing will get a full understanding of their results.
‘How to Deal’
“Accumulating the information and studying it is good,” he said. “My concern is whether individuals are getting guidance on how to deal with the information.”
“People are being told they have a certain gene variant. In a mass population, that increases the risk of some diseases by, say, two-fold. That might be true in a mass population, but in any single individual’s genome, it’s not certain what that means.”
The Harvard researchers are struggling with these same issues, and are still working to streamline and improve their approach to giving results to study participants, Thakuria said.
“As we get more information from participants like you, we’ll gain a much better understanding of how to do it,” Thakuria said.
I still felt like someone who kept shaking a toy Magic 8 Ball and getting the message: “Concentrate and ask again.” I decided to do a little research on my own. I found a 2010 study in the journal Blood showing that when the JAK2 variant was added to the genomes of mice, the animals later suffered from disorders similar to those seen in people with the gene.
This is just one of several animal studies suggesting that the JAK2 variant contributes directly to blood disorders, said John Crispino, a professor at Northwestern University Feinberg School of Medicine, who studies the gene. Skeptics point out that drugs that interfere with JAK2 don’t cure patients suffering from the gene-linked blood disorders.
“The field is mixed,” he said. “My bias is that the JAK2 variant contributes to the pathology of the disease.”
I wanted to find out what kind of people have the JAK2 mutation I have, and what’s happened to them. In addition to Sanders, the Indiana firefighter, I spoke with Bob Rosen, chairman of the MPN Research Foundation, a Chicago-based advocacy group for people with myeloproliferative disorders, and he had a surprise for me.
Red Blood Cells
About 14 years ago, Rosen went to a doctor because of pain in his fingers and toes. A complete blood count revealed high levels of red blood cells. He was diagnosed with polycythemia vera and was first treated with phlebotomy. He now takes a drug that controls his blood cell levels. With his treatment, he’s still able to work out, and had been playing basketball on the day I called him.
“I’ve been lucky,” he said. “The risk is that, over time, new symptoms will emerge or there will be a progression to something worse.”
A small percentage of patients with polycythemia vera can develop more serious conditions, such as primary myelofibrosis and certain leukemias, Rosen said. I hadn’t realized this, or hadn’t absorbed it, until now.
Then, another surprise arrived. Looking at my report, I saw it had been updated electronically, as the genome project research team had told me would happen from time to time. Now, the second entry on my list of variants was labeled “APOE-C130R” -- that’s another name for the APOE4 gene associated with increased risk of Alzheimer’s disease.
I kept reading, recalling that I had been told my ApoE result wasn’t accessible with the technology used to sequence my genome. As it turned out, the technology had worked after all. I was at increased risk for Alzheimer’s.
This was exactly the kind of news I had hoped I wouldn’t receive.
A few days later I got an e-mail from Ball, of the Harvard team.
“Sorry this was missed earlier,” she said in the e-mail. She recommended that I look at the studies she’d collected on APOE4, some of which casts doubt on the role of the variant as a strong factor in causing Alzheimer’s. According to one estimate, people who have one copy of the gene, as I do, have a 3 percent increased risk of developing the disease by age 80.
Better to Know
One of my parents must have had this gene variant in order for me to get it. Yet my mother is in her late 70s and my father is 80; neither of them has Alzheimer’s disease. The longer I thought about it, the less I worried.
I talked with my two children, Hanna and James, about their feelings regarding the JAK2 and Alzheimer’s gene variants. My daughter, a sophomore in college, said she thinks it’s an advantage to be aware of a health threat.
“If there’s a treatment for it, you could start earlier,” she said. “It’s better to know.”
My next stop was to see my doctor. While she didn’t want her name used in this story, she agreed to let me write about our conversations and paraphrase her comments.
I followed an aide into an exam room. Nothing about my body had changed since the genome test was done. I still had normal blood pressure and pulse, and my weight was steady.
My doctor had heard of the JAK2 variant. If the result was confirmed, I would need to have my blood count tested. If there was an oversupply of red blood cells or platelets, or signs of damaged bone marrow, we would start thinking about treatment, such as removing blood. She asked me how I was feeling.
“I feel fine,” I said. “I’m not sick.”
I didn’t mention that every time I thought about the JAK2 variant, itching followed. I had read that itching was one of the symptoms of polycythemia vera. Even as I write these words, I’m scratching my forehead. I never feel itchy when not thinking about my genome. I also started noticing memory lapses.
This kind of behavior is often called “medical student syndrome,” because doctors in training who are learning to diagnose new diseases turn their skills on themselves. I assumed it was this syndrome I was suffering from, rather than a blood disorder.
It seemed like a good time to return to the Boston office of Aubrey Milunsky, the director of the Boston University Center for Human Genetics who had warned me in May that having my genome sequenced would just cause me needless worry.
“Why would you want to know that?” he had asked me then.
Milunsky was well-acquainted with the JAK2 variant on my report. Just as the team at Harvard had said, he mentioned that there was little known about the long-term impact of the variant in people. He noted that it’s also associated with some cases of dangerous clotting in abdominal blood vessels.
“You know it’s there, but you don’t know what it means,” he said. “You’re smack in the territory of inviting anxiety into your life. And this may have no meaning whatsoever in your entire life.”
I disagreed. The results had actually taken some uncertainty out of my life, I told Milunsky. We all bear some health risks, and that’s why doctors recommend, for instance, that everyone get regular checkups and those 50 and older undergo tests for colon cancer. I have a rare mutation linked to rare conditions, most cases of which can be treated. Wouldn’t it make sense for me to undergo a blood test regularly to see whether my blood counts had changed?
Such vigilance might be beneficial, and it might not, Milunsky said. I might live the rest of my life with my health unaffected by the variant. Yet the exercise had shown that I had discovered things I’d rather not know, he said. Others who undergo the same procedure will surely find out that they have mutations that practically guarantee they will develop serious and perhaps even fatal diseases, he said.
Indeed, a 1999 study in the American Journal of Human Genetics found that about 1 percent of 4,527 people who were told they had the gene that causes Huntington’s disease, a progressive nervous system disorder, attempted or committed suicide, or were hospitalized for psychiatric reasons.
Medical researchers are still trying to determine when it makes sense to do more common tests for breast and prostate cancer. A certain percentage of people who get positive results on these screening exams will go on to have unneeded treatment that may cause harm. In October, a government panel recommended that blood tests used to screen for prostate cancer should only be performed on men with symptoms. The same panel said in 2009 that women should start getting mammograms at age 50, rather than 40.
On Jan. 25, at about 11 p.m., I got a phone call from Thakuria. We had arranged to speak late in the day to accommodate busy schedules.
“The mutation confirmed,” he said. He didn’t say “JAK2,” but I knew that was what he was talking about.
The next step for me is to have my white and red blood-cell levels measured, along with those of platelets. Doctors will also study the appearance of these cells under a microscope and check to see how much oxygen my blood can carry. I expect these tests to be normal. If they aren’t, it’s possible that I’ll start getting blood drawn from my system or drug treatment for polycythemia vera. I may need to take a blood thinner, such as aspirin, to counteract the effects of excess platelets. Should I have evidence of more serious disease, stronger treatment may be needed.
“I’m not going to lie to you: I’d rather you didn’t have it,” Thakuria said. “This isn’t like one of those mutations that have specific recommendations. There are no guidelines here. This is part of being on the frontier.”