'Cool' vaccines

We all know the usefulness of certain thermophiles (I'm looking at you, Taq polymerase), but up here in Canada, with our vast arctic tundra, we should be looking for uses for cold-loving organisms - a resource we're more likely to have in abundance.

A group at the University of Victoria has done just that, using genes psychrophilic bacteria to develop temperature-sensitive vaccines.

One at a time, the team swapped out nine so-called essential genes—involved, for instance, in DNA repair or cell division—in F. novicida for their counterparts from Arctic bacteria, such as Colwellia psychrerythraea, a marine microbe that lives in polar waters and ice. Francisella normally dies at 45˚C; introducing the cold-loving genes lowered that threshold by up to 12˚C, depending on the gene and the species it was borrowed from.

When the researchers injected these altered strains into the relatively cool tails of rats, they found that the microbes reproduced locally but didn't spread to the warmer spleen and lungs, where they would normally replicate as well. The key test was whether the strains could act as vaccines. F. novicida is lethal to mice, but when the researchers injected the temperature-sensitive strains, the animals didn't get sick—and they were protected from an otherwise fatal dose of the unaltered F. novicida given 3 weeks later. [Source]

The idea for a temperature-sensitive vaccine is already out there, with a particular flu vaccine capable of replicating in the throat and nose, but not the lungs. The goal is to create safer live vaccines, but could be put to other uses such as study of dangerous pathogens by creating versions that can't replicate in the warm human body, possibly reducing the need for the strict containment measures to keep researchers safe.

The full research article is available free from PNAS.

Science: Brought to you by Pepsi

If you've been watching the blogs this week, you may have noticed an uproar at ScienceBlogs over a new corporate blog, Food Frontiers paid for and featuring bloggers from PepsiCo's R&D department.

In some ways, this was a cool idea. There's a lot of food science that we don't hear about, and it would be fascinating to get a glimpse, even through a filter, of what kind of stuff is being done by the R&D department of a major multinational. After all, they have scientists and do research too. Better Off Ted was a great sitcom, but somehow I don't think weaponizing pumpkins is really typical of what goes on.

In other ways, it was a terrible idea. Or at least badly implemented. Part of the mission of the blog was to discuss advances in nutrition and health policy. There's an obvious conflict of interest here for a purveyor of junk food. This source of potential bias, and the concern that this might simply be a propaganda arm for Pepsi loomed over the project.

Whether the blog would be more the former or the later (or some [un]acceptable mix), we'll never know. Several ScienceBloggers took issue, and made a fuss threatening to leave the network (and in some cases following through). Others took a wait-and-see approach. After all, this all happened before any real content appeared on the offending blog. Sb admin scrambled to fix the mess, first changing the format so it was more obviously paid content but eventually scrapping the whole thing.

A round-up of ScienceBlogs posts about the Pepsi fiasco, including admin response can be found here (scroll down)

A list of bloggers leaving the network (and new digs) is being maintained here.

The role of industry at a collective like ScienceBlogs, and how to properly include them is a complicated and interesting issue. As made clear by the range of responses to the initial introduction of the Pepsiblog, not an easy one to get people to agree on.

Gender Imbalance in Science

There is a gender imbalance in science. This is most obvious when looking at math, physics or engineering programs. It's easy to look around biomedical labs, see the number of women, and assume this isn't a problem for the biological sciences. And indeed, in the biological sciences, women make up 62% of bachelor's recipients and 56% of graduate students¹. Beyond that, the numbers drop off for a number of reasons. Again, in the biological sciences, only 41% of postdoctoral fellows, 33% of tenure-track and 22% of tenured scientists are women. (Nevermind the fact that their salaries also tend to be lower)

Those numbers are pretty shameful. Some might argue that it doesn't matter, as long as the science being done is good (though I'm really not sure who they might be). The problem is, it isn't. Even the research being done is gender biased, as highlighted by a series of recent editorials in Nature. The first points out that there's a gender bias in clinical trials: except for a few key areas (eg. breast, cervical or ovarian cancers) women are underrepresented

Generally, women remain underrepresented in biomedical research. Studies published in 2000 and in 2008 concluded that women were still not included in mixed-sex cardiovascular trials in numbers that reflect the disease prevalence among the general population. A survey of studies published in 2004 in nine influential medical journals found that only 37% of participants were women (24% when restricted to drug trials), and only 13% of studies analysed data by sex.

It's no secret that women and men have different physiologies, and can be differently affected by diseases and their treatments. So why should sex differences not be considered when designing a clinical trial? You can't treat differently if you don't know the differences, and even where gender is known to affect outcomes, there's still no difference in treatment

A 2005 study of 300 new drug applications between 1995 and 2000 found that even those drugs that showed substantial differences in how they were absorbed, metabolized and excreted by men and women had no sex-specific dosage recommendations on their labels. This may be part of the reason why women are 1.5 times more likely to develop an adverse reaction to prescription drugs than men.

And if you're a pregnant woman, it gets even worse. You're forced to either forego treatment or potentially settle for drugs of unknown effectiveness or safety (for you or the fetus), since pregnant women are usually excluded from trials and new drugs are often not approved for them. This despite the obvious fact, that the second article points out, that "pregnant women get sick, and sick women get pregnant." Obviously diving right into clinical trials with pregnant women is a bit risky, in no small part for the fetus (though a controlled clinical trial is probably still safer than rolling the dice with off-label use), but there are ways this can be approached.

There is an obvious alternative: small, well-designed trials for pregnant women, starting with phase I safety trials that would begin at the same time as phase III efficacy trials in the general population. With this staggered approach, pregnant women and fetuses would not be exposed to any compounds that failed in phase I and II trials.

This strategy is simple, and makes sense: it allows pregnant women the same standard of evidence-based care afforded to everybody else (even better, if you consider the lack of sex consideration described above), accounting for their own particular changes while mitigating risk.

Most surprising, to me at least, is the fact that gender bias even extends to animal models. In some ways, it makes sense to keep models simple and avoid potential complications from hormone cycles. Depsite the fact that male mice tend to fight when caged together and single housing takes both space and money, a survey of 2000 studies done in 2009 found a male bias in animals used.

We found a male bias in 8 out of 10 biological disciplines, most pronounced in neuroscience (5.5 males to 1 female), pharmacology (5 males to 1 female) and physiology (3.7 males to 1 female).

Though this might be more convenient or have a practical rationale, it doesn't necessarily result in the best model. So we have biased models feeding into imbalanced clinical trials, with women getting the short end at each step. And the end result:

However justifiable these imbalances may be on a case-by-case basis, their cumulative effect is pernicious: medicine as it is currently applied to women is less evidence-based than that being applied to men.

Which is just sad.

--
¹All numbers based on US statistics from the NSF, 2006.

Cheeky monkeys showing off their memory.

Check out how much better a chimpanzee's memory is than yours. Aside: Strange how a Japanese researcher is using Japanese written words on the test screen but uses Western/European Arabic numerals for the actual test on the monkeys. Are Japanese numbers too difficult for the monkeys?

Cancer Carnival #35

Once again, it's the first Friday of the month. Right between Canada Day and Independence Day, and in the middle of World Cup month so it's a bit of a light carnival this time around.

Over at Health and Life, our friend David has a post about melanoma and a new drug to treat it:

Ipilimumab is a monoclonal antibody that targets cytotoxic T lymphocyte associated antigen 4 (CTLA-4). This marker is associated with promoting a regulatory response by the immune system, slowing it down. By knocking it out, ipilimumab may shift the body’s immune response from inaction into action.

Health and Life often features new drug info and is a good place for pharm-minded folks.

At the Stem Cell Network blog, I have a post up about new developments in the world of hematopoiesis and touch upon some of the implications they might have for cancer research.

[A]cute myeloid leukemia (AML) is a cancer of the blood. As the name implies, it is the result of uncontrolled growth of cells from the myeloid lineage caused by dysregulation of the corresponding stem cell. Effective treatment requires the identification and targeting of the appropriate cells.

The Spittoon, the 23andMe blog, highlights 2 new cancer-associated SNPs. First is a genetic variant contributing to melanoma risk and mole count.

When Duffy’s team examined data from about 2,000 adolescents of European ancestry living in Australia, they found that each copy of a T at variant rs12203592 was associated with a significant increase in numbers of “flat” nevi (the most common type of nevus). When they looked at data from the parents of the adolescents, however, they saw no such effect. In fact, the data suggested that the C version of rs12203592 – not the T version – was associated with higher nevus counts in older people. Comparing these results with data from thousands of individuals from the UK confirmed the differing age-dependent effects of rs12203592.

Mole counts is something we've talked about before. The Spittoon post goes on to describe how these same variants affect melanoma risk. The second set of SNPs have to do with testicular cancer, reported in Nature Genetics.

Clare Turnbull and colleagues analyzed the DNA of 979 men with testicular cancer and 4,947 controls, all of European descent. Many of these men were included in the group’s previous study. The four SNPs most strongly associated with testicular cancer were then followed up in an additional sample of 664 cases and 3,456 controls, where evidence of association was also found.

Elsewhere in the blogosphere, Orac discusses cancer overdiagnosis and overtreatment, ERV notes the difficulties in epigenetic approaches to cancer treatment, HighlightHealth points to new information about vitamin D and cancer (which seems contrary to research from a few years ago) and for the epidemiologists, The Pump Handle dissects the recent President's Cancer Panel report.

That's it for this month's Cancer Research Blog Carnival. For older editions, visit the Carnival Homepage. Don't forget, the CRBC has subscription options; you can follow by email or RSS feed. An aggregated feed of credible, rotating health and medicine blog carnivals is also available. For a broader collection of science-related blog carnivals, sign up for the Science, Medicine, Environment and Nature Blog Carnival Twitter Feed.

Chelation therapy quack sues Quackwatch

You may have heard of chelation therapy: it involves using chelating agents, such as EDTA either IV or orally to scavenge metal ions in the blood and promote their excretion in the urine. It is a standard of care therapy for heavy metal poisoning. However "alternative medicine" proponents have been touting it as a miracle "detoxifying" treatment for all kinds of ailments from coronary heart disease to autism. And it's not without concerns, according to wikipedia:

"side effects include fever, headache, nausea, stomach upset, vomiting, convulsions, bone marrow depression (dropping blood cell counts), a drop in blood pressure, cardiac arrhythmias, respiratory arrest, and hypocalcemia. Other concerns include kidney failure, which can require permanent life-limiting and expensive dialysis, or cause death. "

Chelation therapy has been responsible for over 30 deaths, many of which were autistic children. The reason is quite simple: we need metal ions for our body to work. If you've ever looked at a periodic table you know that elements essential for life such as sodium, calcium, iron, potassium are also metals so it's not just lead and mercury you're removing.

To justify the detoxifying, many of these quacks perform urine analysis after giving a "provoking agent" which artificially increases metal excretion in the urine to scare patients into getting treatment. not only is that deceptive, but there is absolutely no evidence, despite numerous studies, that chelation therapy has any benefits outside of heavy metal poisoning.

Quackwatch, a site which is a beacon of reason and often the lone voice to expose quacks is being sued for $10M by one of these companies. How typical. These companies are flush with cash from taking advantage of credulous patients and when you point out that the treatment has no scientific validity and is potentially harmful they fight reason with the blunt tool of litigation. Libel law is the greatest threat to free speech since lone individuals often cannot afford to legal proceedings against larger corporation. But, if you feel so inclined, quackwatch is taking donations to help cover the cost... At least we can fight back by exposing these quacks. Suing only attracts more attention to you, hopefully knowledge and reason can do the rest.

Inadvertently funny lab stuff

This was written on a mouse cage by the vet...

Psychopath Brains

Here is a quick NPR article that about a scientist who studies the brain and discovers that his own brain is a psychopath.

Ten Questions to Ask an Alien

Carl Sagan in The Demon-Haunted World:

It's a stimulating exercise to think of questions to which no human today knows the answers, but where a correct answer would immediately be recognized as such. It's even more challenging to formulate such questions in fields other than mathematics. Perhaps we should hold a contest and collect the best responses in "Ten Questions to Ask an Alien."

The connection to aliens stems from how one might test claims from individuals who say they have contact with extra-terrestrial visitors, who are presumably far more scientifically and technologically advanced than we are. The examples given are proof of Fermat's Last Theorem or Goldbach's conjecture, both mathematics problems (the former no longer being eligible, as it has since been solved).

I have no prize to offer for such a contest, but what are some other (preferably non-mathematics) questions we could include on such a list?

The Finnish Defense

I was bouncing around the blogosphere when I stumbled upon this description of a thesis defense in Finland:

As well as the student and the opponent, there is a kustos, who sits in the middle making sure everything runs smoothly, and pouring the water. All three are dressed in top and tails, or something as fancy. When they enter, everyone stands and the kustos announces the beginning of the thesis. The student starts by giving a short talk about the main themes of the thesis, after which they invite the opponent to pass their critical opinion of the thesis. The opponent then stands and give a short summary of the background to the thesis, and where it sits in the wider scheme of things. Whilst he does that, the student has to stand to. Then the real defence starts...

A lot of it sounds similar to the process here: we have a chair to guide proceedings and examiners (opponents?), and the whole thing is open to an audience. But tuxedos? A formal dinner and dance - with speeches? And check out the sweet hat for the kustos. Then there's possibly the best part:

The public's job is to sit quietly, and judge the quality of the defence - afterwards they decide if the opponent passes or not.

Maybe we can turn it into some sort of reality show? Survivor: Thesis defense.

Futurama on Homeopathy

It's back, baby! Futurama returns to the television airwaves tonight after almost 7 years off the air, with all its jokes about stem cells, global warming and quantum physics. Like their take on homeopathy:



One thousand years in the future, and still no evidence...

If this house is a-rockin' ...

About 10 minutes ago, an earthquake hit which was felt pretty well in the Ottawa area. My house was noticeably shaking for several seconds, followed by minor after-tremors. No damage done here, but it probably the strongest one I've felt in the area. I haven't seen anything official, but estimates are 5+ on the Richter Scale (estimates I've seen have ranged from 5.1 to 5.5), or about as much energy as the Nagasaki atomic bomb.

Ottawa is actually fairly seismically active, with quakes happening on average once every 5 days. Those are usually minor, and not felt by people. In Canada, the Geological Survey has us ranked third at risk among urban centres, after Vancouver and Montreal. You can see the estimated hazard, and take a look at previous local earthquakes here.

The USGS (US Geological Survey) also tracks earthquakes worldwide and claims 'real-time', but the Ottawa area tremors aren't up yet.

Publishing Fluff

We all know that the number of papers published every year is growing rapidly, but does that mean we are more productive and more creative? Some of the old timers (you know the type) will tell you, no new research is being done, we are just rehashing old science and incrementally improving on it. Is the quality of papers decreasing ? Some data seems to point that way:

"While brilliant and progressive research continues apace here and there, the amount of redundant, inconsequential, and outright poor research has swelled in recent decades, filling countless pages in journals and monographs. Consider this tally from Science two decades ago: Only 45 percent of the articles published in the 4,500 top scientific journals were cited within the first five years after publication. In recent years, the figure seems to have dropped further. In a 2009 article in Online Information Review, Péter Jacsó found that 40.6 percent of the articles published in the top science and social-science journals (the figures do not include the humanities) were cited in the period 2002 to 2006."

The problem is that as the quantity of fluff paper increases, peer review suffers because the system is overwhelmed, and the bar lowers.

Caffeine Withdrawal

Bad news, coffee drinkers: your morning joe may not be having the wonderful effects you think it does. And if you're a heavy consumer, it gets even worse. A recent paper in Neuropsychopharmacology looks at the effects of caffeine (approximately equivalent to 2 cups in the morning) on non-, moderate- or high-caffeine consumers. From the abstract:

With frequent consumption, substantial tolerance develops to the anxiogenic effect of caffeine, even in genetically susceptible individuals, but no net benefit for alertness is gained, as caffeine abstinence reduces alertness and consumption merely returns it to baseline.

The data showed that after a night of abstinence - participants were instructed to consume no caffeine after 7pm the previous evening - heavy caffeine consumers (on average ~350mg per day) showed no benefit to alertness from caffeine, but rather a precipitous decline in alertness when given placebo, compared to light- or non-consumers. They also reported a large increase in headaches when deprived of caffeine. How bad were they? Almost 4% of the group withdrew from the study due to headaches and feeling sick. This all suggests that rather than actually improving alertness in heavy consumers, the morning coffee ritual merely mitigates withdrawal effects, returning them to 'baseline'.

Surprisingly, in low- or non-consumers caffeine showed no difference in alertness, compared to placebo, but did result in increased anxiety and slight increase in headaches. The authors suggest this is due to discrepancies between this and earlier studies. Previous research on the effects of caffeine on alertness seems to have relied mostly on self-reported caffeine consumption. In this case, reporting was validated and compliance enforced based on saliva levels of caffeine and its metabolites.

The authors also identified a genetic component involved in modulating the anxiety effects of caffeine. A SNP in the adenosine A_2a gene (ADORA2A) "showed greater susceptibility to caffeine-induced anxiety", and while people of that particular genotype habitually consumed more caffeine on average, the effects on anxiety were only observed in the low end consumers. Moderate to high consumers seemed to be tolerized to the effects.

It's also worth pointing out that 90% of the population from which participants were drawn (adults living in Bristol, UK) fall into the moderate to high caffeine consumption category (>40mg/day). If that's representative of western society, then most of us are sub-optimal without our morning hit. It also explains the widespread notion that coffee improves alertness: it does, but only because we're suffering without it.

The People vs. NPG

Science publishing is a curious business. Content is provided for free by working scientists. That content is then peer-reviewed, also for free. Publication and dissemination costs are dropping, as paper publishing gives way to electronic distribution. So of course it only makes sense to increase prices. That's what's happening at the University of California. Nature publishing group are pushing for an increase in subscription costs for UC from an average of $4500 per journal to a whopping $17500 each. A 400% increase. Across the 67 Nature group journals, that's a substantial sum. This is prompting UC to drop subscriptions to NPG journals and to boycott their products altogether.

Nature protests, of course, claiming price increases are capped at 7% per year and the large UC increase is due to deep discounts they receive that are no longer tenable. This may be the case, but given the profitability of science publishing and the fact that the consumers of the product also do most of the heavy lifting (writing and reviewing manuscripts) it's a PR battle that Nature can't win.

One great metaphor for the state of science publishing is Fight Club soap: “We were selling their own fat asses back to them.” Considering UC has contributed around 5300 articles to Nature journals over the past 6 years, the phrase that comes to mind is "biting the hand that feeds."

For a good round-up of news and blog posts relating to the UC-Nature dispute (and open access in general) check out Jim Till's blog: "Be openly accessible or be obscure"

Friday Fun: Rube Goldberg Machine

The band OK Go makes some pretty good music videos. They're all well choreographed (for example, their famous treadmill video), but my favourite has to be for the song This Too Shall Pass which features a massive Rube Goldberg machine:



I also quite like their latest video, End Love that does some cool stuff with timelapse and compression - and is even more impressive since it's one continuous camera shot!

Blood, Teeth and Stem Cells

The Bayblab has been a bit neglected lately, but that doesn't mean we're not still blogging. Head over to the Stem Cell Network blog to check out some new posts. I have a couple of recent pieces up. The first is about a potential new dental implant that uses a special scaffold to attract and differentiate stem cells, growing new teeth in place. The second is a first look at a new paper that challenges some assumptions about hematopoiesis.

Cancer Carnival #34

It's the first Friday of the month, which means it's time for the Cancer Research Blog Carnival!

May was Neurofibromatosis (NF) Awareness Month, with NF Awareness Day falling on May 20. HighlightHealth highlights the occasion with 10 things to be aware of, beginning with a description of the condition.

Neurofibromatosis (NF) is a genetically inherited disorder that predisposes individuals to the development of a variety of benign and malignant tumors in the central and peripheral nervious systems. The disorder affects neural crest cells and causes tumors to grow along various types of nerves and can also affect the development of bones and skin.

HighlightHealth also offers some preliminary coverage of the Children's Tumor Foundation's NF conference. This year's conference will feature constant updates and videos from the floor which will be accessible here. Staying with the NF theme, we also have the story of Jaqueline, a girl (now 2 years old) who was diagnosed with NF at 4 months and is now the inspiration for a children's character with the same disease.

On the topic of conference coverage, Alexey at Hematopoiesis has some coverage of the recent AACR meeting, including a link to what he describes as the most interesting talk of the meeting on the subject of cancer stem cells.

This talk was the most interesting for me maybe from the entire annual 2010 AACR meeting. Because it made me to look at cancer stem cell concept from other side - side of cancer non-stem cells.

The post offers some highlights, or you can watch the entire talk here. The AACR has over 80 hours of audio, with accompanying slides where available accessible for free on their website.

At the 23andMe blog, The Spittoon, the latest SNPwatch article profiles new genetic associations for nasopharyngeal cancer.

Researchers from Singapore, China and the United States studied about 5,000 people with NPC and 5,000 controls, as well as more than 250 families, all of southern Chinese descent. As expected, a strong genetic effect was seen in areas of the genome that encode the previously identified immune markers. But variants in three other regions were also associated with NPC risk. Two of these associations were statistically significant. The third SNP did not make the cut off, but was highly suggestive.

Click the link to find out more.

Here at the Bayblab, AC reports on a study that claims killing of cancer cells by homeopathic preparations. Is there something to it, or is this a breakdown of the peer review process? What's worse is that the paper is being flaunted by pushers of alternative medicine.

Most shockingly, according to the New Scientist, this study was mentioned in the British parliament as an argument for more funding for alternative medicine.

Nevermind the fact that it has been thoroughly picked apart again and again.

Finally, Orac revisits the issue of cell phones and cancer, commenting on a recent paper from the Internation Journal of Epidemiology.

That's it for this month's Cancer Research Blog Carnival. For older editions, visit the Carnival Homepage. Don't forget, the CRBC has subscription options; you can follow by email or RSS feed. An aggregated feed of credible, rotating health and medicine blog carnivals is also available. For a broader collection of science-related blog carnivals, sign up for the Science, Medicine, Environment and Nature Blog Carnival Twitter Feed.

Homeopathy cures breast cancer!

Every once in a while, perhaps more often than we'd like to admit, peer review fails. This time a paper published in the International Journal of Oncology claims that homeopathic preparations (Carcinosin, Phytolacca, Conium and Thuja) are cytotoxic to breast cancer cell lines. Now I don't mind homeopathic formulations being tested scientifically, although I'm sure MD Anderson Cancer Center could have put that money to better use, but I couldn't help but be suspicious. New Scientist points the finger at the peer review process, and rightfully so. I didn't even need to read the paper, just took a look at their figures: no measurement of the active elements shown (although we're supposed to take their word for it), no statistics shown on the MTT assay and clearly the diluent (EtOH) can account for the effect (now alchohol has memory too?) and most glaringly the western blots showing the mechanism are lacking proper controls for the various timepoints. In fact it tells us exactly what happened, changes in the cyclins and caspases suggests the cells are over-confluent and dying off. Most shockingly, according to the New Scientist, this study was mentioned in the British parliament as an argument for more funding for alternative medicine. But even if peer review is "fixed", it's almost inevitable that wrong findings are going to be published, perhaps what we should do is teach parliamentarians how to weigh evidence.

At least we know that homeopathic medicine can sometimes demonstrably save lives, as the case of Billy Joel's daughter's attempted suicide with homeopathic sleeping pills. I guess she hadn't heard of the 10:23 campaign.

Adventures in Dreamland

There's a story making the rounds based on an an abstract presented at the Science of Consciousness Conference which is an extension of previously published work that claims that video game players more frequently experience control over their dreams. From the Livescience description of the work:

"If you're spending hours a day in a virtual reality, if nothing else it's practice," said Jayne Gackenbach, a psychologist at Grant MacEwan University in Canada. "Gamers are used to controlling their game environments, so that can translate into dreams."

They also suggest that because of the aptitude for lucid dreaming, gamers may experience fewer nightmares

[G]amers experienced less or even reversed threat simulation (in which the dreamer became the threatening presence), with fewer aggression dreams overall. [...] "What happens with gamers is that something inexplicable happens," Gackenbach explained. "They don't run away, they turn and fight back. They're more aggressive than the norms."

So if you're suffering from bad dreams, it might be worth trying some video games before bed. Maybe you'll turn those horrifying nightmares into a nice, relaxing game of Doom.