Release date: 2018-06-11

In the late 1970s, an unidentified man with hemoglobin level (Hb) was sent to the Namsos Hospital in Norway, and the family members of the man were also diagnosed with the disease. As a treatment doctor for this family, Kjell Kanelønning thoroughly examined the patient and his family, but no cause was found. Until the emergence of CRISPR technology 35 years later, the cause of this familial blood disease was finally cracked.

Dr. Anders Waage (left) and Dr. Anders Sundan, both with the Norwegian University of Science and Technology, played a critical role in understanding how a Norwegian family could have such high hemoglobin levels. Credit: NTNU

"The normal Hb value is between 12.5 and 17 (ie grams of hemoglobin per 100 ml of blood), and the Hb value of people with this disease is around 20. This value far exceeds the stimulant limit ( The main indicator of doping is the increase in hemoglobin in the blood,” said Anders Waage, professor of clinical and molecular medicine at the Norwegian University of Science and Technology.

Waage is also a doctor. In the early 1990s, when he met this family from Trøndelag County at St. Olavs Hospital, he decided to get involved in the story. Through testing, Waage found that family members of the patient were neither drug-taking nor sick, and half of the family members were born with this condition.

Later, more researchers began to be interested in this case, including Bernt Ly at the University Hospital of Oslo. In 1983, he and Kanelloning and others wrote a scientific article on this phenomenon. Waage recalls: "It seems that all the clues they tracked at the time are dead, and nothing can be checked."

As time passed, Waage successively ordered new tests and investigations, but did not find clues. Researchers are constantly asking questions about what will happen next.

At the time, a Finnish skier appeared in the medical literature, and he won several gold medals at the World Championships and the Olympics. The test showed that his hemoglobin level was 22, which was only explained by stimulants. However, when Finnish doctors examined other family members of skiers, they found that more than 30 of them had an average Hb level of more than 20.

By the end of the 1990s, after medical methods improved, the researchers found that the erythropoietin (EPO) hormone receptor in the Finnish family had a congenital mutation that caused the receptor to remain excited (although the EPO did not Body combination). This causes excessive red blood cell production and an increase in the amount of Hb in the blood. So far, scientists have confirmed that this condition is congenital and called it familial polycythemia. Despite the same high Hb results, it is clear that this is not caused by the infusion of blood stimulants.

For Waage, research by Finnish families means that the family of Trøndelag in Norway may eventually find the answer. “We can use the same method as the Finns. In 1998, a master's thesis wrote this case. The student observed the EPO receptors in Norwegian families to determine if their mutations were similar to Finnish families,” he said.

"But the answer is no. Students haven't found anything, and we're back in place," said Anders Sundan, co-head of the study.

Waage and Sundan admit that they felt a little discouraged at the time. Since this has not had a big impact on the family, no one is trying to push this research. In addition, there was no new method at the time, and the researchers did not seem to have any other solutions except waiting.

01. A little discovery

Time was pushed to 2004, and Waage participated in the annual meeting of the European Hematology Association. There, he heard a speech by Professor Radek C. Skoda of the University of Basel. Later, Waage contacted Skoda to discuss the family problem of Trøndelag. Skoda was very interested in this phenomenon and they made contact. In the next few years, they collected more information and exchanged new data and opinions.

With the continuous improvement of methods, testing and analysis tools in the first decade of the new millennium, this research finally made a breakthrough in 2008. The researchers found that the limited areas of the genome were identical among all family members affected by increased levels of hemoglobin. This region contains 215 genes that have been sequenced. To everyone's surprise, they discovered mutations in the EPO gene. Family members with high Hb values ​​have mutations, while family members with normal Hb values ​​have no mutations. This finding points to a mistake in the EPO itself.

02. Want more

After this discovery, the project was interrupted for a while. "We could have been satisfied with finding the mutation that caused this, that is, the mutation in the EPO gene is the cause of familial polycythemia. Such a new discovery is interesting in itself, but there is still an unresolved problem that is bothering us." The researchers pointed out.

They expect that this mutation may result in impaired function. So how is this all connected? This is what they want to continue to explain. A possible answer may be slowly maturing, but answering the question is not easy due to lack of methods.

03. The gospel is coming

In 2016, Waage received an email from Dr. Skoda saying that he did a lot of molecular work and achieved good results. With the advent of CRISPR gene editing technology, researchers are free to cut and paste DNA fragments and create new gene sequences.

The first thing the team did was to insert the mutation into a cell that produces EPO. Sure enough, when the mutation was inserted, the cell produced 10 times more EPO. When the EPO content increased, the erythrocyte production increased and the hemoglobin value rose. high. In the end, they found the right mutation.

04. Curiosity drives

Waage said: "For 35 years, this research has been driven by curiosity. Four generations of affected family members have increased the number of people with elevated or normal Hb, making it easier to find links with mutations. But the most important The tremendous advances in technology during this period have made it possible to prove that mutations do cause an increase in Hb levels."

05. Unique family of rare creatures

So, what is the significance of such research beyond this type of family? Obviously, this finding has a transfer value that helps explain the corresponding mutational changes in other diseases. "This is self-contradictory. Under this cause, the loss of one base leads to an increase in yield," Waage said.

“After 25 years, we discovered the mutation that led to this situation; after 35 years, we can explain why this mutation causes an increase in erythropoiesis. On this way, we met a Finnish skier and accelerated our search for answers. The pace. This is a rough and interesting journey, but fortunately, it has finally paid off." Waage said, "At this point, the mystery of Trøndelag blood has officially announced."

The above results are titled "A Gain-of-Function Mutation in EPO in Familial Erythrocytosis" and published in the top medical journal New England Journal of Medicine.

06. Affect health?

For affected family members, this mutation does not cause disease, but may trigger a common headache that can be treated with traditional bloodletting. Once the excess blood is cleared, they will feel good.

So what about their physique? To the surprise of researchers, patients with high levels of Hb at birth are different from those with elevated levels of Hb through stimulants. There is no doubt that increasing the level of Hb with additional EPO is very effective in improving health. However, people who have high levels of EPO and Hb at birth do not receive additional health promotion effects.

Reference materials:

1) Family blood mystery solved

2) A Gain-of-Function Mutation in EPO in Familial Erythrocytosis

Source: Bio-Exploration

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