DNA Science Blog

The hands of a person with Liebenberg syndrome resemble feet; the arms resemble legs. (Credit: Dr. Malte Spielmann)

Flipping the X-ray showed Stefan Mundlos, MD, that his hunch was right – the patient’s arms were peculiar and stiff because the elbows were actually knees.

The recent report from Dr. Mundlos’ group at the Max Planck Institute for Molecular Genetics, complete with a genetic explanation for the condition, flew under the radar of  the press-release-driven science news aggregators. But I noticed it because I worked on this sort of thing in grad school – flies with legs growing out of their heads.

LITTLE-KNOWN LIEBENBERG SYNDROME
An ungoogleable researcher named F. Liebenberg described in 1973 a family with the condition that would take his name: “A pedigree with unusual anomalies of the elbows, wrists and hands in 5 generations.” In the white South African family, four males and six females had stiff elbows and wrists, and short fingers held in a way that made them look strangely out of place. The pedigree revealed classic autosomal dominant inheritance – each child of a weird-limbed person had a 50:50 shot at being so too.

A second family appeared in the pages of the Journal of Medical Genetics in 2000. Those researchers noted that when a patient stood in the “anatomical position” – palms forward – he or she couldn’t bend the arms at the elbow, and the restricted movement had been present since birth.

In X-rays of patients, the elbow joints looked too big. Those of a 6-month-old were the size of elbows of a 3½-year-old, with stubby fingers. Similarly, a 2½-year -old’s elbow was the size of an 8-year-old’s. And like an episode of Law and Order in which a suspect showing up in the first 15 minutes can’t possibly be the perp, those researchers implicated a gene on chromosome 17. That wasn’t it.

Then in 2010 a report appeared on identical twin girls with the curious stiff elbows and long arms of Liebenberg syndrome, in Plastic and Reconstructive Surgery. These researchers noted that the lengths and shapes of the fingers and toes were the same.

IF IT LOOKS LIKE A DUCK …
Noting that the muscles and tendons of the elbows, as well as the bones, weren’t quite right, Dr. Mundlos and colleagues, experts in the distinctions between vertebrate forelimbs and hindlimbs, realized that the stiff elbows were acting like knees.

The human elbow joint is a hinge in one plane and rotates the forearm in another. The knee is a bit tighter. It extends the lower leg but the kneecap stabilizes the lateral rotation, which is why I constantly injure it in zumba class.

The Max Planck researchers analyzed three unrelated families with Liebenberg syndrome. “The phenotype wasn’t easy to interpret at first glance. It looked like a malformation of the elbow joint and an abnormality of the wrist bones. But wrist bone abnormalities aren’t unusual, in particular fusion of bones,” Dr. Mundlos explained.

But the Liebenberg elbows had a peculiar enlargement, and that was a major clue.

The areas in the white dots are patella — knee — that are parts of the elbow joint. (Credit: Malte Spielmann)

“Normally the elbow joint consists of the humerus, which sits in a socket of an elongation of the elbow, the olecranon, with the radius forming a smaller part of this complex joint. In the patients the olecranon was missing and the joint had a flat appearance, unlike the normal hinge joint of the elbow,” Dr. Mundlos said.

It was when Dr. Mundlos examined a patient’s X-ray from a different perspective that the truth popped out. “I realized that the entire limb had the appearance of a leg. Normally you would look at the upper limb X-ray with the hand up whereas the lower limb is looked at foot down. If you turn the X-ray around, it looks just like a leg,” he recalled.

To anyone familiar with developmental biology, a body part in the wrong place evokes one word: HOMEOTIC. (Warning: spellcheck and autofill convert this to homoerotic.)

HOMEOTIC MUTATIONS: A DETOUR IN DEVELOPMENT (AND IN MY CAREER)
A homeotic mutation mixes up body parts, so that a fly grows a leg on its head or antennae on its mouth. Assignment of body parts begins in the early embryo, when cells look alike but are already fated to become what they will become, thanks to gradients of “morphogen” proteins that program a particular region to elaborate particular structures. Mix up the messages, and a leg becomes an antenna, or an elbow a knee.

Just months after I got my PhD in Thom Kaufman’s lab at Indiana University circa 1980, where I savagely murdered millions of fruit flies, post-doc Matt Scott and fellow grad student Amy Weiner discovered how homeotics happen. They identified the homeobox. This 180-base-sequence encodes a protein domain that binds other proteins that turn on sets of other genes – crafting an embryo, section by section. Researchers at the University of Basel found the homeobox at about the same time. (For a fly’s eye view of life with homeosis see The Making of a Mutant, A Fruit Fly Love Story, which I will re-post here for Valentine’s Day.)

Once developmental biologists knew what to look for, homeoboxes turned up in all manner of genomes, affecting the positions of petals, legs, and larval segments. Humans have four clusters of homeotic genes, plus controls.

Homeotic genes line up on their chromosomes in the precise order in which they’re deployed in development, like chapters in an instruction manual to build a body. And they’re ancient. A fruit fly given a mutant homeotic gene from a chicken sports an antennal leg, one species reading the DNA sequence of a very distant other. The homeotic mutants from the Kaufman lab even starred in an episode of The X-Files, about which I recall little except that it featured a Cher impersonator.

In an Antennapedia fly, the antennae develop as legs. (Credit: Rudi Turner)

I left bench science because I’d thought homeotic mutations were a quirk of only fruit flies, mice, and mosquitoes. But after the homeobox discovery, researchers quickly found them in people. In lymphomas, white blood cells detour onto the wrong lineage, and in DiGeorge syndrome, the abnormal ears, nose, mouth, and throat echo the abnormalities in Antennapedia, the legs-on-the-head fly in the photo. Extra and fused fingers and various bony alterations also stem from homeotic mutations.

But nothing could quite match, in a human anomaly, the dramatically mutant fruit flies — until I saw photos of children’s faces with lower jaws turned into upper jaws, in the May 2012 issue of the American Journal of Human Genetics). (See Scientific American blogs for that story.)

The partial arm-to-leg transformation in people, once you know what it is, is even more astonishing.

FINDING THE ARM-TO-LEG MUTATION, USING TOOLS OLD AND NEW

The homeotic hypothesis explained a lot about Liebenberg syndrome.

This wrist is more like an ankle. (Credit: Malte Spielmann)

“The transformation affects the bones, tendons and muscles of the elbows, wrists and hands. The olecranon of the elbow is completely missing in the patients and the bones of the wrist form a large structure similar to the bones of the ankle. In the 3D CT scans of the elbow you can see a structure similar to the patella of the knee that is fused to the head of the humerus. The bones of the hands are too long and look similar to bones of the feet,” explained Malte Spielmann, MD, lead author of the paper.

Although the researchers ultimately used techniques we are accustomed to these days – genome sequencing, and comparative genomic hybridization (CGH) to detect deletions and copy number variants – their search began as many genetic searches have since the 1950s: with abnormal chromosomes.

Two of the three Liebenberg syndrome families have deletions (missing DNA), and the third has a translocation (two chromosomes exchanging parts). The families share a glitch in the same general region of chromosome 5, providing a toehold in the genome.

Genome sequencing didn’t turn up any likely suspects in the translocation family, but CGH found a 134 kilobase deletion in their genomes. Apparently 134,000 DNA bases were lost when the translocation initially happened, like lopping off letters when cutting-and-pasting text.

The missing DNA in all three families corresponded to the same “gene desert,” a genome region festooned with so-called “dark matter” that doesn’t encode protein. But one candidate DNA sequence did emerge from the regulatory wasteland: a gene called PITX1.

The gene doesn’t encode protein but controls other genes that do. And not only is the gene “highly conserved” – in many species and therefore pretty important – but it controls limb development in mouse embryos.

The researchers had found their gene.

In the Liebenberg families, missing genetic material places an enhancer gene near PITX1, altering its expression in a way that mixes up developmental signals. And so the forming arm gets mixed up, and fashions part of a leg — at first glance barely noticeable, as in this doll. Fortunately the condition appears more an annoying oddity than a disease, and because the gangly arms don’t seem to disrupt everyday life too much, you won’t find Liebenberg syndrome in the rare disease databases like CheckOrphan, NORD, or the global genes project.

LARGER LESSONS
I like the arm-to-leg story so much that I hardly know where to begin.

#1 I feel better at having spent four years trying to figure out how flies grew legs on their heads, yet worse for having left the field.

#2 I marvel anew at the elegant evolutionary tale that the homeotic mutations tell. When mutation derails development so similarly in such different species as a plant and a person, descent from a common ancestor is the most logical explanation.

#3 Looking at an image from an unusual perspective revealed what no one else had seen. With all the fuss over genome sequencing and nano-everything, we shouldn’t lose sight of the power of larger-scale observation in science.

#4 The homeotic mutations steer development to an alternate pathway. They symbolize, for me, my veering from the path to becoming a scientist shortly after getting my doctorate.

The late paleontologist and science writer Stephen Jay Gould helped me. In his essay “Hopeful Monsters” published in the October 1980 issue of Natural History magazine, reprinted in his 1983 book “Hen’s Teeth and Horse’s Toes,” he wrote about the work in the Kaufman lab, mentioning us lowly graduate students – Barbara Wakimoto, Tulle Hazelrigg, and me.

Thrilled, I wrote to him. And he wrote back, five hand-scrawled pages, encouraging me to follow my instincts to become a writer at a time when many were telling me not to stray from science.

Two decades later, I was to thank him again, unfortunately in an obituary. And now, a decade later, I do so yet again. Thank you, Steve, for telling an unsure graduate student that it’s okay to follow an unusual path.

And congrats to Drs. Mundlos and Spielmann and their co-workers for their insightful discovery.

One symptom of Becker muscular dystrophy is fatigue and injury of exercising muscles, such as in gripping a weight.

Becker muscular dystrophy is a muscle wasting disease that is rarer and less severe than the more familiar Duchenne muscular dystrophy. Both conditions are basically untreatable. But according to a study published today in Science Translational Medicine, Cialis may alleviate the associated muscle fatigue and damage.

Yes, Cialis. The erectile dysfunction drug.

To anyone who’s followed the Viagra story, use of its cousin Cialis to treat muscle disease is not so much repurposing as it is a logical extension, based on regulating blood flow.

Viagra, developed in 1989, began its ascent three years later, when participants in a clinical trial to treat angina, which is chest pain due to blocked blood flow, reported strikingly improved erections. Taking a pill to treat what was about to evolve from “impotence” to “erectile dysfunction” trumped penile implants and injections, or older approaches of ingesting camel hump fat, jackal bile, or various herbs. Pfizer introduced Viagra to the world in 1998.

BOOSTING BLOOD FLOW – IN PENISES, LUNGS, AND FOREARMS
The biochemistry is actually fairly complicated. Here’s a short version (skip to next section if you like.)

In order for blood to fill out a vessel, nitric oxide, a simple gas, relaxes the smooth muscle in the vessel wall by binding cGMP (cyclic guanosine 3’5’-monophosphate). Drugs like Viagra and Cialis inhibit the enzyme (phosphodiesterase 5) that breaks down cGMP. So with more available cGMP, the vessel widens, providing more oxygen to the surrounding muscle.

Different phosphodiesterases work in different body parts. Blocking the enzyme in a penis sustains an erection; in the lungs, it counters high blood pressure. And now a team led by Ronald Victor, MD, at Cedars-Sinai Medical Center, has successfully tested Cialis on men with Becker muscular dystrophy. Their work adds an important new piece to the picture of the biochemistry behind control of blood flow.

Maintaining supplies of NO requires another enzyme, appropriately-named nitric oxide synthase (NOS). It must nestle into the smooth muscle cell’s outer membrane (sarcolemma) to produce the needed NO, and another protein, dystrophin, does this. Dystrophin is what is missing, abnormal, or misplaced in Duchenne and Becker muscular dystrophies. Without its escort, what little NOS remains ends up in the cytosol, the liquidy insides of the smooth muscle cell, rather than in the sarcolemma, where it must be tethered to function.

Cialis keeps cGMP around longer, giving what little NO is produced more of a chance to work. And it does.

THE NEW STUDY
Cialis improved muscle function in mdx mice, which have the same dystrophin mutations as people. “From the mouse paper we thought the drug could be a blockbuster in humans” for muscular dystrophy, Dr. Victor told me.

The new study was straightforward. First, the researchers compared blood flow to the forearm at rest in 10 BMD patients and 7 healthy controls – it was the same.

Next the men performed a handgrip exercise while the lower halves of their bodies were in a chamber that had negative pressure, a common test to simulate cardiovascular stress. Normally the body maintains blood pressure by countering the ballooning of blood vessels in the legs with constriction elsewhere, but it tempers the constriction so that other body parts still get blood. The healthy men did this. But in the men with BMD, the blood vessels in the exercised forearm stayed narrowed, impairing blood flow. This is why the disease causes muscle damage and fatigue with exercise.

In a second experiment, each man with BMD took one Cialis (aka tadalafil) or placebo pill, had blood flow to the exercised forearm assessed, waited 2 weeks, then took the opposite pill.

“The tadalafil effect was both marked and immediate, occurring with a single dose,” the researchers write, in 8 of the 10 men, with no effect of placebo. The other two men had unusual mutations that might indicate their disease was too mild to show a response. Dr. Victor hopes that an ongoing multicenter prospective trial will support the findings of success.

He’s understandably ecstatic; he’s worked on this problem for two decades. “So little research has been done on Becker because it’s so rare. I hope we’ll provide the evidence to make this another indication for the drug. We finally have some hope for a therapeutic benefit for people with muscular dystrophy, and it’s really exciting.”

Dr. Victor is, however, concerned that patients with muscle disorders will seek the drugs before the larger trial can validate the findings. Yet at the same time, he and his co-workers envision additional new markets, pointing to the work of Ronald Cohn, MD, at Johns Hopkins University. His team’s work suggests that the drugs may be useful in boosting blood flow in neuropathies such as amyotrophic lateral sclerosis and spinal muscular atrophy, in the low-muscle-tone hypotonias, and in a host of myopathies (metabolic, mitochondrial, congenital, inflammatory, steroid-induced and critical illness associated).

Ground squirrels maintain muscle tone while hibernating — their physiology may hold clues to muscle-wasting diseases. (Photo: Dr. Wendy Josephs)

The research may actually veer back to non-human animals, thanks to Dr. Cohn’s discovery that hibernating ground squirrels maintain blood flow to muscles in a way that other mammals can’t. “Squirrels can still target NOS. There must be some important secrets there,” Dr. Victor said.

NOT A PERFORMANCE-ENHANCER
Since many people have muscle conditions and many men take Cialis or Viagra, I wondered whether anyone had inadvertently discovered that their ED pills relieved their tired muscles. A guest blog, “Viagra for muscular dystrophy and publicity for accidental insight” indeed tells such a tale.

In 2005, a 57-year-old man with limb-girdle muscular dystrophy asked his doctor, Jeoffry B. Gordon, MD, MPH of San Diego, for Viagra for the usual reason. The patient reported back that in addition to an improved sex life, his muscles felt stronger. He happily did standing push-ups and chair and balance exercises to test his new abilities, which waxed and waned with the taking of the blue pills.

I tried to find Dr. Gordon but got caught up in the morass of doc websites that never actually provide any info. His blog laments the medical journals, media outlets, organizations, and even Pfizer itself, that ignored his report of a beneficial effect of Viagra on muscle strength, seven years ago.

The lack of interest in Dr. Gordon’s anecdotal blog, low on the totem pole of medical publishing, bodes well for my concern that when the news breaks (if it does, one can never tell) about Cialis and Becker muscular dystrophy, men (and maybe some women) will go the Lance Armstrong route and try to use the pills to boost athletic performance.

But it probably won’t work.

“The drug doesn’t enhance performance, it doesn’t make people supernormal. These drugs seem to work under stressful conditions, such as exercise of diseased muscles,” Dr. Victor cautions. This is one reason why he was so careful about doing a double-blinded, placebo-controlled experiment.

THE BIGGER PICTURE
I think repurposed drugs are the greatest thing since Spanx. I recently blogged here about the repurposing of a shelved childhood brain tumor drug finding new use to treat the ultra-rare rapid-aging disease progeria, and perhaps run-of-the-mill atherosclerosis. I love that ED drugs may help people with muscle diseases.

My interest in repurposing drugs is a bit of a turnaround, because for the past few years I’ve been immersed in writing my book, “The Forever Fix: Gene Therapy and the Boy Who Saved It” (shameless holiday-time book plug, paperback due out 1/8). Gene therapy is about as opposite repurposing drugs as one can get.

Hannah Sames has giant axonal neuropathy, a very rare disease that is similar to ALS. Here she is with her mom, Lori. (photo: Dr. Wendy Josephs)

The book’s title comes from Lori Sames, whose little girl Hannah has giant axonal neuropathy. And even though Hannah’s Hope Fund is trying desperately to raise funds for a phase 1 clinical trial of gene therapy, reports on the first approved gene therapy – in Europe, for Glybera, on November 2 – are sobering.

Glybera is a gene therapy to treat lipoprotein lipase deficiency, which causes pancreatitis. The cost is staggering: about $2 million per patient. Even if it is a “forever fix,” who can afford it?

So I think a bioinformatics approach makes more sense. Wed the information pouring out of human genome sequencing to the stockpiles of drugs, those on the market and those warehoused awaiting homes. Using what we’ve already got makes more sense in treating patients now – particularly those with rare diseases who lie under the radar of new drug discovery.

Even after writing ten editions of a human genetics textbook, I don’t want to know my genome sequence. Yet.

Famous folk have been writing about their genome sequences for a few years now. But when I received two such reports at once last week – about genetics researcher Ron Crystal, MD, and a hypothetical (I think) story about President Obama, I knew it was time to take action.

Or, in my case, inaction.

After writing ten editions of a human genetics textbook and lots of articles, you’d think I’d be first in line to get my genome sequenced. But I prefer ignorance.

The quest to know ourselves by our DNA sequences began in the late 1980s, with the conception of the human genome project, and reached a milestone with the actual genome sequencing.

Revisiting the Genome Race

I still have my dog-eared copies of the journals unveiling the first draft of “the” human genome, from February 2001. The Science report hailed from the Celera Genomics/Craig Venter camp, with 5 individuals contributing to that composite genome, including CV himself, who has since gone on to creating life. The Nature report represented the International Human Genome Sequencing Consortium, which used genome pieces from several de-identified individuals.

On June 26, 2000, Francis Collins, MD, PhD and Craig Venter, PhD, flanked President Clinton in the White House rose garden to announce the great sequencing, because that was the only available date on the calendar. Both groups had made nice at the end of the race. Celera actually crossed the finish line first, as Dr. Venter told me that February off the record, lest the looming new edition of my textbook be obsolete. Today the race seems irrelevant.

The First Two: Craig Venter and James Watson

By 2007, individuals began to have their genomes sequenced, and speak and write about it. Dr. Venter was first, his genome presented in PLoS Biology. He pondered the implications at the American Society of Human Genetics annual meeting a year later.

Dr. Venter learned from his genome sequence that he has blue eyes and a tendency toward antisocial behavior, substance abuse, and novelty seeking. He found out he’s a fast caffeine metabolizer. “I can have two double lattes and wash it down with a Red Bull and not be affected by it,” he snarkily told the crowd. He also learned of elevated risk for Alzheimer disease and cardiovascular disease.

Next came James Watson, PhD, of double helix fame and first head of the human genome project. He discussed his genome at the 12th International Congress of Human Genetics in Montreal in October 2011, where Kevin Davies, PhD, author of “The $1,000 Genome” introduced him. Dr. Davies has subjected himself to all manner of genome probings too. Here’s the printable part of what Dr. Watson said:

Why did he do it? “Why not? I had no objection, with the exception of not wanting to know ApoE4. My grandmother had Alzheimer’s.” (Watson’s published genome sequence omits that risk gene, but people imputed it from the surrounding sequence.)

What did he learn that was useful? “Finding that I am a slow metabolizer of antipsychotics and beta blockers.” His son nearly died from an antipsychotic. “So I now know that if I go psychotic, I can’t take those drugs.” And he learned why beta blockers for an irregular heartbeat knocked him out. He switched drugs.

What information wasn’t helpful?  “They told me I was a carrier for BRCA1. I thought I would have to phone my nieces because their mother had breast cancer. But I asked Mary-Claire King, who discovered the gene, and she said no, I had a harmless variant. So I’m glad I didn’t call my nieces because then they would have paid that disgraceful sum of money to Myriad Genetics.”

Dr. Watson ended with a situation he knows well. “I’d like to see children who have mental illness sequenced with their parents. Finding a mutation would make parents see that it was genetic injustice. Knowing that won’t make their child healthy, but they won’t have the double whammy of thinking they did something wrong.”

Dr. Venter wryly summed up the great personal value of he and Dr. Watson knowing their sequences. “You probably wouldn’t suspect this based on our appearances, but we are both bald, white scientists.”

Genome Sequencing in Sickness and in Health

Genome and exome sequencing are extremely valuable in diagnosing people whose symptoms don’t match known disorders. “Every time someone goes into a children’s hospital with a serious disease, it would be immoral NOT to sequence him,” Dr. Watson said. The first and most famous case is that of young Nicholas Volker and his intestinal condition; I’ve followed that of 4-year-old Gavin Stevens’s blindness gene. The cases of exome sequencing solving medical mysteries are mounting fast.

Steve Jobs and Christopher Hitchens had their cancer genomes sequenced, pancreatic and esophageal, respectively, and the information guided drug choices. Henry Louis Gates Jr. had his done to trace his ancestry. Glenn Close reportedly did it to better understand mental illness in her family, and I can’t guess why Ozzy Osbourne did it.

Ron Crystal, chairman of genetic medicine at Weill Cornell Medical College, had his genome sequenced to provide a control in a project to sequence the genomes of the people of Qatar. He discovered a mutation that explained his heavy bleeding following an injury from rappelling off a frozen waterfall a few years ago. He also discovered Viking roots, a recessive disease of children, and confirmed his baldness. But he voiced fears: his family learning things they didn’t want to know, even someone using his DNA sequence to frame him for a crime or to clone him.

Dr. Crystal isn’t the only one to cite potential repercussions of knowing one’s genome sequence. Said Seong-Jin Kim, the first Korean to have his genome sequenced, and that of his wife and two daughters. “Genetic disease in Korea is thought to disgrace families, and so it’s difficult to convince families with diseases to be sequenced.” A bad result could be regarded as a curse. But he was interested in using sequencing to better understand gastric cancer, which is the most common form in Asia. “Did it change attitudes? After we released our sequence, the number of sequencing companies increased.”

Why I Don’t Want to Know

I don’t want to know my genome sequence because of a fear that someone will clone me, but because the state of the science provides both too much and too little information.

On the TMI front, a genome sequence is a mega incidentaloma, an avalanche of information I don’t want. A panel discussion on the value of genome/exome sequencing at the international congress last year was telling.

Opinions ranged from moderator Han G. Brunner, of University Hospital St. Radboud in Nijmegen, the Netherlands, who asserted that “genome sequencing will yield an excess of information that is useless, uninterpretable, and possibly damaging to the patient” to Radoje Drmanac, co-founder and CSO of Complete Genomics, who claimed “We should have our genomes sequenced as early as possible. In my mind, this is not a question.” (Disclosure: Just before the panel discussion, I ate mozzarella sticks from Complete Genomics when I wandered into a cocktail party whilst hunting and gathering. I wonder if they got my DNA from the napkin.)

At the top of the list of diseases I don’t want to know about are those of the brain, Woody Allen’s second favorite organ. If I can’t prevent or delay them, why spend years worrying?

On the too little information front, we need to know more than a string of DNA letters or a list of gene variants. We need to know how our genes interact. It’s like reading a novel and considering each word in a vacuum, compared to understanding the unfolding story.

Learning our genetic story will require deciphering all possible gene interactions. Until then, I might learn about a disease-causing mutation, but not another that counters it, and then have to live with the knowledge. Computers and researchers will need to dissect and compare many thousands of sequenced human genomes to deduce the gene interactions.

All the needed analysis is costly. Bruce Korf, MD, PhD, director of the Heflin Center for Human Genetics at the University of Alabama at Birmingham has said, “We are close to having a $1,000 genome, but this may be accompanied by a $1 million interpretation.” And when Stephen Quake, a Stanford University engineer and co-inventor of a DNA sequencing device, laid his genetic self bare in the pages of The Lancet in 2010, interpretation required 32 physicians.

Like the others mentioned, Dr. Quake found the drug information the most valuable. He leads a very healthy lifestyle, but has gene variants that raise risk of cardiovascular disease. His genome revealed that a statin drug could save his life, the bloodthinner Plavix won’t work, nor would the diabetes drug metformin. But could carefully-chosen panels of single-gene pharmacogenetic tests provide the same information, based on the age-old tool of genetic counselors, asking good questions to build a useful family history?

Convince Me

Next week I’ll be at the American Society of Human Genetics annual meeting, attending workshops on exome/genome sequencing and hunting for more mozzarella sticks. And I’ll see if anyone can convince me to have my genome done.

Perhaps I’ll do it, eventually, as part of the Personal Genomes Project, for the greater good, but elect not to know the results. After all, I already know the obvious, like Craig Venter knows he’s bald and has blue eyes.

An osteoarthritis mutation manifested itself as an inability to play an F chord at age 33. A p53 mutation and then another that bloomed in response to years of orthodontia X-rays gave me thyroid cancer a few years after I gave up the guitar. And I don’t need a genetic test to know I didn’t inherit my father and grandfather’s psychotic depression.

Ron Crystal, even though he’s among the sequenced, has the right idea: don’t smoke, exercise, eat a healthy diet, and don’t worry about DNA sequences.

That’s good enough for me – at least for now.