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Tracking Down the Origins of Cystic Fibrosis in Ancient Europe

Human Lungs CF
The airways inside the human lung. (Magic mine/Shutterstock.com)

Imagine the thrill of discovery when more than 10 years of research on the origin of a common genetic disease, cystic fibrosis (CF), results in tracing it to a group of distinct but mysterious Europeans who lived about 5,000 years ago.

CF is the most common, potentially lethal, inherited disease among Caucasians—about one in 40 carry the so-called F508del mutation. Typically only beneficial mutations, which provide a survival advantage, spread widely through a population.

CF hinders the release of digestive enzymes from the pancreas, which triggers malnutrition, causes lung disease that is eventually fatal and produces high levels of salt in sweat that can be life-threatening.

CF Symptom Diagram
Depending on the mutation a patient carries, they may experience some or all symptoms of cystic fibrosis. (Blausen.com staff (2014), CC BY-SA)

In recent years, scientists have revealed many aspects of this deadly lung disease which have led to routine early diagnosis in screened babies, better treatments and longer lives. On the other hand, the scientific community hasn’t been able to figure out when, where and why the mutation became so common. Collaborating with an extraordinary team of European scientists such as David Barton in Ireland and Milan Macek in the Czech Republic, in particular a group of brilliant geneticists in Brest, France led by Emmanuelle Génin and Claude Férec, we believe that we now know where and when the original mutation arose and in which ancient tribe of people.

We share these findings in an article in the European Journal of Human Genetics which represents the culmination of 20 years’ work involving nine countries.

What is cystic fibrosis?

My quest to determine how CF arose and why it’s so common began soon after scientists discovered the CFTR gene causing the disease in 1989. The most common mutation of that gene that causes the disease was called F508del. Two copies of the mutation—one inherited from the mother and the other from the father—caused the lethal disease. But, inheriting just a single copy caused no symptoms, and made the person a “carrier.”

I had been employed at the University of Wisconsin since 1977 as a physician-scientist focusing on the early diagnosis of CF through newborn screening. Before the gene discovery, we identified babies at high risk for CF using a blood test that measured levels of protein called immunoreactive trypsinogen (IRT). High levels of IRT suggested the baby had CF. When I learned of the gene discovery, I was convinced that it would be a game-changer for both screening test development and epidemiological research.

That’s because with the gene we could offer parents a more informative test. We could tell them not just whether their child had CF, but also whether they carried two copies of a CFTR mutation, which caused disease, or just one copy which made them a carrier.

CF Mutation
Parents carrying one good copy of the CF gene (R) and one bad copy of the mutated CF gene (r) are called carriers. When both parents transmit a bad copy of the CF gene to their offspring, the child will suffer from cystic fibrosis. Children who inherit just one bad copy will be carriers like their parents and can transmit the gene to their children. (Cburnett, CC BY-SA)

One might ask what is the connection between studying CF newborn screening and learning about the disease origin. The answer lies in how our research team in Wisconsin transformed a biochemical screening test using the IRT marker to a two-tiered method called IRT/DNA.

Because about 90 percent of CF patients in the U.S. and Europe have at least one F508del mutation, we began analyzing newborn blood for its presence whenever the IRT level was high. But when this two-step IRT/DNA screening is done, not only are patients with the disease diagnosed but also tenfold more infants who are genetic carriers of the disease are identified.

As preconception-, prenatal- and neonatal screening for CF have proliferated during the past two decades, the many thousands of individuals who discovered they were F508del carriers and their concerned parents often raised questions about the origin and significance of carrying this mutation themselves or in their children. Would they suffer with one copy? Was there a health benefit? It has been frustrating for a pediatrician specializing in CF to have no answer for them.

The challenge of finding origin of the CF mutation

I wanted to zero in on when this genetic mutation first starting appearing. Pinpointing this period would allow us to understand how it could have evolved to provide a benefit—at least initially—to those people in Europe who had it. To expand my research, I decided to take a sabbatical and train in epidemiology while taking courses in 1993 at the London School of Hygiene and Tropical Medicine.

The timing was perfect because the field of ancient DNA research was starting to blossom. New breakthrough techniques like the Polymerase Chain Reaction made it possible to study the DNA of mummies and other human archaeological specimens from prehistoric burials. For example, early studies were performed on the DNA from the 5,000-year-old Tyrolean Iceman, which later became known as Ötzi.

Ancient Burial
A typical prehistoric burial in a crouched fetal position. (Philip Farrell, CC BY-SA)

I decided that we might be able to discover the origin of CF by analyzing the DNA in the teeth of Iron Age people buried between 700-100 B.C. in cemeteries throughout Europe.

Using this strategy, I teamed up with archaeologists and anthropologists such as Maria Teschler-Nicolaat the Natural History Museum in Vienna, who provided access to 32 skeletons buried around 350 B.C. near Vienna. Geneticists in France collected DNA from the ancient molars and analyzed the DNA. To our surprise, we discovered the presence of the F508del mutation in DNA from three of 32 skeletons.

This discovery of F508del in Central European Iron Age burials radiocarbon-dated to 350 B.C. suggested to us that the original CF mutation may have arisen earlier. But obtaining Bronze Age and Neolithic specimens for such direct studies proved difficult because fewer burials are available, skeletons are not as well-preserved and each cemetery merely represents a tribe or village. So rather than depend on ancient DNA, we shifted our strategy to examine the genes of modern humans to figure out when this mutation first arose.

Why would a harmful mutation spread?

To find the origin of CF in modern patients, we knew we needed to learn more about the signature mutation—F508del—in people who are carriers or have the disease.

This tiny mutation causes loss of one amino acid out of the 1,480 amino acid chain and changes the shape of a protein on the surface of the cell that moves chloride in and out of the cell. When this protein is mutated, people carrying two copies of it—one from the mother and one from the father—are plagued with thick sticky mucus in their lungs, pancreas and other organs. The mucus in their lungs allows bacteria to thrive, destroying the tissue and eventually causing the lungs to fail. In the pancreas, the thick secretions prevent the gland from delivering the enzymes the body needs to digest food.

So why would such a harmful mutation continue to be transmitted from generation to generation?

Iron and Bronze Age Teeth and Bones
The Natural History Museum in Vienna, Austria, houses a large collection of Iron Age and Bronze Age skeletons which are curated by Dr. Maria Teschler-Nicola. These collections were the source of teeth and bones for investigation of ancient DNA and studies on ‘The Ancient Origin of Cystic Fibrosis.’ (Philip Farrell, CC BY-ND)

A mutation as harmful as F508del would never have survived among people with two copies of the mutated CFTR gene because they likely died soon after birth. On the other hand, those with one mutation may have a survival advantage, as predicted in Darwin’s “survival of the fittest” theory.

Perhaps the best example of a mutation favoring survival under stressful environmental conditions can be found in Africa, where fatal malaria has been endemic for centuries. The parasite that causes malaria infects the red blood cells in which the major constituent is the oxygen-carrying protein hemoglobin. Individuals who carry the normal hemoglobin gene are vulnerable to this mosquito-borne disease. But those who are carriers of the mutated “hemoglobin S” gene, with only one copy, are protected from severe malaria. However two copies of the hemoglobin S gene causes sickle cell disease, which can be fatal.

Here there is a clear advantage to carrying one mutant gene—in fact, about one in 10 Africans carries a single copy. Thus, for many centuries an environmental factor has favored the survival of individuals carrying a single copy of the sickle hemoglobin mutation.

Sickle Cell Gene
Individuals who carry two copies of the sickle cell gene suffer from sickle cell anemia, in which the blood cells become rigid sickle shapes and get stuck in the blood vessels, causing pain. Normal red blood cells are flexible discs that slide easily through vessels. (Designua/Shutterstock.com)

Similarly we wondered whether there was a health benefit to carrying a single copy of this specific CF mutation during exposures to environmentally stressful conditions. Perhaps, we reasoned, that’s why the F508del mutation was common among Caucasian Europeans and Europe-derived populations.

Clues from modern DNA

To figure out the advantage of transmitting a single mutated F508del gene from generation to generation, we first had to determine when and where the mutation arose so that we could uncover the benefit this mutation conferred.

We obtained DNA samples from 190 CF patients bearing F508del and their parents residing in geographically distinct European populations from Ireland to Greece plus a Germany-derived population in the U.S. We then identified a collection of genetic markers—essentially sequences of DNA—within the CF gene and flanking locations on the chromosome. By identifying when these mutations emerged in the populations we studied, we were able to estimate the age of the most recent common ancestor.

Next, by rigorous computer analyses, we estimated the age of the CF mutation in each population residing in the various countries.

Sickle Cell and Malaria
Two copies of the sickle cell gene cause the disease. But carrying one copy reduces the risk of malaria. The gene is widespread among people who live in regions of the world (red) where malaria is endemic. ( ellepigrafica)

We then determined that the age of the oldest common ancestor is between 4,600 and 4,725 years and arose in southwestern Europe, probably in settlements along the Atlantic Ocean and perhaps in the region of France or Portugal. We believe that the mutation spread quickly from there to Britain and Ireland, and then later to central and southeastern European populations such as Greece, where F508del was introduced only about 1,000 years ago.

Who spread the CF mutation throughout Europe?

Thus, our newly published data suggest that the F508del mutation arose in the early Bronze Age and spread from west to southeast Europe during ancient migrations.

Moreover, taking the archaeological record into account, our results allow us to introduce a novel concept by suggesting that a population known as the Bell Beaker folk were the probable migrating population responsible for the early dissemination of F508del in prehistoric Europe. They appeared at the transition from the Late Neolithic period, around 4000 B.C., to the Early Bronze Age during the third millennium B.C. somewhere in Western Europe. They were distinguished by their ceramic beakers, pioneering copper and bronze metallurgy north of the Alps and great mobility. All studies, in fact, show that they were into heavy migration, traveling all over Western Europe.

Bell Beaker Sites
Distribution of Bell Beaker sites throughout Europe. (DieKraft via Wikimedia Commons)

Over approximately 1,000 years, a network of small families and/or elite tribes spread their culture from west to east into regions that correspond closely to the present-day European Union, where the highest incidence of CF is found. Their migrations are linked to the advent of Western and Central European metallurgy, as they manufactured and traded metal goods, especially weapons, while traveling over long distances. It is also speculated that their travels were motivated by establishing marriage networks. Most relevant to our study is evidence that they migrated in a direction and over a time period that fit well with our results. Recent genomic data suggest that both migration and cultural transmission played a major role in diffusion of the “Beaker Complex” and led to a “profound demographic transformation” of Britain and elsewhere after 2400 B.C.

Determining when F508del was first introduced in Europe and discovering where it arose should provide new insights about the high prevalence of carriers—and whether the mutation confers an evolutionary advantage. For instance, Bronze Age Europeans, while migrating extensively, were apparently spared from exposure to endemic infectious diseases or epidemics; thus, protection from an infectious disease, as in the sickle cell mutation, through this genetic mutation seems unlikely.

As more information on Bronze Age people and their practices during migrations become available through archaeological and genomics research, more clues about environmental factors that favored people who had this gene variant should emerge. Then, we may be able to answer questions from patients and parents about why they have a CFTR mutation in their family and what advantage this endows.

Bell Beaker Artifacts
Examples of tools and ceramics created by the Bell Beaker people. (Benutzer:Thomas Ihle via German Wikipedia, CC BY-SA) 

This article was originally published on The Conversation. The ConversationMatthew E. Baker, Professor of Geography and Environmental Systems, University of Maryland, Baltimore County

The cheeky Gnomes taking over Wroclaw

The cheeky Gnomes taking over Wroclaw

Cute as they may be, each statue is a nod to the Orange Alternative, an anti-Soviet resistance movement that helped bring down Poland’s oppressive communist regime in the 1980s.

Wrocław is Poland at its most charming and, for many, its least pronounceable (it’s ‘vrohtz-wahv’). Situated sublimely on the banks of the Odra river, the ‘Polish Venice’ boasts 130 bridges connecting 12 islands, one of…

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The cheeky Gnomes taking over Wroclaw

Cute as they may be, each statue is a nod to the Orange Alternative, an anti-Soviet resistance movement that helped bring down Poland’s oppressive communist regime in the 1980s.

Wrocław is Poland at its most charming and, for many, its least pronounceable (it’s ‘vrohtz-wahv’). Situated sublimely on the banks of the Odra river, the ‘Polish Venice’ boasts 130 bridges connecting 12 islands, one of Europe’s most breath-taking market squares, and a parade of pastel-coloured Renaissance mansions flanked by gas streetlamps that are still lit by hand each night.

But hidden beneath the city’s Gothic spires and Baroque palaces, there’s a tiny world waiting to be discovered: a legion of little people, each no more than a foot tall, lurking in the alleyways, peeking out from the doorways and swinging from the lampposts. Cheeky, bronze and oozing with personality, these pint-sized statues are the dwarves of Wrocław, and they’ve started running rampant.

A parade of pastel-coloured Renaissance mansions ring Wrocław’s massive Market Square (Credit: Credit: Eliot Stein)

A parade of pastel-coloured Renaissance mansions ring Wrocław’s massive Market Square (Credit: Eliot Stein)

 

No-one knows just how many of these merry munchkins exist anymore, but officials estimate that there are now more than 400 of the little fellas going about their business. On my way from the bus station to the Old Town, I spotted a reclining dwarf cheerily sunning himself in the park, stubbed my toe on a bearded blighter working on a laptop near a cafe, and instinctively moved out of the way when I saw two boot-sized firemen rushing to put out a blaze.

Most visitors have no idea why these gnomes are so important

Stay long enough and you may find an entire society of dwarf merchants, bankers, buskers, professors and postmen. There’s a doctor holding a mini stethoscope, a gardener pushing a teeny wheelbarrow and a dwarf dentist extracting itty-bitty dwarf teeth. One is snoring by a hotel, two are kissing in front of the marriage registration office and 19 are performing a dwarf symphony outside the city’s concert hall.

“We lost count of their population several years ago,” admitted Robert Rasała, who manages the official dwarf information centre in the city’s market square. “Now, people are coming from all over the world to hunt for them, but most visitors have no idea why they’re so important.”

A tiny bronze dwarf withdraws money at the ATM steps away from a bank in Wrocław’s Market Square (Credit: Credit: Eliot Stein)

A tiny bronze dwarf withdraws money at the ATM steps away from a bank in Wrocław’s Market Square  (Credit: Eliot Stein)

Twee as they may be, each statue is actually a nod to the Orange Alternative, an anti-Soviet resistance movement born in Wrocław that used dwarves as its symbol and helped topple Poland’s oppressive communist regime in the 1980s.

The dwarves gave us something to laugh at

Armed with spray cans and led by an artist at the University of Wrocław named Waldemar ‘Major’ Fydrych, the group peacefully protested the government’s censorship of free speech and public gatherings during the period of martial law from 1981 to 1983 by defacing communist propaganda with surrealist-inspired street art – specifically, paintings of mischievous little gnomes.

“It was a terrible, dangerous time. You couldn’t go out on the streets at night and there were tanks and soldiers in the main square,” said Arkadiusz Förster, a journalist for Poland’s national Gazeta Wyborcza newspaper. “The dwarves gave us something to laugh at, and that was the whole idea: to show how absurd the situation was and encourage people not to be afraid.”

Wrocław’s two most famous dwarves, nicknamed Sisyphus, push against each other (Credit: Credit: Eliot Stein)

Wrocław’s two most famous dwarves, nicknamed Sisyphus, push against each other (Credit: Eliot Stein)

As the movement gained popularity, Fydrych began leading whimsical public marches through the streets of Wrocław, advocating for ‘dwarves’ rights’. Police tried to crack down on these subversive pro-gnome gatherings, but the resulting arrests made national news and only succeeded in making the authorities look ridiculous. Soon, tiny dwarf drawings began popping up on streets throughout Poland. The movement culminated on 1 June 1988, when 10,000 protestors descended on downtown Wrocław wearing orange cone-shaped hats and chanting ‘Freedom for the dwarves!’.

“That event became known as the Revolution of Dwarves,” Förster said. “It showed the world that communism was unravelling, and that people of all ages could join together to fight against the system peacefully.”

It showed the world that communism was unravelling

In 2001, the city decided to commemorate its history of artistic anti-communist rebellion by placing a bronze statue of a large dwarf – named Papa Dwarf – on Świdnicka street, where members of the Orange Alternative used to gather. Four years later, a local sculptor named Tomasz Moczek had an idea: what if he created tiny bronze dwarves, each representing a different part of Wroclaw’s history or daily life and placed them around the city?

Tomasz Moczek’s favourite dwarf, The Butcher, peers solemnly towards Wrocław’s medieval slaughterhouse (Credit: Credit: Eliot Stein)

Tomasz Moczek’s favourite dwarf, The Butcher, peers solemnly towards Wrocław’s medieval slaughterhouse (Credit: Eliot Stein)

Seeing the Dwarves

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Today, there is only one original dwarf drawing on the walls of Wrocław created by the Orange Alternative. To find it, head to St. Smoluchowskiego 22.

Don’t want to download an app or purchase an official Wrocław dwarf map to go gnome-spotting? No problem. Check out this Google Mapof some of the Old Town’s most famous little residents.

Pair history with dwarf-hunting during the free Dwarves and Communismtour.

Wrocław’s mayor commissioned Moczek to create the first five, and his early designs – including a hatchet-wielding butcher staring solemnly at the city’s medieval slaughterhouse and a trio of gnomes working together to push a human-sized shopping cart outside a city market – proved so popular that they’ve now spawned a sizable sub-population.

Today, Moczek has created more than 100 of Wrocław’s gnomes, and inspired a collection of young sculptors to design delightfully quirky dwarf statues for local charities, shops and organisations. As the gnomes’ population has grown, people from all over the planet have started coming to find as many of these remarkably imaginative 1ft-tall wonders as possible.

“I wanted to create something that’s completely integrated into the city – something that seems like it’s always been there that you’re just now discovering.” Moczek said in his studio, holding up a model of the first dwarf he ever created: a crouching gnome washing his clothes in the Odra river.

“How come that dwarf isn’t wearing shoes?” I asked.

“He took them off so they wouldn’t get wet,” Moczek said. “Each dwarf has his own distinct character. I just create them as they are.”

Sculptor Tomasz Moczek insists this dwarf removed his shoes because he didn’t want to get them wet while washing in the river (Credit: Credit: Eliot Stein)

Sculptor Tomasz Moczek insists this dwarf removed his shoes because he didn’t want to get them wet while washing in the river (Credit: Eliot Stein)

In fact, the city recently created an official website to help people better acquaint themselves with its littlest residents. Each has a name, a detailed backstory and unique habits. You can vote for your favourites, register new arrivals or catch up on the latest dwarf gossip. There are also dwarf-hunting maps, apps and walking tours; an annual September festival with a ‘Great Dwarf Parade’; and a winter tradition where locals dress the dwarves in little scarves, hats and mittens to help them stay warm.

After inviting me into his workroom, Moczek led me on a walking tour through Wrocław’s Old Town to point out his favourite petite progeny and reveal his process.

It takes three months to create each 4kg to 5kg creation, he explained, and it all starts with a sketch. He then creates a clay mould of the design that acts as a negative for the silicone and gypsum model that follows. Moczek makes four small holes in the model and carefully pours hot wax into it, making sure that the form has the same thickness throughout its body. After he completes any final retouching, he places the model into a 700C oven for 12 hours. The wax melts, leaving a cavity, and Moczek pours molten bronze into this area to make a cast. He then reheats it up to 1200C as the little dwarf gains mass and grows into a street-ready statue.

It takes sculptor Tomasz Moczek three months to make each gnome (Credit: Credit: Eliot Stein)

It takes sculptor Tomasz Moczek three months to make each gnome (Credit: Eliot Stein)

“The hardest part is the moment I have to give them away,” Moczek said, bending down to examine Sleepyhead, who holds a teeny spear and was supposed to guard a knee-high gate leading to the mythical ‘Dwarf City’, but fell asleep on the job. “Sometimes, I like to go to their new resting places to see how they’re doing.”

As we approach Moczek’s most famous figurines – a pair of pals pushing a granite ball in opposite directions (named Sisyphus) – I asked him if he’s old enough to remember life in Wrocław during martial law, and he grew quiet.

“I was nine years old and wanted to get ice cream with my mother,” he said, staring at the ground. “We went outside and saw tanks coming and people running away. My mother fell down and got trampled. I didn’t know what to do so I just threw rocks at the tanks and hoped they’d stop.”

Tomasz Moczek: "Maybe it’s just art, but for me, it’s something more." (Credit: Credit: Eliot Stein)

Tomasz Moczek: “Maybe it’s just art, but for me, it’s something more.” (Credit: Eliot Stein)

As Moczek raised his head, a stone-faced older gentleman slowly approached the two bronze figurines. The man bent down, snapped a picture and couldn’t help but laugh at the sight of mischievous little dwarves tramping through the streets.

“Maybe it’s just art,” Moczek said, flashing a smile. “But for me, it’s something more.”

By Eliot Stein 18 October 2017  BBC Travel

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