I hate to tell you this, but the fact is, there is no such thing as the human genome. For a good cause, some well-meaning scientists obfuscated the truth that all genomes are different so we could make scientific progress. The Human Genome Project (HGP) was a real thing, and generated a “consensus” or “reference” genome that has been a fantastic boon to science and medicine, no question. This rough draft framework contains the 99% of DNA sequence that all humans share.
In years past, we could examine one gene at a time, like inferring the plot of a novel by looking at a single line of text. Now, at long last we have in front of us the entire book. A growing library, in fact. The gene geeks are proud of our accomplishments thus far, but real excitement lies still in the future… the amazing potential these books undoubtedly hold. Understanding biology in deep evolutionary detail!
Wise guy sidebar: [Curing all diseases! Clean energy! World peace! Is there a little bit of hype surrounding genomics? Sure…maybe… Hey, where would we be without hype machines? Would you want to live in a world where Coca-Cola was just carbonated diabetes? Hm, wait… Where was I? Oh, yeah, genome sequencing and cures.
”Great,” I hear you saying, “whole book. Good for you. Where are the cures?” Well, we’re working on it, OK? We’re working on it hard. We have our top minds working around the clock. And by top minds, I mean our scientists are smart but are not as smart as folks that write Sponge Bob Squarepants…Nor are they are smart as the financial types who shorted biotechnology stocks after hearing all the hype, but near as we could get. ]
"So what’s the hold up? That guy in that article you read about genomics seemed so sure a breakthrough was just around the corner!" Weeellll, Turns out, teasing out the connection between a genome sequence and disease, between DNA and medical advice is really hard. Not hard like calculus is hard. Not hard like finding a decent bagel in the midwest is hard…I mean hard like putting a camel through the eye of a needle hard. Middle East peace hard. Hard like maybe we are looking at the entire problem the wrong way hard. How can we make sense of all this DNA data in a way that is helpful to our patients??
Along comes a scientist by the name of George Church came up with a brilliant idea: let’s croudsource the search for answers in our DNA.
[This is a paraphrase of the original insight, which was, “we have no idea what we are doing.”]
The only significant problem with the idea of croudsourcing whole genome data analysis is one of privacy. In order to do this, the personal genetic data of people would have to be shared openly. And this poses an inherent risk that people could be identified by their DNA signature.
Next: People were identified by their DNA signature.
Fox Keller E, Harel D (2007) Beyond the Gene. PLoS ONE 2(11): e1231.
Fox Keller and David Harel put a tremendous amount of thought and work into this piece and it deserves a respectful reading. They seek to improve the entire field of genetics by reframing basic concepts and coining neologisms (dene and been). The purpose of this exercise is an attempt to bring clarity to a field that has become increasingly complex over the past 20 years. The authors may be ahead of their time, but clearly geneticist did not welcome their nomenclature nor have they taken it up int the six years since the article was published. Why not?
1. The field of genetics currently is arguably composed of a number of “competing constituencies:” traditional model organism geneticists, computational/statistical geneticists, forward geneticists (eg cell biologists and disease modelers), human geneticists, clinical geneticists and physicians, private sector technology vendors and the lay public and patients. Rather than collaborate with any prominent members of any of these groups, the authors provide insights as a philosopher/historian and a computer scientist. Sigh. Their ambition is remarkable. Their arrogance is breathtaking.
2. Their framework might help historians of science and computer scientists outside the field to understand the complexities of genes, genotype and environment, but for molecular geneticists the article provides an elegant framework, brilliant in a way, that is of little immediate use.
3. Although I certainly agree with the authors that the term “gene” is complex and difficult to define, my personal language bugaboo is “the genome.” This is an analogous language problem—while we can easily define the genome as the sum total of all the genes in an organism, the language draws us back into the problem again that the DNA is insufficient so we need the epigenome the transcriptome, etc. The fact is that no two humans have the same genome. How much trouble we have gotten ourselves in by spending so much time getting people used to saying “the human genome.” In each cancer patient’s tumor exists a multitude of genomes that are related but distinct from one another and may be extremely different between patients. What is then “the cancer genome??”
4. Ironically, Mark Ptashne published a piece also in 2007 on the use of language, the term “epigenetic,” but he couched his piece in highly practical terms. Directed at people in his field by one of its members. To my understanding, this is how specialty language evolves. Not from advice from without but from the practical issues that arise inside the community.
At the end of the day, Leonid Kruglyak tweeted it well and succinctly:
"straw-man view of genes that geneticists don’t hold; critique irrelevant to how we do and interpret experiments."
Grand Rounds lecture from November. Tells the ACA11 story and also some unpublished data on the search for myeloma risk genes. Apologies, the sound volume is very low (need good sound system to hear).
Update after talking with folks from NCI about http://grants.nih.gov/grants/guide/pa-files/PAR-13-081.html
If you haven’t read Gina Kolata’s astonishing piece in the New York Times about the power of genomics and it’s application to leukemia, then you must read it now:
My response is one of great pride and admiration for my friends and colleagues at Wash U. I have been priviledged to work with Tim Ley in the AML sequencing efforts and feel that this was “my team” that has performed this miraculous feat. My mother’s first question was, “why didn’t they mention you?” (Thanks, mom!) It’s because my lab works on the genetics/genomics of multiple myeloma—a different disease. Dr. Wartman and I have done work together (http://www.jci.org/articles/view/45284) , but that was not the focus of the piece. I am obsessed with figuring out how to take these technologies and apply them for the good of myeloma patients. In this effort, I am working with Drs. Ravi Vij and Keith Stockerl-Goldstein.
We are working on novel uses for sequencing technology behind the scenes and I anticipate these will be transformative for the way we practice oncology. Let me get some data and get back to you!
Gave some thought about Roberts’ Obamacare decision. Read many stories, but not yet one that picked up on these here points I find fascinating. First and foremost is the depth of Chief Justice Roberts brilliant, history-making work. Not being sarcastic in this post, BTW but (later) I indulge in coy understatement. Chief Justice Roberts just gave us a masterwork of both Judicial power and restraint. Many were surprised by his decision. Most people, myself included, thought that everyone in the world was consumed only with selfish political interests but Roberts stood up and announced in a clear voice that the United States is a country of laws and that he for one strives to transcend animal instincts as he carries out his public duties. We don’t really know yet what Roberts’ opinions are regarding Obamacare. I bet he agrees with 80% of the hardcore Republican base on most things including Obamacare. But, stubbornly, he insists of the goals of professionalism to have his opinion guided by facts and careful reading of legislative text.
Roberts, for reasons unclear to many, decided to carefully read the Affordable Care Act (ACA). Undoubtedly, he realized, the ACA is a tremendous legislative accomplishment. Many conservative conservative colleagues treat Obamacare dismissively and are content to ignore the thorny fact that the ACA was passed by both houses of Congress and signed into law by the President of the United States. Not an insignificant bit of paper, this is a legislative solution to the US healthcare system’s inefficiencies, inequities and incomplete coverage. Roberts is not concerned with whether it will work, that is not the issue before the court. Roberts does not disagree with those that believe Obamacare will be a disaster. But the fact is that this reform has been gestating for the better part of a century and must be respected. The idea that we could simply scrap it and start over is a facile promise made to gather funds from fellow hard liners.
Roberts is certainly aware that a) that escalating healthcare costs are a threat to our nation’s financial integrity ; and b) health costs have started to come down already as free markets started bracing themselves for full enactment of the law. Brilliant men can be wrong about future effects. The fact is that while it is still a possibility that the ACA drives us deeper into debt, it is also a possibility that we are in the midst of a momentous turning point if this keeps up. Overturning the law would reverse course and might well return us to unsustainable cost escalations. Roberts, it might be imagined, might not want to be responsible for destroying the country by reversing the Act.
Where some see romance in the idea of overturning the law, a return to chaos of the legislative process for this huge part of the US economy (and the primary source of growth in that past couple of years) might not be a good idea also. Roberts does not have to pretend that Obamacare came from Obama. The insurance mandate and insurance exchanges idea were conservative ideas, and smart ones designed to achieve the goals of reform using free markets. According to conservative theory, an efficient and transparent free market in healthcare insurance would lead to lower costs, making socialized medicine unnecessary for taking care of the poor and sick. The success of Obamacare is tied to the belief that free markets can move mountains.
One last point. We found out that John Roberts is a man of integrity and intelligence and I stand with him for his courage, intelligence and ideals. However, this decision also scares me, as it should many on the left. It does not seem to have dawned just how profoundly conservative Roberts decision was and how it paves the way for an extremely conservative legacy. Obamacare is the law of the land because it is based on Congress’ right to impose taxes. But the Commerce Clause has for decades been the basis for much legislative overreach, and liberals should be on notice that this Court is not your friend.
Saturday, boy it is hot. Biked to lab, now cleaning off desk (and procrastinating here). Trying to teach US language and culture to new Chinese in my lab using Twitter and popular movies. My choice first: A Few Good Men. They are smart and earnest but language skills need work. The first one who comes into my office and says, “No kidding, Kaffe, I’m gonna hang your boy from an f-ing yardarm,” gets a prize.
This is an interesting list of college degree majors that wont get you a job:
10. EconomicsUnemployment rate: 9.4 percent
Starting pay: $48,000 9. Area Ethnic and Civilization StudiesUnemployment rate: 10.1 percent
Starting pay: $35,000
8. HistoryUnemployment rate: 10.2 percent
Starting pay: $32,000
7. AnthropologyUnemployment rate: 10.5 percent
Starting pay: $28,000
6. Philosophy and Religious StudiesUnemployment rate: 10.8 percent
Starting pay: $30,000
5. Information SystemsUnemployment rate: 11.7 percent
Starting pay: $43,000
4. Commercial Art and Graphic DesignUnemployment rate: 11.8 percent
Starting pay: $32,000
3. Fine ArtsUnemployment rate: 12.6 percent
Starting pay: $30,000
2. Film, Video and Photographic ArtsUnemployment rate: 12.9 percent
Starting pay: $30,000
1. ArchitectureUnemployment rate: 13.9 percent Starting pay: $36,000
For more on the college degrees that are least likely to land you a job interview, check out the infographic below from Best Degree Programs.
Otis Brawley takes us all to school. One can only hope we are near a tipping point for real change in the medical-industrial complex.
I don’t normally go to physician staff meetings, but this one had Steve Lipstein speaking on “the future of healthcare.” Mr. Lipstein is the CEO of BJC Healthcare, the parent organization of Barnes-Jewish Hospital (where I attend on the Leukemia and Stem Cell Transplantation service). Obamacare is a fascination of mine. I won’t capture everything he said, but here are some high points I took away:
BJC Healthcare is the largest employer in Missouri. The annual operating budget is $3.6B. BJC added jobs during the Great Recession, and the organization takes very seriously its multi-focal mission that includes being a stable local employer. BJH jobs can not be outsourced.
BJH also takes very seriously its mission as a regional safety net. A large element of health disparities is economic: the median income of St Louis city residents is $14K; the median income in neighboring Chesterfield (St. Louis county) is $140K. (!!!)
Mr. Lipstein had slides about economics provided him by the Fed: two things immediately apparent on a graph of US debt held by the public: debt spikes coincide with wars, and these debts take many many years to pay off. The Civil War debt wasn’t paid off until 1916. It took 35 years to pay down WWII debt. So, he said explicitly, anyone that argues that candidate A versus candidate B has the power to fix the debt within a single term is being disingenuous. We are just beginning to pay off a mammoth war-related public debt. The aging of our population with increased fixed expenditures creates major head winds. Paying down this debt will take many years and will require tough decisions. We are all going to have to figure out how to do more, with less.
Currently, about 85% of US physicians receive compensation on a fee-for-service basis and this will change no matter the fate of Obamacare or who is president. Obamacare attempts to manage the transition away from fee-for-service within 10 years, which is fast. For the foreseeable future, physician payment will be a complex amalgam of different compensation models. Healthcare will undergo tremendous changes over the next decade. But impossible to foresee exactly how things will play out. BJC strategy for the current environment is “to learn as much as we can.”
"The Affordable Care Act is still constitutional, and for many reasons, we hope it remains so." I chatted with him afterwards and I said he didn’t sound like a raving socialist. He laughed and said that he has been accused of it.
"Primary care nationally is broken. How are we going to fix it?"
"I do worry about research funding. Where is future growth going to come from?"
Afterwards, one of the panelists joked that the two words he remembered from the talk were: “chaos” and “debt.”
Sobering. But change is exciting, and rest assured, change is coming.
An interesting article from a tweep (Dr. Robert West follow him at @westr):
Interesting morning where 3 issues came up at once:
1. The story itself: lightning critique: arsenic-transformed cells secrete soluble factors that affect normal stem cells. It’s an interesting system that may be useful to find new information, but two reported facts are not novel: a) arsenic in low/chronic doses is a carcinogen and b) cancer cells secrete soluble pro-inflammatory cytokines. The headline that arsenic harms stem cells seems on the face to be misstating the research.
2. The (unintended) misinformation effect: the story fails to mention that arsenic is very useful today in treating patients with acute promyelocytic leukemia (APL). And for the lay audience, by “very useful,” I mean, arsenic is a wonder drug (used in specific ways). Lives saved, hands clapped together in tearful joy kind of useful. Check out:
3. The turn for the weird: on my initial viewing of the original story at http://generef.com/newsstory.rss.html?pid=104985, there was a banner ad attacking my university by name with a picture of a cat. (Disappeared on repeat viewing, as they do). People can say what they like on banner ads. However, academic medical centers are here to save human lives. I love cats. I love all of God’s creatures. I also love human beings and have dedicated my life to medical research. For anyone still worried about the cats: we take animal welfare very seriously here: