The majority of high impact medicines originate from curiosity driven research, American scientists found recently. Oncode Institute aims to give fundamental research the space back it lost in recent decades.

Fundamental Science: an uncertain endeavour into uncharted territory

Hidde Boersma

Even if you have only distantly followed medical or molecular news, you must have heard the term CRISPR. There is hardly any lab that doesn't use this new gene editing technique. It is deployed in agriculture to harness plants against pests, in molecular biology to elucidate functions of genes, and in medicine to strengthen the immune system to attack tumours. It even has reignited the public debate on designer babies.

But few know of its history. The first mention of CRISPR was already in 1993, by Danish researches studying bacteria in yoghurt. They stumbled upon a peculiar string of repetitive sequences of DNA in these organisms, interspaced with DNA of what seemed viral origin. In relative anonymity, together with researchers from Wageningen University, they tried to elucidate its function, only to report in 2005 that it served as a bacterial immune response to bacteriophages, a bacterial equivalent to viruses. They showed that the viral DNA between the repetitive sequences serves as a beacon for recognising intruders, guiding a molecular scissor to cut its DNA, thus averting an infection.

It took another couple of years for two groups of American researchers to unlock its immense potential for molecular and medical research: using the acquired mechanistic knowledge it became possible to guide the scissor to cut exactly at a desired point in the sequence of DNA in an organism of choice. This enabled scientists to edit DNA in a very precise, fast and cheap manner, starting nothing less than a revolution in molecular science. This all wouldn't be possible if it wasn't for fundamental research.

Research into uncharted territory might be an uncertain endeavour, but has the highest potential for surprising and innovative results.

It turns out the story of CRISPR doesn't stand on its own. In April of 2018, American researchers at Harvard University showed that 8 out 10 of the most transformative medicines of the last decades had their basis in curiosity driven research. This includes for instance the very popular ACE inhibitors for lowering blood pressure, which originated from fundamental research on how blood pressure is regulated in the body and on how the enzyme angiotensin functions, both studied in a time when high blood pressure wasn't even recognised as a risk factor for heart problems.

Madelon Maurice in her lab at UMC Utrecht – Photo credit: UMC Utrecht

For people actually working in the lab these results don't come as a surprise. “You have to look into the white spots of our knowledge,” Ton Rijnders, Chief Scientific Leadership at Lygature, who also worked at Organon, now part of MSD, says. “Research that builds on existing findings might yield refined medicines by accumulating knowledge, but it is unlikely to lead to the discovery of novel molecular mechanisms and to transformative drugs.” Madelon Maurice, professor of molecular cell biology at the University of Utrecht chips in: “Research into uncharted territory might be an uncertain endeavour, but has the highest potential for surprising and innovative results.”

Still, funding trends are in the opposite direction. Earlier this year the KNAW publicly appealed for more funding for curiosity driven research, as numbers are dwindling the last decades. For most grants, researchers are obliged to find collaboration with industry partners. “It is easier to get funding for well trotted paths, than for new roads,” Rijnders says. He refers to a recent study that showed that 90 percent of the funding for research on kinases, important regulatory enzymes, go to the 20 to 30 best known varieties, while there are over 300 kinases that are all important in health and disease. “We are funding in circles,” he says. “Projects are always funded on the basis of earlier results, wild ideas stand no chance. Unrestricted grants require a certain trust. They might also lead to nothing.”

Welcome in the real world, where science is difficult and does take time

Admittedly, it takes a long time for investments in curiosity driven research to show its merits. Between the first mention of CRISPR in scientific literature and the first person receiving a CRISPR based medicine, lies 30 years of research. And this is approximately the average, the Harvard scientists calculated. “Welcome in the real world, where science is difficult and does take time” Rijnders says. Maurice is optimistic nonetheless: “The American study also found that the lag time between the initial discovery and an actual medicine shortened from an average of 36 years in 1985 to 26 years now. They couldn't pinpoint the reason, but the process of translation is somehow working faster.” The foundation of institutes like Oncode will hopefully add to a further reduction of lag time.

Ton Rijnders, General Director of Oncode Institute

Maurice adds that the research performed at Oncode not only aims to obtain new fundamental knowledge. “Several Oncode teams, including René Bernards and his team, are investigating how the combination of existing medicines, both simultaneously and in series, might improve the treatment of cancer. These studies are expected to lead to impactful findings in a shorter time frame.”

We have to start looking past the competitive model of science

Both scientists feel that if we want to stimulate curiosity more, the current research climate needs change. “We have to start looking past the competitive model of science,” Rijnders says. “At the moment research groups still try to outsmart and scoop each other, as breakthroughs and high profile papers are a way of securing a next grant. But biology is so immensely complex, it simply is too much for one group to tackle. We need to work together.”

One of the ways to do so, is to stimulate interdisciplinary research. “Science is still too pillarized,” Maurice says. “Working with people who have a different view or come from a different background, really opens the way to enter uncharted territories.” Rijnders remembers Organon doing something similar when he was working there: “We were a small company, so we tried to stay ahead by collaborating with people and companies from other fields, hoping it made us more innovative.

Maurice has her own ways of stimulating creativity and curiosity in her group. “I try to create a very open and free lab culture, where students, PhD's, and post docs all feel at ease to express themselves and come up with new ideas. In today's research climate it is hard to really solely go for curiosity driven research, but I aim to let PhDs combine a high risk, high gain line of research with other lines that offer more guaranteed success.” Rijnders thinks research works best if people are selected not only on their research capabilities but also on the softer characteristics, like openness and willingness to collaborate. All in the hope that more transformative medicines will serve humanity the coming decades.

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