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.
Friday, February 27, 2009
Wednesday, February 18, 2009
Nutty Notions
Sorry for the cutesy title, but I just had a jam-packed weekend celebrating the Spawn's first birthday with an insane number of family and friends. As a result, my brain is gelatinizing (picture the new Alec Baldwin commercial) - or maybe in the process of de-gelatinizing.
The Spawn's first birthday was a bit more challenging than most because he's an allergy baby. Yeah, I know - an immunologist with an allergy baby. Life is just filled with little ironies. Right now he can't eat milk, soy, egg, sesame or peanut. We have to carry around an epipen with us at all times. I go for shock value when he visits someone's house without me. My spiel - "This is how you use the epipen. He's never had a serious problem, but it's better to know how to use it and not have to than to not know how to use it and have a dead baby". I always make sure to say 'dead baby', because the shock value alone makes people pay attention.
Poor guy - fortunately he doesn't know what he's missing. I had no problem finding a decent vegan cake, but let me tell you how disgusting allergy-free frosting is. I tried making it with lard (not so appealling to a vegetarian) and buying an allergy-free frosting at the store. Both were shiny, hard, and not overly tasty (judging by the yucky face).
But onto the point of my blog for the day. Kids often outgrow milk, soy, egg, and sesame, but only 20% of kids ougrow peanut allergies. Unfortunately, peanut allergies are the most insidious and scary of the lot. There's positive news out of Mt. Sinai though. In a paper published in the Feb 2009 issue of J Allergy Clin Immunol, a group led by Dr. Xiu-Min Li found that long-term anaphylaxis protection was observed in mice treated with a combination Chinese herbal remedy - FAHF-2. Through unknown mechanism, it skews the peanut allergen immune response from Th2 to Th1 (could this also be a new adjuvant?).
This drug is currently in phase I trials for safety and dosage (results should be available by the end of 2009), but the safety data is promising because of its long term use in herbal medicine.
For those who scoff at herbal medicine, aspirin was originally an herbal medicine (from willow) as was penicillin (mold). While most herbal remedies are probably crap, we shouldn't scorn natural or traditional sources for potential new drug therapies.
Mouse success and human success are very different things (even I can cure cancer in mice), but this therapy is definitely something to watch if you're a parent of a kid with allergies.
Abstract:
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WH4-4VJKVPP-X&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=6eea32664dfdbf3fbf11c5577ffa6414
The Spawn's first birthday was a bit more challenging than most because he's an allergy baby. Yeah, I know - an immunologist with an allergy baby. Life is just filled with little ironies. Right now he can't eat milk, soy, egg, sesame or peanut. We have to carry around an epipen with us at all times. I go for shock value when he visits someone's house without me. My spiel - "This is how you use the epipen. He's never had a serious problem, but it's better to know how to use it and not have to than to not know how to use it and have a dead baby". I always make sure to say 'dead baby', because the shock value alone makes people pay attention.
Poor guy - fortunately he doesn't know what he's missing. I had no problem finding a decent vegan cake, but let me tell you how disgusting allergy-free frosting is. I tried making it with lard (not so appealling to a vegetarian) and buying an allergy-free frosting at the store. Both were shiny, hard, and not overly tasty (judging by the yucky face).
But onto the point of my blog for the day. Kids often outgrow milk, soy, egg, and sesame, but only 20% of kids ougrow peanut allergies. Unfortunately, peanut allergies are the most insidious and scary of the lot. There's positive news out of Mt. Sinai though. In a paper published in the Feb 2009 issue of J Allergy Clin Immunol, a group led by Dr. Xiu-Min Li found that long-term anaphylaxis protection was observed in mice treated with a combination Chinese herbal remedy - FAHF-2. Through unknown mechanism, it skews the peanut allergen immune response from Th2 to Th1 (could this also be a new adjuvant?).
This drug is currently in phase I trials for safety and dosage (results should be available by the end of 2009), but the safety data is promising because of its long term use in herbal medicine.
For those who scoff at herbal medicine, aspirin was originally an herbal medicine (from willow) as was penicillin (mold). While most herbal remedies are probably crap, we shouldn't scorn natural or traditional sources for potential new drug therapies.
Mouse success and human success are very different things (even I can cure cancer in mice), but this therapy is definitely something to watch if you're a parent of a kid with allergies.
Abstract:
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WH4-4VJKVPP-X&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=6eea32664dfdbf3fbf11c5577ffa6414
Monday, February 9, 2009
Quality of Life (or lack thereof)
Despite my desperate desire to do another postdoc (or, more accurately, my desperate desire to leave the position I'm currently trapped in), I want to talk about quality of life in science.
This weekend, I caught up on my reading of my favorite comic strip -PhD (Piled Higher and Deeper) comics (www.phdcomics.com). PhD comics is written by a now assistant professor, although he started when he was a grad student I think. I highly recommend this comic for anyone who 1) is in graduate school 2) is dating/friends/married to someone in graduate school 3) is a PI who has graduate students or, mostly importantly, 4) is thinking about going to graduate school. I read this strip and relate to all of the jokes/situations and personally know people (many people) who fill each of the sterotypes.
What does this have to do with quality of life in science? My reading of PhD comics reminded me of a key truth - quality of life in science sucks. People work long hours and are motivated by guilt because their coworkers are working longer hours. Their bosses expect even longer hours. They get paid nothing, even at the prof level. Two career paths who work comparable hours are investment bankers and lawyers - yet fresh from college I-bankers make more money than tenured professors.
Interesting, a recent study (http://online.wsj.com/article/SB123119236117055127.html) lists 'biologist' as #4 on the best jobs list. Apparently the survey didn't actually assess job satisfaction or sleep deprivation. Scientists, who are supposedly logical, should not want to be scientists. But people become scientists because they're driven. It's a calling, like the priesthood (and for many scientists, has similar results on their sex life). But it's the culture, not the actual duties, that impact quality of life so negatively. A consultant has to travel, because they can't do their job without traveling. But, while there are some 15 hour experiments, most scientists could stop after 10 hours a day and lead relatively normal lives.
Who maintains the culture? I think it's the PIs. It's sort of like hazing - I had to go through this so you do too. Every PI I've ever talked to has 'funny' stories about the terrible things they had to do as students/postdocs. This isn't exactly like medicine - where you can arguably believe that residents working 90+ hour weeks are seeing more patients and therefore will be better doctors someday. I did not learn more by doing 50 instead of 40 gel shift experiments. I hope when I get through my own period of hazing, I remember and provide for a better quality of life for my students and fellows. The cycle has to stop somewhere.
This weekend, I caught up on my reading of my favorite comic strip -PhD (Piled Higher and Deeper) comics (www.phdcomics.com). PhD comics is written by a now assistant professor, although he started when he was a grad student I think. I highly recommend this comic for anyone who 1) is in graduate school 2) is dating/friends/married to someone in graduate school 3) is a PI who has graduate students or, mostly importantly, 4) is thinking about going to graduate school. I read this strip and relate to all of the jokes/situations and personally know people (many people) who fill each of the sterotypes.
What does this have to do with quality of life in science? My reading of PhD comics reminded me of a key truth - quality of life in science sucks. People work long hours and are motivated by guilt because their coworkers are working longer hours. Their bosses expect even longer hours. They get paid nothing, even at the prof level. Two career paths who work comparable hours are investment bankers and lawyers - yet fresh from college I-bankers make more money than tenured professors.
Interesting, a recent study (http://online.wsj.com/article/SB123119236117055127.html) lists 'biologist' as #4 on the best jobs list. Apparently the survey didn't actually assess job satisfaction or sleep deprivation. Scientists, who are supposedly logical, should not want to be scientists. But people become scientists because they're driven. It's a calling, like the priesthood (and for many scientists, has similar results on their sex life). But it's the culture, not the actual duties, that impact quality of life so negatively. A consultant has to travel, because they can't do their job without traveling. But, while there are some 15 hour experiments, most scientists could stop after 10 hours a day and lead relatively normal lives.
Who maintains the culture? I think it's the PIs. It's sort of like hazing - I had to go through this so you do too. Every PI I've ever talked to has 'funny' stories about the terrible things they had to do as students/postdocs. This isn't exactly like medicine - where you can arguably believe that residents working 90+ hour weeks are seeing more patients and therefore will be better doctors someday. I did not learn more by doing 50 instead of 40 gel shift experiments. I hope when I get through my own period of hazing, I remember and provide for a better quality of life for my students and fellows. The cycle has to stop somewhere.
Monday, February 2, 2009
CEOs and Sports Coaches – Joining the Club
Being a CEO or a Professional Sports Coach (whichever sport you prefer) has gotta be the best gig going. What do these positions have in common, you ask? In most positions, including the execs and assistant coaches one notch down the totem pole, your hire-ability is based on past performance. You’re good at what you do and people decide to give you more responsibility, see if you can take it to the next level. If you’re a corporate executive, this means that you’ve come up with some new synergy that’s saving your company millions. If you’re an assistant coach in the NFL, it means you’ve got a defense hotter than an old lady’s hair on a Florida summer day – you make Peyton Manning look like Kyle Orton. At any level but the top, you work your butt off, hoping that one day you’ll get the winning ticket to a very exclusive club.
CEOs and Professional Sports Coaches, on the other hand, have no accountability at all. You can run your company into the ground and still get hired at another company – because of your “experience”. I don’t know about you, but as a shareholder I wouldn’t want someone with the experience of bankrupting a company at the helm. Or again, let’s take Professional Sports. Rod Marinelli, who led the Detroit Lions to the worst record in sports history, now has a position as an Assistant Head Coach with the Chicago Bears. What was Lovie Smith thinking? – “Hey, this guy is the worst of all time, we need him on our team.” Mark my words – Phillip Schoonover of Circuit City, Richard Fuld Jr of Lehman, and even James Cayne, the famous bridge-player of Bear Stearns, will all have new positions in a couple of years when the heat dies down.
Heck, let’s throw politics in here too. The political club is a family club. In our supposed meritocracy, how likely is that that the father and son Bushes were both the best candidates to run our country? Are they really that genetically superior? And now they’re talking about Jeb running – Canada here I come! Let’s assume Jeb is comparable with George. Why would we want to continue what was arguably one of the least successful presidencies in our history? Shouldn’t our economic collapse, endless war, and poor reputation abroad rule him out of the running? And what about Caroline Kennedy (who admittedly has left consideration for the New York Senatorial seat)? Just because Daddy was a decent politician doesn’t give her any skills. My Daddy was a mechanic and I probably couldn’t even change the battery in my car.
What does all this have to do with science? It’s all the same thing. Science is supposed to be objective and fair – you’re funded based on the quality of your ideas and published based on the merit of your work, but it works just like sports or business or politics. People get funding because they’ve had funding. They get published in high profile journals because they had a big name at an important university. Peer review isn’t double blind – reviewers know who they’re reviewing and make allowances for “famous” scientists that they wouldn’t make for the new assistant professor or brilliant postdoc. The average age of the first R01 grant for new investigators in 2007 was 42. These people are considered “young” investigators. I, for one, don’t consider 42 to be young. In mathematics, you’re past your prime at 25. Computer science entrepreneurs are in their teens and 20s. Scientists in their 20s and 30s have the passion and freedom to take risks, to make the truly great discoveries and not just pad their CVs. Imagine the biomedical breakthroughs that we’ve missed because the system is broken, because of the old-boys club. Who needs a malaria vaccine or a cure for childhood leukemia anyway?
So what does this mean for the standard schlub – Joe Stuck-in-a-Rut or Dr. Nancy I-Can’t-Get-A-Faculty-Position-Because-an-80-yr-old-Guy-is-Clinging-to-his-Lab-and-Hogging-All-the-Funding? How can we break into the upper echelon – become one of the deservedly maligned elite? Before he left the NIH, Elias Zerhouni changed the funding rules to favour first-time R01 applicants. It’s not a solution, but it’s a start. The system IS broken – our best and brightest are trapped in indentured servitude (postdocs) during what should be their most productive years. And I’m not even going to start on the below sub-standard pay these “hopes for the future” receive. (How can you attract the best talent if you pay an administrative assistant more straight out of college than you pay your 30-year-old Ivy League PhD postdoc? But I’ll save THAT for another time).
We have to change the culture of Science. Postdoctoral organizations (aka unions) are a start, but it’s hard to gain much bargaining power when by definition the position is a 2-5 year slot. Sure, postdocs are leaving academic science to go into industry, consulting, policy, editing (like me). But with the technological challenges the world is currently facing, we need MORE scientists, not less. If the Bush administration has taught me anything, it’s that we can’t rely on government to solve our problems. My dream is a series of independent institutes, not unlike academia, where young scientists can have the capital to fund their riskiest dreams. It’s not a practical plan, but we need somewhere to start fresh and leave the old culture behind. In order for things to change, we need funding from outside the government – always a dinosaur behind the times – funding that will pay commiserate with our specialized skills, reward creativity and not conservative small-scale “safe” experimental plans, and allow for decent quality of life.
Where will this money come from? – that’s where I fall flat. I’m not a financier. Industry is a prime target, but how do you do basic research with industrial backing? Philanthropic organizations could do it, but how do we convince people to donate money to such risky ventures? Of course, successes would inevitably pay for themselves (and the myriad failures that would likely result), but until then where would we get the money? Maybe from the CEOS and Professional Sports Coaches or others who are already in the club? Unfortunately, I have a lot of questions but very few answers, vision but no means to make it a reality. So I open the question to you, especially those who are outside the ivory tower. How can we fund young scientists, give them the drive and freedom to address the challenges we face today and in the future? How do we start a new club?
CEOs and Professional Sports Coaches, on the other hand, have no accountability at all. You can run your company into the ground and still get hired at another company – because of your “experience”. I don’t know about you, but as a shareholder I wouldn’t want someone with the experience of bankrupting a company at the helm. Or again, let’s take Professional Sports. Rod Marinelli, who led the Detroit Lions to the worst record in sports history, now has a position as an Assistant Head Coach with the Chicago Bears. What was Lovie Smith thinking? – “Hey, this guy is the worst of all time, we need him on our team.” Mark my words – Phillip Schoonover of Circuit City, Richard Fuld Jr of Lehman, and even James Cayne, the famous bridge-player of Bear Stearns, will all have new positions in a couple of years when the heat dies down.
Heck, let’s throw politics in here too. The political club is a family club. In our supposed meritocracy, how likely is that that the father and son Bushes were both the best candidates to run our country? Are they really that genetically superior? And now they’re talking about Jeb running – Canada here I come! Let’s assume Jeb is comparable with George. Why would we want to continue what was arguably one of the least successful presidencies in our history? Shouldn’t our economic collapse, endless war, and poor reputation abroad rule him out of the running? And what about Caroline Kennedy (who admittedly has left consideration for the New York Senatorial seat)? Just because Daddy was a decent politician doesn’t give her any skills. My Daddy was a mechanic and I probably couldn’t even change the battery in my car.
What does all this have to do with science? It’s all the same thing. Science is supposed to be objective and fair – you’re funded based on the quality of your ideas and published based on the merit of your work, but it works just like sports or business or politics. People get funding because they’ve had funding. They get published in high profile journals because they had a big name at an important university. Peer review isn’t double blind – reviewers know who they’re reviewing and make allowances for “famous” scientists that they wouldn’t make for the new assistant professor or brilliant postdoc. The average age of the first R01 grant for new investigators in 2007 was 42. These people are considered “young” investigators. I, for one, don’t consider 42 to be young. In mathematics, you’re past your prime at 25. Computer science entrepreneurs are in their teens and 20s. Scientists in their 20s and 30s have the passion and freedom to take risks, to make the truly great discoveries and not just pad their CVs. Imagine the biomedical breakthroughs that we’ve missed because the system is broken, because of the old-boys club. Who needs a malaria vaccine or a cure for childhood leukemia anyway?
So what does this mean for the standard schlub – Joe Stuck-in-a-Rut or Dr. Nancy I-Can’t-Get-A-Faculty-Position-Because-an-80-yr-old-Guy-is-Clinging-to-his-Lab-and-Hogging-All-the-Funding? How can we break into the upper echelon – become one of the deservedly maligned elite? Before he left the NIH, Elias Zerhouni changed the funding rules to favour first-time R01 applicants. It’s not a solution, but it’s a start. The system IS broken – our best and brightest are trapped in indentured servitude (postdocs) during what should be their most productive years. And I’m not even going to start on the below sub-standard pay these “hopes for the future” receive. (How can you attract the best talent if you pay an administrative assistant more straight out of college than you pay your 30-year-old Ivy League PhD postdoc? But I’ll save THAT for another time).
We have to change the culture of Science. Postdoctoral organizations (aka unions) are a start, but it’s hard to gain much bargaining power when by definition the position is a 2-5 year slot. Sure, postdocs are leaving academic science to go into industry, consulting, policy, editing (like me). But with the technological challenges the world is currently facing, we need MORE scientists, not less. If the Bush administration has taught me anything, it’s that we can’t rely on government to solve our problems. My dream is a series of independent institutes, not unlike academia, where young scientists can have the capital to fund their riskiest dreams. It’s not a practical plan, but we need somewhere to start fresh and leave the old culture behind. In order for things to change, we need funding from outside the government – always a dinosaur behind the times – funding that will pay commiserate with our specialized skills, reward creativity and not conservative small-scale “safe” experimental plans, and allow for decent quality of life.
Where will this money come from? – that’s where I fall flat. I’m not a financier. Industry is a prime target, but how do you do basic research with industrial backing? Philanthropic organizations could do it, but how do we convince people to donate money to such risky ventures? Of course, successes would inevitably pay for themselves (and the myriad failures that would likely result), but until then where would we get the money? Maybe from the CEOS and Professional Sports Coaches or others who are already in the club? Unfortunately, I have a lot of questions but very few answers, vision but no means to make it a reality. So I open the question to you, especially those who are outside the ivory tower. How can we fund young scientists, give them the drive and freedom to address the challenges we face today and in the future? How do we start a new club?
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