SCOTUS decision on gene patents is bad biology, and bad for science

I’m pleased the Supreme Court has decided to reject the idea of patenting genes, as such case law would be restrictive to scientific discovery and also just feels fundamentally icky. From a legal perspective, as far as I understand patent law (not a lawyer here), it also seemed to fail on the more basic level of novelty and obviousness. The methods used to discover such genes were not what was invented. And one could conceive of “gene trolls” that would seek out gene aberrations and sit on them, just like other patent trolls, waiting for a payout and hindering scientific and medical progress.

Unfortunately, the second half of the SCOTUS decision makes little sense to me from a scientific perspective, or my unsophisticated understanding of the law. From the NYT coverage:

The price of the test, often more than $3,000, was partly a product of Myriad’s patent, putting it out of reach for some women. The company filed patent infringement suits against others who conducted testing based on the gene. The price of the test “should come down significantly,” said Dr. Harry Ostrer, one of the plaintiffs in the case decided Thursday. The ruling, he said, “will have an immediate impact on people’s health.”

The court’s ruling will also shape the course of scientific research and medical testing in other fields, and it may alter the willingness of businesses to invest in the expensive work of isolating and understanding genetic material.

The decision hewed closely to the position of the Obama administration, which had argued that isolated DNA could not be patented, but that complementary DNA, or cDNA, which is an artificial construct, could. The patentability of cDNA could limit some of the impact on industry from the decision.

This strikes me as completely undermining the nature of the first part of the decision, and scientifically and legally unsound. Now, most of us understand the basics of molecular biology, but all you need to know to understand the significance of this is that DNA is transcribed into RNA, which is then translated into protein. In the process of transcription of DNA to RNA, large sections of the RNA are spliced out (the introns) and the remaining pieces (exons – which are expressed) are what get translated into the final protein sequence by little machines called ribosomes. Scientists are usually more interested in the final, mature RNA sequence after splicing, since that’s what results in function (for now ignoring regulatory elements in introns etc.). To study these sequences, they harvest RNA from cells, and reverse transcribe that information using an enzyme called a “reverse transcriptase” to turn that sequence into cDNA, which is more stable, can then be made double stranded, variously manipulated, cloned into plasmids or amplified by techniques like the polymerase chain reaction.

The Supreme Court has decided that since cDNA is artificial (is it really? We make it with enzymes stolen from viruses so viruses make cDNA too right?), cDNAs can be patented. But the exact same information from the mature RNA is in the cDNA! What’s the damn difference? This is like saying you couldn’t patent a recipe on paper, but if you transfer it word for word onto sheepskin, it becomes patentable. Does this make sense to anyone? Am I taking crazy pills or is this basically saying you can’t patent genes, unless you copy the information into a new format? Unless the cDNA is truly novel, and not isolated or cloned from a human or other organism, this strikes me as simply sleight-of-hand.

This decision is terrible and not the victory science advocates would like to believe, at least to my understanding of what has been done. I’ll read the actual decision once I’m home from work, but just from the news coverage, I’m disturbed.

**Update** As I read the decision it appears that our esteemed Justices don’t really understand biology, and as a result, have made a frankly stupid decision. Sentences that make me cringe include, “cDNA is not a “product of nature
,” so it is patent eligible under §101.” Umm, no, cDNA is found in nature. We use natural enzymes to make it! Viruses make their reverse-transcribed genes all the time. Also, check out this boneheaded statement, “cDNA does not present the same obstacles to patentability as naturally occurring, isolated DNA segments. Its creation results in an exons-only molecule, which is not naturally occurring.” Agggh! What about the mRNA that is was copied from? Are they saying cDNAs are the only form of “exons” only molecule? This is either bad biology, or poor sentence construction. Or maybe they think cDNA comes from stitching together sections of genomic DNA by some other process?

Then they appear to reject the idea you should be able to patent the only type of DNA that arguably should be patentable:

This case, it is important to note, does not involve method claims, patents on new applications of knowledge about the BRCA1 and BRCA2 genes, or the patentability of DNA in which the order of the naturally occurring nucleotides has been altered.

So, copy the information from mRNA to a cDNA and you’ve created something “new” (bullshit) but change that DNA sequence yourself for potentially novel and interesting results and that won’t necessarily be patentable? Idiots!

Check out this nonsense:

That may be so, but the lab technician unquestionably creates something new when cDNA is made. cDNA retains the naturally occurring exons of DNA, but it is distinct from the DNA from which it was derived. As a result, cDNA is not a “product of nature” and is patent eligible under §101, except insofar as very short series of DNA may have no intervening introns to remove when creating cDNA. In that situation,a short strand of cDNA may be indistinguishable from natural DNA.

The mere fact that they describe this as a mere technical process should be a hint. The human adds nothing. The justices seem to suggest that by taking advantage of the cell’s splicing apparatus, you have created something new, but you have not! You have merely copied the information from the mRNA onto a new media.

Add to this the bizarre rejection of the first section of the decision by Scalia, which only describes facts about biology (he rejects basic science that’s been established for 50 years!) , and I have to ask, why do we let these 9 non-experts decide anything related to technology? How was their extensive education so flawed with regards to biology? Who is educating them on biology now in preparation for a case such as this? Whoever it is needs to be fired. They have written law based on such a flawed conception of basic biology (and one actually abstains from acknowledging the existence of molecular biology!), that we now have this stupid idea that mere transcription of genetic information to a new media should be protected under patent! The source of this idea seems to come from the opinions of the lower court judges who seemed to think that any cutting or synthesizing of DNA to make a “new” molecule should be patentable. That would suggest using any restriction enzyme that cuts genomic DNA creates millions of new patentable molecules. It is equivalent to suggesting that by cutting a wire made up of 4 recurring metals fused together in some order, one is creating new patentable wires because their chemical composition is different from the original wire, but that’s nonsense, because what makes DNA a molecule of any patentable interest is not it’s simple chemical composition or the changes in chemical composition when subjected to enzyme treatments or synthesis reactions, it’s the information contained within the order of the chemicals in the chain. The chemical composition, in terms of the absolute quantity of each of the base-pairs is unlikely even change by such a process. The only thing that matters is the information contained in the code.

The Supremes, and I guess whichever clerk wrote this for Clarence Thomas (not that I esteem his intellect, but that’s how these things work right?) have failed Bio 101. As a result this decision is stupid, unscientific, and worse, bad law. This should not have been reported as any kind of victory for science, but rather is a muddled, ignorant, and unhelpful decision that awards patent protection to the mere transcription of information from one media to another using methods in existence for the last 30 years.

2nd US Hospital to do full face transplant – today at University of Maryland

The news was just publicly announced that the University of Maryland is now the 2nd hospital to perform full face transplant in the US. Just a handful of these procedures have been performed around the world, and they are enormously complex ethically, surgically and medically.

To begin with, long before the surgery even became a possibility, there have been years of work put into setting up such a novel transplant program. Besides obtaining approval for what is still an experimental procedure from an IRB, it is necessary to very carefully screen a population of potential recipients. A face transplant is still quite high risk, especially if the surgery fails because it has the potential to cause serious morbidity and mortality. So, patients selected for transplant have to be vetted very carefully. In the case of the first Chinese transplant, the patient stopped taking immunosuppressive drugs in favor of traditional Chinese remedies, and died soon after. This emphasizes the importance of choosing potential recipients that will reliably take their medications as rejection can be catastrophic.

This surgery took approximately 32 hours from start to finish, and involved a huge multidisciplinary team including multiple transplant and plastic surgeons to perform the procedure. These procedures involve very complex microsurgery to reattach the vascular supply, muscles and nerves to the graft, and, since the jaw and tongue were also transplanted, bones as well.

The surgery is also just the beginning. A life-long course of immunosuppression is required, at least until we can reliably determine how to induce immune tolerance to transplanted organs (this is an exciting field which has also been in the news). And since the jaw contains marrow, there is a risk of graft versus host disease from the transplanted bone.

Then there are the complex ethical issues with facial transplant.

More below the fold…
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CSPI overblows the cancer risk of caramel coloring in soda

The safety of soda has been in the news a lot lately. The news even seems bad for diet coke, which hits close to home for me given my diet coke addiction. The worst seems to be this correlative study proposing a link between diet sodas and stroke risk:

The study, which followed more than 2,500 New Yorkers for nine or more years, found that people who drank diet soda every day had a 61 percent higher risk of vascular events, including stroke and heart attack, than those who completely eschewed the diet drinks, according to researchers who presented their results today at the American Stroke Association’s International Stroke Conference in Los Angeles.

Disturbing news, however, it’s still just a correlative finding from the Northern Manhattan studyand until things are studied more rigorously, I probably won’t quit my current caffeine source. After all, it can reflect patients who are drinking diet drinks because they are diabetic, a known cardiovascular risk factor not excluded in their analysis.

Now the Center for Science in the Public Interest (CSPI) has entered the soda fray with a report suggesting the caramel coloring has unacceptably high levels of a carcinogen called 4-methylimidazole.

An independent study commissioned by the Center for Science in the Public Interest (CSPI) uncovered 4-methylimidazole, or 4-MI, in Coke, Diet Coke, Pepsi and Diet Pepsi at levels 4.8 times greater than those allowed in beverages in California.

4-MI is a byproduct of the reaction that produces the caramel coloring in brown sodas. The chemical has been found to be carcinogenic in animal studies.

The state of California has banned 4-MI in any amount that could potentially lead to one cancer case in 100,000 people. However the levels found in these 4 leading Cola brands indicated a lifetime risk of 5 cancers out of 100,000, assuming that people drink one soft drink per day. That risk rises to 10 cancers out of 100,000 people who drink only soft drinks containing caramel coloring.

.

But what is the evidence this level of 4-MI could pose a health risk?

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Accountability in Science Journalism: two recent examples of failures in the NYT and Forbes

ResearchBlogging.orgEd Yong demands higher accountability in science journalism and has made me think of how in the last two days I’ve run across two examples of shoddy reporting. These two articles I think encompass a large part of the problem, the first from the NYT, represents the common failure of science reporters to be critical of correlative results. While lacking egregious factual errors, in accepting the authors’ conclusions without vetting the results of the actual paper, the journalist has created a misleading article. The second, from Forbes, represents the worst kind of corporate news hackery, and shows the pathetic gullibility of reporters regurgitating the fanciful nonsense of drug companies without any apparent attempt to vet or fact-check their story. With a google search the facts are smashed.

The first article Digital records may not cut costs, I think is typical of most science reporting. That is, it’s not grossly incompetent but it overstates the case of the article involved and fails to amplify the shortcomings of the research.

The NYT article is describing this article from Health Affairs, which caught my eye before the NYT article was even published because I believe electronic medical records (EMRs) will prevent redundancies and lower costs. So, am I wrong? Will EMRs save us money or possibly increase redundancy as the HA article suggests?

I haven’t given up hope. This article is a correlative study based on survey data, and proves precisely nothing.

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Drug Shortages Reveal the Free Market is Failing Our Sickest Patients

**Update, the NYT has an editorial in their Sunday edition recommending the passage of two bills in congress requiring advanced notice from drug manufacturers in event of likely shortage.

i-1ae05c713060a45402a652d348e56148-pngHealth affairs discusses the increasingly frequent shortages of critical, life-saving, generic drugs. This is a serious problem that seems mostly limited to the U.S. healthcare system, and may adversely affect you or someone you know.

Many of the same drugs are not in such short and unpredictable supply in Europe, where in some cases they carry higher prices. This provides one major clue to the root cause: It’s the money.

Three of every four drugs on the US government’s shortage list were sterile injectable drugs, according to a report by HHS. For the most part, these are relatively low-cost generics. Simply put, most of those drugs are not very profitable to produce and sell, or supplies of them would not have dried up.

At an online presentation for journalists in November, Valerie Jensen, associate director of the FDA’s Drug Shortage Program, provided a casebook example. She mentioned the price of the tried-and-true sedative propofol, a lethal dose of which was found to have caused the death of singer Michael Jackson: The cost is forty-eight cents for a twenty-milliliter vial. “The older, sterile injectables are not economically attractive” for manufacturers to produce and market, Jensen said. Other generic drugs can have higher profit margins.

Propofol, one of the most frequently used drugs by anesthesiologists, is in increasingly short supply. I get emails from my hospital about which drugs are in short supply as physicians then try to ration these drugs for the most critical cases. In my own experience in the last year I’ve seen shortages of everything from injectable calcium gluconate (for electrolyte deficits), to levophed (a life-saving pressor used in critical care), metoclopramide (anti-nausea), and fentanyl (a powerful and useful short-acting narcotic). The FDA has a full list of recent shortages and it’s scary. Parents are having trouble finding drugs for their kids’ ADHD, vital chemotherapeutics like daunorubicin and doxorubicin are in short supply, dexamethasone (a powerful steroid), valium, digoxin (a staple of congestive heart failure and anti-arrhythmic treatment), diltiazem (hypertension and anti-arrhythmic), phenytoin (anti-epileptic also often used in acute brain injury), furosemide (an ubiquitous diuretic), haloperidol (anti-psychotic and sedative), isoniazid (a antibiotic used in TB), ketorolac (an excellent anti-inflammatory and analgesic), levofloxacin (a quinalone broad spectrum antibiotic), methotrexate (immune modulator), midazolam (a great short acting sedative), naltrexone (for reversing opioid overdose), vasopressin (another pressor) all are in short supply.

The drugs affected span all classes, what they have in common is they are all generic. Since there is too much competition in generics and too little profit margin, drug companies do not have a financial incentive to maintain adequate stocks to keep the drugs cheap and available. Shortages, if anything, increase profits because then the prices become artificially inflated.

Manufacturers, not surprisingly, blame the FDA, however the FDA hasn’t changed its standards despite increasing problems with shortages due to contamination or impurity. And that’s just for manufacturers in this country, fully 80% of the medications are produced, or active ingredients are produced, abroad. The main problem seems to be a concentration of production to a handful of companies that have adequate production capacity to compete in the generic market:

There is also a high level of concentration in US manufacturing for such drugs. That leaves little redundancy in the market as there would be for, say, generic statins. Three companies in particular–Hospira, Teva, and the Bedford Laboratories division of Boehringer Ingelheim–have been involved in selling 71 percent of the sterile injectable market by volume, the government says.7 All three have had manufacturing problems in the past two years.

With such consolidation as well as tight inventory management practices, the specialized manufacturers of injectable drugs lack the flexibility to adapt to manufacturing disruptions. If one plant shuts down, it may overburden the limited remaining competitors or choke off the supply entirely.

It’s hard to estimate the effects of these shortages, I don’t have good data on the damage done nationwide, only my personal experience. In particular, I remember during an ICU rotation running out of levophed, an incredibly important pressor that helps patients who are in shock from becoming fatally hypotensive.

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NHS has broken the cycle!

A few days ago I asked how do we break this cycle of news reports based on terrible misreading of the scientific literature literature. All these reports do is spread misinformation and undermine trust in scientific research.

Well, the British National Health System has the answer! Via Ben Goldacre, I’ve found my new, favorite website, Behind the Headlines at NHS. It’s the Snopes.com equivalent for shoddy science journalism. Every day they examine what health news is making the headlines, share it with scientific and clinical experts, and they report on the science in a way that’s actually accurate.

So, ignoring the question of why don’t journalists do their job correctly in the first place so we don’t need this service, I’m thrilled to hear of its existence. It seems inefficient though. First university PR departments and journalists have to mangle the science, then we need to have scientists put it back together again. We should just have scientists report on the literature, like at scienceblogs! Instead we have a bunch of incompetent boobs spoon-feeding the public total garbage without anyone writing in to complain when they turn in stories that are essentially complete fiction.

For instance read about Man Flu story at Behind the Headlines, then look at the Daily Mail article or BBC reporting that started this mess.

The authors of this dreck should be fired for journalistic incompetence, and the scientist she quoted (if indeed she was quoted correctly) should consider never talking to a journalist again as they make it appear that she doesn’t even understand her own research. The scientists too in this instance appear culpable as it seems they were happy to help spread completely simplistic, and I think frankly false interpretations of their data.

Luckily, the NHS is providing a public service to the citizens of the UK, and indeed the world, by replacing such nonsense reporting with thoughtful, considered articles that actually explain the science and inform the public.

Are Patients in Universal Healthcare Countries Less Satisfied?

ResearchBlogging.orgA dishonest campaign has started against healthcare reform in this country and the first shot has come from Conservatives for Patients Rights (CPR), a group purporting to show that patients in universal health systems suffer from government interference in health care. To bolster their argument, they have a pile of anecdotes from people around the world who have suffered at the hands of evil government-run systems. The problem, of course, is that anecdotes are not data, it is impossible to determine the veracity or reasonableness of these claims, and there is no way, ethically or practically, to respond to claims against doctors in these systems.

And should we be surprised? Every other country in the industrialized world has universal healthcare. Some are government run, single payer systems, others are mixtures of private and public funding to guarantee universal coverage. I would be shocked if you couldn’t find a few people to provide testimonials about how they’re angry at their coverage. After all, Michael Moore made an entire movie about such testimonials against our system.

So what do we do? How do we find out the truth when the ideologues and financially interested parties have started a campaign to muddy the water with anecdotal attacks?

We look at the data of course. And surprise, surprise it doesn’t support CPR’s assertions that our system couldn’t stand some improvement.

During the next couple of weeks, I think we should talk about what healthcare looks like here in the US and around the world. Rather than a few horror stories, let’s take an in-depth look at what’s happening in universal systems, and whether or not we should consider a change.

Let’s start with an examination of some data from the literature on different experiences people have with these healthcare systems.
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Obesity – A new study and what it means to be a “healthy weight”

ResearchBlogging.orgIn response to the conversation on “Obesity, Evolution and Delayed Gratification” on the main page and Razib’s coverage of a fascinating new study on the relationship to the lactase gene and obesity, I thought now would be a good time to write about an important new study that helps define the boundaries of what normal and healthy weights are in humans.

This study, entitled Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies is a whopper of a meta-analysis. That is, a study that increases the power of other similar studies by combining their results so that, in this case, data from hundreds of thousands of patients can be aggregated. Meta-analyses have their flaws, and I criticize them frequently when poorly-done or poor-quality studies end up being averaged-in with the results of better-designed studies, but this one is large enough and thorough enough that its results should not be dismissed.

What this study describes is the mortality, and causes of mortality, one observes when one sorts people by body mass index. Body mass index also has it’s flaws but it is a useful, if imperfect method of describing one’s relative contribution of body fat to their total mass. It is calculated by taking and individual’s body weight in kilograms and dividing by the square of their height in meters. “Normal” is defined between 18.5-25, overweight is 25-30, and obese is greater than 30. These numbers do not describe all people well, and you may be an exception to these predictions. This usually occurs if you have a large amount of muscle mass relative to your height, so Arnold Schwarzenegger would be obese according to these scales. However, most people are not Arnold Schwarzenegger and the scale fits, it’s better not to let the perfect spoil the good. One must also remember that it would be unethical to design a study in which we prospectively made people overweight or obese, since we suspect that will cause poor health, so this is necessarily a correlative study of BMI and health. But this information combined with what we know about mechanisms of cardiovascular disease, diabetes, etc., makes a lot of sense, and I believe in the context of the literature we can make a safe assumption the effects we see are causal.

Overall what the study suggests is that the current 18.5-25 recommended BMI is probably about right, BMI of 25-30 marginally increases morbidity and mortality, and BMIs much greater than 30 significantly shorten one’s life. The reason I like this study is that they have aggregated such a huge data set, they demonstrate a clear dose-response curve between obesity and mortality, and they’ve done a better job than most in teasing out the relationship between health, weight, smoking and other co-morbidities at all BMIs.

Let’s take a look at some of the data.
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What should a national health care system look like?

I was pleased to see president Obama deliver this address yesterday:

I was even more pleased because he has gathered the traditional opponents of healthcare reform around him and has convinced them to commit to reform in the US system. This is a positive sign. However, I’m concerned because, as with all political debates that challenge a dominant ideology – in this case free-market fundamentalism – we will soon see the denialists come out of the woodwork to disparage any attempt at achieving reforms that may result in universal health care coverage. This has, in fact, already begun, and typical of the tactics they selectively mention the British NHS. If you care to read a balanced article on the history and function of the NHS, you’ll probably agree it is wrongly demonized. What you will also see is that the denialists will ignore a few key facts which include:

1. The United States is the last industrialized nation that lacks a universal healthcare system. Once again, thanks to obstructive policies led by the free market fundamentalists, the US is trailing the rest of the world.
2. The US spends more per capita on healthcare than any other nation in the world.
3. Despite spending more, we get less. We have tens of millions who are uncovered – which does not mean they do not receive healthcare at all. They instead are treated in ERs, urgent care centers, or receive substandard care, and the state ends up picking up the bill anyway. So even without a planned universal health care system, you end up picking up the (higher) bill because the state has a vested interest in protecting hospitals from the economic collapse that would occur if they had to pick up the tab on every impoverished patient who doctors are ethically and legally obligated to treat.
4. Many national healthcare systems work. We will not hear about this from the ideologues who will soon harangue us with cherry-picked horror stories of long wait times and underfunded hospitals. You will likely not hear about Sweden or Italy or France, and I promise you will never hear them talk about Australia. For them to do so would be to admit to defeat of their fundamental premise that universal health care can not work.
5. Failures of national health systems are not related to universality but instead are due to chronic underfunding by government. If the British spent as much per capita as we did, they wouldn’t have the shortfalls in manpower and beds that they do.

We will of course hear a lot of chest thumping from the thick-browed morons about how the US is already perfect and can not learn anything from the rest of the world. We will hear how every other system in the world is imperfect, and that is why any reform is impossible. We will hear how this will lead to communism and socialism despite the fact that every other industrialized nation in the world has universal healthcare and amazingly they didn’t all go commy. In short, we are about to hear a bunch of denialist garbage designed to delay, to obstruct, to block, and drag down any meaningful action in healthcare.

But before that happens, let’s have a more balanced discussion on what a universal healthcare system could look like in the US.

Any discussion of changes in the US medical system must begin with a statement of principles guiding reforms in the system. Let’s start with some of the principles I would include, and I think most of us could agree on:
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