022709 - The failings of medicine

As a scientist, you tend to trust that medical doctors are rational scientific beings, and that medicine is a scientific pursuit. As a researcher, you're immersed in rational approach to drug design. If, as a bench scientist, I want to find a therapy to a particular illness, I'll learn everything I can about the illness. Making an observation is never enough to get published, you need to show molecular mechanism to be considered in even the most specialized journals.

For example, instead of infecting a mouse with TB and observing that they have T-cell-mediated response, a CD8-mediated T cell response, or even a class Ib-restricted CD8-mediated T cell response, you have to identify which molecule(s) secreted/expressed by the class-Ib-restricted CD8+ T cells is responsible. And this can't just be a suggestion, you have to over-express the molecule to show the response gets better, and then inhibit the molecule to show the response gets worse. Then, and only then, can you claim that you have a new potential therapeutic drug target, which may or may not work in humans. Logically, it should, but unfortunately human immunology is just different enough from mouse immunology to make this kind of a crapshoot.

As outlined above by my over-specific example, candidate drug discovery from the scientific perspective is incredibly rational, and it's easy to fall into the trap of thinking that all therapies currently on the market were derived in a similar fashion. That is total bullshit.

Medical doctors (and the pharmaceutical companies that supply them with drugs) are not scientists, no matter what they may claim. Treatment of various diseases is based on what people have randomly (er, empirically, sorry) determined works. Often in the case of new medicines, especially in the past, doctors tried new medicines, found them to be safe and effective, and only later bothered to figure out what exactly they did to the human body. No wonder there were so many side effects. Take thymidine kinase inhibitors, common treatment for certain types of cancers. Gleevec isn't specific to a particular type of thymidine kinase. Just because it's a magic bullet miracle drug doesn't mean that we know what's going on. Sure, you can't do detailed mechanistic studies in humans, but the coronary side-effects of Avandia suggest that a greater understanding of the mechanism behind the drugs could be highly beneficial.

Which brings me to my point. The Breadwinner's grandfather has been recently diagnosed with dementia. In the course of one year, he went from a walking/talking/driving grandfatherly figure to a man in a nursing home that doesn't recognize his own grandson and only talks when someone's blocking his view of the TV. In ONE YEAR.

A bit of a case history. His original MRI showed "brain shrinkage", apparently a complex medical term for - 'yeah, it looks like you have some sort of dementia, although we can't do a differential diagnosis because we really don't know anything about the brain'. The treatment - 'sorry, sucks to be you, sit back and try to enjoy the rest of your addled life'. This man is in his early 70s, not 110 - they didn't even put him on any drugs, let alone try to get him involved in a clinical trial or do genetic testing to see if this is something that may affect his relatives (such as the Breadwinner or the Spawn). After significant deterioration (and an intervention on the part of myself, the Breadwinner, and his sister), the Breadwinner's mother saw a special on NPH (normal pressure hydrocephalus) on Good Morning America and decided to take him to a neurologist. After months of trying to get an appointment while he deteriorated further, still on no drugs, he finally had a spinal tap that indicated a shunt might really help him. Note at this point that the man was still living at home, and able to have a minimal conversation. His care was being monitored by his wife, who really has no idea what the doctors are saying, but was loving and could still manage. They put the shunt in, and he seemed to be doing better when ANOTHER neurologist noticed that his hands were trembling. Must be Parkinson's, right? What is this - the Dr. Gregory House school of diagnostic medicine? Let's just treat him for one thing after another until you find something that works!. While having patients get progressively worse and "brilliant" doctors be consistently wrong makes for exciting television, in real life random (again, empirical, sorry) therapies are probably not the best treatment course. He reacted badly to the medicine and now barely speaks, can no longer move, and is in a nursing home.

What is the take-home message from this story? I'm enfuriated that the 'state of the art' in elder care dementia is 'it just happens, too bad, I guess we can't do anything about it'. Bullshit. Unfortunately, that's the state of the art in most cancer care. 'Shoot, we tried one thing after the other and none of them worked, I guess you're just going to die'. Assumptions and laziness are fatal in medicine (which is one of the reasons I never wanted to be an MD - don't want anyone's death on my conscience). Doctors are not rational beings, and you have to make sure you take your patient care into your own hands. I guess my advice is that if anything serious is wrong with you, go to an academic center. Even if they don't care about you, they care about their research and you'll be treated with the best possible care.

But back to my main point. These doctors had no idea if the Breadwinner's grandfather had Parkinson's (no tests were run other than the 3 min hand shaking observation) in the first place. Then they gave him a medicine that they didn't full understand, nor tried to (WHY did he have a bad reaction? Maybe you can learn from this mistake to not turn another patient into a vegetable?) I know, it's probably asking too much to expect people who dedidated their lives to helping others to actually intellectually think about the causes of their failure.

But it's not their fault alone. The medical system in general is broken, partially due to the insurance-driven care system and partially due to the lack of funding for basic and translatable research. MDs have to see as many patients as possible and don't have time to get to know the patients, take complete case histories, observe other "non-related" symptoms. They have to cover their asses with malpractice insurance, and so don't want to know why things go wrong. If they found the reason that the Parkinson's drug harmed the Breadwinner's grandfather, they'd have to admit wrongdoing and would open themselves up to a lawsuit. Not that we'd sue, but this is a litigious society and I understand their worries. The costs of malpractice insurance in some states are so high that OBGYNs have stopped delivering babies because they actually come out in the red in the process. I hope, probably futilly, that Obama's new plan for health care reform will actually improve things. We'll see, but change is necessary.

All that being said, I want to get back to science, real science, for a second. There are three studies out this week that shed new light on the molecular mechanisms governing Alzheimer's disease (and perhaps other forms of dementia). Two talk about the interaction between the accumulation of amyloid protein and endogenous prions (think mad cow disease, only not infectious). Could misfolded proteins be the cause of all these problems? A third shows that the astrocyte network is activated in Alzheimer's patients, perhaps causing the over-all cognitive problems (which do not appear to be associated with individual nerve loss). All three studies suggest, in the scientific way, rational drug candidates for the treatment of dementia, and I hope that they translate to actual, rational therapies. Maybe by the time the Breadwinner is in his 70s, with adequate funding and proper healthy care reform, one of these studies could end up preventing this from happening to him.