Fundamental biological research is a non-negotiable, essential first step for any meaningful medical advancement. This should be self-evident. Without a foundational understanding of how a system works, how can we hope to intervene in it with precision or reliability? While serendipity has historically played a role in some scientific discoveries — penicillin, lithium for mood disorders, even the accidental origin of sildenafil — such happy accidents are not a sound or sustainable strategy for systematic biomedical research. Yet some of our misguided, and, frankly, irrational attempts at “getting lucky” and accidentally (more like magically) stumbling upon cures for complex diseases like dementia or cancers are still wasting millions, perhaps billions of federal dollars. This approach is wasteful, imprecise, and increasingly divorced from how science actually works.
Of course we would all be thrilled if this worked out and the infamous penicillin discovery story was the way we did science. But that’s not how rigorous science operates. The inconvenient but empirically validated reality is that medical breakthroughs — particularly for multifactorial, chronic diseases — arise from comprehensive, systematic, and above all reproducible research. This process is rarely glamorous. It is slow, expensive, and intellectually demanding. But it works. And it begins with step one: basic research into the molecular, cellular, and physiological underpinnings of biological systems.
From the fundamental classes of biomolecules to complex tissue-level interactions, basic research generates the critical scaffolding upon which all applied research is built – enabling us to understand the base processes that constitute this infinitely complex, yet satisfyingly consistent and **predictable ** phenomena that we call “carbon-based life”. Yes, even the most complex biological phenomena remain remarkably predictable — if we have accurate models of their underlying structure, composition, and interaction rules. Indeed, isn’t it comforting to remember that by comprehending the elegant and simple principles of inheritance, old man Gregor (who by the way was actually an ordained priest) could reliably and consistently predict the colour of the flowers, the shape of the seeds and many other characteristics of the humble pea plants, thus giving us the basis for the vast, astonishingly complex and stoically beautiful field of genetics, which continues to shape modern medicine and biotechnology.
The message couldn’t be clearer: when you understand the rules that govern a system, only then can you hope to control or modify it. But there’s no skipping Step One. There is no way around it, no shortcuts, no “getting lucky”, no easy fixes. There is no viable path to transformative biomedical innovation that bypasses foundational discovery science. High-quality, reproducible research is a titanic undertaking: it is slow, difficult, it requires an army of highly trained researchers, many lifetimes of relentless effort, sound methodology, statistically valid sample sizes, and reliable, transparent analysis pipelines. It is the only path that gives us a fighting chance at solving problems as complex as neurodegeneration, cancers, or antimicrobial resistance.
This is not to be confused with stubborn orthodoxy. There’s a crucial difference between rejecting innovation and maintaining rigorous standards for evidence. Science must remain open to paradigm shifts when they are empirically warranted — for example, the recognition of epigenetic mechanisms or the role of the microbiome. While confusing intellectual rigor with closed-mindedness is a dangerous misstep, equally problematic is the trend toward low-risk, embarrassingly derivative work and recycling outdated, flawed hypotheses simply because they are easier to fund or publish. Indeed, there was a time when we treated infections by “bloodletting” and prayer, so any idea that didn’t involve spirits and holy water could be very nearly thought of as a “good attempt” at the time, but we are a long way past those times. Incrementalism has its place, but it should not be the dominant strategy when facing the scale of biomedical challenges before us.
As has often been said, repeating the same strategy and expecting different results is a poor substitute for innovation. Yet, this is the approach taken by many researchers and institutions — whether due to conceptual limitations, inertia, lack of funding, or systemic disincentives. Some are constrained by the available technology or infrastructure. Others may lack the training or scientific imagination. And, alas, some of us have forgotten what scientific research is all about and are trying to make a quick buck at the expense of the patients and any prospects for actual scientific advancement. The latter, I submit, have no business pretending to be scientists, and should consider other career paths. While no one in science is free of error, it’s vital that we continuously scrutinize whether our collective strategy is aligned with the scale of the problems we face.
If the future, and very possibly the survival of the human race holds on our ability to come through and actually do the job right, isn’t it more strategically sound to at least attempt to do the tedious rational thing, with sound experimental design, statistically valid sample size and solid analysis methodology, which at least stands a chance to produce some real results, hopefully in time to save our shebs, than keep taking shots in the darkness and hoping for a lucky break? If we had unlimited resources we could do both – and settle for a really expensive lesson in distinguishing between probability and possibility (you know, for those who are still mathematically challenged), but unfortunately we are limited in resources, namely, time.
Only very recently in the chaotic years of COVID-19 pandemic we had a reassuring example where doing things the difficult but correct way actually worked. When faced with a global emergency that threatened us as a species, did we say, “oh, let’s treat this virus with vitamin C and see if that does anything?” No, the mRNA vaccines that were developed within a record time to save the day were not the product of luck, but of decades of basic research in RNA biology, lipid delivery systems, immunology, and structural virology. When the virus emerged, we sequenced its genome within weeks, analyzed its structural proteins, and designed vaccines based on platform technologies that had been painstakingly refined over many years. Clinical testing phases were compressed — not skipped — through regulatory acceleration and massive logistical support. The result was one of the most impressive examples of biomedical coordination in modern history. We saw, in real time, that doing things the hard, correct way actually works — but only when we put the planet on a timeout, had adequate funding and literally had our existence threatened.
It follows, then, that our current default strategy for chronic diseases — in particular neurodegenerative and psychiatric disorders — demands reevaluation. We cannot afford to continue making minor variations on centuries old frameworks developed before the discovery of DNA. Yes, derivative research has its place in validating or extending prior findings. But we must not allow it to become a substitute for genuine scientific progress that we so desperately need.
So, is it too much to ask of our honourable government leaders and “authorities in the field” to reconsider their current strategy of “one potato two potato”, perhaps become reacquainted with the last two decades of empirical evidence and methodological advancement and do the right thing?
As we confront increasingly complex biological threats, we must prioritize strategies grounded in rigorous experimental design, mechanistic understanding, and genuine scientific inquiry. It is not a matter of intellectual fashion but of scientific survival.
Because, as it stands, we have no Plan B.