Posts Tagged ‘George Church’

UPDATED 12/05/2020


In the future, George Church believes, almost everything will be better because of genetics. If you have a medical problem, your doctor will be able to customize a treatment based on your specific DNA pattern. When you fill up your car, you won’t be draining the world’s dwindling supply of crude oil, because the fuel will come from microbes that have been genetically altered to produce biofuel. When you visit the zoo, you’ll be able to take your children to the woolly mammoth or passenger pigeon exhibits, because these animals will no longer be extinct. You’ll be able to do these things, that is, if the future turns out the way Church envisions it—and he’s doing everything he can to see that it does.

UPDATED 12/05/2020

George Church backs a startup solution to the massive gene therapy manufacturing bottleneck

Source: https://endpts.com/george-church-backs-a-startup-solution-to-the-massive-gene-therapy-manufacturing-bottleneck/
Jason Mast: Associate Editor
George Church and his graduate students have spent the last decade seeding startups on the razor’s edge between biology and science fiction: gene therapy to prevent aging, CRISPRed pigs that can be used to harvest organs for transplant, and home kits to test your poop for healthy or unhealthy bacteria. (OK, maybe they’re not all on that razor’s edge.)

But now a new spinout from the Department of Genetics’ second floor is tackling a far humbler problem — one that major company after major company has stumbled over as they tried to get cures for rare diseases and other gene therapies into the clinic and past regulators: How the hell do you build these?

CEO Lex Vovner of 64x Bio

“There’s a lot happening for new therapies but not enough attention around this problem,” Lex Rovner, who was a post-doc at Church’s lab from 2015 to 2018, told Endpoints News. “And if we don’t figure out how to fix this, many of these therapies won’t even reach patients.”

This week, with Church and a couple other prominent scientists as co-founders, Rovner launched 64x Bio to tackle one key part of the manufacturing bottleneck. They won’t be looking to retrofit plants or build gene therapy factories, as Big Pharma and big biotech are now spending billions to do. Instead, with $4.5 million in seed cash, they will try to engineer the individual cells that churn out a critical component of the therapies.

George Church
The goal is to build cells that are fine-tuned to do nothing but spit out the viral vectors that researchers and drug developers use to shuttle gene therapies into the body. Different vectors have different demands; 64x Bio will look to make efficient cellular factories for each.

“While a few general ways to increase vector production may exist, each unique vector serotype and payload poses a specific challenge,” Church said in an emailed statement. “Our platform enables us to fine tune custom solutions for these distinct combinations that are particularly hard to overcome.”

Before joining Church’s lab, Rovner did her graduate work at Yale, where she studied how to engineer bacteria to produce new kinds of protein for drugs or other purposes. And after leaving Church’s lab in 2018, she initially set out to build a manufacturing startup with a broad focus.

Yet as she spoke with hundreds of biotech executives on LinkedIn and in coffee shops around Cambridge, the same issue kept popping up: They liked their gene therapy technology in the lab but they didn’t know how to scale it up.

“Everyone kept saying the same thing,” Rovner said. “We basically realized there’s this huge problem.”

The issue would soon make headlines in industry publications: bluebird delaying the launch of Zynteglo, Novartis delaying the launch of Zolgensma in the EU, Axovant delaying the start of their Parkinson’s trial.

Part of the problem, Rovner said, is that gene therapies are delivered on viral vectors. You can build these vectors in mammalian cell lines by feeding them a small circular strand of DNA called a plasmid. The problem is that mammalian cells have, over billions of years, evolved tools and defenses precisely to avoid making viruses. (Lest the mammal they live in die of infection).

There are genetic mutations that can turn off some of the internal defenses and unleash a cell’s ability to produce virus, but they’re rare and hard to find. Other platforms, Rovner said, try to find these mutations by using CRISPR to knock out genes in different cells and then screening each of them individually, a process that can require hundreds of thousands of different 100-well plates, with each well containing a different group of mutant cells.

“It’s just not practical, and so these platforms never find the cells,” Rovner said.

64x Bio will try to find them by building a library of millions of mutant mammalian cells and then using a molecular “barcoding” technique to screen those cells in a single pool. The technique, Rovner said, lets them trace how much vector any given cell produces, allowing researchers to quickly identify super-producing cells and their mutations.

The technology was developed partially in-house but draws from IP at Harvard and the Wyss Institute. Harvard’s Pam Silver and Wyss’s Jeffrey Way are co-founders.

The company is now based in SoMa in San Francisco. With the seed cash from Fifty Years, Refactor and First Round Capital, Rovner is recruiting and looking to raise a Series A soon. They’re in talks with pharma and biotech partners, while they try to validate the first preclinical and clinical applications.

Gene therapy is one focus, but Rovner said the platform works for anything that involves viral vector, including vaccines and oncolytic viruses. You just have to find the right mutation.

“It’s the rare cell you’re looking for,” she said.

Jason Mast
Associate Editor
Jason Mas

In 2005 he launched the Personal Genome Project, with the goal of sequencing and sharing the DNA of 100,000 volunteers. With an open-source database of that size, he believes, researchers everywhere will be able to meaningfully pursue the critical task of correlating genetic patterns with physical traits, illnesses, and exposure to environmental factors to find new cures for diseases and to gain basic insights into what makes each of us the way we are. Church, tagged as subject hu43860C, was first in line for testing. Since then, more than 13,000 people in the U.S., Canada, and the U.K. have volunteered to join him, helping to establish what he playfully calls the Facebook of DNA.

Church has made a career of defying the impossible. Propelled by the dizzying speed of technological advancement since then, the Personal Genome Project is just one of Church’s many attempts to overcome obstacles standing between him and the future.

“It’s not for everyone,” he says. “But I see a trend here. Openness has changed since many of us were young. People didn’t use to talk about sexuality or cancer in polite society. This is the Facebook generation.” If individuals were told which diseases or medical conditions they were genetically predisposed to, they could adjust their behavior accordingly, he reasoned. Although universal testing still isn’t practical today, the cost of sequencing an individual genome has dropped dramatically in recent years, from about $7 million in 2007 to as little as $1,000 today.

“It’s all too easy to dismiss the future,” he says. “People confuse what’s impossible today with what’s impossible tomorrow.”, especially through the emerging discipline of “synthetic” biology. The basic idea behind synthetic biology, he explained, was that natural organisms could be reprogrammed to do things they wouldn’t normally do, things that might be useful to people. In pursuit of this, researchers had learned not only how to read the genetic code of organisms but also how to write new code and insert it into organisms. Besides making plastic, microbes altered in this way had produced carpet fibers, treated wastewater, generated electricity, manufactured jet fuel, created hemoglobin, and fabricated new drugs. But this was only the tip of the iceberg, Church wrote. The same technique could also be used on people.

“Every cell in our body, whether it’s a bacterial cell or a human cell, has a genome,” he says. “You can extract that genome—it’s kind of like a linear tape—and you can read it by a variety of methods. Similarly, like a string of letters that you can read, you can also change it. You can write, you can edit it, and then you can put it back in the cell.”

This April, the Broad Institute, where Church holds a faculty appointment, was awarded a patent for a new method of genome editing called CRISPR (clustered regularly interspersed short palindromic repeats), which Church says is one of the most effective tools ever developed for synthetic biology. By studying the way that certain bacteria defend themselves against viruses, researchers figured out how to precisely cut DNA at any location on the genome and insert new material there to alter its function. Last month, researchers at MIT announced they had used CRISPR to cure mice of a rare liver disease that also afflicts humans. At the same time, researchers at Virginia Tech said they were experimenting on plants with CRISPR to control salt tolerance, improve crop yield, and create resistance to pathogens.

The possibilities for CRISPR technology seem almost limitless, Church says. If researchers have stored a genetic sequence in a computer, they can order a robot to produce a piece of DNA from the data. That piece can then be put into a cell to change the genome. Church believes that CRISPR is so promising that last year he co-founded a genome-editing company, Editas, to develop drugs for currently incurable diseases.

Source: news.nationalgeographic.com

See on Scoop.itCardiovascular and vascular imaging

Read Full Post »

Reporter: Aviva Lev-Ari, PhD, RN

Personal Tale of JL’s Whole Genome Sequencing

Word Cloud by Daniel Menzin

Unexpected scary findings: the tale of John Lauerman’s whole genome sequencing

FEBRUARY 15, 2012
Joe Thakuria draws John Lauerman's blood
Joe Thakuria draws John Lauerman’s blood for whole genome sequencing. By Madeleine Price Ball, licensed under CC-BY-SA.

Madeleine Price Ball, PhD is a PGP research scientist in George Church’s lab at Harvard Medical School.

Several months ago John Lauerman, a reporter for Bloomberg News, approached the Personal Genome Project interested in having his whole genome sequenced. While we have hundreds of genomes in the sequencing pipeline, of the dozen or so genomes we have sequenced to-date, so far the results have been for the most part uneventful.

Lauerman’s case was different: we found something rare and “famous”, and something that nobody could have anticipated by looking through family history: a mutation that was acquired rather than inherited. This genetic variant (JAK2-V617F) is one of a number of mutations that can accumulate in blood stem cells, a precursor that could lead to several rare blood diseases.

Last night Lauerman published his experience, and we encourage all participants to read it. It confronts us with a scenario that seems likely to affect others who forge into this new and unknown territory: the very real possibility that whole genome sequencing may uncover something unexpected, ambiguous, and scary. This certainly isn’t an outcome we anticipate for most participants, but it is a rare possibility all should be aware of. Would you rather know that you carry such a variant, even if that knowledge might not help your health at all? Although some would decline, PGP participants are the sort of people who say: “Yes, I’ll take that risk, I’d rather know!” [see footnote]

His experience also illustrates potential for the Personal Genome Project to guide health care, for himself and for those who follow. The JAK2-V617F variant is so rarely seen in healthy individuals, we have very little understanding of what to expect. It has almost always been seen after a patient is diagnosed with a disease, not before. Will he develop one of these diseases? If so, which one? Perhaps many people carry the variant but never develop any symptoms of disease. In coming years Lauerman will likely continue to monitor his blood for signs of disease. It is possible that he will never develop the disease, and we hope this is the case. On the other hand, through monitoring he may detect disease sooner than he otherwise would have. By making his experiences public, his case can inform future individuals who confront the same finding.

As we move onward to sequencing hundreds and thousands of genomes, we can’t promise such interpretations will be made in a timely manner. We’re working with other groups to improve our ability to interpret genomes — and PGP participants are the perfect testbed for this development! — but it’s much harder than you might think. Genome data is made public in 30 days, but months or even years could pass before a serious and potentially scary variant is noticed. Participating in the PGP not only means that you risk learning ambiguous and scary news, but that it may be uncovered long after your data has been made public. We are always grateful to participants who choose to step into that unknown territory of genome sequencing, and who share their data so that others may learn.

Footnote: In the early stages of enrollment, individuals interested in joining the Personal Genome Project are asked to think about whether there are specific types of genetic information that they might not want to learn about themselves. Our examples include medical conditions with no effective cures or therapies, cancer, degenerative diseases, and stigmatized traits (e.g. mental illness). We do not offer the review or redacting of such information on a case-by-case basis. Only participants who wish to take the risk of learning such information are allowed to proceed with enrollment.




Harvard Mapping My DNA Turns Scary as Threatening Gene Emerges

By John Lauerman – Feb 15, 2012 12:01 AM ET

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:

Sophie Liu, research scientist at Complete Genomics Inc., at a sequencing center at the company’s research facility in Mountain View, California. Photographer: David Paul Morris/Bloomberg

Feb. 15 (Bloomberg) — Bloomberg News reporter John Lauerman talks about the results of his genome sequencing. The genome contains the DNA instructions for making all the body’s cells and tissues. Lauerman discussed the report with a team from Harvard Medical School’s Personal Genome Project, who will use the results in their efforts to better understand variations in the human genome and their implications for health and disease. (Source: Bloomberg)

Joseph Thakuria, clinical director of the Personal Genome Project draws blood from Bloomberg reporter John Lauerman for the Project at Harvard Medical School in Boston on Sept. 13, 2011. Photographer: Madeleine Price Ball/Harvard Medical School via Bloomberg

Deep Breath

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.

Genome-Sequencing Report

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. (LIFE) 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 (ROG) made a $5.7 billion hostile bid forIllumina Inc. (ILMN), which said it will also soon have machines that can provide 24-hour genome sequencing. Google Inc. (GOOG) and Amazon.com Inc. were investing in technologies to manage the tidal wave of information coming from these machines.

Personal Struggle

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.

Good Report

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.

Unclear View

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.”

New Chapter?

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.

‘Very Rare’

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.

Blood Disorders

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.

Ask Again

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.

Animal Studies

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 theMPN 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.

Another Surprise

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.

‘Not Sick’

“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.”

Useful Vigilance

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.

Huntington’s Disease

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.

‘Mutation Confirmed’

“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.”

To contact the reporter on this story: John Lauerman in Boston at jlauerman@bloomberg.net

To contact the editor responsible for this story: Jonathan Kaufman at




Read Full Post »

%d bloggers like this: