A belated epitaph to academic Drago Ikic.

Viruses, epidemic, pandemic, immunity, vaccine. Those are the most-searched items on internet search engines in the time of corona. They say this new reality we found ourselves in has restored our faith in science. This up-and-down swearing on scientists has gone so far over the past weeks and months that perpetuating this matrix of idolatry and fanaticism has come to resemble a religion. Phrases like “historic” and “revolutionary” times were used, as well as “paradigm shifts”. The inflation of opinions in this battle of survival has reached unprecedented levels. Fear is innate to humans, as is the drive for survival, leading us to actively face our fears and persevere. “The invisible enemy” has challenged our future, our health, our economies, our stability, our security.

Under a torrent of texts and scenarios, amid a frantic search for the vaccine, we’ve found ourselves in a jungle, barely able to see the trees. And in this cacophony we are living in, voices have risen once again in Croatia on the revitalisation of the Institute of Immunology. Institute 2.0, so to speak. A place erased from the global relevance map by provincial politics, petty interests, cronyism, and corruption. At the front lines of the battle against the coronavirus, the name of this institution is dragged around like a dead cat, from seeing devils in the protagonists of its breakdown to calls from newly-minted sovereignists for its revitalisation since, as they say, the Institute of Immunology patented and sold vaccines everywhere from the Middle East to the Soviet Union.

AB OVO

When using the state-of-the-art tool of modern research technology, also known as Google, you will not find many hits on Drago Ikic. The top of the first result page consists of two in-memoriam pieces written after his death in 2004, a one-sentence Wikipedia entry, and one reference in the Croatian Academy of Arts and Sciences. Drago Ikic, the founder and chairman of the Institute of Immunology during its heyday, went into retirement before the age of the Internet, which would explain why his name may not be found even on the Institute’s website, www.imz.hr.

Under the section titled “About the Institute” there is a caption on the genealogy of the Institute, which tells the entire history of the institution, but fails to mention the name of its founder and his role in that history. That great history, which he built. Before the age of the Internet. And this is despite the fact that the bust of Drago Ikic still stands in front of this institution which mutated from a global leader and pioneer into some sort of a tedious virus, which surfaces seasonally in pointless and shallow discussions in out-of-the-way taverns. In times of corona, in times of digital revolution, in times when science sits on the throne usually reserved for religion before it is brought into question by Internet white noise of opinion or before it drags itself down from the pedestal by politicking, I felt it was important to finally talk about the name of Drago Ikic in our small country on the periphery of Europe. To talk about his life’s work and his global mission. Anywhere else in the world, his story would have become a bestseller or a blockbuster a long time ago. Archetypically, the story of Drago Ikic would be a story of what we today call “leadership,” a story of our past, present, and future. A story of the one who leads and not follows. And a story of why that makes such an enormous difference. 1950s were a dynamic time. On the wings of renewal, the world was leaving behind the darkness of WWII, multilateral institutions were founded even though the division into blocs had already begun to cool down the space of the new bipolar world and those who found themselves stuck in the cracks. It was an important time for science, for which a new space was opened, one of international cooperation, of technological development. The years following the war were marked by a huge increase of infectious diseases, epidemics of flu, tuberculosis, polio, but it was also a time of global efforts taken to establish a public health care system and finding cures and vaccines within multilateral formats under the umbrella of the World Health Organisation.

It was also a time of risk, competition, of newfound great forces competing in the scientific arena. But then, as well as now, there was space and people who understood that the mankind was in a race for health and public wellbeing, which was more important than blocs, states, nations, and politics. Today, as the borders were closing, as the war rhetoric was being thrown around, as we were searching for national solutions and talking about a biotechnological race, the global health community opened its borders and archives, establishing a global cooperation which, they say, has never been witnessed to such an extent. All the normative imperatives of academic credit were put aside, new information about the virus is being freely exchanged, hundreds of world laboratories are doing clinical testing. The vaccine, they say, must be available to all. “I never hear scientists — true scientists, good quality scientists — speak in terms of nationality. My nation, your nation. My language, your language. My geographic location, your geographic location. This is something that is really distant from true top-level scientists,” Dr Francesco Perrone, who is leading a coronavirus clinical trials in Italy, told the New York Times in April.

HISTORIC MEETING IN THE TOWN OF OPATIJA

The middle of the 20th century was a dynamic age. Leading world experts wanted to go one step further. Since infectious diseases had high mortality rates, and due to the development of cell biology, virology, and immunology, a small number of experts scattered all over the globe realised that there can be no progress in immunisation without the development of human cell research. The icon of of US and world virology, Leonard Hayflick, was one of those experts. His discovery that human cells multiply a limited amount of times in in-vitro conditions was called – the Hayflick limit. He discovered the etiological agent of atypical pneumonia, he was the first to cultivate plasma, and in 1959 he developed the first inverted microscope, the key in researching cell culture.

All contemporary microscopes of that type come from his prototype which can today be seen in the Smithsonian institute. Hayflick, now an old man, was interviewed two years ago by an American journalist on the crucial global developments in the area of immunology in the 50s and 60s, the first idea on the use of cultures from human cells for the development of vaccines. Hayflick said: “Many things were occurring simultaneously. The crucial one was that the use of the human cells became of interest to a Yugoslavian virologist Drago Ikic, who ran the Institute of Immunology in Zagreb. Ikic was a significant figure because he became so convinced that the use of human cells would replace the ones from primate monkeys’ kidneys and other cell cultures also used for vaccine production, that he took it upon himself to promote this idea internationally. One of the first things he did – which is critically important – was to organise a conference in the Yugoslavian resort town of Opatija. That was a very important and, to some extent, famous meeting, in respect to all the events that occurred subsequently. Leading world figures in cell culture were invited to the Opatija meeting, including Charles Pomerat, Harry Eagle and others, all major figures in the field of virology.

They were all assembled there by Drago Ikic to create an atmosphere of acceptance for the use of these cells. And he essentially achieved that result at that meeting, which is why it was so significant. Vaccine manufacturer representatives were there, who saw the future that included the use of these cells, which also underlined the importance of the conference.

So, who was Drago Ikic, the man who managed to assemble the entire world in the Grand Hotel in Opatija and change the course of scientific history?

I KNOW THAT I KNOW NOTHING

Through the irony of his famous “I know that I know nothing,” Socrates showed his students how their knowledge was based on false and unsubstantiated concepts and treacherous human perception. Life with viruses and bacteria, working on understanding this invisible world which is older than mankind, but affects it so much, means forever knowing that one knows nothing and that we are always building on the knowledge we gain, working for the common good.

That is where the story of Drago Ikic, born towards the end of WWI, begins. After studying medicine he specialised in the fields of bacteriology, hygiene and vaccinology in Paris, Geneva, Zurich, London, and Copenhagen. From 1953 up until he founded the Institute of Immunology in 1961, he was in charge of control and testing of immunobiological products at the Central Hygiene Institute. He was also director of the institute for control and testing immunobiological products, as well as director of the institute for preparing serums and vaccines. He was the chair of the Institute of Immunology since its foundation until he retired. Ikic realised the importance of the role of public healthcare early and, on top of his own continuous education and creating a global network, he would sent young generations of scientists abroad, building foundations for success. He bought the first electronic microscope, he innovated and entered each battle armed with arguments.

In a lengthy article published in the issue of Croatian journal Periodicum Biologorum dedicated to Ikic, professor Renata Mazuran summed up all of his accomplishments. Mid 1940s, towards the end and in the aftermath of WWII, Ikic focused on bacterial vaccines due to sweeping epidemics of diphtheria and typhus. As a member of the Yugoslavian commission for testing vaccines against abdominal typhus, Ikic confirmed the protective value of inactivated typhus vaccine through laboratory testing. He also saw the potential of improving bacterial vaccines in the development of living, oral vaccines, which turned out to be the future of bacteriology. However, at the end of 1950s, shortly before the previously meeting in Opatija, he became more and more intrigued by viral vaccines, because he recognised the potential of diploid cell cultures of human origin for the development of viral vaccines.

There is no cure for viral diseases. The only solution is a vaccine. After Opatija, the situation changed and Ikic, along with five world leading experts – Plotkin, Eagle, Koprowski, Hayflick, and Perkins – signed his name to the now encyclopaedic article in Science journal in 1969, in which they define the principles for the selection of diploid cell substrates. It was precisely Harry Koprowski who developed the first vaccine to contain the living, albeit weakened, virus. The vaccine was against poliomyelitis, and Drago Ikic conducted one of the largest testings by immunizing a million and three hundred thousand people. Not a single case of post-vaccine polio was recorded. Ikic tackled the development of viral vaccines with his team from the Institute of Immunology. The experience and understanding of biological standardisation and quality enabled Ikic’s team to perfect the delicate and demanding process of viral vaccine production. The biggest accomplishment is probably the measles vaccine – Edmondston-Zagreb. In 1963, he had the original type of the Edmonston-Musser virus from the United States, and he began the process of basic research on human diploid cells he carefully subcultivated. Four years later, the world had a vaccine, which was accepted by the World Health Organisation in large vaccine campaigns for eradicating measles, and which was globally distributed through UNICEF.

Several comparative studies of globally used measles vaccines showed that the one developed by the Institute of Immunology gave the best seroconversion. The second great accomplishment was a rubeola vaccine, which was first developed in America. Ikic and his collaborators adapted the vaccine to diploid cell culture, and the vaccine was registered in Yugoslavia before the US. American regulatory agencies still preferred primary cell culture as a product substrate. However, human diploid cells became the world standard of reference for the production of viral vaccines. Ikic and his time had success after success, all of them written in the history of immunology. Over two decades, they conducted a mass-scale campaign for eradicating smallpox. More than 30 million people were inoculated with the Berna-Zagreb vaccine.

They created and produced a flu vaccine and conducted field research in 1964 and 1968 when the flu pandemic was ravaging Croatia. After the Institute of Immunology was founded, due to his experience with animal antitoxins, Ikic was working on the development of medicines based on human blood and plasma. He registered immunoglobulin in Zagreb. The development and clinical use of human leukocyte interferon has been Ikic’s domain from the very beginning. In 1972 it was licenced in Croatia, and within the next three years more than five hundred patients with malign and viral diseases were undergoing interferon therapy. Ikic’s interest in interferon continues to live on and give hope to the word. Academic Dragan Dekaris wrote that the successes of the Institute of Immunology can be attributed primarily to Ikic’s abilities and his vision of the development of production and control of vaccines, serums, antitoxins, and interferons.

Let us take a leap forward, to modern times and the months in which Croatia is holding the Presidency of the European Union. EU member countries in April supported the action plan called “ERA against the coronavirus”, which relies on general tools and goals of the European research area. Many European measures include millions intended for research projects, mobilisation of innovation, funding coordination, creating models on improving preparedness in the event of contagion, millions of Euros were mobilised within the initiative for innovative medicines, and, in order to boost global cooperation, the EU coordinated international initiatives within the global research cooperation for preparedness for infectious diseases, which consists of 29 financing institutions from five continents and WHO.

It has also contributed with millions to the coalition for innovations in the field of epidemic preparedness and, within the framework of European and developing countries’ partnership in the field of clinical studies, financed support programmes for the research of the coronavirus and boosting research capacities in Sub-Saharan Africa. Not a single centre from our region is a part of the Global Virus Network, which connects leading global virology centres and works on the novel coronavirus as the strongest coordinating body of world virology centres. The first criterion for membership in the network is that the chairperson of the institute is an internationally respected virologist, the second is that the centre is active. Croatia has scientists, teams, a new development platform as part of the EU and, if it had continued to build it, it would still have the trust of that part of the world which used to belong to the Non-Aligned movement. The world is still a vast space for the good, for jumping into action, and only ideas, knowledge, and courage are needed in order for that step to be made.

VIRUSES, BACTERIA, AND HUMANS

The Institute of Immunology is clinically dead. The strands of viruses and cells are still kept there. Apart from enormous investments and playing catch-up with those who modernised production, which is incredibly complicated in itself, there needs to be an in-depth analysis of the Institute. But, in order for that to happen, someone who will have the knowledge and the ability to step up to the plate will be needed, someone who is many things in one person. Maybe people will draw parallels and conclusions on the systems of the past and the system now, the international framework, on the relevance of Yugoslavia compared to modern Croatia.

But, Drago Ikic was a pioneer of a system which is more relevant today than ever before, which is crucial for the potential of a sustainable future within the global framework, which is financially independent and profitable. History showed that none of the directors of the Institute of Immunology who came after Ikic, especially after the Institute’s breakdown which came with the fight for freedom, knew how to survive in the existing conditions, let alone take the next step. There was nibbling around the edges, moves were made, on purpose or by accident, which slowly eroded what was left of the Institute. The old was not perfected, the new was not created. No one had any ideas, let along the ability to lead and adapt to the new circumstances. Perhaps there was no real desire to do it. Names, moves, and the chronology of the downfall are not the topic of this text. This is a homage to one of the world’s leading experts for vaccines, who cooperated with all the key experts in the world, who was free and shared his knowledge. He never asked anyone for money because he made the money himself. Eighty percent of what was produced was exported. Not that that didn’t provoke jealousy, but the party knew better than to meddle with the authority of knowledge and ability to manage the Institute in which the employees boasted the highest average salaries. Ikic built an international reputation and global competitiveness which managed to survive in the environment of self-management.

The life’s work of academic Ikic is based on his ideas, knowledge, and ambitions, and the whole team worked as one. Before he retired, he made enough money to fund the new building. It still has not been built, and Ikic, even after retirement, found work for himself as the member of the Croatian Academy of Arts and Sciences. He founded the reference centre for research and standardisation of immunology substances of the academy, he applied for US funds and travelled to the US for work often. He only seemed to settle down when he turned 90. Rumours have it that the breakdown of the Institute of Immunology was troubling him. But he was not the man of many words. He died at the time when the Institute itself was officially proclaimed dead.

The bust in front of the Institute building was unveiled as a surprise, two years before he died. The photographs from the event show his wise eyes and an honest, shy smile. Around the same time, he also received the Order of Danica Hrvatska Rudjer Boskovic for his contribution to science. He put it in the same drawer with other medals he received – for work, for contribution to the people, republic’s award for life’s work and republic’s Rudjer Boskovic award. Ikic was a member of the British Royal Society of Medicine, American Association for Advancement of Science, a body of experts for standardisation of the World Health Organisation that he led, as well as an honorary member of the I. I. Mechnikov Association in the Soviet Union.

LONG DISTANCE RUNNER

Academic Drago Ikic led the Department of Medical Sciences at the Croatian Academy of Arts and Sciences. In the publication issued one year after his death, academic Marko Pecina wrote that Ikic “has personified our department both within and outside the Academy, which was an honour to all of us.” Pecina added: “Privately, I kept hearing about the greatness of man and scientist Drago Ikic and I learned about the reputation he enjoyed, and continues to enjoy in the world. I didn’t know the professor Ikic of that time, but I knew him long enough to know I will admire this man of few words, but many great acts, for the rest of my life. I was always happy to run into academic Ikic on the path to the lake Kraljicin Zdenac (Queen’s Well). Those few minutes of conversation were a great privilege to me. I admired, and still admire, academic Ikic’s personality as well.” As a young man Ikic was a long-distance runner, later he took up hiking, and in the end, he became a walker. The then-head of the Croatian Academy of Arts and Sciences, Zvonko Kusic, who is now the Prime Minister’s advisor, wrote in the same publication in 2015: “Today we congratulate those who publish their work in a prestigious journal, and academic Ikic published a work with Hilary Koprowski in Science journal all the way back in 1969. The level he achieved, which reached global scale, has probably never been achieved in our science…” Listing his fantastic global scientific contributions, Kusic wrote: “He succeeded in creating a scientific, academic, and market basis for the production of vaccines, which was extremely difficult to do globally at that time. It is unthinkable that Croatia today could be globally competitive in any field.” I reread that last sentence over and over again. If someone who was at the helm of the Academy and today works as an advisor to the Prime Minister for social issues, believes it is impossible that Croatia can be competitive on a global level, perhaps we should believe him. As a distinguished medical expert in thyroid problems and the head of the Academy, he later accepted the position of chairing the government’s council for facing the consequences of totalitarian regimes. “Without facing our pasts, there can be no reconciliation, and without reconciliation, there can be no future,” Kusic said.

The facts of the history of science are important for facing the past. And it is important for Croatia’s future to tackle the present and deal with the cancer growing on Croatia’s thyroid: cronyism and corruption. A small country must be opened and globalised. It must be able to find its added value and competitiveness because anything else means death. Estonia is number 31 on the list of global competitiveness, Slovenia 35, and Croatia 63. As we leaf through the pages of Croatia’s scientific thought at this time, we can single out some names on the list who are scattered around the world and others who have stayed here, working hard to create that added value. With all due respect to all our distinguished scientists who do their jobs with commitment, honesty, and substance – like the team from the Hospital for Infectious Diseases in Zagreb or the University Hospital Centre in the city of Rijeka, who are working on isolating the novel coronavirus and keeping the embers of hope alive – there are no names in the global scientific community today which would come from Croatia.

The biography of a man who, according to those who knew him well, was committed to finding solutions and meeting goals. A man whose every word sounded astute. A biography which grew without hoarding wealth. A biography which combines all the key topics of the modern world and its future – multilateralism, authentic leadership, freedom of thought and understanding the strategic importance and connection of research, development, and education with production, industry, economy. A biography which represents the true importance of sovereignty offered only by knowledge, providing it with global influence and relevance. A biography which was not tied to any political regime, but to its own international competitiveness which bore fruit to the benefit of the community and society.

PEOPLE LOVE POPULAR PHRASES

After the World Health Organisation named the Institute of Immunology its collaborative laboratory, and Drago Ikic its main researcher, in 1973, author signed by the initials M. G. wrote in the Matica review: “Such a significant affirmation to a scientific institution which thus became one of the best in the world of its kind, as well as a recognition to its leader, did not cause much of a stir in our daily press. Even though the Institute of Immunology is one of the very few immunology centres in the world, even though the results of its research papers and discoveries are recognised everywhere in the world, public space in our country fails to give it the attention it deserves. That is why, when visiting the Institute’s director, Drago Ikic, we spontaneously asked: How do you interpret this modest attention given to scientific institutions? Ikic responded: ‘What is written about more than anything else? That what people want to read about. And most people prefer popular reports. It’s difficult to write in a popular style about scientific issues. It’s no wonder that scientific institutions and the work done there are not adequately covered in the daily press and everyday channels of sharing information.’”

If your walks ever take you to the Rockefeller Street in Zagreb, remove the cobwebs on the bust of Drago Ikic which stands in front of the Institute’s building, place a flower at its base if you have one handy. Perhaps only as a symbol of understanding the heart of academic Ikic’s life’s work, a symbol of understanding the key problem of one small, peripheral, uncompetitive European country, the key under which, buried deeply, lie the understanding of the importance of freedom of ideas, the creativity of human mind. Not in a sense of creating overproduced advertisements for foreign businesses on the Croatian market, but for something authentic, strategically important and plugged into the world with crackling electricity.

Some are leaders, some are followers. Authority and leadership are often treated like synonyms. But, in the case of Drago Ikic, I want to talk about leadership as something that stems from global social influence instead of power. Leadership needs other people, it includes a goal, not just influence without a planned outcome. A leader maximises the efforts of others. In a service held he held on March 20, 1925, in Westminster Abbey, Frederick Lewis Donaldson, a priest and renowned social rights and peace activist in the Anglican Church, listed the seven social sins: wealth without work, pleasure without conscience, knowledge without character, commerce without morality, science without humanity, worship without sacrifice, and politics without principle.

I thought it was important that, in the age of Internet, a small record should exist on a man so important in the history of world science. Perhaps it really no longer matters what may or may not be done with the Institute of Immunology, or what the next step should be for Croatian science. Even though people still prefer popular reports, as Ikic said, perhaps it is still important for them, as a part of this world, to have something that inspires them.