Asthma is the most common chronic disease in childhood and the most common reason children are hospitalized. The 2019 Novo Nordisk Prize recipient, Hans Bisgaard, found that giving fish oil to women during pregnancy reduces the risk of their children getting asthma by 30% and significantly more if they have a certain genetic profile. His latest result shows that fish oil also influences the development of the child’s nervous system, including cognition.
Children need to be able to participate in exercise and physical activity to develop their physical agility. However, children with asthma have problems breathing when they run. Most children with asthma therefore stop exercising. Today, 235 million people worldwide have asthma. It is the most common disease among children, and the physical effects of having asthma are far from the only ones.
“If you can’t participate, then you are not picked for the team. And if you’re not picked for a football team in school, you feel different than the others, so preventing the disease is crucial. We found that we can avoid 30% of all cases of asthma among children by giving pregnant mothers fish oil. Further, if we can also screen the mothers’ blood for the FADS gene, we can say specifically: you have the right genes, you do not have to take fish oil; or you do not have the right genes, so you should really take the fish oil. We call this precision prevention,” explains Hans Bisgaard, Professor, COPSAC, Copenhagen University Hospital, Herlev-Gentofte.
Unethical not to include children in research
Like many other children with asthma, Hans Bisgaard experienced the physical and psychological effects of asthma as a child. This is one of the main reasons why he has dedicated the last 35 years of his life to investigating the causes of asthma and improving the treatment of children with asthma. His lifelong dream is to prevent or cure asthma to avoid the psychological stigma he experienced as a child.
“My doctor gave me a note for the school saying that I should not play football, and I was told to sit on the line to watch the football. Clearly that affects you, and I think it still affects me today.”
After finishing school, Hans Bisgaard became a medical student. He wanted to specialize in orthopaedic surgery because he was good with his hands, but jobs were lacking in that field. Instead, he started as a physician at a children’s hospital and there he found his lifelong career interest.
“I built my research in paediatrics for several reasons – one was that there is very little science, very little evidence in what we are doing today, and that annoyed me. We did what we usually do, and at that time it was because people thought you cannot involve children in research. That was considered unethical, but my viewpoint was that it is more unethical if you do not involve them. Because if you do not involve them in research, well, what you are doing in daily practice without evidence is unethical.”
Hans Bisgaard knew from his own experience that young children with asthma were undertreated. The attitude at that time was that, since most children outgrow the disease, it was better not to treat them.
“I thought: ‘Yeah right, they do outgrow it,’ but in the meantime I believe the obligation of a doctor is to try to cure and for certain to improve their life. I mean you could use the same argument in the emergency room: ‘You have broken your leg, but that will cure itself, if you just wait.’”
From firefighter to fire inspector
Hans Bisgaard began his scientific career in the late 1980s with a clear focus on inflammation in asthma, especially pioneering studies on the role of cysteinyl leukotrienes in asthma, which provided major results for developing the cysteinyl leukotriene antagonist, montelukast, which nowadays is a backbone in asthma treatment, especially for young children. Soon after, his attention was drawn to the possible use of steroids for treatment.
“When we started introducing inhaled steroids, that sparked an outcry. How can you give steroids to a young child who is growing? But we did a lot of those studies, and it was highly efficacious and safe, so because of that, this paradigm changed from giving the old treatment to using this, which is still the mainstay of treatment today.”
However, Bisgaard’s group wanted more, so although he began his research career trying to develop treatments, he now turned his attention to understanding asthma.
“I would say that treatment today is excellent, so we quickly learned how to ‘put out the fire’, but I thought it would be better to prevent the fire, so we changed the strategy from treatments – being the firefighter – to being the fire inspector who prevents the fire, and that is what we have been doing for the past 20 years. Trying to prevent this disorder from developing.”
Up against a dogma
In the mid-1990s, Hans Bisgaard and his group developed a method for measuring lung function among children older than 2 years. These methods proved critical for the clinical evaluation of lung function among young children and to document the effect of treatment. Studying the lung function of very young children also led to a big surprise.
“We collected secretion samples from the children and sent them for analysis. We found pathogenic bacteria – those typically associated with pneumonia – in 20% of the children, which was very much a surprise to me, because everybody thought that lungs are normally sterile. That has been the dogma in the textbooks, but we showed that 20% were actually carrying bacteria without having symptoms.”
Because the children had no symptoms when the sample was taken, the researchers chose not to treat them further. But 5 years later they decided to examine the children again.
“Those who had bacteria in the airways had a four-fold increased prevalence of asthma, so apparently there was a link between the bacteria and asthma. But is it the chicken or the egg? Do you have this colonization because you have asthma or do you get asthma because of the bacteria? That is still an open question.”
The results were published in the prestigious New England Journal of Medicine. Likewise, in 2011, Bisgaard’s group used DNA sequencing-based techniques to demonstrate an association between the infant gut microbiome and allergy at school age and that 1-year-old children with an immature bacterial composition of gut bacteria have an increased risk of developing asthma.
“One of the truly remarkable findings from our cohort is the discovery that reduced bacterial diversity in the infant’s intestinal flora is associated with an increased risk of allergic sensitization. We also demonstrated that the unstimulated topical immune signature is upregulated in the neonates who are colonized.”
The asthma goldmine
An outstanding asset for many of the exceptional scientific contributions from his group is based on an initiative by Hans Bisgaard in 1998 of establishing Copenhagen Prospective Studies on Asthma in Childhood (COPSAC). Hans Bisgaard’s group has carried out two decades of research based on the longitudinal cohort studies COPSAC2000 and COPSAC2010 – a unique combination of detailed clinical phenotyping, basic research methods and randomized clinical trials.
“This has been a cornerstone for the research we have performed in the past 20 years. We follow the mother during pregnancy. We follow the young child up through life. We see them every 6 months, and we examine them for clinical outcomes such as asthma, eczema, allergies, lung function, bronchial responsiveness, growth and puberty. We take samples of urine, blood and hair, measure height and lung function, skin strips, sampling from the nose, from the airways, from faeces – you name it. Everything.“
The initial programme – COPSAC2000 – involved 411 children born to mothers with asthma between 1998 and 2001. Impressively, the children in this programme have been monitored at the COPSAC research unit from birth and every 6 months for 7 years, and yearly thereafter. The COPSAC participants have just completed the 18-year visit, with an impressive follow-up rate of almost 90%.
“That is totally unique to Denmark. That is why they come to us from Harvard, from New York University and the University of Chicago. They come to us because we have this amazing material. This is something where we have really pushed the clinical research, and I think it is really a goldmine.”
One valuable gold nugget the researchers dug out of the mine was genomic information. From the COPSAC2010 cohort, Hans Bisgaard’s group has contributed to the highly important discovery of the filaggrin mutation, which today remains the strongest known genetic variant leading to atopic diseases such as asthma, rhinitis and eczema. This study was published in Nature Genetics.
“Similarly, in a unique design in the Danish National Patient Registry, we also found a totally new gene that is very plausible. The gene is expressed in the airways, and we know its structure.“
Within a relatively small group of children, in another study published in Nature Genetics, Hans Bisgaard and colleagues replicated all known asthma genes and discovered the new CDHR3 variant, which is a functional variant expressed in the airways and a functional rhinovirus receptor, suggesting this as a potential important novel target for industry in the hunt for new ways to manage asthma. Hans Bisgaard’s group was also the first to demonstrate interaction between asthma genetics and airway viruses.
“Our combination of detailed and comprehensive clinical phenotyping, basic research methods and clinical trials in the COPSAC cohorts is the cornerstone of my research strategy. You can do whatever fancy DNA analysis you want to, but if you do not have the clinical foundation and know how to translate between the two, you are in trouble. Today, we are recognized internationally as unique for that specific reason.”
Crazy people change the world
Today, translation is a buzzword and fashionable, but 35 years ago, when Hans Bisgaard started doing it, it was far from fashionable. But Hans Bisgaard knew already then, that solving the asthma puzzle required getting basic researchers and clinicians to talk to each other.
“Trying to bring the two together – at least at that time – did not happen often, but I have always done it. Bringing clinicians and basic scientists together has always been part of my research, because it is so rewarding. Everybody liked it. The basic scientists said: ‘Wow, a child’, but the paediatricians were rewarded by finding evidence that they could not find themselves.”
However, according to Hans Bisgaard, building bridges between clinical science and basic science takes more than just great data. You need to have a team with open-minded people, who do not stay in the silos they come from and who – every now and then – can accept to be stupid in the eyes of their basic or clinical colleagues.
“I am an entrepreneur. So I am good at initiating projects and carrying them through to a result. Fortunately, I have great people from different scientific fields around me. It does not make sense to hire smart people and then tell them what to do. We hire smart people so they can tell us what to do. Because the people who are crazy enough to think that they can change the world are the ones who push humanity forward.”
Boys catch up with girls
Lifestyle changes in Western societies have resulted in a decreasing intake of micronutrients such as vitamin D and omega-3 fatty acids. In 2016, Hans Bisgaard published a clinical trial for mothers in the third trimester of pregnancy in the COPSAC2010 cohort that turned out to be his major career breakthrough.
“In a study of 700 pregnant women, we gave fish oil to one group and olive oil to the other. We then followed the children for, now 8 years, but broke the code and published around age 5, and we saw that those kids whose mothers had fish oil had a 30% reduction in asthma, which is huge.“
Further, the study showed that the women who lacked one or two alleles of the FADS gene did not benefit from the fish oil.
“So combining the two, we are able to do precision prevention. We can analyse the fatty acids in the blood of the mother. We can analyse for the FADS gene and, combining the two, we can say specifically: ‘You must have a supplement of fatty acids, but you do not have to, because your blood level is okay, you have the right genes, you do not have to.’”
Further, taking omega-3 fatty acids also led to a reduced risk of lower respiratory tract infections in childhood, improved cognitive and motor development and improved growth.
“Language development was accelerated by 3 weeks. Their milestones, when they can walk and talk, were accelerated. They saw improved growth by 6 years. We did cognitive tests by age 2 years and showed that girls normally are more intelligent than boys, but if the mother had received this supplementation with fish oil, the boys caught up with the girls.“
A canary in the coal mine
The fish oil treatment appeared to have an amazing effect, which Hans Bisgaard emphasizes is a multi-organ effect, since one intervention affected both the inflammation system in the airways, the nervous system and growth.
“Three totally independent compartments – meaning that there is some shared underlying mechanism, since taking fish oil affects three different compartments. I think this is fascinating, and it brings me to my favourite hypothesis and keeps me awake at night.”
This is just one indication of a shared underlying mechanism. Another one is the fact that caesarean section increases the risk of asthma, rheumatoid arthritis, inflammatory bowel disease and leukaemia. Together with the evidence of a genetic overlap, Hans Bisgaard is convinced there is a connection.
“I believe that asthma is the canary in the coal mine. In the old days, when the canaries stopped singing in the coal mine, you better get out, because there was some gas leak. I see asthma in early life as this canary. It indicates that something is going wrong and you might have a trajectory towards various inflammatory disorders. Asthma is a good sensor, because it starts early in life and is very common.”
The 2019 Novo Nordisk Prize was awarded on Friday, 15 March to Hans Bisgaard, Professor, COPSAC, Copenhagen University Hospital, Herlev-Gentofte.