Thursday, May 31, 2007

How it All Started

I found this very interesting Nature article about our innate mathematical ability. It essentially shows that our nonsymbolic arithmetical capabilities (i.e. manipulation of, say, dots) precedes and even dominates over our symbolic capabilities (manipulation of actual "numbers"). They showed that preschoolers with no training in arithmetic were able to complete addition and comparison tasks better than chance, and that their performance in nonsymbolic tasks followed a similar pattern to adults. They concluded, or at least suggested, that once we learn arithmetic, we form a mapping of the arithmetical symbols (i.e. numbers and operators) onto real visual arrays of objects. In other words, we don't do math in our heads; we move dots around.

I've always been interested in the roots of math. It's become such an important part of our culture and education that we sometimes forget what it really is. As was said in an excellent and famous book about the origins of math, math originated from our ancestors' realization that three dots and three oranges and three mountains and three days are really just manifestations of the same abstract concept: three. So perhaps we evolved some sort of number recognition software. When you think about it, it's a pretty impressive trait. Dots, oranges, mountains, and days aren't remotely related, and yet we, as well as other higher animals, have the ability to recognize the link. And then to think of all the wonderful discoveries about our view of the universe have been made because of this link. It's astounding.


Mouth Pipetting

A lost art, mouth pipetting, has fallen out of favour with the lab crowd as there exist many technological aids for accurate pipetting. Still you can find people who think that pipetting quick and accurate may require mouth pipetting. Two past supervisors of mine routinely mouth pipetted and once I made the mistake of pointing out how dangerous it was. I was given a look of disgust that indicated I did not have enough respect for their vastly superior research experience (which they definitely both have). However they also come from times when safety was less of a concern and greater risks were part of research.
Here's a good anecdote I found in a discussion group:
Back in the mists of time circa 1971 I left school and got my first job as a laboratory assistant for a company that made electric cookers and fires based in Burnley. My job was to sample and undertake quantitative analysis of electroplating solutions and cleaning solutions. I was 17 at the time. Mouth pipetting was routine in those days. Anyway to cut a long story short, I was pipetting 2N caustic soda when a colleague distracted me and I ended up with a mouthful. 2 weeks of nothing but cold milk and cold soup were enough to convince me that mouth pipetting was not the way.
But just for the reasons of showing people not what to do there is some people demonstrating this lost art.
Also I think that mouth pipetting is still used for some purposes. I guess that preimplantation mouse embryos are still mouth pipetted but it increases SAPK/JNK and c-fos.


Venomous mammals

Until recently, I was completely unaware that some mammals are venomous. This discovery dates from over 50 years ago, yet it is a neglected area of research considering how much attention is given to other venomous phyla for their medicinal properties. I had seen the spurs on the hind legs of platypoda, but most monotremes (other than the platypus) have spurs without functional venom glands.

Yet shrews actually have a venomous bite: the bottom canines have deep grooves which deliver the venom produced by specialized salivary glands. These insectivores use the venom to paralyse their preys for up to 16 days, so that they can store them for a later snack. The active component of the venom, called blarinasin (BLTX), shares about 50% identity with human tissue kallikreins. This mode of action is the same employed by other venomous species such as the rattlesnake: "BLTX converted kininogens to kinins, which may be one of the toxic pathogens, and had dilatory effects on the blood vessel walls. The acute toxicity and proteolytic activity of BLTX were strongly inhibited by aprotinin, a kallikrein inhibitor, suggesting that its toxicity is due to a kallikrein-like activity of the venom". A bioprospecting company based in the maritime, at Mt Allison University, is looking to develop this toxin for neuropathic pain applications.

Solenodon are also venomous. They are possibly one of the funniest looking mammals (shown above), like the lovechild of a shrew and an elephant, measuring about 30cm, grunting like a pig, with tits on its ass, and glands in the armpits that make it smell like a goat. As a note to intelligent design believers, they are susceptible to their own venom (better not bite your tongue), they freeze when they sense danger, and they have difficulty running, often stumbling and tripping over their own toes and tumbling over, making them easy targets. Originally from the Caribbean, they are all but extinct due to pets. I guess the bite didn't pack enough punch.

Finally, I was surprised to learn that there is a venomous primate on the island of Borneo and much of South-East Asia. The slow loris is a nocturnal animal which secretes a toxin in its saliva, and mothers lick their offspring before letting them forage for protection.


Wednesday, May 30, 2007

The day the Universe went Gangster

There's a great doco on the history of science by James Burke called, "The day the universe changed." It goes through some of the great scientific realizations of history in many parts and was filmed in 1985. It's hilarious when he starts talking about the personal computer and shows a behemoth of an apple. Scarily he makes some predictions that are quite accurate. Anyways I ran into an amusing flash animation of "Damn it feels good to be James Burke" to the tune of "Damn it feels good to be a gangsta."


Tuesday, May 29, 2007

Who wants to be an organ donor?

The ever permissive Dutch are embarking on a new way to select organ recipients. Big Donor, a new reality show from the producers of Big Brother. In this program, to air later this week, a terminally ill cancer patient will donate a healthy kidney to one of three contestants. The final decision will be up to viewers. After watching short films about the lives of each contestent, a winner will be chosen American Idol-style: by texting in their vote. The producers claim the goal is to raise awareness about the long waiting list, but seems more like a step towards selling organs. It's just unfortunate that the reality title "Survivor" was already taken.


Tetragametic chimerism

I have a riddle for you: "The patient, who we will call Jane, needed a kidney transplant, and so her family underwent blood tests to see if any of them would make a suitable donor. When the results
came back, Jane was hoping for good news. Instead she received a hammer blow. The letter told her outright that two of her three sons could not be hers."
Well if you've paid attention to the title of this post you probably already know the answer. Jane is a chimera. She is a mix of cells from two twin sisters, conceived from two pair of gametes, that somehow got mingled up into one person. There are 30 or so reported cases of true tetragametic chimerism in the literature, often because they lead to hermaphroditism when the chimera is of a male and a female twin. However many more lurk around us without knowing. It may be just a few cells in the blood, or a patch in one organ, and you would probably never know...except from when you get blood type or genotype discrepancies. Such a case actually popped up recently when Tyler Hamilton was charged with blood doping after competing in a cycling race. He had two blood types in his veins, but it wasn't because of blood transfusion, he is a chimera. And the prevalence is mind boggling: 20-30% of the pregnancies that start out as twins end up as a single baby, and nearly 70% of all people may be chimeras. Although not everyone agrees with these statistics, it may explain, weird auto-immune disorders. And perhaps some transsexual people really are a girl trapped in a man's body, literally. here.


Synthetic Biology

We have discussed 'biohacking/biopunk' topics before on the bayblab. Here is an interesting essay on synthetic biology possibilities. It's a bit 'out there' but an entertaining read.
Things such as:
"It’s easy to imagine grafting an electric eel’s electromagnetic sensitivity into our brains so we can pick up wireless signals. There’d have to be an fail-safe off switch, of course, but the net effect could be amazing. We’d have true telepathy, and the ability to form group minds."
make me laugh.


Useless appendages

Here is a funny compilation of vestigial structures that are totally useless. One of them caught my eye (I swear it's not the male nipple): "With all of the pain, time, and money that are put into dealing with wisdom teeth, humans have become just a little more than tired of these remnants from their large jawed ancestors. But regardless of how much they are despised, the wisdom teeth remain, and force their way into mouths regardless of the pain inflicted. There are two possible reasons why the wisdom teeth have become vestigial. The first is that the human jaw has become smaller than its ancestors' and the wisdom teeth are trying to grow into a jaw that is much too small. The second reason may have to do with dental hygiene. A few thousand years ago, it might be common for an 18 year old man to have lost several, probably most, of his teeth, and the incoming wisdom teeth would prove useful. Now that humans brush their teeth twice a day, it's possible to keep one's teeth for a lifetime. The drawback is that the wisdom teeth still want to come in, and when they do, they usually need to be extracted to prevent any serious pain."


Red hair was sexually selected

We recently had a debate as to which animals have colour vision. Being avid fly fishermen, we debated wether the colour of the fly really does anything. Can fish see colour? Obviously tropical fish are very colourful but can they appreciate it? Well it turns out, that fish may in fact see more colours than we do. Some of them can see ultraviolet as well as infrared. In fact if you look at reef fish with a UV filter, all kinds of new interesting patterns emerge. The goldfish for example has 4 different cones sensitive to different wavelengths. This brings up the question as to why evolution drives the selection for colour vision. Our ability to see red, green and blue is actually a recent event in our common ancestors with primates. The proposed hypothesis for the evolution of red vision is that it enabled the foraging of ripe fruits in the green background of the vegetation. From then on, red hair, and red appendages were positively selected for in primates by sexual selection. Red hair effectively became sexually desirable, and a red bottom for example, would be a very good cue of the receptivity of the female monkey.


Monday, May 28, 2007

Quack of the Week: Dr. Mike Ackermann (Arm Yourself and Shoot to Kill: That's How We Make Countries Safer)

Ok so we try to focus on science here at the bayblab, and I think it's best to be apolitical as a scientist - but I can't resist commenting on this story. I'm neither anti-left wing nor right-wing politics - we need both - but I am anti-stupid politics. And generally, the current Conservative government takes the cake in the stupid department.

Here's Nova Scotia Dr. (obviously never worked in an emergency room) Mike Ackermann's solution to gun violence in our schools:

"If even 1 per cent of the students and staff at Virginia Tech had been allowed to exercise their right to self defence, then this tragedy would have been stopped in its very beginning and dozens of lives would have been saved," Dr. Mike Ackermann, a Nova Scotia physician, wrote in a letter to the Ottawa Sun in April. "There are never any mass killings at shooting ranges; only at schools and other so-called `gun-free zones.'"

Yes, that's right Dr. Retard, schools are gun free zones. That's because, last I checked, people were supposed to be getting an education there, not meeting in the schoolyard at high noon for a shootout at 20 paces.

Sounds like Dr. Mike is more interested in representing the St. Mary's Shooters Association (he is President), rather than the health interests of Canadians. Good to know he's one of the many pro-wild west "experts" on the current parliamentry committee on gun control. Hmmm...I wonder what the recommendations will be? An AK-47 for every teacher??!!


Saturday, May 26, 2007

Creationist periodic table

Hours of fun thanks to the reDiscovery Institute!


Friday, May 25, 2007

Ginko, a million women and the A-bomb

Since we're talking about female hormones I wanted to point out the recent "million woman" study on the effects of HRT on the incidence of ovarian cancer published in the Lancet. The conclusion: "Women who use HRT are at an increased risk of both incident and fatal ovarian cancer. Since 1991, use of HRT has resulted in some 1300 additional ovarian cancers and 1000 additional deaths from the malignancy in the UK.". There had been many contradictory studies in the past, but this one by its sheer size is the definitive nail in that coffin.

If only we had other studies of this size looking at herbal supplements we could put a nail in that coffin too. Ginkgo, in the same journal, was proposed to have protective effects: "4.2% of 721 controls compared to 1.6% of 668 cases regularly used Ginkgo biloba for an estimated relative risk (and 95% confidence interval) of 0.41 (0.20,0.84) (p=0.01); and the effect was most apparent in women with non-mucinous types of ovarian cancer, RR=0.33 (0.15,0.74) (p=0.007). In vitro experiments with normal and ovarian cancer cells showed that Ginkgo extract and its components, quercetin and ginkgolide A and B, have significant anti-proliferative effects ( approximately 40%) in serous ovarian cancer cells, but little effect in mucinous (RMUG-L) cells." However the honorary baybs Lisa and Val pointed out in the latest issue of the NOCA newsletter (in the picture above), Ginkgo may also be intefering with metabolism of some chemo drugs.

Now all of this was a segway to a spanish youtube news clip I just watched. Now don't ask me why I would listen to such a thing, I am addicted to the internets. But the point is that it talked about how after the A-bomb went off in Hiroshima, the only trees that survived at the blast site were 4 ginkgo trees. Now the funny part was that they attributed that to the fact that ginkgo trees are very primitive (and they are primitive gymnosperms), and that they were around when oxygen content in the atmosphere was higher (also true, ever wondered how dinosaur could be so big) and that therefore they were good at fighting oxydative damage resulting from ionising radiation (????). And that therefore by taking supplements you could protect yourself from radiation!!! brilliant.


Menstruation and Menopause in Monkeys

Menstruation is the cyclic shedding of the endometrium in the absence of pregnancy. Although many people believe their cats or wild Peruvian poodles also have menstrual bleeds, only great apes and humans do, and what is seen in pets is actually bleeding associated with ovulation. Most other mammals will simply resorb the lining. It's actually not clear what the evolutionary advantage of the shedding is. Some people have speculated that it cleans the womb from potential pathogens, based on the high macrophage content of the menstrual blood. Others have proposed it was a primitive visual cue, to reassure men that if they mate, the child will be theirs and also, that if they leave their menstruating females for a long hunting trip, they will not come back to an impregnated female.
Great apes are also subject to menopause, although again it is not clear why menopause seems to be a triggered, regulated cessation of reproductive capacity and menstruation. Some monkeys, like capuchins (Johnny the monkey!), rhesus, as well as whales and elephants are also thought to undergo menopause. The grandmother theory proposes that the loss of fertility and sexual drive frees up a lot of time to nurture existing offspring and 2nd generation offsprings. A recent study of gorillas in captivity at the Brookfield zoo showed changes in behaviour of females undergoing menopause, including what seemed to be reactions to hot flashes and sudden and irregular increases in libido, particularly directed at younger males.



For those watching the Ottawa Senators win the Stanley Cup most likely you will be drinking beer. A good article on random beer information is available at the scientific american website. But for a more thorough information check out the beer wikipedia entry.


Thursday, May 24, 2007

In honor of Stanley Miller

Stanley Miller is famous for his groundbreaking experiment in the 50's, where he recapitulated the atmospheric conditions of the young earth, added some water and some UV light and created amino acid, thereby showing that the components of life can be created abiotically. He was also an advocate of the peptidic origin of life (as opposed to the RNA). He passed away this week. He was one of the scientists that truly inspired me when I was very young, and the inspiration for Amino-Rx.


Wednesday, May 23, 2007

The Cure for Cancer is Now an Open-Source Project

Ever think you had the idea to cure cancer, if only you could just do the experiments you wanted to, the way you wanted, in the lab you designed, the resources you picked out, and the collaborators you wanted to work with? Your time has come. A bunch of US hedge-fund money has been dedicated to an annual $ 1,000,000 Gotham Award for Cancer Research. Basically it's an open-source grant competition. You write up your idea for a high-risk, high-innovation cancer research project, and submit it to the website. The advisory board, made up of a who's who of US cancer researchers, including ISI's most cited scientist Bert Vogelstein, makes sure it's a serious proposal, then posts it on their websites. Others can read, discuss and post commentaries blog-style, and you can then revise your proposal as you see fit. After 8 months or so, based on proposals and authors responses to questions on the website, the $1,000,000 is awarded. The ideas will also be made available to groups interesting in funding cancer research, and if they like your proposal they have the option of contacting you to contribute funds. I think this is great - part reality TV in that pretty much anyone can enter (will Joe Blow from Idaho submit the cure to cancer from a computer in his parent's basement in his tightie-whities?) and part open science. It's interesting that we were just discussing on the bayblab how open publishing a la PLOS One will probably not become mainstream under the current funding structure because it tends to reward prestige, and now here are the inklings of what I think might be a superior, open-source research funding structure for the future. Web-enabled microgranting, direct from the donor to the researcher?


BMI Seminar Plug

I couldn't resist hyping next week's BMI seminar (Tuesday, May 29 10:15 AM) by Dr. Andrew Pelling, a research fellow from the London Center for Nanotechnology, University College, based entirely on my impression of the title: "Punch, Drunk, Love - Emerging Biology and Physics from Living Cells and Developing Butterflies". If his website is any indication, we should be in for a cool (or visually appealing at the very least) talk.


On the pill, off the rag

The FDA has just approved the use of Lybrel (Wyeth) as a birth control pill. The pill, not yet approved for use in Canada, is a combination of levonorgestrel and ethinyl estradiol - two hormones already in use as contraceptives. In contrast to traditional oral contraceptives which typically have an 21 day on, 7 day off (or placebo) cycle, Lybrel is taken daily and inhibits both ovulation and uterine changes required for menstruation. Of course, as with any drug, there are always fun potential side effects which include:
  • unscheduled bleeding (while menstruation stops, 18% of women dropped out of the study due to unscheduled bleeding and spotting)
  • fluid retention
  • spotty darkening of the skin (not so great for those on the pill to control acne)
  • other various side effects such as nausea, depression and headache.

Does an end to menstruation spell an end to PMS? How long until this pill is marketed that way? Now if we can just get them to start working on my hangover pill.


Tuesday, May 22, 2007

Imaging Aids Reduce Diagnostic Accuracy

I've sometimes been described as a Luddite because of my resistance to adopt certain technologies (though my iPod and laptop would beg to differ). In a recent case of man vs. machine published in the New England Journal of Medicine compares mammograms subjected to computer-aided detection (CAD) to those screened without computer assistance. CAD software, approved for use in 1998, analyzes mammogram images and marks suspicious areas which are then reviewed by a radiologist. The NCI sponsored study found that CAD did not increase cancer-detection rate, in contrast to early studies that showed a 10-15% increase in diagnosis rate - similar to the increase found with a second human opinion. Instead, this much more comprehensive study found a significant increase in false positive rate, resulting in more call-backs and biopsies, and increased burden on the system and ulitmately an increase in cost for breast screening.

From the NCI press release:
"This study points out the need for the use of other techniques to find cancer at its earliest stages. NCI is incorporating techniques for imaging at the molecular level into many of its studies and is also conducting studies to improve the use of CAD and conventional mammography," said John E. Niederhuber, M.D., NCI Director. "In the end, technology facilitates screening. Ultimately, treatment requires radiologists working with the examining physician and the responsible surgeon to put everything together. We worry about false positives, but we certainly don't want to miss any cancers, either."


Random numbers

Over lunch we were discussing random numbers. If you look at random patterns and you compare it with a big enough dataset, you will find statistically significant correlations. In fact, some people claim that random numbers can predict the future, and even predicted 9/11. More importantly you can use random or non-random biological systems to predict the stock market and get rich, provided you have rats and know how to use excel... The latest paper in nature biotech used high-resolution, non-invasive imaging techniques (ie: CT scan) , to quantify 138 "visual" traits. By comparing this dataset with tissue microarray of nearly 7000 genes, the authors were able to train their software to be able to "reconstruct" the transcriptome of a tumour simply by looking at it. Now to a certain degree, it is intuitive: if there are lots of blood vessels, there probably is a high expression of angiogenic molecules, and cell shape is somewhat linked to the cell type. However, being able to deduce over 80% of the transcriptome by imaging only 28 traits seems dubious. Still, this is a good news for "personalized" medicine: better imaging, of things like tumour blood vessels, means better predictions for chemotherapy and more accurate prognosis...


Choose yer poison

The Brazilian wandering spider (Phoneutria spp.) is an aggressive and highly venomous spider regarded by some as the most dangerous spider in the world. The venom of this rather large spider, often found in banana fields is a painful erection that can last over an hour. Scientists are now isolated the component of the venom that mediates this effect and are pursuing it as a potential therapy for penile dysfunction.
Another intersting venom is produced by the Irukandji jellyfish. This small jellyfish provides a sting that is not remarkable... at first... and then turns into hell on earth. After about a thirty minute delay the victim develops "Irukandji syndrome" whose symptoms include severe backache, muscle pain and cramping, chest and abdominal pain, constant vomiting, anxiety (strong wish to dy in many cases), hypertension and pulmonary edema. This last 4-30 hours in most cases but may not clear up for a week.
From Wikipedia:
The severity of pain is apparent in a Discovery Channel show on Carukia barnesi when two researchers (Jamie Seymour and Teresa Carrette) are stung. Even under the "maximum dose of morphine" Teresa remarked that she "wished she could rip her skin off", and is later seen writhing uncontrollably from the pain, while lying on her hospital bed. In a particularly disturbing shot, we see Teresa's feet contorting and digging into the bed. When the camera pulls out to a wide shot, she is rubbing her face, her body is contorting in agony, and her legs are rapidly sliding and kicking around on the bed. Jamie, at his worst, is also seen writhing in pain, curled up like a ball and barely able to speak. Jamie said he wished that he was stung by Chironex fleckeri instead since "the pain goes away in 20 minutes or you die". Another recent program that aired on the Discovery Channel entitled "Stings, Fangs and Spines" featured a 20 minute spot on Irukandji Syndrome. In the segment, a young Australian woman was stung and developed a severe case of Irukandji syndrome. In a testament to the severity of pain involved, a re-enactment (featuring the actual victim portraying herself) shows her screaming and violently thrashing around on the hospital bed in an almost convulsive state, for the bulk of the segment. She later commented that this unbearable pain lasted for hours, and "I didn't think it was possible for anyone to endure that level of pain without turning into a vegetable".

The insane thing is that in 1964 Dr. Jack Barnes confirmed the cause of this syndrome by capturing a jellyfish and purposely stinging himself, a lifeguard and his 9 year old son (!!). Now that's science!


Vitamin D, wonder drug

We've discussed vitamin D on the bayblab before, particularly as a cancer fighter and it's possible link to seasonal affective disorder (SAD). Recent research has shown that a single dose of vitamin D can give a long term preventative effect against the mycobacteria that causes tuberculosis.

A related mycobacterium found in the soil, Mycobacterium vaccae has been shown to improve mood by activating the peripheral immune system leading to serotonin release (published in Neuroscience). Do vitamin D's reported mood altering effects work the same way: by activating the immune system?


Science question of the day

Ok suppose two identical twins have sex with a woman only hours apart, and she becomes pregnant, is there a way to trace the father? Obviously the standard DNA tests will not work, but are there any epigenetic alternatives? One of the problems is that methylation of the genome is reset at an early embryonic stage. While there may be imprinting, is it possible to match it to the father's "consensus" sperm imprinting, or is it sperm cell specific? Any ideas?


Friday, May 18, 2007

Bugs in PLOS ONE

PLoS ONE is the sujet du jour in the bay today. The quality of the submissions in PLoS has been increasing, but how long will that last? We had a journal club concerning a new report in PLoS about P53 mutations in ovarian cancer suggesting that patients with mutated p53 actually respond better to chemotherapy, probably because they have a harder time repairing damage, but can still undergo apoptosis in a p53-independent manner. The findings are not as novel as they might sound since it's been known for a while that in some instances, the oh-so-famous p53 tumour supressor can misbehave. P53 loss of function renders cells suceptible to DNA dammage and p53-mediated senescence of stromal cells may be required for the initiation of certain types of tumour. At the end of the talk, some of the PIs expressed their mistrust of this free-for-all that is PLoS ONE. Is this a generation gap in science? Are we just so used to the wikipedia, facebook, youtube, digg, blog sharing networks that we think science should be freed, liberated. I think if we've learned anything from the internet, it is that the masses are generally less intelligent than the individuals that they are comprised of.

Take the latest hot paper in PLoS ONE, "Order in spontaneous behavior". In that paper they hooked up fruit flies to a flight simulator, and because the fly can generate erratic patterns of flight that are endogenous to their neuronal circuitry at that instance, and not merely pre-wired, the authors concluded that they have a form of free will. Free will as the author points out, is an oxymoron: "the term ‘will’ would not apply if our actions were completely random and it would not be ‘free’ if they were entirely determined. So if there is free will, it must be somewhere between chance and necessity - which is exactly where fly behavior comes to lie."

This echoes what Einstein believed: "I don’t believe in the freedom of the will. Schopenhauer’s saying, that a human can very well do what he wants, but can not will what he wants, accompanies me in all of life’s circumstances and reconciles me with the actions of humans, even when they are truly distressing. This knowledge of the non-freedom of the will protects me from losing my good humor and taking much too seriously myself and my fellow humans as acting and judging individuals".

Which leads me to the quality of the reviewers on PLoS. Most PI's are obviously too busy to give free time to peer-review stuff on the internet that wont get them any type of recognition. Furthermore it blurs the line between "expert in the field" peer review and "random degenerate grad student" review. And really, when the best young minds are free to write anything on the internet, what comes out is probably "I for one welcome our new cyborg fruit fly overlords". What we lack is accountability and a positive reward in your career from contributing to peer-review, or publishing in non-traditional journals (is it even a journal?).

On the one hand some of the reviews appear quite adequate, yet some seem to be overly philosophical, probably because they were written from out-of-field scientists and not experts: "The findings actually have nothing to do with free will. Free will is a feeling I have (when I do something deliberately) that I am doing what I am doing because I feel like it: a feeling that my willing it is the cause of my doing it. It is undeniably true that that is what it feels like to do something deliberately. But whether what feels like the cause -- feeling -- is indeed the cause of my doing is an entirely different matter. The real cause might, for example, be a fractal order mechanism of the kind reported by Maye et al. But that mechanism is the causal mechanism it is irrespective of whether it happens to be accompanied by (or generates) feelings. And it certainly does not explain how or why we (let alone the fruit fly) feel anything at all. And without feeling there is no free will, just mechanisms, whether deterministic or nondeterministic -- unless we are ready to believe in telekinesis."

But what really took me over the edge, is this blog spamming on that paper's annotations. It's one thing for the bayblab to spam digg, but this is a taste of what's to come to the scientific discussion and peer review process if it remains open...


Thursday, May 17, 2007

House of Psycedelic Drugs

I hate the TV show House. Not because I find that it's innaccurate as lots of people do. It's just the character of House is so abbrasive. Someone needs to punch him and then kick him in his bad leg while he's down. The wife enjoys House and therefore I am forced to endure some of it. Last episode House gave a young patient mushrooms (psilocybin) for cluster headaches. Pardon? Apparently phycedelic drugs are useful for cluster headaches. The Multidisciplinary Association for Psycedelic Studies (MAPS) is all about encouraging research into these popular recreational drugs for treatment of some medical conditions. In addition to psilocybin for cluster headaches there is marijuana for chronic wasting disease and ecstasy (MDMA) for post tramatic stress disorder (PTSD). Here is a great Nature article on the founder of MAPS and other info on psycedelic therapies. While some of the stuff on the MAPS website is super sketchy (like this account of a mother and son peyote trip as a right of passage) and I was initially very skeptical about this avenue of research however there probably is some really good research that can be done in this area if it wasn't for laws about limiting access to 'fun' recreational drugs. There is no denying their bioactivity and compared to some approved drugs probably have less toxicity. So before I have to deal with another House episode perhaps I should make sure that I'm well prepared for the inevitable induction of a House induced cluster headache.


Wednesday, May 16, 2007

more bayTUNES

I see that we're posting music recommendations here. As my good friend Adam says "anybody who doesn't listen to Smog is a fucking idiot". I agree. He's our generation's Dylan/Young/Simon/insert over-rated boomer icon here (PS, I like all of these guys... but really, get over them). If you've never heard him, listen (with an open mind) to last year's phenomenal A River Ain't Too Much to Love, or any of his three masterpieces Red Apple Falls, Dongs of Sevotion (a personal favourite), or Knock Knock and prepare to be blown-away. For you track-oriented types, some suggestions are dress sexy at my funeral, ex-con, i break horses, bloodflow, chosen one, say valley maker, the well, cold-blooded old times, hit the ground running, teenage spaceship and pretty-much anything else you can get ahold of.

Also, on par with Smog is Bonnie "Prince" Billy, whose album I See a Darkness is my favourite of all time.

Both artists are on Drag City and will blow you away if you give them a chance (unless you're a douche; in which case, there's no point in trying to help you).


Ptashne on scientific communication

In a recent post I mentioned a man by the name of Mark Ptashne (currently at MSK, but once a notorious member of the "Harvard Mafia"). An understudy of of Jim Watson, he took a hard-edged (and to some, mean-spirited) approach to science. Whenever I think of him, I think of two things: his seminal (ewww... I hate that word) work on the discovery of the lambda repressor, and a quote from an anonymous former post-doc: " I like Mark, but if push came to shove, and Mark was cornered, he would be ruthless. If it took a couple of grad students and post-docs being sunk to the bottom of the Chalres River, metaphorically speaking, to save his own hide, he would do it". Now that's class.

Anywho, the whole reason that I posted this, is as an introduction to a short contribution Ptashne made to the newest issue of Current Biology about scientific communication. He sounds like a pompous ass, but he makes some great points. I highly recommend you give it a read.


Joel's science heroes #1

I've never posted on a blog, and rarely read them, so I don't really know what this whole thing's all about. However, I've been asked to contribute, so I'll start by sharing one of my passions. Knowing a bit about the great people who consistently do great things. I'll occassionally post interesting (to me) mini bios of some of the people whose lifetime achievements inspire me (and may inspire readers as well): my science heroes. Also, sorry if this is a bit long, but there's a lot to say about Science Hero #1.

My primary science hero is David Baltimore. What we know as a result of his intellectual endeavours is startling. He was always an exceptional student, but interestingly, during his undergrad, he lived in the shadow of an upperclassman by the name of Howard Temin (see below). He went on to grad school at Rockefeller, where he earned the knickname "the little emperor" from the esteemed facutly, as he never took shit from nobody; even Nobel laureates on the faculty would find themselves in over their heads when they attempted to criticize Baltimore's work.

He eventually went on to discover reverse transcriptase, which overthrew the "central dogma" (and for which he shared the 1975 Nobel Prize for Physiology or Medicine (at the age of 37!!!) with the aforementioned Temin, who independently proved the existence of reverse transcription). He also discovered the biochemical basis of VDJ recombination and NF-kB, among many other great accomlishments. He was also a pioneer in the development viral vectors for gene therapy. He continues to consistently produce top-notch science.

He was the founding director of the Whitehead Institute (interesting aside: while at MIT, he was one of three Nobel laureates in the biology department who were collectively referred to as the Good (Phil Sharp, who is a rediculously-kind man), the Bad (Baltimore, who was considered arrogant) and the Ugly (Susumu Tonegawa, who is supposedly a remarkbly unpleasant man). He has also served as the president of both Rockefeller University and Caltech. Additionally, he was an important influence on regulatory policies on recombinant DNA and has been a huge influence in HIV funding in the US.

He is well known for the "Imanishi-Kari affair", in which a collaborator was accused of falsifying data in a Cell paper. He stood by his collaborator, insisted that any abuse or allegations being thrown at her be thrown at him as well, and refused to retract the paper. A long, arduous, and well-publicized misconduct hearing led to his dismissal from the presidency of Rockefeller and polarization of the science world. His one-time friends, such as Wally Gilber turned on him. Mark Ptashne (presumably seeing trouble on the horizon from one of his main competitors) took the "whistle-blower" into his lab. However, in the end, Baltimore was vindicated, the results were proven true, and the "whislte-blower" was discredited. Baltimore moved-on with his life and became the president of the esteemed Caltech.

Finally, the number of incredible scientists that have trained with Baltimore is astonishing: some notables include Inder Verma (Salk), Gary Nabel (NIH), Richard Mulligan (Harvard), Sankar Ghosh (Yale), Steve Smale (HHMI/UCLA), Steve Goff (HHMI/Columbia), Frederick Alt (HHMI/Harvard), Victor Ambros (Dartmouth), and David Knipe (Harvard) among many, many more.

That's why David Baltimore is one of my science heroes.


Milk and Dairy

A recent conversation with some baybs in the lunch room naturally turned to a bayblab favourite topic: lactation. I turns out that the notion that human breast milk is considered 'dairy' is offensive. This lead to the question of what exactly IS considered, and whether human milk is among them. While a weak etymological argument for them can be made, eggs, which are closely associated with dairy, are definitely not (my apologies for confusing one of their opinions on the matter). What about human milk, then? The Wikipedia entry on the subject seems to suggest that some sort of processing or standardization is implied with the word dairy, but I suspect few would argue that raw cow's milk is not dairy. Human milk is a 'foodstuff', but there are no dairies for processing. Or are there? Dairies may not exist, but breastmilk banks certainly do, though in limited number. Seven exist in North America where, after rigorous screening (smokers need not apply) and physician consent, women can donate excess milk which is then pasteurized and sold to families in need (with a proper prescription). All that said, you would be ill-advised to drawn any comparisons between a breast-feeding mother and a dairy cow.


More bayTUNES

At the recommendation of my latest issue of WIRED magazine, I recently downloaded acquired last year's Girl Talk album: Night Ripper. This kinetic mashup of over 160 artists with heavy hip-hop flavour may be better suited to the nightclubs than the lab, but if you've always wanted to hear Boston mashed with Ludacris, Sonic Youth with Missy Elliott or Public Enemy with James Brown, it's worth checking out. And if you don't like it, don't worry: He still has his day job as a biomedical engineer.


Tuesday, May 15, 2007

Creating Novel Plants Soon to be A Project for Basement Biohackers

In a big step forward for synthetic biology, researchers in Missouri have successfully created an artificial Maize chromosome. Although similar feats have been achieved in yeast and bacteria, this is a first for multi-cellular life. According to some projections, it should therefore be easy to get your custom made plant chromosomes by 2010. Forget about transgenes, in the 2010s it'll be all about transchromosomes.


Hacking Taste

We've previously discussed on the bayblab the fact that bananas are all sterile clones, on the brink of mass extinction with the right pest or disease. Could the durian be on a similar track? Several different clones of the fruit, described by some as 'smelling like cheese and tasting like meat', exist, and scientists in the Thai government have controversially succeeded in engineering the fruit to have a less objectionable odor. Will the more pleasant odor create an explosion in the fruit's popularity, or will purists insist that a durian by any other name shouldn't smell so sweet? We'll have to track some down for a live tasting on the next podcast.

Those wanting to eat the fruit, but without the unpleasant taste may want to look into Miraculin. This protein, derived from the fruit of a west African shrub has the unusual ability to not only block the sour receptors of the tongue, but also trick the body into thinking their food is sweet! This little sensory hack could have you winning all the lemon eating contests you want, all the while thinking you're munching on candy. In a world of aspartame and other horrible synthetic sweeteners, miraculin could be a step towards a natural 'artificial' sweetener. Just don't over do it, the effect can last for as long as two hours which could make for some odd tasting steak.


How cancer quacks profit from science

Here at the bayblab, we routinely cure cancer, so when we hear of a miracle cure in the media we tend to be skeptical. More often than not, it tends to be an exaggeration of some in-vitro findings that are blown out of proportion by some over-eager journalist with a poor understanding of medical science. Unfortunately, often the scientist is misquoted, and the conspiracy theory of big pharmas not wanting to deliver a cure resurfaces. Of course this is bad for the scientist, it's bad for the general population who constantly ears about cancer being cured without any concrete drugs being offered, and it is bad for the patient, because cancer quacks will prey on their hopes. DCA, which was studied at the University of Alberta, is a simple chemical that can be used to combat the warburg effect (which we'll explain in the upcoming episode 9 of the podcast). It was even featured on "the current" on CBC last week. The findings published in Cancer Cell were promising, but need to be further investigated. However that doesn't stop cancer quacks to turn in a profit while pushing DCA to desperately ill cancer patients, a chemical that is highly toxic, a carcinogen, and teratogenic. This article explains how this remarkable discovery was perverted by unscrupulous people.


Why girls can't throw

After much research into this area, I am ready to reveal my shocking discovery. Have you ever wondered why girls are so bad at throwing overarm?
"In one of the better-known investigations, boys and girls were asked to throw a softball with their dominant and then with their nondominant hands. Surprisingly, at almost any age, when they throw with their nondominant hands, boys achieve only slightly better scores than girls. And boys, no matter how well they throw with their dominant hands, tend to "throw like a girl" with the nondominant."
This of course can only mean one thing: girls have two left arms! This doesn't mean they can't train it to throw well... Overarm throwing is clearly serious business, and a lot needs to be taken into account.

The only remaining question is in a competition of throwing (poo?) who is best, Man or Monkey: "This research examined hand preference and postural characteristics of aimed throwing in capuchin monkeys and humans. We sought to directly compare the throwing performances of these primates, particularly the extent to which target distance influences hand preference, throwing posture, and throwing accuracy. For both species we found positive correlations between target distances for throwing accuracy, direction and strength of hand preference, percentage of bipedal vs tripedal throws, and percentage of overarm vs underarm throws. Throwing accuracy did not vary as a function of right vs left hand use although for monkeys throwing accuracy was positively associated with hand preference strength. We noted a sex difference among humans as males threw more accurately than did females. Between-species analysis indicated that humans exhibited greater right- vs left-hand use, greater hand preference strength, a greater relative percentage of bipedal vs tripedal throws, and a lower relative percentage of overarm vs underarm throws than did monkeys. We believe that the capuchin monkey is an informative nonhuman primate model of aimed throwing in humans and that research examining the throwing behavior of capuchins provides insight into the neurological and behavioral characteristics that underlie coordinated multi-joint movements across the primate order."


Monday, May 14, 2007

Human foraging activity

The nature podcast, (more sponsors less beer than the bayblab podcast) this week had an interesting piece on the evolution of a gene that is involved in foraging activity of drosophila. There are two isoforms and they maintain themselves in the population because if everyone else is a forager it is beneficial to stay where the food is. This gene is linked with other insect behaviors such as in honey bees and encodes a guanosine 3',5'-monophosphate (cGMP)-dependent protein kinase (PKG). I was really curious to see what the human behavioral equivalent to foraging was, I feel a bit like a forager. The closest human homologue is PRKG1 and actually has not been studied that much as only 6 papers show up on a pubmed search. One paper tries to establish a connection to attention deficit disorder and another to obesity. Both turn up negative, however that doesn't mean that this gene isn't going to turn up to be super important as evidenced by the fact that there is already a patent on this homologue. Also interestingly the polymorphism in the human homologue is in the 3'UTR.


Good news everyone!

If you're a regular on the bayblab, or have listened to our last podcast, you know we have a beef with a certain cancer quack here in ottawa. Well an informant tells me there was a little raid conducted there last week under the guise of the royal college of physicians and surgeons. It seems our friend may have had the visit of some law enforcement officers. Perhaps the royal college reads the bayblab... Now this made my Monday morning.... Suck it Bill.
From the Ottawa citizen: "Ottawa police helped investigators from the College of Physicians and Surgeons of Ontario execute a search warrant in the Glebe Thursday morning. Two uniformed officers and a detective helped college investigators execute a warrant at a Fifth Avenue business at 10 a.m. No arrests were made and no charges were laid. Police said their only role was to help with the warrant's execution, and referred questions about the investigation to the college. Kathryn Clarke, spokeswoman for the regulating body, said the Regulated Health Professions Act did not allow her to discuss details of a potential investigation. "It's only if the college refers a doctor to discipline that information comes into the public arena," she said."

Update: I'm noticing a lot of traffic coming to this site thanks to Healthwatcher now linking to us about the CCRG and our scoop of its investigation by the college of surgeon and physicians. I'm also seeing a lot of journalists and counsellors from the city of Ottawa coming to this site. Feel free to contact us at if you want an account of our multiple encounters with Bill O'Neil, how he's been long known to the cancer research community here in Ottawa or have access to all our recorded information about his dealings with us.


Saturday, May 12, 2007

Pharming Interferon in Tobacco Plants

Those of us who work with VSV know interferon as a secreted protein that can protect cells from viral infection. The interferon response is also the basis for selective tumor cell killing by many experimental oncolytic viruses.

However interferon is also biotherapeutic of significance in its own right - it is the world's third most produced biological, second only to insulin and erythropoietin. Interferon-alpha is currently administered as first-line treatment in Hepatitis C and is also approved for Hepatitis B and some types of cancer. Another variant of interferon (beta) is approved for use in multiple sclerosis patients.

But biologicals ain't cheap. A years worth of IFN treatment for HepC costs $26, 000 USD, placing a huge burden on health care systems and making it inaccessible to the majority of infected individuals worldwide, who lack the privilege of luxurious health care. One of the major reasons for the high cost of biologicals such as IFN lies in production. Currently, IFN is produced in cultured cell lines, which require stringent growth conditions and laborious sterile handling procedures. In an effort to lower production costs, this new paper describes the production of human interferon in the chloroplasts of tobacco plants. Thus the protein is produced through standard agriculture, leaves are harvested (each makes 3mgs of IFN) and the protein is purified through a relatively straightforward and scalable process. I couldn't find a patent for this technology on Google patents, and Henry Daniell's lab, which conducted this research, seems to have a specific policy of developing biotechnology that is globally accessible. Hopefully plants like these will lead pave the way to cheap, disseminated biological production capacities to meet local demand across the world.


Friday, May 11, 2007

Quack of the week

The quack of the week winner is Jim Rutz, who is the spokesman for the worldwide house church community, founder of the open church ministries and author of such illustrious books as "The Meaning of Life". He recently earned his quack badge by writing a series of articles against soy and how it is making kids gay. I am not kidding : "Research is now showing that when you feed your baby soy formula, you're giving him or her the equivalent of five birth control pills a day. A baby's endocrine system just can't cope with that kind of massive assault, so some damage is inevitable. At the extreme, the damage can be fatal."

Unfortunately he doesn't quote the source, because I'd like to know where they found that soy can be fatal o infants. In fact the most recent research about soy and post-natal sexual development in the journal of Toxicology Science states that "
There were no effects in females dosed with 4 mg/kg genistein, the predicted exposure level for infants drinking soy-based infant formulas. There were no consistent effects on male offspring at either dose level of genistein."

So I have a hard time figuring out how Jim came to the conclusion that: "Homosexuals often argue that their homosexuality is inborn because "I can't remember a time when I wasn't homosexual." No, homosexuality is always deviant. But now many of them can truthfully say that they can't remember a time when excess estrogen wasn't influencing them."

Yes Jim that's what's wrong with America: Tofu. Goddam liberals and their phytoestrogens...


Bayblab podcast Episode8

Episode 8 is now available (rss on the right)! It's a special podcast live from space with Stephen Hawking, as we discuss how you can make sperm cells from bone marrow, how plasma gasification may be useful for waste disposal, we expose a cancer quack and much more...Special thanks to Jaime Corinaldi for his most excellent music. MC Hawking better beware of this new scientist on the block. And a guest star appearance by Leigh Miller!

This may be the best one so far, lets see what the critics have to say: "The bayblab is so much better [than Science Friday]. It even has Stephen Hawking. All Ira Flatow can claim is that he’s interrupted people who are talking about Stephen Hawking." Ben Ferguson


Thursday, May 10, 2007

1010 by 2010

That's 1010 base pairs of DNA sequenced or synthesized by one person in a single day. That's a hell of a lot. More than enough to cover the whole human genome several times. And that's just one person. Imagine how much a factory full of monkey could do. If you think this sounds ridiculous, read the rationale for the prediction in this great article. As shown below, the projection is based on the current exponential growth of biotechnology, mimicking the trend known as Moore's law, where the number of transistors that can be fit on a microchip has been growing exponentially for the last 50-60 years. The article makes some interesting comparisons between the two industries and also features some of the best discussion I've read on the future of biotechnology and its place in society.


License the Technology Before You Play With Your Cat, Travel at Lightspeed

That's right. If you've ever teased your cat with a laser pointer or traveled across galaxies for money, you may just get sued.

Govern yourself accordingly.

Method of exercising a cat

US Patent Issued on August 22, 1995
No. 144473 filed on 1993-11-02


A method for inducing cats to exercise consists of directing a beam of invisible light produced by a hand-held laser apparatus onto the floor or wall or other opaque surface in the vicinity of the cat, then moving the laser so as to cause the bright pattern of light to move in an irregular way fascinating to cats, and to any other animal with a chase instinct.

Of course that's not nearly as ridiculous as the anti-gravity spaceship patent:

United States Patent 6,960,975
Volfson November 1, 2005

Space vehicle propelled by the pressure of inflationary vacuum state


A space vehicle propelled by the pressure of inflationary vacuum state is provided comprising a hollow superconductive shield, an inner shield, a power source, a support structure, upper and lower means for generating an electromagnetic field, and a flux modulation controller. A cooled hollow superconductive shield is energized by an electromagnetic field resulting in the quantized vortices of lattice ions projecting a gravitomagnetic field that forms a spacetime curvature anomaly outside the space vehicle. The spacetime curvature imbalance, the spacetime curvature being the same as gravity, provides for the space vehicle's propulsion. The space vehicle, surrounded by the spacetime anomaly, may move at a speed approaching the light-speed characteristic for the modified locale.

Inventors: Volfson; Boris (Huntington, IN)
Appl. No.: 11/079,670
Filed: March 14, 2005


Two Cool Resources

Doing some surfing, I came across some pretty neat resources. For armchair astronomers, the first is WikiSky, a sort of Google Earth of the heavens. Overlay constellations, find and view photos of celestial objects or just see what stars are overhead right now.

The second is the Encyclopedia of Life. This site aims to be a wikipedia of known species, including photos, maps and including links to journal articles and published genomes. This 'interactive zoo' will have different layers of access from 'novice' to 'expert' featuring more detailed species information. The site isn't up and running yet, but the demo pages (like those linked above) look pretty slick. Read more about it over at Wired magazine.



Most mammals will eat the placenta after giving birth, in part to hide it from predators that might smell it, and in part to get nourishment. A few mammals do not, including camels and marsupials which simply reabsorb their primitive placenta. Recently it has become almost trendy for women to eat their placenta after giving birth, with some going to great lengths and even suing hospitals in order to bring the meal home with them. Now I understand wanting to have a "natural" birth, but this crosses the line. However if this is your thing, you can find some recipes here, and here, including placenta lasagna, placenta cocktail or roasted placenta. The royal college of obstetrician has already stated that mother do not need to eat their placenta for proper nutrition in our society, so why do people do it? It seems there is a belief that hormones within the placenta such as progesterone, prostaglandins and endogenous opoids might help with post-partum depression and birth pains and production of milk. While there are probably some hormones crossing the intestinal barrier, I doubt one dose will do much for post-partum depression. And preserving it to eat a little everyday will probably deliver doses too small. Wouldn't you get sick of eating the same thing everyday? Dogs eat their placenta after they give birth too. They also eat their own shit. Clearly, "natural" is not always the way to go. And why stop at the placenta, my mice and rats occasionally eat the babies too, if only I could find recipes...


Glow in the dark terrorists

A recent paper in Nature Chemical Biology (arm and leg subscription required) describes a engineered yeast strain engineered to sniff out TNT. First they had to clone many G protein signalling components into a yeast strain such that mammalian olfactory receptor signalling functioned. Then they screened a library of cDNAs from olfactory receptors to obtain a rat olfactory receptor that responds to TNT. This signaling pathway then initiated the expression of green fluorescent protein, thus the yeast glowed green when in the presence of trace amounts of TNT and an awesome biosensor is born. Great work from Dr. Danny Dhanasekaran at Temple University School of Medicine.


Wednesday, May 09, 2007

I've got kallikreins on the mind

Thanks to some %^&#@ journal editor, I find myself having to update the introduction of a paper on kallikreins. To my surprise, it seems that one of the member of that superfamily (made famous by PSA or kallikrein 3), is neuropsin. Type II Neuropsin seems to have evolved quite recently (5 MY) and is expressed in the frontal lobe of humans and not of other great apes. It may have functions in learning and memory, and it is already speculated that if reintroduced in chimps, they may become indistinguishable from Kamel.

If you are wondering about the artwork above it's anal bum cover : "Nietzsche's Monkey": You haven't heard anything that sounds quite like this. Graduate students in Rhetoric, Critical Theory, and Post-modernist studies will be glad to know someone is finally writing music for them."


Monday, May 07, 2007

Embryonic Stem Cells (tm) by Invitrogen

Caught a great talk today at the OHRI by visiting speaker Mahendra S. Rao, who is probably the world's leading scientist in embryonic/neural stem cell therapies. The talk featured an overwhelmingly impressive wealth of data on neural stem cell biology, particularly pertaining to transplant studies. Most of this work was done in his former capacity as head of the NIH's stem cell program.

What was most interesting about the talk was the work Rao is now leading as VP Stem Cell research at Invitrogen Corp (in the more ES-cell research friendly state of California). He recently took up this post after leaving the NIH as a result of their decision to abandon ES cell research in light of the Bush administration's strong anti ES cell research policies. From what he presented of his new project at Invitrogen, it's obvious they are now about to kick some serious ass in the arena of clinical therapeutic development. They've got GMP-friendly, FDA-approved and production-scalable technologies and ES cell lines ready to go. Couple with that Invitrogen's recent moves that has established the company as the leader in gene expression and cell culture technologies, and what you have is imminent domination of the biological therapies scene. Looks like one of the first applications they will go after is Parkinson's disease, using ES-derived neurons to replenish dopamine producers in the substantia nigra.

Interestingly, while transplanted ES-derived neurons are suitable for applications such as Parkinson's as they can survive long-term in recipient's brain, Rao mentioned that their potential in other regenerative therapies is limited by the fact that we do not yet know how to make the transplanted cells properly integrate into existing neuronal circuitry. Strong impetus for a lot of interesting research in probing neural connectivity...



This morning on my bicycle commute I was listening to the Science magazine podcast which is no bayblab podcast but it's good enough for commuting. On the latest episode I was informed that there is no place in the lower 48 states of the United States where you can get more than 35km from a road. Thirty-five kilometers away from civilization is isolated but I still found that stat pretty shocking. The above map shows the 'roadless volume' of areas in the united states. I ganked it from the origonal article in Science magazine (high priced subscription required). 'Roadless volume' meaning area times the distance from a road such that a city block would look like a pyramid with the point being in the center since it is the furthest from the roads. I wonder what this data looks like for a country like canada with large uninhabited areas. There is also a video in the supplymentary material but it's quicktime so I can't get it to work. I have to say that the United States does an excellent job with their parks, (they are large and well managed) and there is actually an effort to preserve roadless area in the US.