It is now almost 50 years since Jan Holmgren started in his research field – almost by accident. He was 26, had recently been awarded his PhD, and his superior offered him his own laboratory and two PhD students – if he chose to research cholera.
“I was given a free hand to do almost whatever I wanted, as long as it concerned cholera,” he says.
Married his PhD student
The first PhD student was Ann-Mari Svennerholm, who later married Jan Holmgren, and who has worked together with him during all these years. They are both professors at the Department of Biomedicine at the University of Gothenburg.
“I had originally planned to become a psychiatrist, but I found working with research in developing countries so interesting that I changed tracks,” says Ann-Mari Svennerholm.
The reason why it was cholera was because Jan Holmgren’s superior at the time, the world-famous immunologist Örjan Ouchterlony, had worked with a major cholera epidemic in Egypt in the 1940s.
One of the researchers he had met there later contacted him, wanting help to develop a better vaccine. A new epidemic was spreading across the world, and recent studies had shown that the injection vaccine that had been available for 90 years was almost ineffective.
Two parallel tracks
Their cholera laboratory began working in 1970, and came to run along two parallel tracks that could be easily combined. One was to explain the mechanism of the disease. A US researcher had just purified a protein that could be the toxin that caused cholera diarrhoea. Jan Holmgren therefore started work together with his other PhD student, Ivar Lönnroth, to understand how the protein was constructed and functioned.
Ann-Mari Svennerholm worked on the other track, which tried to map the immune defence against cholera, and how this could be stimulated using vaccine.
“Attempting to tackle both these major issues at the same time without blinking was of course arrogant. But in research you need luck as well, which we had,” establishes Jan Holmgren.
He and Ivar Lönnroth could soon show how the toxin was constructed, and how it gave rise to diarrhoea in laboratory animals. At first, they had difficulty publishing their results, as they contradicted earlier research, but in autumn 1973 Jan Holmgren was invited to speak at a major cholera conference in USA. This was a turning point.
“Cholera suddenly became the best understood infectious disease in terms of molecular function. At the same time, Ann-Mari’s thesis work showed how the protective mechanisms in the gut worked in laboratory animals. We were unique in having those twin tracks.”
Vaccine studies in Bangladesh
Some of the first vaccine trials on humans were conducted in Bangladesh in 1979. The research centre they collaborated with there had a small, simple clinic in a village, where those vaccinated came to talk about their health.
“To thank them for participating, we could help treating minor illnesses; we had a small bag with medicines such as cough mixtures and antibiotics,” says Ann-Mari Svennerholm.
Her study showed that oral vaccine resulted in the strongest immunity, as it best stimulated the local immune defence in the gut.
In the migration work from laboratory animals to humans, the research team collaborated well with bodies such as the then-extant Swedish Bacteriological Laboratory, which manufactured vaccine for clinical studies. Jan Holmgren thinks that there were advantages in collaborating with a governmental laboratory.
“They don’t need to consider factors such as patents, protection and profits so much. If it had been a private company, we would surely have been more tied down. But now it was possible for us to transfer technology freely,” he establishes.
The Swedish vaccine was named Dukoral, and in 1983 the World Health Organization (WHO) supported them in a big field trial in Bangladesh. This was an expensive study involving 90 000 persons, where the Swedish vaccine was compared to another vaccine and placebo, and followed up for several years.
Licenced throughout the EU
The positive results meant that in 1993, Dukoral was licenced throughout the EU – just over 20 years from the start. But Jan Holmgren doesn’t think this feels like such a long time. The problems came later.
“Although we had produced an effective and relatively cheap vaccine, it has taken a long time for the WHO and other authorities to work on controlling cholera using vaccine.”
He thinks this might be because they were worried that a cholera vaccine would become so popular that countries would neglect building up both the treatment of other diarrhoea diseases, and also infrastructure for water and sewage. He says that it is only after the earthquake catastrophe in Haiti in 2010 that attitudes have changed.
“After Haiti, they changed tracks completely; now, authorities perhaps place even too much trust in what cholera vaccine can achieve.”
He considers that one reason why cholera vaccine was not manufactured in sufficient quantity was that there was no commercial market – it is aimed at the poorest populations in the the poorest countries. But Dukoral has had one advantage, as it also protects against ‘tourist diarrhoea’, which is caused by E. coli bacteria, ETEC.
The team is now working on developing an ultra-cheap cholera vaccine, costing half a dollar per dose, and a vaccine in capsule form. For 30 years, Ann-Mari Svennerholm has also worked on developing a specific vaccine against ETEC, which is also the most common cause of diarrhoea in children in developing countries.
Fixed point in their specialist knowledge
Over the years, the research team has worked on the basis of what Jan Holmgren calls the ‘windscreen wiper effect’:
“If you have a fixed point in your specialist knowledge, then you can afford to have a broad perspective, and apply that knowledge also in other areas.”
His driver during all these years has been curiosity.
“‘How does it work?’ That’s the fascination of basic research, to understand more about disease mechanisms and see whether they are applicable in other systems.”
They have found that the construction of the cholera toxin is a model also for other toxins, and they have been following tracks that have turned out to be promising in laboratory animals, but have not yet been used in humans. Examples are vaccines against Type 1 diabetes, arthritis, MS-type symptoms and eye disease.
Ann-Mari Svennerholm thinks that their entire research journey has been incredibly stimulating.
“The best bit has been moving from basic research studies to testing the products in developing countries and seeing how they work. That is fantastic, and not many people get to have that opportunity.”
Their research team has received funds from both Swedish funding bodies, such as the Swedish Research Council, the Wallenberg Foundations, the Swedish Foundation for Strategic Research, and the Swedish International Development Cooperation Agency, and from international ones, such as the Gates Foundation and various EU programmes. When they started in the 1970s, there were few who competed for funds. Today there is much more money – but also many more who are fighting for research funding.
Ann-Mari Svennerholm’s most important advice to junior researchers is to not give up.
“Junior researchers must learn that there are no easy matches, it takes time. You have to be very stubborn and never give up, even if you suffer reverses, you just have to keep on going until things fall into place.”