Days of Awe: The clinical trial drug that might save my husband's life
bessstillman.substack.com
bessstillman.substack.com
This just shouldn't be necessary. In 2023, we as a race should be able to figure out a better way to efficiently channel patients with needs towards clinical trials that might serve those needs.
(And I say this as someone who works in this industry.)
It feels like it's implying that humans today are fundamentally different from humans in the past. In fact it feels dangerous to me that we often speak of ourselves as almost a different species from humans in history. From an evolutionary perspective humans from any moment in recorded history are basically indistinguishable. Our brain capacity hasn't changed. We're not kinder. We're not less selfish.
We do know more about many things (and less about some things). We have better tools. We've refined more matter into new forms. We have access to more useful energy. But those changes don't change who people are.
No human at any point in history should be content with the state of things, but I don't think that struggle is easier today than it ever has been. We're pushing the boulder up the hill and we'll never reach the top, but should never stop pushing.
Being in the industry, I'm glad you're not content with the state of things. It takes people like you, so thank you for your effort to make our world a better place. Even if we may disagree with nuances of the motivation.
When people say this (myself included), I think it's a normative statement, not a positive one. Of course we're the same humans we have been for thousands of years. But the act of calling out our failings as a society can itself, sometimes, spur people to try to change it for the better.
In 2023, we are (positively) essentially the same as our ancestors. But also in 2023, we should (normatively) strive to be better than them, and to be conscious of our failings when we don't.
But is there any reason why people are excluded despite seeking out the trial runners, and have a terminal illness that their drug/procedure MIGHT help with?
I assume the chance it won’t work is legally dealt with for all trial patients, so I’m assuming that’s not the issue.
If they don’t fit the test profile, is there any risk to just simply acknowledging them as an outlier and letting them in anyway? You have one consistent cohort you’re studying, and a “who knows, maybe?” cohort of preliminary results from these Hail Mary folks. That seems useful, even if it lacks the sort of rigour of a group you selected.
This part definitely feels very broken to me. People going for clinical trials are often somewhat desperate, giving them that extra uncertainty to play with doesn't help.
The truth is there is also a lot of arbitrariness. For example, brain mets are often used as an exclusionary factor for studies, because, although a drug is evaluating mets as part of asking "will this drug work for cancer throughout the body?" a drug company will LATER have a study that focuses on whether it works on brain mets, thus excluding a huge swatch of patients. If a cancer tends to met to the brain, it really doesn't need a different study. It needs to include real-world patient populations. But that's because the studies are meant to get a drug to market.
I feel strongly that policies need to change. The FDA plays a big role in making the process problematic (a longer point for another time), but, curiously, the NIH actually is one of the most functional (for patients) research centers.
He was great until blood clots caused more issues like taking morphine to calm smooth muscle to help him breathe. Morphine just that tiny pill caused terrible constipation (opioids are terrible).
My point being Dad would take anything just to feel even slightly better it meant he was still here. Death is terrifying and as long as you can limp along whatever makes it better is something people want. Really at that point you try to get to a point where you may just die in your sleep not knowing you did.
Dad considered it but as a Catholic and just as a choice by anyone it was even more terrifying than just a natural death. You have to make the active choice and I think that is what scared him. Plus at the time I wasn't really seeing the anxiety he had he was good at masking it.
He died in palliative care with assistance for any pain which was more mental than physical.
Why would you say something like this, especially given your dad's situation? yes they can cause constipation, but without opioids the pain would be much, much worse. To me it's a no-brainer, and nobody is forcing you to take opioids if you would rather the pain. I think opioids are a wonderful gift of nature to us and I'm immensely glad we have them. It terrifies me to think that we are so demonizing them now that they are withholding them from people who need them, and telling them to "take extra stength tylenol" instead. It's barbaric and cruel.
>Morphine just that tiny pill caused terrible constipation (opioids are terrible)
Because of that, I would rather trade those moments of watching me die in the most agonizing, painful way imaginable, for the better memories - the times before I got sick.
I watched my grandmother die, of cancer - there is nothing, literally nothing - that would allow me to put someone else thru that - at least not without their full consent, and making sure they knew of what was to come.
Then there's the problem that some have a few of the people closest to them in one camp, fully accepting, and some in the other camp, which can be terrible (I've seen it especially with people I know where it's their parent who was dying, with different siblings going either way).
That’s the thing. You might read “drug extends median overall survival by 3 months”.
Big deal right?
Well that’s the median. In reality it looks more like:
- 5% see a complete response (cure)
- 40% see a partial response
- 55% see no response
And of those 40% who see a partial response the median is 3 months but the range is 1 to 29 months.
So now do you do it? 1 in 20 chance of a cure and 1 in 20 chance of two more years of life and a 1 in 10 chance of 1 more year of life.
Who cares, you're dead.
I guess I would try to figure out, based on the people around me, how I could make them happiest long term (which I think is the same thing you're saying)
Yes it's difficult to support someone in their last days, and it's never pretty, but it's not their fault. It also didn't make forget all the other years I had with my grandpa.
The end doesn't have to make you forget the rest.
Just my experience and I don't discount that that same experience could have been traumatizing for someone else.
It's gut wrenching that I am just a CT scan away to being in the same (somewhat comparable) situation.
I shouldn't compare fates and still my mind wanders around the topic every time.
The facts they both present in a scientific manner (like remission rates) scare me to my bone. I cannot fathom what he and his loved ones are going through and that makes it even clearer what I have burdened on my wife, children and family.
I know this comment is ultimately me shouting "please let us both live" with many words and maybe this is me being a self serving asshole, maybe it is that. I don't know anymore.
I would love to offer the promise that everything is going to be alright but I cannot. I am just scared as hell and somehow I needed to get this out.
[^1]:"All", as opposed to just scientists and clinicians.
- How precise do you want the simulation? Do you want physical processes fully simulated? You'd need that to get an accurate simulation of molecular interactions, but full physical simulation is computationally expensive even for single, simple molecules.
- Even simplificated simulations are hard. Simulating just the shape of DNA strands is computationally very expensive (usually done with Monte Carlo simulations).
- How many cells do you simulate? The body has ~37 trillion cells. Even if it only took one processor cycle to simulate a cell, you'd need 9250 4GHz processors. That should give an idea of how hard it would be to simulate just an organ.
- How do you take into account interactions? There's a lot of difficulty in understanding how drugs affect the whole human system. Lots of trials show promising results against in-vitro cells and then fail spectacularly in animal models. There's a lot influencing how drugs work and single cellular processes are just a small part of it. The body is incredibly complex.
- How do you validate the models? It's not like we can go into a cell and see where the molecules are. We don't have enough visibility into actual cellular processes to build such complex models to a sufficient degree of accuracy.
Compared to even a single human cell, a monstruous language model is a trivial thing.
Five years ago, I would have said that we were further away from having a computer correctly interpret a joke (i.e., I would have agreed with [2]) than from simulating E.Coli. The thing is, people went and did (both) anyway. But they did one more than the other. Research effort and capital flowed, and now we have LLMs. IMO, a big reason for this paradox is that there is no stigma in wanting to make a computer smarter, and everybody started playing with computer code and data and due to the huge amount of effort, there have been results. But when it comes to the very things that keep us alive, we are not so eager to play with computer code. That, I think, has less to do with the complexity of the subject and more with a certain moral disposition...which is the thing I find perplexing.
[^1]: https://www.frontiersin.org/articles/10.3389/fchem.2023.1106...
[^2]: https://karpathy.github.io/2012/10/22/state-of-computer-visi...
Honestly it's the first time I hear about moral stigma having anything to do with research. Again, I think you underestimate how much harder it is to simulate biological processes than LLMs. Even from the paper you've linked, you'll see the massive amount of simplifications they had to do: they're using a minimal cell, not all metabolites are included, multimeric proteins are left out/replaced, spatial distributions are simplified, the simulation timescale is below 10μs, they do not simulate reactive processes, they do not talk about how much time did they need to perform the simulation... Don't get me wrong, it's a massive achievement. But the amount of computation that needs to be done just to simulate a single cell is absolutely massive, let alone simulating multiple cells in a system. Considering how much it would cost it's no wonder other avenues are explored first.
I would emphatically suggest starting here: Read scientific papers. Read the academic literature.
Read. Know you can read.
And, please bear with me: Know that your doctors most probably do not read.
It sounds so paranoid or bitter. I haven’t found another way to put it into words.
If only for the fact that doctors are usually very busy people. Many of them are probably overworked.
And even among those doctors that do read, a doctor will not be able to view the literature from the urgent perspective of the individual. We are all specialists in ourselves, know the details of our lives, our family history.
It is possible for a layman to read academic literature. To the point that you can help the doctor help you. Don’t tell anyone you can’t read.
There is a severe disease in my close family. The doctors missed the diagnosis for years. Diagnosis happened through sheer luck, insistent advice from a nurse speaking “out of their place”, and our persistence. At diagnosis, biomarkers were so far out of range that it can be known that death would most probably have occurred within days.
After this, we read academic literature.
After this, we trust the doctor like we trust our parachute.
As proof that a layman can read academic literature to save their life and preserve their health:
After the diagnosis, papers we have read have clearly shown that a course of action ordered by a doctor is wrong, harmful, potentially life-threatening. Multiple times. Harmful prescriptions, or abject denial of severe side-effects known to occur in some people. We have had to step in and intercede. The crucial part: This has then been confirmed by another doctor’s opinion. Multiple times.
Don’t tell anyone you can’t read.
→ should have been →
Don’t let anyone tell you you can’t read.
Relatedly, I am in a Facebook group for $condition, and I can’t tell you how many times I’ve seen people post that a doctor prescribed them $treatment. Although $treatment is a very common thing to give to healthy people, $treatment is KNOWN to potentially cause death in patients with $condition. The other patients in the group always jump in and alert the original poster to the danger, but I can’t believe it still happens week after week and year after year.
My point is that fully outsourcing your healthcare—even to specialists—is a very bad idea, especially if you might have a rare condition of any sort. No doctor will ever care about you/your family member the way that you do. And they are always so pressed for time that mistakes are to be expected.
good luck, jake. may your days be filled with appreciation and love and tranquility.
My point is not to say that patients have it easy, but that both parties have their burdens to bear, and it is not necessary for every essay to cover both sides.
Edit: I see you have deleted your comment, which is a shame, I don’t think you should be afraid to express this sentiment.