When Mutation Counters Infection: From Sickle Cell to Ebola

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Brass_scales_with_flat_trays_balanced While pharmaceutical companies focus on drug discovery for Ebola virus disease, a powerful clue is coming from a rare “Jewish genetic disease” that destroys the brain. People with Niemann-Pick C1 disease can’t get Ebola, adding to the list of disease pairs that arise from a fascinating form of natural selection.

Balanced polymorphism, aka heterozygote advantage, is a terrific illustration of ongoing evolution. And it pits the human body against all sorts of invaders – prions, viruses, bacteria, protozoa, and fungi.

sickleThe textbook example of balanced polymorphism is the protection that being a carrier for sickle cell disease confers against malaria, published in 1954.

The blood of a person with full-blown sickle cell disease is too thick to accommodate the malaria parasite, and the red blood cells too bent to house them. A carrier has enough sickled cells to quell the parasite, but not enough to block circulation and cause the pain and anemia of the inherited disease. Alpha thalassemia, hemoglobin C and G6PD deficiency are other single-gene diseases that affect red blood cells in ways that lower risk of malaria.

The link between genetic disease and Ebola virus disease dates from 2011, when Thijn Brummelkamp, PhD and co-workers, at the Whitehead Institute for Biomedical Research, reported in Nature that cells of people with the rare single-gene Niemann-Pick C1 disease keep out Ebola.

Ebola virus particles (NHGRI)

Ebola virus particles (NHGRI)

The gene that is mutant in Niemann-Pick C1 disease encodes a transporter protein that normally binds cholesterol — and it’s also the receptor for Ebola virus. Carriers of the inherited disease, with half the normal number of transporters, might have some protection against the viral disease. (A recent article in the Wall Street Journal discusses the carrier situation, but doesn’t cite the standard sickle cell example – commenters did.)

The tango between us and our pathogens is more complex than examples within ourselves of conditions canceling each other out. The poor clotting of hemophilia shields against dangerous blood clotting; the extremely low serum cholesterol level of Smith-Lemli-Opitz syndrome, which causes intellectual disability and a host of strange birth defects, counters cardiovascular disease. These don’t involve a second party.

Examples of balanced polymorphism are like mystery stories, beginning with the clue of why a seemingly harmful recessive genetic disease hangs around. New mutation is one answer, but more common is the protection that the heterozygous state offers. Here are some of the stories.

CFTR ion channel, open and blocked

CFTR ion channel, open and blocked

CYSTIC FIBROSIS AND DIARRHEAL DISEASE
In cholera a bacterial toxin opens chloride channels in small intestine cells, and salt and water pour out in a torrent of diarrhea. The misfolded CFTR protein behind many cases of cystic fibrosis, which is a chloride channel, does the opposite, failing to reach the cell surface and trapping salt and water inside cells, drying secretions. A person with misfolded CFTR won’t get cholera, while a CF carrier, with enough working chloride channels to breathe okay, but not enough to welcome toxin-spewing pathogens, suffers neither disease.

The cholera epidemics that have swept through human history favored individuals who carry or have CF. But geography and history suggest that the story goes farther back, because CF arose in western Europe and cholera in Africa. Perhaps a different diarrheal infection, typhoid fever, triggered the initial favoring of mutant CF alleles that perhaps arose from mutation.

The bacterium behind typhoid fever, Salmonella typhi, enters small intestine cells through CFTR channels. In people with severe CF the channels are too mangled to reach the cell surface. Bacteria can’t enter. Cells of CF carriers only let in a few bacteria. Protection against infections that produce the runs may therefore have kept CF around.

The Guthrie test began the era of newborn screening -- half a century ago.

The Guthrie test began the era of newborn screening — half a century ago.

PKU AND A FUNGAL TOXIN
Testing for phenylketonuria – PKU – ushered in the era of newborn screening with the Guthrie test, invented in 1957 and one of my favorite genetics stories. It tests blood from a newborn’s heel so that dietary intervention can prevent the profound intellectual disability of the disease.

PKU is a classic “inborn error of metabolism.” A missing enzyme causes the amino acid phenylalanine to build up, devastating the nervous system. Carriers have excess phenylalanine — not enough to damage their brains, but enough to counter the effects of a fungal poison called ochratoxin A that causes spontaneous abortion.

In 1986, PKU guru L. I. Woolf published a brief letter in the American Journal of Human Genetics explaining how a fungus could maintain a rare inherited disease of humans. Ochratoxin A is a derivative of phenylalanine that binds to the enzyme that places phenylalanine into proteins as they form. With one of the 20 amino acid types blocked from joining proteins, the embryo quickly stops developing – unless the pregnant woman’s body makes excess phenylalanine, which counters the effects of the toxin. That happens in PKU carriers. Thanks to newborn screening PKU is caught early enough today to be treated, but ochratoxin causes a kidney disease in Eastern Europe called Balkan endemic nephropathy.

Ochratoxin on moldy grain altered genetic history

Ochratoxin A on moldy grain altered genetic history

It isn’t coincidence that PKU is most prevalent in Ireland and Scotland. In the dampness of those lands, the Aspergillis and Penicillium fungi that produce the toxin grow on grains, which people were forced to eat during times of famine. Because pregnant PKU carriers were more likely to have healthy children than non-carriers, who suffered miscarriage due to the fungal toxin, the PKU mutation increased in the population. That’s natural selection. Evolution. It happens.

Mad_cowPRIONS AND CANNIBALISM
Prions are proteins that can fold into infectious forms that cause transmissible spongiform encephalopathies. The most familiar are those that come from eating the proteins, such as mad cow disease. The classic example is kuru, which caused brain degeneration among the Foré people in Papua New Guinea in women and children eating the brains of honored dead relatives. The Australian government halted the practice in the mid-1950s.

But we also make our own prion protein – the gene that encodes it is on chromosome 20. Normal prion protein is abundant in the brain, and likely plays a role in synaptic plasticity in early development. This story is more complicated than those of Ebola, CF, and PKU, because the same protein comes from inside and outside the body, and it is the protein, in abnormal form, that is the pathogen. Prion protein is a shape-shifter, able to assume the infectious form right inside ourselves.

Back to New Guinea. Some of the female Foré brain eaters are still alive, and an investigation of the prion protein gene among 30 of them revealed that 23 are heterozygotes for the prion protein gene on chromosome 20, meaning that they have two slightly different versions of the gene. Population genetics statistics predicted only 15 of them should have been so.

The carriers have the amino acid valine at amino acid position 129 on one chromosome 20 and a methionine on the other. And this somehow prevents the infectious misfolding. Plus, everyone in the UK who developed mad cow disease had only methionine at position 129.

And so cannibalism may have fueled the overrepresentation of carriers of the infectious form of prion protein. Protected, the carriers slowly accumulated in the population.

Brass_scales_with_flat_trays_balancedWHY IT MATTERS
For many years, the central dogma reigned, the idea that DNA encodes RNA which encodes protein. Our genomes were thought to encode protein, and do nothing else, although people hypothesized vague “controls” amongst our regular genes.

Then introns (non-protein-encoding parts of genes) came along in 1977 and turned our simplistic view on its head. Most of us in genetics never thought the “rest” of the genome was “junk.” If I remember correctly, that was an unfortunate utterance from Francis Crick that the media ran with, and it stuck.

Today we know that the human genome comes complete with all manner of controls. Some are indeed embedded in the non-protein encoding sequences that make up most of the genome. Other controls are in short RNAs that fold themselves up in ways that glom onto and turn off certain genes, and in the numbers of short repeated sequences that pepper genomes. The human genome is a little like a fancy TV with a zillion remotes that somehow knows how to control itself without the user knowing how it all works.

Balanced polymorphism is yet another form of genetic information. It reveals a story, a subtext to our genes written by our own actions throughout history, and the scourges that felled some of our ancestors, enabling individuals carrying particular mutations to survive to reproduce, perpetuating those mutations.

Making sense of the intriguing pairings of genetic and infectious diseases can reveal ways to fight those infections. Let’s hope this approach works for Ebola virus disease.

(Parts of this post are based on passages in my textbook, Human Genetics: Concepts and Applications (Amazon doesn’t yet list the new, 11th, edition). For each edition I struggle to limit myself to 2 examples of balanced polymorphism. It is difficult to choose!)

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Eman Reports From Ebola Ground Zero

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The arrow shows Emmanuel Gokpolu at an awareness meeting in Monrovia.

The arrow shows Emmanuel Gokpolu at an awareness meeting in Monrovia.

The last post here at DNA Science continued Emmanuel Gokpolu’s reporting from Ebola ground zero in Monrovia, and surrounding communities. The Ebola outbreak interrupted Eman’s medical education, so now he is teaching his people about strategies to minimize risk of infection. Eman and I began a very special friendship when he contacted me when using my human genetics textbook in college, years ago.

This post of Eman’s emails picks up in early October. That was when Ebola jumped overnight from a topic rarely reported in the U.S., to major news once it had, perhaps inevitably, arrived here. My questions are in italics.

OCTOBER 3
Eman, what is your reaction to the belated response among many in the US to Ebola’s spread?

I read some comments on CNN about the outbreak in Africa, and it was disgusting. I didn’t believe humans could be so unsympathetic. I earmarked a few:

“Africans are uncivilized, so they always get infected by some sh..t.”

“Stop those barbarians from coming to America immediately.”

“Why is our government spending our taxes on those c _ nts?” and so forth.

I’m not happy that it’s in the US, but I’m sure it will change some perceptions.

OCTOBER 12
In the US infected patients are isolated and given supportive care immediately, experimental drugs when possible. What is the situation in Liberia?

A man posts a list of rules of how to prevent spread of Ebola.

A man posts a list of rules of how to prevent spread of Ebola.

Considering our traditional practices of bathing the dead at home, monkey and bushmeat as delicacies, our weak healthcare system and day-to-day interactions, I always thought this virus could spread at an incredible rate. Not enough has been done to curb the spread. Hundreds of homes do not even have buckets for washing hands. In fact, the health systems have not been reinforced to deal with seasonal diseases like diarrhea and cholera and this has led to many deaths.

Our own governments are at fault too! Imagine, our government set up an Ebola response team without a medical practitioner on board; not even a medical student. Isn’t that absurd?! Others have made it a money-eating (corruption) show; $100,000 USD meant for tracking cases gets missing and even donated buckets get sold. America alone is not to blame.

OCTOBER 18
How are you using your medical and communication skills?

I have been busy with Ebola workshops this week. I chair a youth organization called “Determined Youth for Progress” that has been working a lot sensitizing communities about Ebola prevention. We luckily got a grant to carry out more sensitizing and buy more buckets and chlorine (bleach) for distribution.

We will also be doing virus contact tracing (people will be tasked with identifying people who may have come into contact with sufferers). We will also be sending out short text messages every morning to tell family and friends about the virus:

“Dear friend,
You have received this text because I’m well. I’m well because I follow the rules. Please do the same: wash your hands regularly, do not touch sick people rather, report them to health authorities by calling 4455.”

We also want to look into tutoring kids at their homes because schools are closed, and creating awareness messages through short poems.

Getting funding is always difficult, but our volunteers have been great! Tomorrow, we carry out a big community clean-up. We’re on Facebook: Determined Youth for Progress (One post: “Ebola is everybody’s business. Let’s spread the message.”)

3 ebolaOCTOBER 21
Should exposed individuals in the U.S. use public transportation? Subways? Cruise ships? Planes? Bicycles?

People should know how dangerous the virus is. Allowing infected persons to be in crowded places, on cruise ships, or in planes poses greater risk to others.

I believe we can win the fight against Ebola from the level of community involvement. Everyone must cooperate in some way to win this fight, especially in listening to the experts.

NOVEMBER 2

Is the epidemic abating?
There are signs that progress is being made in battling the epidemic, but we have been telling people to stick with the rules, to avoid newer cases. For example, I was in Bomi County yesterday and found out that there were seven cases handled for a week with nothing new coming. The number of cases per week is gradually reducing and we remain hopeful that we can turn the tide in a few months.

The New York Times recently reported that fewer Ebola cases are in hospitals. What does this mean?

Most hospitals are closed. This has made the situation even more difficult. There are cases where people died because of no access to hospitals. This in part is due to the shortage of PPEs (Personal Protective Equipment). Health workers are afraid to treat even the simplest of conditions due to this. All cases are being handled by the ETU (Ebola Treatment Units).

4How is your community work progressing?
I have been busy with the community organization I chair (Determined Youth for Progress), organizing Ebola awareness workshops, sensitizing rural communities on the prevention and spread of the virus, and working with bigger organizations like the Gbowee Peace Foundation Africa to get grant support for our projects. It’s been really challenging, but we are making progress. We have been able to reach a lot of rural communities and the reports we get from there show that we made an impact.

Quarantine is a highly contentious issue in the U.S. Do you think it is necessary?

It’s sad that people returning from Africa think they are being stigmatized by being quarantined. I think the intention is to avoid another outbreak. It’s a little sticky for me to discuss because someone might say Africans don’t know what civil liberty really is because most often, our leaders seize them. lol.

If it is in any way stopping people from volunteering to curb the outbreak, they should consider doing the quarantine in the country where the person worked before coming to the U.S. That is, if Mr. X worked in Guinea and decided to go back, he should be quarantined in Guinea before going back to the US. Health workers must also understand that it is for the safety of their family and friends that they have been subjected to such methods. As harsh as it might seem, if nothing of such is done, they might pose a threat to others.

5 lecture againWhat have you learned from the current Ebola situation?
Basically, the epidemic has exposed our weak healthcare systems and taught us how dangerous it is to underestimate disease outbreaks.

Ebola has been much more devastating compared to other outbreaks like cholera, malaria and typhoid in such a short period of time. It has broken families and held countries under siege. The world needs to take this as an example and be on the alert.

Thanks so much, Eman. Be well.

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Eman’s Emails from Liberia: Through September

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Emmanuel Gokpolu and son Larry, from Liberia.

Eman Gokpolu and son Larry, from Liberia.

Emmanuel Gokpolu, who lives in Liberia, calls me Mom, although he has a wonderful real mother. In Africa, family isn’t only about DNA.

Eman contacted me in 2007, after using my human genetics textbook in college. My husband Larry and I had been putting him through medical school in Monrovia — until Ebola happened. Now the funds go for gloves, long sleeve shirts, detergents, food and medicine, to keep Eman and his family, including his almost-one-year-old son, little Larry, safe.

This week Eman asked me to share his emails, which began arriving before many people here had heard of Ebola, or cared much about it if they had. Then the disease seemed, and was, half a world away.

The world is a small place.

JULY 28

“Hi Mom and Dad, hope all is well with you. It’s not that good here. The Ebola virus has everyone living in fear. One of our professors, a doctor, died from the virus yesterday. Imagine? So much fear. Please keep us in your meditations. Your son

AUGUST 6
These have been some of the worst days we have witnessed.

Public facilities and gatherings have been discouraged, schools have been closed, some marketplaces and even clinics closed just to curb the incursion of this virus. Worst of all, some heartless people have been poisoning pumps and wells.

Medical students have only been used to sensitize communities on the outbreak and prevention. There was not much we could do due to lack of medical supplies. This virus mostly affects health workers and caregivers.

We could have done much better to stop this virus from killing so many people if not for denial that the virus exists. You won’t believe this: in the midst of all these deaths, people still doubt that this virus exists! In fact, people are blaming the West, while others say it’s government propaganda. Others are even claiming that health workers are deliberately killing people to extract body organs.

Family members and loved ones do not easily accept when their relatives are diagnosed. People consider the virus more a stigma than a sickness.

As a medical student Eman can't treat people, so he is a  "sensitizer," educating people on how to avoid infection.

As a medical student Eman can’t treat people, so he is a “sensitizer,” educating people on how to avoid infection.

I’ve been working with a local organization that I chair to sensitize people in my community. It’s been a huge job with little material to work with but overall, it’s been great.

The family is fine and we are all keeping safe. It’s only Larry that has not been doing that well. He got sick, been vomiting, red eyes and high temperature. We got so afraid and had to call the Ebola response unit because these are all signs and symptoms of the virus. We are relieved that he’s negative and is being treated.

Hugs, Eman

AUGUST 7

Ebola is on the rise day by day. The death toll keeps mounting. President Sirleaf has declared a 90-day state of emergency.

Fear of the virus has prompted many hospital workers to abandon clinics – many are now shut. Because of this, many diseases like typhoid and malaria that are prevalent during the rainy season are untreated and there could be preventable deaths. We are living in fear.

Public transport vehicles have been ordered to reduce the number of passengers. Also, physical contact sports have suspended all practices and games, but more awareness needs to be done. During my organization’s community awareness campaigns, we noticed that some people hardly even know of the virus. Unhealthy practices that might spread the virus are still done.

Basically, the message here is to wash our hands as often as possible. Go to public places and you will see buckets with chlorinated water to wash your hands before entering.

Mom, this situation is very serious and the outside world might not know it.

(Wikimedia Commons)

(Wikimedia Commons)

AUGUST 10 (I tried to interest editors in Eman’s story, but got resounding rejection. This is his response to news of my failure.)

Tell them that our hospitals have closed due to their inability to tackle this virus, that even our medical doctors and nurses have fallen to this virus, and that our schools are closed and we live under a state of emergency, meaning our rights are suspended. Above all, tell them that we lack the experts to conquer this virus. Make them understand that this is no fiction or fairy tale. This is reality and people are dying and desperately need help.

(I quoted a short Eman email here mid-August, because media reports were so oversimplified, mixing up RNA and DNA, genome sequences and genetic code, that I felt I had to spell out the science, in “How Ebola Kills.”)

AUGUST 11
Two of my ex high school mates have died of the Ebola virus as have nurses from St. Joseph Catholic hospital. This hospital has been hit the hardest with more than 6 health workers dead from the virus and 10 more positive. It just doesn’t get better. More needs to be done, I keep saying. Our health system is just too weak for this outbreak. It was too weak before the outbreak.

The state of emergency has made things tough. The prices of food have skyrocketed and if something is not done, it might be another emergency! The health authorities have put into place measures to curb the spread of the virus but the cases keep coming. Among these measures are:

• Every business has chlorinated water in buckets outside for washing hands for those entering. This includes banks, churches etc.
• Schools are closed indefinitely
• Taxis are only allowed three persons in the back.
• Checkpoints have been set up to control the movement of people.

Sadly, there has been no decrease in the number of cases. My family has decided to send the younger kids up country to our mom where they will be monitored. Also, due to the increase in food prices, we have to reduce the number of people. Food is in short supply. We have heard that health experts are coming from the US and Nigeria, but none yet.

Sonn and grandson (4)AUGUST 12

I am using a phone to email you. Public gatherings are not encouraged, so I don’t see an Internet cafe as safe.

I just lost my elementary health science teacher to Ebola. It hurts so much. We can’t give up though.

Today, another Ebola case made health workers abandon an entire clinic. Two patients in critical condition were taken to the Goodwill clinic. Upon finding out they had Ebola, the workers escaped. This shows how unequipped and unprepared our health workers are to tackle this outbreak. Also, families knowingly keep love ones in their homes attempting to treat them, infecting themselves.

A friend from my community went to Guinea to visit his family before the outbreak. His father got infected and died and his mother and two sisters are infected too and seriously ill. He doesn’t know if he’s infected. He called today and broke down in tears. This is so scary!

The ZMapp is here and will be given to two doctors. Other health workers’ families have to sign that they acknowledge that it is a trial drug and might have unknown side effects which, if it occurs, will not hold the company or government responsible.

eman and flagsFrom a personal perspective, I have a few doubts. Why didn’t the US government present this trial drug until two of its citizens got infected? Why hasn’t anyone tried the serums of those who survived the virus? WHO says there are only 12 doses. What happens after those 12? Lots of questions in my mind.

Seeing loved ones die with no options to save them is just so ridiculous! I wish I could do something to help. Just staying safe at the moment. Survival is cardinal right now.

AUGUST 17

I know we have got you worried but I must tell you that it is more than you see on TV. Everyone is so, so afraid! From the way this situation has been handled, I fear for the worst. Would you imagine that there is a single burial team to dispose of Ebola-related dead bodies? As a result, people are exposed day in, day out. In fact, there are only a few isolation centers, making them overcrowded. This government is joking with our lives.

With the millions coming in as aid, we should be somewhere but the situation is becoming even worse. If I had a voice, I would recommend that aid be sent through NGOs instead of the government.

An Ebola quarantine site was attacked and looted, and most of the patients have escaped. This is going to put more fear into the population. All of this is happening because people are denying the virus. Keep me in your meditations.

Ebola_virionsAUGUST 18
Need help!

(Eman developed fever and pain. Relieved that it was “just” hookworms and malaria, he was hospitalized for a week.)

AUGUST 25
There’s some not very good news. The virus has struck on the street where I live; the physician from a clinic in my area. That makes it very, very scary. In spite of that, I applied to volunteer with MSF. Still awaiting their call. I only fear for the community because this is going to be my daily routine when I’m a doctor. We all have to help now, but maybe in a safe way.

SEPTEMBER 15
Mom, You have to pray for us harder. Things are getting worse by the day; more than 1300 deaths and thousands more infected. WHO projects even more terrible times. We just don’t know what to do.

Supplies might not take us through the 90 days as prices have gone the highest. Larry is running out of food, and his medications too. We all have to take preventive malaria pills in case we encounter mosquitoes. Even worse, all quarantines are over capacity and new patients are told to go home. Quarantines are out of food and beds. It’s a nightmare!

SEPTEMBER 19
We just can’t wait to see those troops on the ground. They have to be fast before we all perish!

little LarryThe economy is crashing. Importers have stopped importing basic commodities. Milk and medicines for babies are so expensive. Basic goods prices have doubled or tripled, especially drugs. The syrups for Larry, once opened, cannot be used more than a week because we do not have the means to store them for long, so we have to spend huge sums buying the same drugs. His milk was $22; it’s now $35. If something is not done quickly, there is sure going to be a food crisis.

SEPTEMBER 24

School is closed indefinitely but I have to keep reading and researching. I have been following the Ebola virus and vaccine trial closely. I’ve read a lot of articles on the virus and mutations it is undergoing. I hope it doesn’t become airborne; just one of many possibilities. Keeping it safe. Hugs. Eman”

SEPTEMBER 30 (me again)

Ebola arrived in the US with Thomas Eric Duncan, visiting from Liberia. He showed up at Texas Presbyterian Hospital in Dallas, where some of the medical staff appeared not to know how to keep viruses out of one’s body.

ebola deathsAs the U.S. finally began to wake up and my inbox overflow with reports on Ebola, I began emailing Eman everything I received, even the embargoed news releases and papers available only to journalists. His need to know all he could was insatiable, and the ignorance here has stunned both of us. I continue to find scientific errors both in hurried reports to clinicians as well as in the top magazines. (Vanity Fair’s “Hell in the Hot Zone,” by Jeffrey E. Stern in September, is a notable exception — it’s terrific.)

STEM education, anyone?

Emmanuel Gokpolu, medical student and community organizer at the epicenter of the Ebola epidemic, who has lived with cholera and cerebral malaria and amoebiasis, can tell westerners a thing or two about this virus.

Eman’s story will continue next week, picking up at the start of October — a turning point here, but just another horrific day in Liberia.

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Another Reason Freezing Employees’ Eggs is a Terrible Idea

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Graafian_Follicle,_Human_Ovary_(3595010317)Facebook and Apple’s decision to offer female employees a $20,000 benefit to freeze their eggs indicates a stunning disregard for the complexities of reproductive biology.

The Center for Genetics and Society issued a news release that listed societal, technological, and biological concerns: the danger of freezing eggs to both the woman and the individual that may one day arise from that egg, and adverse effects that include infertility, cancer, and even death. I’m recovering now from surgery to remove an 18-pound ovarian cyst, so I’m especially sensitive to tinkering with ovaries in any way.

Marcy Darnovsky, PhD, executive director of the Center for Genetics and Society, summed up the bigger picture beautifully, which deals with intent, not biology: “Why are Facebook and Apple endorsing a technique that encourages their employees to put their health at risk? Paying for egg freezing is being presented as a benefit for women, but it may be that discouraging women from balancing work and family is really a benefit to the companies.”

Trisomy 18

Trisomy 18

I’d like to add another layer to the discussion: we just don’t know that much about WHY older eggs tend to end up with a wrong number of chromosomes. A terrific recent research report in the American Journal of Human Genetics addresses exactly this issue: how do older eggs mis-sort their chromosomes? I wonder if the egg-freezing advocates at Facebook and Apple read it.

OLD EGGS
I always felt weird, as a genetic counselor, telling a woman older than 35 that she was of “advanced maternal age.” But back in the days of amnio, before non-invasive prenatal testing became available circa 2012, we did indeed consider these women high-risk.

The maternal age effect for trisomy 21 Down syndrome

The maternal age effect for trisomy 21 Down syndrome

The “maternal age effect” is real: ovulating eggs with extra or missing chromosomes (aneuploidy) does happen more frequently as a woman ages. The risk of a woman carrying a trisomic fetus is 2 to 3% if she’s in her twenties, but exceeds 30% if she’s in her forties.

But the advice of who should have amnio was more technological than biological: At age 35, the risk of aneuploidy matched the risk of amnio being followed by miscarriage. Younger than that, in the absence of a family history of aneuploidy, the risk of the procedure outweighs the risk of the problem. Although amnio risks fell precipitously over the years, for some reason that age of 35 remained a standard.

In my textbooks and classes, I’d flippantly call the phenomenon the “rotten egg theory,” but it’s technically termed the “production-line hypothesis,” an idea first hatched in 1968 by Alan Henderson and Robert Edwards, who pioneered in vitro fertilization. The hypothesis states that the oocytes that have been hanging around in the ovary the longest accumulate the most errors.

As my cyst, named Waldo, grew this past summer, I had plenty of opportunities to ponder the mysterious biology of the human ovary. The male of the species, not surprisingly, is simpler: he begins manufacturing sperm at puberty and continues to do so throughout life, without a monthly reminder of the process. A female starts making eggs when she herself is a 5-month fetus. That means a pregnant woman holds the future eggs that could become her granddaughters.

AN EGG’S VIEW OF FERTILIZATION
Just before birth, a female has a million or so eggs stopped at a stage of meiosis (the form of cell division that makes gametes) when the two chromosomes of each pair tend to wrap around each other and exchange parts, a little like two people hugging and trading hats and belts. Apparently, this crossing over is very important for the ability of each chromosome pair to disperse into separate cells as division continues.

700px-Order_of_changes_in_ovary.svgAn ovary housing developing eggs does indeed look like a production line, with baby eggs enlarging and developing as they reach the periphery. An ovary is a little like a bag of microwave popcorn.

By puberty, about 400,000 eggies remain in a woman’s two ovaries. Each month, a few eggs awaken and take a few more steps in meiosis, halting at the very brink of chromosome pair separation, like 23 pairs of aligned square dancers. At the mid-cycle hormone surge, the biggest egg pops out.

Ovulation! The lucky female cell drops into the waving arms of a waiting Fallopian tube and moves towards the uterus.

If a blast of sperm arrives and one dude penetrates the egg’s membrane, the female cell, finally, finishes up meiosis. The egg then concentrates most of itself – cytoplasm, organelles, nutrients — into one daughter cell, along with exactly one copy of each chromosome type. The puny other cell, a polar body, exits the body, its function to siphon off the second chromosome set while concentrating supplies for the fertilized egg. Unless probed in a genetic test, as a previous post described, the polar body is flushed out.

If the egg escapes a sperm’s penetration, it too exits as the menstrual flow, meiosis unfinished. The female cycle may make us crampy and crabby, but biologically speaking, it is most elegant and not at all wasteful, only completing meiosis when it makes sense to do so.

Meiosis_crossoverUNDERSTANDING OVARIES
In the study reported in July, Terry Hassold, PhD, from Washington State University and colleagues took a closer look at events in the human fetal ovary. And they discovered that one assumption of the production line hypothesis, that the oldest eggs cross over less and that’s why they may drop or add a chromosome, simply isn’t true.

The researchers used immunofluorescence microscopy to label proteins that mark crossovers, examining 8,518 cells from 191 samples from ovaries removed at 14 to 26 weeks of gestation. The material came from  elective abortions.

Results were surprising, considering how entrenched the production line idea was.

The extent of crossing over varied, not greatly, between ovaries and even within ovaries. More importantly, the researchers found no correlation between age of either the egg or the woman and the extent of crossing over.

“If the production-line hypothesis were true, you’d expect lots of abnormal cells and you would expect them all to be happening late. We do see a pretty high incidence of abnormal cells, but they’re just as likely to be happening early as late,” first author and doctoral candidate Ross Rowsey told WSU News. The effect might not have shown up in earlier studies that inferred crossing over from cells taken after birth because that approach didn’t look at what was going on in fetal ovaries.

The beauty of scientific inquiry, as I pointed out last week, is that when one hypothesis is disproven, investigators follow another. And in the case of the misjudged eggs, another possible explanation is that the reason for an extra or missing chromosome is ebbing levels with age of a protein called cohesin that, as the spellcheck-confounding name implies, glues chromosomes together, facilitating the exchanging of parts. Experiments from other species are now pursuing the cohesin hypothesis.

The bigger picture is that Facebook and Apple are attempting to pay female employees to undergo a very risky procedure with not-well-understood consequences, when we don’t even know the mechanism behind the maternal age effect. Hasn’t the current Ebola crisis taught us not to ignore biology?

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SCID-X1 Gene Therapy, Take 2

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Like the mythical Phoenix, gene therapy for SCID-X1 has risen from its ashes.

Like the mythical Phoenix, gene therapy for SCID-X1 has risen from its ashes.

Beneath all the bad news about viruses this week lies a good virus: the one that underlies gene therapy for X-linked severe combined immunodeficiency (SCID-X1).

Altered viruses are the vehicles that transfer healthy human genes into the cells of people in whom the genes aren’t working, providing a slew of new “forever fixes.” Nearly 100 gene transfer protocols are now in late-stage clinical trials.

The long-anticipated research report in the New England Journal of Medicine sets gene therapy back on track, after a previous clinical trial treated the disease but triggered leukemia. The ongoing saga is also a terrific example of how scientific inquiry catalyzes medical progress.

BUBBLE BOY DISEASE

SCID-X1 became widely known as “bubble boy disease” in 1976, when John Travolta played David Vetter in the film “The Boy In The Plastic Bubble.” It was a year after he rocketed to fame as sweathog Vinnie Barbarino on the TV program “Welcome Back Kotter.”

David Vetter lived in a spacesuit when outside his bubble. (NASA)

David Vetter lived in a spacesuit when outside his bubble. (NASA)

David Vetter was born at a hospital in Texas in 1971 and was immediately placed into a habitrail-like apparatus. His parents knew a son would have a 50:50 chance of inheriting the condition because they’d already lost a newborn to it.

For years, David wanted out of the bubble. The doctors let that happen when he was 13, to receive his sister’s bone marrow in an attempt to cure his immune deficiency. But David succumbed within weeks to lymphoma seeded by the Epstein-Barr virus in her donated cells.

By 1993, researchers better understood the disease. SCID-X1 impairs the gamma chain of the interleukin-2 receptor (IL2RG), which triggers an immune system shut-down: first T cells and natural killer cells, then B cells, so that the body makes neither cytokines nor antibodies.

“Because IL2RG is needed for many cytokine receptors and immune cell development, kids die of viral infections in a year,” said David Williams, MD, chief of the division of hematology/oncology and director of translational research, Boston Children’s Hospital, at the American Society of Gene and Cell Therapy annual meeting last May where he discussed interim trial results.

EARLY WORK

With the mechanism so well understood and a clear route through the bloodstream, gene therapy for SCID-X1 seemed obvious, especially because it had already been underway for another form of SCID, ADA deficiency, since 1990. Gene therapy for SCID-X1 could help children who do not have a bone marrow donor.

A Trojan horse is a metaphor for gene therapy. An engineered viral vector  is the horse.

A Trojan horse is a metaphor for gene therapy. An engineered viral vector is the horse.

Alain Fischer, MD, PhD, of the Necker Hospital for Sick Children in Paris and colleagues conducted mouse experiments in 1994, applied to begin clinical trials by 1997, and by 1999, the first boy, an 8-month-old, received his own bone marrow cells carrying healthy SCID-X1 genes, delivered in a retroviral vector. The team waited until the April 18, 2002, New England Journal of Medicine to publish results on the first 5 children treated, to allow enough time to track building immunity.

In the months after the paper came out, one of the boys developed a swollen liver and spleen, and his white blood cell count began to climb. By summer’s end, blood tests clearly indicated leukemia.

It was exquisitely bad timing.

The gene therapy community was still reeling from the death of 18-year-old Jesse Gelsinger in 1999, from gene therapy for a very different disorder. Although 18 of the 20 boys given the gene therapy for SCID-X1 established immunity, 5 developed leukemia, and one would ultimately die from it.

FINDING THE CULPRIT

In the fall of 2002, when only one boy had leukemia, it seemed a family history of cancer or recent chickenpox infection might have been at fault. But then a second boy developed leukemia. By October 2003, the research team nailed the culprit: the vector had integrated into an oncogene called LMO2.

Retroviruses normally home to very active genes, oncogenes among them. But the vector used in the first-attempt SCID-X1 gene therapy included DNA sequences that enhanced the oncogene’s activity, revving up cell division.

And so an international team (including besides Boston Children’s and the Necker Hospital, also Great Ormond Street Hospital, Cincinnati Children’s Hospital Medical Center and UCLA Mattel Children’s Hospital) began again, in what several researchers at the gene therapy meeting in May called a “do-over.”

In the second go-round, the viral controls were replaced with DNA sequences strong enough to make enough of the errant IL2RG gene, but less likely, if able at all, to ramp up oncogene action. The new breed of viral vectors now used in gene therapy are comfortingly termed “self-inactivating,” or SIN.

THE SECOND TRY AND BEYOND
This time, so far, the gene therapy for SCID-X1 is effective and safe. Seven of 9 boys treated with the new vector have regained immunity, without developing leukemia. Times since treatment range from 16 to 43 months, with a median of 33 months. But because leukemia took up to 5 ½ years to show up in the first study, the current group of boys will be followed for 15 years.

For this second trial, the researchers tracked where the vectors inserted into the boys’ genomes. Compared to the trajectories of the first-generation vectors, the retooled ones seemed to avoid 21 regions that house cancer-associated genes.

Gene therapy for metachromatic leukodystrophy uses lentivirus to the brain. It works too. (Gunter Pusch)

Gene therapy for metachromatic leukodystrophy uses lentivirus to the brain. It works too. (Gunter Pusch)

As work continues on the retroviral approach to treating SCID-X1, a third-generation vector is in the works too. A team at NIH is using SIN lentivirus (disabled and engineered HIV) that doesn’t home to the LMO2 oncogene. It’s being tested on young adults whose transplants have lost effectiveness, with promising results so far.

Success for the ADA deficiency form of SCID is on track too. “More than 50 patients have been treated by gene therapy between trials in Italy, the UK and our trials in the US in the past decade and a half. None have had complications from the gene transfer and most have successful immune reconstitution,” says Donald Kohn, MD, from UCLA and a co-author on this week’s NEJM.

For ADA-SCID, gene therapy “is becoming the treatment of choice for patients lacking a matched sibling donor, surpassing the alternatives of a matched unrelated donor or a half-matched parent donor, and far less costly than ongoing ADA enzyme replacement therapy,” Dr. Kohn adds. Transplants also bring the risk of tissue rejection and graft-versus-host disease.

PROGRESS, NOT PROOF

The ongoing SCID-X1 story illustrates several broader aspects of biomedical research that are often lost in media coverage.

• “Breakthroughs” aren’t usually news, but can reflect decades of work by hundreds of researchers. Teams include undergrads, grad students, technicians, and post-docs, not just the prizewinners or those with the most Twitter followers or TED talks.

• Progress reports are often presented at scientific and medical meetings, and if the media attend, articles follow (although researchers don’t always realize this). That’s why the headlines and endless repetition of press releases via aggregators following publication in a major journal can seem like echoes. They are.

600px-Flat_Earth_Society_Logo• “Scientific proof” doesn’t exist. Every result sparks new questions, and no conclusion is ever final, for what we learn continually teaches us how much more we need to know. If science ever had a final word on something, we’d still think the Earth was flat, that proteins are the genetic material, and that the entire human genome encodes protein.

Dr. Kohn elegantly sums up the significance of the SCID-X1 gene therapy trial results reported this week:

“It’s a reflection of the iterative bench-to-bedside process, with initial clinical observations spurring further research studies and a next generation of treatments brought to the clinic. For this specific disease, SCID-X1, this study represents a do-over in using the indisputable logic of gene therapy to treat this most responsive disorder, using prior lessons to do it even better.”

(The history of SCID-X1 is covered more fully in my book The Forever Fix: Gene Therapy and the Boy Who Saved It.)

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No Ice Buckets or Pink Ribbons for Very Rare Genetic Diseases

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Max Randell, left, has Canavan disease. His brother Alex is going to be a neuroscientist.

Max Randell, left, has Canavan disease. His brother Alex is going to be a neuroscientist.

As enthusiasm for dumping ice on one another fades with autumn and October brings pervasive pink, I wish that attention would turn to families confronting diseases not as well known as ALS and breast cancer.

HOW RARE IS RARE?

According to the  National Organization for Rare Disorders, “rare disease” in the U.S. means affecting fewer than 200,000 people. These conditions number about 6,800, collectively affecting nearly 30 million Americans or 1 in 10 people.

Many rare conditions are single-gene diseases. That means that the chance of more than one family member being affected is quite high (see Mendel’s first law). Unlike those, most (>90%) cases of ALS and breast cancer aren’t inherited as single-gene traits, but are sporadic. Mutations happen during a person’s lifetime in somatic (b0dy) cells, perhaps due to an environmental trigger. A family with sporadic ALS wouldn’t have to worry too much about the patient having passed it to a child; not so a family with Huntington disease. IMG_0831

With many causes of rare diseases, comparing statistics is an apples-and-oranges exercise. But I collected a few anyway, for prevalence (the percentage of a population with a particular disease at a given time).

Breast cancer (all types) affects 122 in 100,000 people. ALS (all types) affects  3.9 per 100,000. Absolute numbers are more meaningful for the rarest of the rare. For example fewer than 100 people worldwide are known to have giant axonal neuropathy, which is similar to ALS in a young child. But unlike ALS, the chance of a sibling of an affected child also inheriting the condition is 1 in 4. Thanks to exome sequencing, even “one-of-a-kind” individuals with strange constellations of symptoms that defy shoehorning into known diagnoses are being understood. The exome kids are tantalizing to journalists (see the New Yorker.)

But so very many diseases aren’t chosen for the New Yorker, or don’t have a Lou Gehrig or Joan Lunden materialize. Doing_the_ALS_Ice_Bucket_Challenge_(14927191426)

WHAT DO RARE DISEASE FAMILIES THINK?

I had mixed feelings about the ice bucket challenge (henceforth “IBC”) for ALS, noting how few people have read my posts here about the disease, compared to important posts like how Dan Brown screwed up genetics in his latest bestseller. So I polled the rare disease families I know about the IBC, and boy did I strike a nerve! They share awe at the brilliance of it, joy at how much was raised for ALS, surprise, and a bit of envy.

“People associated with other diseases became really upset, probably because they wished they had thought of it. It took on a life of its own, and then it just abruptly stopped when people became tired of watching endless videos, and that caused a backlash,” said Ilyce Randell, president and co-founder of Canavan Research Illinois. The organization’s major annual fundraiser celebrates son Max’s birthday — he’ll turn 17 later this month. I’ve been to two of them. (Canavan prevalence: about 10 in 100,000.) This post chronicled Max’s brother Alex’s efforts to fight brain disease.

Laura and Taylor, in happier and healthier times.

Laura and Taylor, in happier and healthier times.

Laura King Edwards is running races in all 50 states to raise awareness and funds for infantile Batten disease, which has robbed her 16-year-old sister Taylor of her sight, mobility, speech, and ability to eat. Laura took the IBC and attempted to extend its reach.

“I did try to post some more educational/advocacy-related links on the Taylor’s Tale Facebook and Twitter pages. Those posts didn’t get much response. People didn’t want information with meat to it – they wanted to watch entertaining videos of their friends. That’s where our challenge comes in – how to identify strategies that are sustainable. Because if I know anything, it’s that the fight against rare disease won’t be won overnight,” she said. (Prevalence of all forms of Batten disease is  2 to 4 of every 100,000).

finley

The IBC seemed to have gotten under the skin, in one way or another, of nearly everyone I contacted.

“We didn’t pay much attention to it, and did not accept the challenge from anyone. We kept the focus on our goal,” said Jennifer Pletcher, whose daughter Finley has Leber congenital amaurosis (LCA) caused by mutation in the RDH12 gene. “Some people actually did the challenge and donated to our foundation, which was cool,” she added, pointing out that October is Blindness Awareness month too. See http://www.1foramillion.com. (Prevalence of her daughter’s condition: 10% of the 2-3 per 100,000 who have any of the 22 genetic forms of LCA.)

RARE GENETIC DISEASES: TO LUMP OR NOT TO LUMP?

Ilyce Randell echoes Jennifer Pletcher’s focus on her family’s disease. This isn’t being selfish, it’s using genetic logic. While rare disease umbrella organizations are enormously helpful in sharing information and strategies, funding clinical trials is a different matter.

Testing a treatment for a single-gene disease requires participants who share mutations in the same gene. Finley Pletcher’s LCA is due to mutation in a different gene than the one that is mutant in Corey Haas, the boy at the heart of my book The Forever Fix. His successful gene therapy targeted his RPE65 gene.

Campaigning to treat all forms of LCA, or all forms of Batten disease, is useful in addressing shared concerns, but might dilute the financial power needed to get a phase 1/2 clinical trial off the ground, or support the daunting cost of a phase 3 trial necessary for FDA approval for marketing.

“Fundraising/awareness campaigns are more effective when we do not try to unite every similar disease. Parents of children affected by Canavan who raise money and direct it to a blanket organization are often times not helping advance research for their own child. We’re raising money for the only researcher who has ever worked with living Canavan patients in a clinical setting. But there are families raising money for ’research’ for ‘allied diseases,’ organizations that do not even fund her work. When it comes to curing my son I’m not in a true alliance with any other disease because all funding is scarce, and different diseases are competing for the same federal funds,” shared Ilyce.

And that competition is fierce. Just two days ago, the U.S. Food and Drug Administration (FDA) announced “awards of 15 grants worth more than $19 million to boost the development of medical device, drug, and biological products for patients with rare diseases.” Six are going to cancers, 2 to infectious diseases, 4 to others that aren’t inherited, and of the 3 that are, two are for sickle cell disease and one for cystic fibrosis – classic textbook genetic diseases. “You have an easier time asking for money for something people have heard of,” said Ilyce. SavingEliza - instagram

Glenn O’Neill is more enthusiastic about the IBC, perhaps because his family’s efforts to “save Eliza” from Sanfilippo syndrome also went viral, before the ice buckets descended . They adapted the “challenge” part of the ice bucket craze.

“On August 12th we started our #Sing2Lines to stop Sanfilippo challenge based on Eliza’s love of music and the fact that she can still sing. You post a video of yourself singing 2 lines of any song, and challenge 5 friends, to give Eliza and other children a voice, and a chance at life,” Glenn said.

They’ve sung their way to more than $75,000 with thousands of entries, including one from actress Andie MacDowell.

128px-Emoji_u1f4b0.svgPAYING FUNDRAISERS

For the rarest of the rare, fundraising efforts are usually family-run, all volunteer. This is not often the case for more common conditions. When any disease organization calls for a donation, it’s a good idea to ask how much of what you donate actually goes to research or patient support. Check out Charity Navigator.

A caller for a large breast cancer organization had the misfortune of getting my husband on the phone last October. Larry volunteers for several not-for-profits that do not pay fundraisers or anyone else, and he immediately interrupted the script to ask whether said organization paid the people who made the phone calls. Yes, they did.

But breast cancer is so common! You must know someone who has it!” insisted the paid caller.

If it’s so common, why can’t you get volunteers to make the phone calls?” Larry asked.

Laura King Edwards weighed in with “Pink for One Heck of a Price Tag“ two years ago, noting that the NFL shelled out $5 million on ads and paraphernalia for their breast cancer awareness blitz. “If I could write a $5 million check to the world’s best Batten disease experts, I believe in my heart that they’d give us a treatment that works,” she wrote.

Others chimed in on the cost of fundraising issue. “For Finley’s Fighters, 100% goes to research. We don’t have overhead cost or paid employees. We rely on sponsors for our events and all other costs come out of the family’s pockets,” said Jennifer Pletcher.

Michael and Mitchell Smedley and their friends brainstormed the Bike the Basin event.

Michael and Mitchell Smedley and their friends brainstormed the Bike the Basin event.

Kristin Smedley, who has two sons with the CRB1 form of LCA, agrees. “I let my supporters know that our fundraising does not pay salaries, it does not pay for office space, it does not pay for public relations firms to get me on TV. We are all volunteers here working out of our kitchens.”

Their annual event, Bike the Basin, raises enough funds to sponsor an annual research meeting for their CRB1 (Curing Retinal Blindness) Foundation– I attended the first one.

I’m not insensitive to the challenges of cancer. I had it. And I watched my mother undergo treatment for metastatic breast cancer. But an entire month of “raising awareness” for breast cancer? Who, exactly, hasn’t heard of it? And who is being ignored as a result?

IN AWE OF JACEY

Of all of the inspiring rare disease family members I’ve “met” during my writing journeys, the most spellbinding is Jacey Mukka. She turns 22 later this month; she didn’t think she’d live past 21.

Jacey has juvenile Huntington disease (JHD). With prevalence 5% of the adult version’s 5.7 cases per 100,000, there isn’t much interest. Clinicaltrials.gov lists only one trial, from the European Huntington’s Disease Network, that tracks kids who have symptoms, rather than still-healthy at-risk individuals who’ve inherited the mutation. For another apples-to-oranges comparison, I entered “glioma,” the type of brain cancer that’s just received 3 of the 15 grants from FDA, into clinicaltrials.gov: 1,439 hits to JHD’s lone one.

Karli, Jacey's little sister.

Karli, Jacey’s little sister.

Jacey’s dad and little sister Karli passed away from HD; Jacey’s older sister has it too. Jacey is very ill, but I don’t want to dwell on her body here. Details are in another post. Instead, I’d like to share her thoughts.

I promised myself when I was younger I would die before my little sister, I would die before my father, I would die if I ever got the temper of my father or started hurting people.

But that didn’t happen. Karli died at age 13, in 2010. Jacey remembers.

Reality still hadn’t hit, until the nurse came in. She said to come say goodbye. No it’s not possible, it can’t be. I went into her room and I saw her lips were blue. Mom and Erica snuggled up to her and she took her last breath. She was free. It hurt worse then I thought ever possible, just hold her bunny and curl up on the couch and cry until you run out of tears, and cry even after that. We gave Daddy her pink rabbit and he held it as tight as he could, and then he died 2 months later.

Max

Max, HD mascot

Jacey started jhdkids.com after hearing families talk about having children even though a parent has the HD mutation, because “the child wouldn’t get sick until it was older and by then they’d have a cure.” Jacey sends hugs and books to the friends she’s made, and raises funds to help them get through life, one day at a time. The website is full of facts, stories, and ideas. And it is vital, if only to a few, because no one’s dumping ice to draw attention to JHD.

I wish the ice bucket challenge had brought more recognition to the hundreds of rare genetic diseases that lie so under-the-radar. Far more lasting than the ICB is Facebook, where I hear daily from my “families.” Facebook connects the individual efforts that are so important to conquering the single-gene diseases, one at a time.

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DNA and Dating: Buyer Beware

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128px-Emoji_u1f4b0.svgLast week’s post dealt with three very serious types of DNA tests. But not all DNA tests detect health-threatening conditions.

A few years ago “Born to Run? Little Ones Get Test for Sports Gene” ran on the front page of the New York Times, above an arresting image of a preschooler having his mouth swabbed for DNA. It’s from 2008, but remains a classic: I still assign it.

800px-FPYC_Soccer_-_02The sports gene company tested for variants of one gene, ACTN3. Two copies of the R577X variant indicate inborn skill at endurance events, and no copies suggest a child stick to sprints. The lucky heterozygotes might excel at both! Never mind that a child has some 20,000 or so other genes affecting physiology.

DISSECTING A DNA DATING WEBSITE
The most damage a sports gene test can do is to keep a child from something she loves because of a DNA-obsessed parent. A more questionable application of DNA testing is in “relationship science,” something I learned about a few weeks ago when a reporter from healthline.com asked me about it. And so I perused the website of the “leader in human genetic compatibility.”

The company offers tests for four genes. Three are members of the human leukocyte antigen (HLA) complex, which encodes the cell-surface proteins that determine who can give body parts to whom and reflects many disease susceptibilities. The fourth gene, SLC6A4, encodes a serotonin transporter.

Both the HLA genes and SLC6A4 have been studied for decades. Yet the test panel doesn’t include ancestry markers, which I think might be more important in mate selection than tissue compatibility.

Wasps get it on. (Elizabeth Cash/John Gibson)

Wasps get it on. (Elizabeth Cash/John Gibson)

HLA TYPING
The company is using HLA typing as a surrogate for scent, claiming that 40% of olfaction comes from the genes. But the existence of human pheromones is still under debate, although they were predicted to exist half a century ago, and many a website will happily sell you some. (The image shows tiny wasps with the wonderful name Nasonia vitripennis mating, thanks to pheromones wafting from the male.)

More telling in the scent department may be the 1995 study of women preferring the sweaty T-shirts of men least like them genetically. Wikipedia credits it with starting the field of genetic matchmaking.

Why wouldn’t humans have pheromones, when so many other animal species do? Plus the HLA genes are so involved in biological compatibility that I suspect they indeed have something to do with scent and pheromones. But do we need a DNA test to tell us when a potential date stinks? Maybe so. That’s one characteristic we can’t yet inspect on our electronic devices.

Bone_Marrow_TransplantKnowing one’s HLA type is not without value, but its hard to say whether one should seek a mate with a different or similar profile. People with different HLA variants may be less likely to pass infections back and forth. But couples with similar variants would be better off if one of them needs a blood transfusion, bone marrow transplant, or part of a liver.

THE SEROTONIN TRANSPORTER
SLC6A4, which encodes a serotonin transporter, is also a logical choice for a dating gene. Like the HLA genes, its variants are associated with several health conditions: sudden infant death syndrome, Alzheimer aggression, depression following emotional trauma, alcoholism, neuroticism, deviant sexual behavior, hypertension and obsessive-compulsive disorder.

(Dr. Yoichi Araki)

(Dr. Yoichi Araki)

The SLC6A4 protein recycles the neurotransmitter serotonin to the reuptake stations on presynaptic neurons in the brain. Serotonin is what’s theoretically scarce in some cases of depression (like pheromones, that hasn’t been definitively shown either), and so the transporter provides a target for the “selective serotonin reuptake inhibitors” like Paxil. It’s also the target of the older tricyclic antidepressants, as well as amphetamines and cocaine.

People can have a short version or a long version of one part of the SLC6A4 gene. In one study, people with two short variants self-reported future dissatisfaction with their marriages if they previously reported high or low emotional behavior (whatever that means). Conversely, if people have at least one “long” version of the serotonin transporter gene, then their emotional behavior does not influence their perceived long-term stability of their marriages.

What the serotonin transporter has to do with dating is beyond me, although I have not dated in centuries. But I think a shared love of dark chocolate, running, and binge-watching Orange is the New Black may be more meaningful measures of day-to-day compatibility than SLC6A4 genotype.

Testimonials on the company’s website attest to the fact that people do believe that choosing dates based on limited genotyping has value. They are falling into the trap of genetic determinism, the idea that DNA is destiny.

Valentines_Book_1940_1“We knew the test would show a great match because we knew we had chemistry when we met. We think the test results show that the Instant Chemistry DNA test can help singles find that person who they have a real connection with,” writes one satisfied customer.

I emailed the company requesting data showing that people with particular genetic profiles are more likely to be compatible, and how the company defines and assesses compatibility. I haven’t heard back yet. However, a news release from July, prompting a flurry of media coverage, informed us that the company is “proving that there is science behind attraction,” with “new, groundbreaking research.” So stay tuned.

ATCG's Image with Group of PeoplePRECEDENTS

Using genetic testing in mate selection is a decades-old strategy. Dor Yeshorim is a program that originated in the Hasidic Jewish community in New York City. It has tested thousands of young people from all over the world for several “Jewish” genetic diseases since a rabbi who had children with Tay-Sachs disease started the program in 1983. Testing is anonymous, using numerical identifiers, and carriers are not told what they carry – just whom to avoid having children with, if they so choose. Their testimonials are the plummeting incidences of some of these diseases in the tested population.

800px-Foundation_(cosmetics)At the other end of the seriousness-of-genetic-testing spectrum, federal regulators are finally cracking down on dubious DNA-based claims. Two years ago I’m embarrassed to admit that I bought “age-defying with DNA advantage cream makeup” because I couldn’t resist the goop in the see-through container swirled into a double helix shape. I’d thought I’d read that FTC had made these genetics references in cosmetics ads disappear, but they forgot to tell Google.

Adding “DNA” to skin cream ads doesn’t really hurt anyone. But making medical claims is a different story.

My favorite study exposing misuse of genetic testing is from the U.S. Government Accountability Office, like the sports gene flurry also from 2008, when  direct-to-consumer genetic-testing debuted. GAO investigators submitted DNA samples from a 9-month-old girl and a 48-year-old man to four “nutrigenetics” companies, but with 14 made up lifestyle/dietary profiles. None of the companies, which offered dietary suggestions and pricey packages of exactly the supplements that an individual purportedly needed to avoid her or his genetic fate, bothered to do a health history.

Lo and behold, the advice from the four companies tracked with the made-up backgrounds and not genetics. And the results reported on very common conditions (to which genes may contribute minimally) and stated the obvious, like not smoking. Concluded the study: “Although these recommendations may be beneficial to consumers in that they constitute common sense health and dietary guidance, DNA analysis is not needed to generate this advice.” Some of the suggestions could even be dangerous, such as vitamin excesses in people with certain medical conditions.

640px-Snake_oil_or_Memory_Elixer_anyoneI don’t know if the FDA, FTC, or GAO are interested in a dating website that preys on those who don’t know much about DNA. My advice for deciding whom to date? Talk to people! Don’t shell out hundreds of dollars to learn about a handful of genes.

(Some of this material comes from chapter 20, Genetic Testing and Treatment, in my textbook Human Genetics: Concepts and Applications, just published by McGraw-Hill in the 11th edition.)

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Genetic Testing For All: Is It Eugenics?

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ATCG's Image with Group of PeopleIn recent weeks, there’s been talk of three types of genetic testing transitioning from targeted populations to the general public: carrier screens for recessive diseases, tests for BRCA mutations, and non-invasive prenatal testing (NIPT) to spot extra chromosomes in fetuses from DNA in the maternal bloodstream.

Are these efforts the leading edge of a new eugenics movement? It might appear that way, but I think not.

(NHGRI)

(NHGRI)

When I began providing genetic counseling 30 years ago at CareNet, a large ob/gyn practice in Schenectady, NY, few patients were candidates for testing: pregnant women of “advanced maternal age” (35+), someone with a family history of a single-gene disorder or whose ethnic background was associated with higher prevalence of a specific inherited disease. Their risks justified the cost and potential dangers of the tests.

Now the picture is rapidly changing as plummeting DNA sequencing costs and improved technologies are removing economics from the equation. It’s becoming feasible to test anyone for anything – a move towards “pan-ethnic” genetic screening that counters the “sickle-cell-is-for-blacks and cystic-fibrosis-is-for-whites” mindset.

So here’s a look at three very different types of genetic tests that are poised to make the leap to the general population. And despite new targets revealed with annotation of human genomes, some of the detection technologies themselves are decades old.

sickle#1: CARRIER SCREENING
Population screening for carriers of single-gene diseases has been around since those for sickle cell disease and Tay-Sachs disease in the early 1970s. We learned a lot from their starkly different results. For years, labs such as Athena Diagnostics, the Baylor College of Medicine Medical Genetics Laboratories, Emory Genetics LaboratoryAmbry GeneticsGeneDx and  others have added genetic tests to their rosters, which now cover hundreds of single-gene diseases, from A (Alport syndrome) to Z (Zellweger syndrome).

HORIZONlogo(CMYK)Other companies have recently visited CareNet, pitching tests for more single-gene diseases for everyone. For example, Natera’s Horizon Carrier Screen tests for 39 conditions and 127 variants of the cystic fibrosis (CF) gene. They provide genetic counseling by phone, which is common these days, given the scarcity of trained genetic counselors, especially outside cities. And Natera can tailor screening panels to specific populations.

In addition to the changing economics, the public is more familiar with DNA-based tests, partly due to the direct-to-consumer testing company 23andMe. Before FDA forbade them from selling carrier tests as “information,” thousands of people learned about recessive diseases from the company’s excellent website.

Cystic fibrosis illustrates the widening of test offerings. Carrier screening began in 2001 for whites and Ashkenazi Jews, following recommendations from the American Congress of Obstetrics and Gynecology and the American College of Medical Genetics. By 2005, with many more mutations identified and the diagnosis broadened, testing expanded to everyone. At CareNet every pregnant patient gets a CF test, along with a factsheet that I wrote.

counsyl-logo-largeCF is just one gene of thousands. Researchers from Counsyl, another newer player, published a key paper reporting on 23,453 patients from ob/gyn, genetics, and infertility clinics screened for 108 disorders. Nearly 24% carried at least one disease-associated recessive mutation! 5.2% (1,210) carried 2 or more, and .33% (78) actually HAD a disease by having inheriting two mutations.

Interestingly, stratifying participants by population group revealed the differences that once fueled restriction of testing. Although overall 24% of the total carried at least one disease, that ranged from 6.3% among Native Americans and 8.5% among East Asians to 47.1% among the Finns and 43.6% among Ashkenazi Jews. Only 15.8% of African-Americans were carriers.

#2 BRCA TESTING FOR ALL
BRCALast week in a controversial Viewpoint in JAMA Mary-Claire King and colleagues suggested “that population-based screening of women for BRCA1 and BRCA2 should become a routine part of clinical practice.” These genes normally participate in DNA repair, and mutations raise risk of several cancers, not just the widely-reported breast and ovarian. (BRCA1 mutations predispose to cancers of the cervix, colon, uterus, and pancreas, and BRCA2 to cancers of the stomach, gallbladder, pancreas and bile ducts, as well as to melanoma.)

Results from the first families that Dr. King analyzed, published in 1990, were Ashkenazi Jewish with several affected members, because it is easier to discover a gene and what it does in a population with very few variants. It turned out that this group has only three mutations, all of which obliterate the genes’ vital function. Sequencing the entire huge gene wasn’t necessary, lowering costs substantially.

Based on the 1990 paper and follow-up, for years we genetic counselors would consider the number of cases of the relevant cancers and ages at diagnosis in families. We used published guidelines to decide to whom to offer BRCA testing.

(NHGRI)

(NHGRI)

That approach invariably missed some cases in families that were small or had few female members. We knew that accruing data on populations beyond the high-risk Ashkenazim would take years, mostly because thousands of mutations exist.

Many people thought Dr. King’s suggestion of wider BRCA screening premature. Criticism centered on the experimental design in the PNAS paper that the Viewpoint addressed, also from the King group. It focused on Ashkenazim because with fewer mutations the data were easier to collect, especially back when the study began.

The researchers tested more than 8,000 healthy Ashkenazi men in Israel for BRCA1 and BRCA2 mutations, and then offered testing to all female relatives of the 175 men found to have mutations. These women, it turned out, indeed had very high risks of developing the associated cancers – and about half of them had NO family history. Following the old guidelines would have missed them. (An important caveat in the Viewpoint cautioned that testing should only be for meaningful mutations – not the many “variants of uncertain significance.”)

But we can’t know which mutations lurk in whom unless we look for them! And not testing members of families that don’t fit the original pattern will miss cases. That’s what happened in my friend’s family.

Maya’s son discovered he had a BRCA mutation after he took a 23andMe test, for fun, back when one could do this. Maya was tested next because she’s Ashkenazi, but it was her husband, who’s Catholic and European, who’d passed on the mutation to their son. Fortunately their daughter escaped the family legacy. But here’s a family in which the cancer can indeed begin in either father or son, and in more distant relatives. The affected individuals are now being tested regularly for the associated cancers – no one is running off to have organs removed. A positive genetic screen result — meaning identification of a gene variant, not a diagnosis — signals a need for vigilence and preventive health care. It’s not a ticket to surgery.

(Shendure lab)

(Shendure lab)

#3 FETAL DNA TESTING
Until recently, testing fetal DNA (NIPT) was only advised for pregnant women at higher risk of the fetus having an extra chromosome 13, 18, or 21, the most common trisomies. That is, women over 35, or who’d had a previous trisomy. Soon it will be offered to all.

Entire fetal genomes can be sequenced from DNA snippets in the maternal bloodstream, which are shorter than the woman’s DNA pieces. But whole genomes are, for now, TMI. The first commercial non-invasive fetal DNA tests detect abnormal chromosome ratios or differences at single sites (SNPs) on those chromosomes in both genomes, in high-risk women. By August 2014, the data indicated that NIPT is safe enough for low-risk women.

At least half a dozen companies now offer NIPT. It will clearly save lives.

“The sweet spot is for women who are deciding whether or not to have an invasive procedure because they are at higher risk due to advanced maternal age, a positive screen of serum markers, or a fetal sonographic abnormality. If testing fetal DNA gives an all-clear, at least for these three chromosomal conditions, then the pregnant woman can avoid the risk of a more invasive procedure, such as amniocentesis,” Diana Bianchi, MD, professor of pediatrics at Tufts University, told me.

Dr. Bianchi  is the mother of the invention, described in this DNA Science blog post. She reported detecting cell-free fetal DNA and suggested noninvasive prenatal testing back in 1996. “Nine to one, women want the blood test first, and a great majority of them have a negative result, so they don’t go on to have amnio or CVS,” she added.

But that benefit wasn’t immediately obvious to critics unfamiliar with the spectrum of prenatal testing options. Dr. Bianchi received threats from people who saw testing fetal DNA as a way to avoid the births of people with Down syndrome and the other trisomies.

Eugenics_congress_logoIS IT EUGENICS?
Eugenics is “the science of improving a human population by controlled breeding.” Mention of the term is often followed by reference to Nazis.

Are recessive disease carrier screening, BRCA mutation testing, and NIPT eugenic, according to the definition? Only one might be, and even that’s questionable. Let’s dismiss the other two first.

BRCA testing alerts relatives to the need for active surveillance for certain cancers, for their own health. At least in my experience in counseling patients, an inherited cancer susceptibility is not a reason to keep one person from having kids with another, or to end a pregnancy, because the cancers are late-onset and treatable. Plus, a person who inherits a BRCA mutation must then undergo a second, somatic mutation in a cell in the organ that develops cancer, according to the classic two-hit mechanism. It isn’t the cancer that’s inherited, but the increased risk.

NIPT is not eugenic in its current guise because trisomies – extra chromosomes – result from mispairing in meiosis. They’re not inherited, they just happen, although a person with a trisomy is more likely to produce “unbalanced gametes” that can perpetuate the situation. But most new trisomies are spontaneous glitches that result from a chromosome pair not parting when it should as sperm or egg form.

The one type of testing that could ultimately have a eugenic effect is carrier screening for recessive diseases. The Counsyl paper concludes that “sequencing the entire genome of each patient would reveal ~10 times as many lethal recessives on average.”

Imagine including one’s personal collection of recessive mutations on a DNA dating site! (See yours truly quoted in The New Science of Matchmaking: Dating Based on Your DNA).

Natera’s description of the Horizon Carrier Screen leads potential patients through Mendel’s first law: an offspring of two carriers of the same condition faces a 25% chance of inheriting the disease. “If you find you are at risk, you can take steps to prevent having a baby with a genetic disease,” the clear explanation continues.

For couples who discover they carry mutations in the same gene, the company offers Spectrum, which uses pre-implantation genetic diagnosis (PGD) to choose embryos conceived in vitro that have not inherited the disease-associated genotype. PGD has been around since 1990, but occasionally headlines trumpet it as new.

So yes, filtering out mutations with rigorous and actionable carrier tests can ultimately alter the gene pool. And because the selection is directional, this appears to be eugenic by  permitting only certain gene variants into the next generation. But this isn’t really eugenics, because the important descriptor of eugenics is INTENT; that of medical genetic screening and testing is CHOICE. The goal of the first is sociological, the second, biological.

Genetic screening and testing often aim to avoid a medical situation in a family, not to “improve” the genetic structure of a future population. And we should never assume that all families will choose that path. I’ve talked to families that have more than one child with spinal muscular atrophy, or with a blood disorder, because preventing the birth of another affected child may seem a rejection of the beloved existing one. (See the DNA Science posts about the Amish for more examples.) Families must be allowed that choice. That’s what genetic counseling is all about.

And so I don’t think that any medical genetic screening or testing is eugenic, and I welcome the coming expansion of the opportunity to learn what’s in some of our DNA to more people.

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Black Pee Disease Offers New View of Arthritic Joints

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AlkaptonuriaA new cause of osteoarthritis identified by research on a rare disease,” ran the headline of a news release a few weeks ago. I was drawn to “rare disease,” even though I actually have osteoarthritis. When I read “alkaptonuria,” I was catapulted back more than a century to the first description of an “inborn error of metabolism.” The release announced a paper in the October Journal of Anatomy, which is behind a paywall.

So oft-told in the genetics lore is the story of understanding alkaptonuria that any geneticist would have recognized the reference instantly, as would most science writers. But the “aggregators” of science news? Not so much.

Google the headline and the parroting appears, oddly enough some of the echoes atop the original news release. One version invented a spin to up the excitement: “Scientists hoped to find out information on a rare disease. What they found instead was a potential cause of osteoarthritis,” with the subhead “An Accidental Discovery.” Please, give the researchers some credit for knowing to look at alkaptonuria as a model for osteoarthritis.

Joints commonly affected in osteoarthritis.

Joints commonly affected in osteoarthritis.

Investigating a rare disorder for insight about a common one is a classic strategy, not simply good luck. Statin drugs, for example, grew out of research on the one-in-a-million children who die young of heart attacks and strokes due to familial hypercholesterolemia (FH). Several DNA Science posts deal with a drug for the rapid-aging disease progeria that may also help those with conventional atherosclerosis.

THE FATHER OF INBORN ERRORS
Alkaptonuria is not quite as rare as FH, but is much more so than osteoarthritis. Alkaptonuria affects 1 in 250,000; osteoarthritis affects 13.9% of those over age 25 and 33.6% of people over age 65. Clinicaltrials.gov lists 5 studies for alkaptonuria (all for the same drug already used for a similar condition), and more than 2,000 for osteoarthritis.

Sir Archibald Garrod

Sir Archibald Garrod

To introduce “inborn errors of metabolism” in my human genetics textbook (new edition out soon!) I tell the tale of Sir Archibald Garrod and alkaptonuria. In earlier editions I wrote that the first sign is “urine that turns black upon standing,” which unfortunately caused legions of college students to think that people with the disease should sit down when they pee. This is why we authors need editors. The urine must stand, not the urinator (see photo above).

Sir Garrod (1857-1936) was a physician at St. Bartholomew’s in London when he investigated the odd disease at the turn of the twentieth century. The initial report in The Lancet in 1902 described the telltale excretion of homogentisic acid in urine that turned black upon standing. Sir Garrod focused on the observation that when one child had black urine, a sibling sometimes did too; 19 of 32 cases were from only 7 families. Plus, parents of affected children were more often first cousins than expected for such a rare condition.

Sir Garrod termed alkaptonuria an “alternative mode of metabolism,” realizing that people vary. He entitled that 1902 paper “The incidence of alkaptonuria: a study in chemical individuality.” It is that individuality that today’s exome and genome sequencing, not to mention genome-wide association studies, seek to reveal at the DNA level.

The phrase “inborn error of metabolism” didn’t appear until Sir Garrod’s Croonian Lectures to the Royal College of Physicians, published in 1909. That paper introduced “Garrod’s tetrad” of alkaptonuria, cystinuria, pentosuria, and albinism, defining an entire class of inherited illnesses.

Timing is critical in the story. Back in 1902, Mendel’s laws had just been rediscovered. That’s why much of  classic Lancet paper addresses whether the preponderance of cousin-cousin parental pairings and familial clustering revealed the recessive inheritance that Mendel had described so elegantly for peas.

Sir Garrod was astonishingly ahead of his time, zeroing in on the “one-gene_one-enzyme“ hypothesis that’s usually attributed to studies in bread mold circa 1941. The enzyme behind alkaptonuria wouldn’t be discovered until 1958, the gene in 1996. In today’s world of massive sequencing projects, I’m still stunned by the insights of long-ago researchers who deduced patterns of inheritance from what they could observe.

Homogentisic acid

Homogentisic acid

DARKENED CARTILAGE
In a nutshell, an inborn error blocks synthesis of an enzyme that is part of a metabolic pathway. Like a garden hose with a kink, stuff before the block builds up, and the stuff after is a dribble, or nothing.

In alkaptonuria, the deficient enzyme is homogentisic acid 1,2-dioxygenase, and the stuff that builds up, homogentisic acid, forms the greenish-black alkapton when exposed to oxygen (when a urine stream hits the air, or a splayed diaper).

431px-StateLibQld_1_49792_Advertisement_for_Dunlop_garden_hosesTyrosine is one of the 20 amino acids of life. Five stepwise reactions break it down, ultimately providing starting materials for production of thyroid and other hormones, the pigment melanin, and entrants to the energy pathways. Block a step, and a specific inborn error results. Alkaptonuria intervenes between steps two and three; blocks at the other points cause tyrosinemia. All hamper utilization of dietary proteins.

Darkened vertebral disc in alkaptonuria

Darkened vertebral disc in alkaptonuria

Early in life, alkaptonuria is mostly a peculiarity. The pigmentation – called ochronosis – typically doesn’t affect health until after age 30, when it darkens and degrades cartilage. The tips of the ears may blacken. Treatment is painkillers and joint replacement surgery to allieve painful arthritis. But alkaptonuria also causes kidney stones, heart valve damage, tendon and muscle rupture, and fractures.

ENTER HORSES
The arthritis of alkaptonuria is like that of the more common osteoarthritis, but is even more like a “novel pathology” of racehorses described by Alan Boyde, a professor of mineralized tissue biology (and a PhD and dentist) at the Barts and the London School of Medicine and Dentistry, in 2011.

Dr. Boyde and his group dissected digits of euthanized racehorses, and probed them non-invasively with “nanoindentation” and a slew of imaging techniques. They found “high density mineralized protrusions” – HDMPs. Hard spikes filling joint spaces. Ouch.

The key term is “non-invasively,” because it turns out that the reason these painful spikes haven’t been seen in those of us with run-of-the-mill osteoarthritis is that the technique to study joints destroys them! (See Heisenberg uncertainty principle: don’t alter what you’re trying to study!)

When Dr. Boyde and colleague Jim Gallagher, PhD, from the University of Liverpool’s Institute of Ageing and Chronic Disease and co-workers replaced a hip joint in a 49-year-old man with alkaptonuria, they decided to take a closer, less-destructive look. So instead of dissolving away hard stuff in the joint so they could see better, the researchers used a microtome to gently slice the tissue, like roast beef at a deli.

They saw HDMPs.

Spikes in a hip joint (University of Liverpool)

Spikes in a hip joint (University of Liverpool)

The researchers elaborate in the paper in The Journal of Anatomy that “despite extensive investigation, there is still a lack of knowledge of the microanatomical changes that ensue in osteoarthritis and their relationship to clinical symptoms. In part, this is because most histopathological studies of arthroses in humans have relied on thin sections of decalcified tissue, in which all evidence of mineral distribution in bone and calcified cartilage is destroyed.”

When the researchers went back to MRIs of the man’s hip, the telltale HDMPs were indeed there – but had gone unnoticed.

Gray340LOOKING AT COMMON OSTEOARTHRITIS
The next step was to look at joints from patients with osteoarthritis, which the investigators did for hip joints from two replacements and six cadavers. Keeping the joints intact again revealed the spikes of calcification. “We found several instances, enough to assure us that the research field should now be on the lookout for them,” the investigators write.

The spikes tend to appear near dead cells. Summed up Dr. Gallagher, “These small, sharp particles could act like an abrasive powder scouring the surfaces of the joint.”

Interestingly, the man with alkaptonuria had complained of severe joint pain, yet conventional X-rays had not shown advanced joint destruction. This reminds me of my husband’s frustrating visit to an orthopedist who informed him that he was imagining his severe back pain because the tools at the doc’s disposal hadn’t shown anything abnormal.

My own osteoarthritis appeared at age 33, as it did in my mother and her mother. Fortunately it only affects my hands, which I discovered upon whacking one of them and suffering surprisingly intense and long-lived pain, at about the same time that I became unable to play an F chord on guitar or form a fist. It’s in my neck and toes, but doesn’t really bother me much.

Random lessons learned from the alkaptonuria/osteoarthritis story:

  • Studying rare diseases in people and animal models (like racehorses) can unveil pathological mechanisms behind more-common, less-severe, counterparts.
  • If a physician claims a condition doesn’t exist, find a practitioner who will look at the problem another way.
  • In medical genetics, old stories are still valuable. It’s not all about genomics.
  • News aggregators and “content providers” who repeat repeat repeat verbatim and work for very little money are killing jobs for science writers, who have the experience to recognize the significance and backstory of news — and so much of science news these days reflects poorly-done studies (a 7-kid autism study on the nightly news?) or isn’t really news at all.
  • A frequent complaint about new editions of textbooks, such as the human anatomy and physiology textbooks I co-author, is that facts don’t change enough to warrant revision, that we know all there is to know about the human body. Not true.
  • The good news for human runners from horses is that development of joint spikes was not significantly associated with number of racing seasons, age, earnings, number of days in training, total distance galloped in one’s career, or presence of wear lines.
  • It’s ok to stand while peeing, even if you have alkaptonuria.

 

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Medical Success Stories: From Cystic Fibrosis to Diabetes

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dnaA skinny little boy, with mocha skin and curly black hair, lived in the apartment building next door when I was growing up in Brooklyn in the 1960s. I don’t remember his name, but I recall that he didn’t live long enough to go to kindergarten. He had cystic fibrosis.

Today’s tots with CF face a far brighter future. A recent report in the Annals of Internal Medicine applied trends in survival from 2000 to 2010 to project life expectancy for children diagnosed in 2010: 37 years for girls and 40 years for boys. (The difference may reflect hormones or the extra creatinine in the more muscular male of the species.) Factoring in the current rate of treatment improvements gives a soaring median survival of 54 years for women and 58 years for men when those kids grow up!

This is spectacular news, although some younger people with severe disease will still contribute to the lower end of the survival curve. (See my write-up in Medscape and a recent post here on the history of CF.)

Cystic fibrosis results from an absent or malformed chloride channel.

Cystic fibrosis results from an absent or malformed chloride channel.

THE CFF PATIENT REGISTRY
The Cystic Fibrosis Foundation Patient Registry began in 1966, about when my young neighbor died. It has followed 26,000 of the nearly 35,000 individuals with CF in the U.S., with 5,000 added over the past decade as treatments have expanded and people with milder symptoms added.

In the early days, deaths were more often due to malnutrition than to the impaired respiration for which the disease is best known.

Success has come from diverse realms.

First came high-calorie diets, digestive enzymes mixed into applesauce, and airway clearance exercises, eventually helped with devices such as vibrating vests. Then came a parade of drugs: antibiotics, mucolytics, and more recently Kalydeco to refold misfolded CFTR (CF transmembrane conductance regulator) protein, a drug so effective that it’s Facebook page is called Kalydeco Miracles. And treatments start sooner in life thanks to universal newborn screening (since 2009) and prenatal carrier testing.

IS CF MORE THAN ONE DISEASE?
The definition of CF continues to evolve as more mutation combinations are identified and their phenotypes described. It has never made sense to me that different mutations in the CFTR gene all produce what we call cystic fibrosis, yet different mutations in the

Hemoglobin

Hemoglobin

beta globin gene cause different clinical entities. Hemoglobin C and sickle cell disease even affect the same amino acid position. The situation in naming single-gene diseases seems a little like how lumpers and splitters see biological classification.

But that may be changing. A recent report in PLOS Genetics suggests that CF is two diseases, defined by whether or not the lungs are affected. At least nine variants of CFTR spare the lungs, but cause male infertility, pancreatitis, or sinusitis — in some men, all three.

“Pancreas cells use CFTR to secrete bicarbonate to neutralize gastric acids. When that doesn’t happen, the acids cause the inflammation, cyst formation and scarring of severe pancreatitis. Bicarbonate transport is critical to thin mucus in the sinuses and for proper sperm function,” explains co-author David C. Whitcomb, MD, PhD and chief of gastroenterology, hepatology and nutrition at the University of Pittsburgh School of Medicine. In times past, CF wasn’t part of the differential diagnosis for men with pancreatitis, chronic sinusitis and infertility, but with working lungs.

CF affects more than the respiratory system.

CF affects more than the respiratory system.

“I know one MD who got through med school a severe asthmatic, now diagnosed with CF. We are diagnosing people better at all ages, and newborns are being screened, which contribute to increase in life expectancy,” says Paul Quinton, PhD, a professor of biomedical sciences at the University of California, Riverside, School of Medicine and medical advisor to Cystic Fibrosis Research Inc.. He has CF.

Dystrophin

Dystrophin

Tracking the natural history of a disease, which patient registries makes possible, is crucial in determining whether a new treatment works. For example, a recent DNA Science post asked whether boys with Duchenne muscular dystrophy who walked farther on a treadmill in a set time after receiving an experimental genetic treatment had really improved, or if their strides were within the range of normal for the disease.

Natural history studies reveal aspects of disease that could be important in developing treatments. For CF, the registry revealed a period of increased risk during adolescence. Until age 10, annual mortality is below 0.5%, but it jumps during the teen years to 3-4% before plateauing at age 25.

An editorial accompanying the Annals of Internal Medicine paper suggests suggests that the tendency of teens to not eat so well and forego treatments and therapies, and increased susceptibility to pathogens such as Pseudomonas aeruginosa and MRSA, might explain the vulnerability.

SURVIVORS OF CHILDHOOD DISEASES
How will the health care system embrace a population of adults with CF?
While the editorialists claim “caring for adults with CF requires a village,” Lisa Tuchman MD, MPH, an adolescent medicine specialist at Children’s National Medical Center, is more positive. “We‘re seeing a trend across all pediatric-onset health conditions. For CF there has been a lot of thoughtful planning and careful analysis, mostly facilitated by the registry.” Dr. Tuchman and Michael Schwartz, MD, from the Pediatric Pulmonary Medicine & Cystic Fibrosis Center, Lehigh Valley Health Network, recently published a study in Pediatrics about successful transition to adult care for people with CF.

I asked Dr. Tuchman whether there are precedents for extended-survival patient populations. “Lots! Over 90% of little kids who get cancer are going to survive, so the system has responded by creating centers for adult survivors of childhood cancers. We see this in sickle cell disease, adult programs because people are living longer with it. And a lot of babies born with HIV disease are now young adults transferred to adult health care systems. It is across the board: metabolic diseases, hemophilia, diabetes. There’s a growing population of adults with pediatric-onset conditions,” she said.

GENE THERAPY
A brute-force attack on symptoms, coupled with a targeted molecular approach, has tamed cystic fibrosis. Although news reports describe Kalydeco as correcting CF at its source, to my geneticist mind, the source of inherited disease is not the protein, but the gene that encodes it. And that’s where gene therapy comes in. It, too, has had recent spectacular successes.

Corey Haas would likely have been blind by now, if not for gene therapy.

Corey Haas would likely have been blind by now, if not for gene therapy.

One of my books chronicles development of gene therapy for Leber congenital amaurosis type 2, which has given vision to more than 200 people, many of them children. Other blinding conditions aren’t far behind.

At the American Society of Gene and Cell Therapy annual meeting last May, I heard similar stories, most notably for adenosine deaminase deficiency and severe combined immune deficiency (SCID) X1. Said Adrian Thrasher, MD, PhD, from Great Ormond Street Hospital for Children of ADA deficiency, “We expect to cure a majority of these kids today if they can have a bone marrow transplant, but if they can’t …” and he then launched into the details of ongoing clinical trials for gene therapy. It works, saving children who would otherwise die in infancy from infection. ADA deficiency, like CF, is no longer a “life-shortening inherited disease.”

And the list will grow, especially as “traditional” gene therapy of supplying working genes shares successes with genome editing techniques that actually replace or fix faulty genes.

Heather Lewis. Gastric bypass surgery banished type 2 diabetes.

Heather Lewis. Gastric bypass surgery banished type 2 diabetes.

GASTRIC BYPASS AND DIABETES
Although I know double-blinded, controlled clinical trials are the best way to demonstrate efficacy of a new treatment, the most compelling example for me was watching my daughter Heather following her gastric bypass surgery last May.

Her type 2 diabetes vanished, in just 4 days.

I’d read the reports of gastric bypass surgery curing diabetes. And Heather’s physician had told me that more than 90% of the bypass patients with diabetes at Albany Medical Center no longer had the disease. The hypothesized mechanisms make sense: dampened secretion of ghrelin, the stomach’s hunger hormone; or forcing glucose out of the bloodstream into the rerouted small intestine to provide energy to digest food that’s a bit chunkier than normal.

Heather’s surgery had been delayed two months because she couldn’t get her A1C down – the 3-month measure of blood glucose. She went from one to two to three oral diabetes drugs, with exercise and a very low carb diet. I even invented a low glycemic index soup/stew that helped a little. But only insulin worked. Looking ahead to a lifetime of treating diabetes is what pushed Heather to have the surgery.

Someday, gastric bypass surgery could be a front-line treatment for type 2 diabetes, even among people of normal weight. In terms of both economics and quality of life, it makes sense. Or perhaps we’ll find a way to less-invasively recreate the altered microbiome of a person after weight loss surgery who no longer has diabetes.

Double Helix with StethoscopeLet’s hope that cystic fibrosis, Leber congenital amaurosis, and type 2 diabetes are only the beginning of a trend towards tackling disease, in a multitude of ways.

(Update: Eman in Liberia from my last post remains healthy, and is trying to volunteer with MSF until med school restarts. And I’m recovering from major surgery, so may miss a week of posting here and there.)

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