Glioma research: Asking right questions

There is an arms race to find the next molecular target. The potential spin-offs are enormous. Royalty payments. Insurance payouts.

Despite insane profits, big pharma has lost its drive to push forward for drug discovery. The easy way is to buy out the biotechnology companies (startups) or chase the clinical conditions which have healthy fat margins (like hypertension). Rare diseases like brain tumours haven’t seen any incremental investments over the past few years because of poor outcomes. Tumour treating field is the only “breakthrough” in recent times for recurrent tumours.

Therefore, the onus lies on informal networks of universities and individual researchers for pushing this narrative forward. Despite the wasted research dollars, there is a lot of promise for translational research.

My proposal has the following (very broad/generic) outline here.

The problem, at the outset, is the cost of sequencing. But it is a necessary evil. Unless we know what type of a tumour we are dealing with or its genetic signature, we cannot hope for proper characterisation. This information needs to be mated to clinical follow up with standard protocols.

Is there any scope for in-vivo monitoring? If yes, what is going to be its timeline? How frequently are we going to see for the mutations? What is the rate of mutations? What is its timescale? When should we intervene?

Another favourite pet theory is the class distinction for stem cells. Do they exist? If yes, why can’t they be reliably identified? What are their niches and what is the best way to target them?

Each sequencing would reveal a wealth of clinical data (both genomics as well as radio-genomics) and spur on more deep dive into the molecular ontology. Yes, that might fulfil the wet dream for molecular targets as well. However, as a radiation oncologist, I am only keen to know whether I can reduce my tumour volumes, how we can reduce the dose to normal structures (brain) and combine efforts with patient-related outcomes.

Bring it on! Let us do it! (Have some laughs!!)

Research and biotech: Asking right questions

The Ken is a wonderful resource for myriad issues.The staff at The Ken is constantly churning out some of the highest quality journalistic write ups in India. Their focus is mostly on start ups, biotech and increasingly now on security of digital assets. The reason why I recommend it is to broad-base your reading sources and think laterally beyond our narrow confines. Financial crunching may not be everyone’s cup of tea but it has spurred me on to understand more about it’s complexity. In the end, it is a deep dive learning experience to write effectively. In the sea of otherwise hopeless mediocrity that Indian journalism has seeped itself, The Ken (and to some extent, Business Standard) redeem themselves.

Today’s post was motivated by an excellent coverage of biotech sector and this prodded me on to think about what the research goals ought to be. Biotech companies are chasing the end of the rainbow for the pot of gold. The reason why US remains the “gold standard” for these companies is because of a perverse incentive that pharmaceutical companies and hospital corporations have to milk the consumer. That’s where the big money is. And these companies are pushing themselves to crack the market in order to get the first mover advantage.

I will not name a few companies that I have worked with (due to non-disclosure agreements with them and that included not calling them names publicly). There were some great individuals, that I had the good fortune to learn from, as well. This aside, they are mostly floundering pushing their luck. In proverbial terms, trying to see what sticks to the wall.

In one presentation, they presented a “case scenario” which showed how the medical oncologist based his decision on genomic details for lung cancer. In another, they were keen to show for cool-rectal cancer. All laudable but with one significant omission. They did not have any follow up for outcomes! Not only this, none for any clinical trial, suitability for a vast majority or how the specific gene sets were chosen to be marketed.

Its stupidity compounded by idiocy. Over and over again.

Sadly, the translational science hasn’t made specific progress and now we have the buzz words like “precision medicine”. Pray, what is precision medicine?

Hype fuels another set of hype cycles. It is a good thing that all of this looks great on dossiers or fanning our collective egos in fancy conferences but they remain a collective effort for intellectual masturbation. We need hard core data sets and equally hard nosed questions before we thrust all of this in front of hapless patients.

The company mentioned in The Ken write up hasn’t specifically mentioned as to how they will find out the difference in the genetic mutations (from primary index lesion) to the current state. I had earlier explored this concept in an editorial arguing for liquid core biopsies as means to monitor the course of treatment in lung cancers because of the range of molecular mutations.

Rest assured, I have a healthy disdain for pharma company sponsored trials with results that appear too good to be true. When it is translated into actual clinical practise, it doesn’t live up to it’s hype. Remember the Cetuximab “landmark trial”? Or even for that matter, Bevacizumab?

Lets pause. Think.

There ought to be healthy skepticism. A side note to fellow radoncs- there is a lot that can be achieved in Radiation Therapy. We need to explore different fractionation schedules or even radiation sensitisers. Combination therapies do-not always work out. That is the subject for another blog post.

Scientific elitism, failure and research.

Dwight D. Eisenhower Source: Wikipedia

I was alerted to an interesting discussion on effects of federally funded research- the rise of scientific elite and “military-industrial complexes“. The thought process was initiated with a compelling article on what President Dwight D. Eisenhower had mentioned in his address about 50 years back.

I quote:

“Today, the solitary inventor, tinkering in his shop, has been overshadowed by task forces of scientists in laboratories and testing fields… ,” Eisenhower warned. “Partly because of the huge costs involved, a government contract becomes a substitute for intellectual curiosity virtually.”

While continuing to respect discovery and scientific research, he said, “We must also be alert to the equal and opposite danger that public policy could itself become the captive of a scientific-technological elite.”

There’s been enough debate in the knowledge circles about the exact import of this. But these words ring real as the years have passed. “Military-Industrial” complex has grown in stature, causing havoc, while the new upstarts in the scientific research world are increasingly elbowing their way in this cosy club from China.

This isn’t a geopolitically nuanced post. It only serves to reflect my concerns about wastage of research efforts and how much it is held hostage to scientific committees. It is a good thing to keep a rein on how the dollars are being invested, but this also comes with the riders on how difficult it is to fail.

All of this has come at the cost of progress and reward to the scientific thought and tinkering.

It is true that the advent of “atomic bomb” spurred on research in the US, but there was defined anxiety to achieve the goals. In Asia, we grapple with the income inequalities and access to equitable healthcare, while in western democracies, they are floundering to create the next breakthrough. Hence, the likes of “project moonshot” because it is recognised that something is required.

It leads us to another question: Has the scientific process and the research methodology gone too bureaucratic in its approach?

Likewise, the cost of publishing the research has become beholden to the established interests. The scientific cabal controls access to literature pushing vanity metrics (which in turn determines means to get further funding). It transpires that if the research isn’t published in a “high impact journal”, it isn’t meritorious enough. The unstated pressure to achieve publications in high impact journals breaks most people resolve to push through them. It only leads to either cronyism, cooking lab results to dress them up and an established PR machinery to impress the charities backing the research efforts.

Who loses out?

The patients. It is because the bulk of published research can neither be reproduced nor translated in clinical domains efficiently.

The spinoff from this has also led to an arms race to find the next big molecular target. The idea is to of course, “sell” it to the pharma company to patent it. While not inherently evil but it feeds the same demon wherein we know how equitable access worsens.

Rinse and repeat.

What are the implications for developing countries?

Herein, lies the rub. It is sad that bulk of doctors have turned away from scientific research because what they see in the patients is not meaningfully communicated in the lab. Dr Ronald Ross discovered the malarial parasite while actively practising medicine. Leannec invented the stethoscope because he needed an efficient way to auscultate the patients presenting to him. He went stumbling from various kind of tubes to something resembling a stethoscope that we now know as- universally ubiquitous.

Ideally, we should be researching the hows and whys of radiation effects on cells, the way it breaks DNA, the downstream effects, minimising the impact on healthy tissues, exploiting the fractionation schedules and a better mathematical modelling. Instead, we are going agog about Amazon and JP Morgan’s of the world stepping in healthcare, ferreting away the precious human health data to their data centres, feeding algorithms and fuelling the hype cycle about AI in healthcare as the next breakthrough. It only reflects how faith in the system has broken down.

Clinician-scientist is a moniker. What we lack is a comprehensive roadmap to what we want to achieve- not concerning survival but a meaningful continuation. As the world celebrates cancer day, it is a call for the radiation oncology community (and the medical profession) to evaluate its priorities and work towards alleviating what we are supposed to do.

What is the way forward?

The way out, forward, is to break shackles of our minds and allow ideas to fail. If I were to have my lab (someday!), I would dedicate a portion of funding only to tinker with the possibilities. Involve people from different fields to brainstorm on what all possible directions the idea can go. Involve mathematics, for example, with probabilities on what can go wrong or right. These are not the core competencies of clinicians but opening up dialogue and communicating with teams looking at the same problem with a different perspective can help enlarge the idea.

“Cure” will not be hope but a purpose and an end all.