Archive for August 2008
If you’re a low-carber, you probably think potatoes are the devil’s food. Actually, Dr Jan Kwasniewski, author of the high-fat Optimal Diet, quite happily promotes potatoes as a carbohydrate source. He would much prefer his patients eat potatoes as their carbohydrate allowance than fruit or vegetables. I agree; I’d rather people eat root tubers than follow pseudo-paeleo principles and get their carbs from inedible IBS-causing leafy greens and nasty, urticaria-inducing berries. As far as I’m concerned, fruits and vegetables have little nutritive value and less calorific value. Why not go without them – even failsafe ones – for a week, and see how much better you feel?
Potatoes are one of the few plant foods tolerated well by failsafers. Most super-responders tolerate them. The ultra-safe super-responder diet is usually sushi rice and well-peeled large white potatoes.
Solanine can be a problem for failsafers and for the general public. Solanine levels tend to rise in potatoes that have started to sprout or go green, though the green colour itself is chlorophyll. Different varieties of potatoes seem to have different levels of solanine. Solanine symptoms are usually gastrointestinal – consisting of hiccups, acid, nausea, and stomach upset including cramps. Solanine can also give you heart palpitations. For the first couple of years or so that I was on the failsafe diet I thought I didn’t tolerate potatoes. I thought that perhaps baking potatoes formed glutamates because of the strange symptoms I was having. Actually, I eventually figured out it was the solanine content. Now I am more careful, I tolerate jacket potatoes very well. I have experimented with a few varieties of potatoes. I definitely don’t do well on generic potatoes packaged as ‘baking potatoes’ – particularly ones with that peculiar creamy flavour – I get heart palpitations and hiccups. Potatoes with too much solanine seem to be the only food on earth that can give me hiccups. However, I do very well on Maris Piper potatoes. I think my Autumn carb staples are going to be potatoes and sweet chestnuts.
One interesting thing you should know about solanine is that it is implicated quite strongly as a cause of colon cancer. I remember reading a critique of another deeply flawed epidemiological study into red meat and colon cancer on Barry Groves’ site. One of the most interesting anomalies in the study was that whilst in most of Europe there was a tiny, tiny correlation between colon cancer and red meat (probably spurious), in Italy, eating red meat appeared to protect against colon cancer. I remember thinking at the time, what do Italians do differently from other Europeans? The difference as I see it is, whilst most of Europe eat main meals of meat and potatoes, in Italy, main meals are of meat and pasta. I suspect the correlation is truly to solanine.
You should always throw out sprouting or green potatoes, and you should always peel your potatoes. Don’t believe any of that nonsense that potato skins “are good for you.” Natives who ate potatoes as a staple in the Andes used to peel their potatoes too. Whenever I’ve come across anyone who’s had a problem with potatoes, it has turned out to be caused by eating the wrong variety, eating the skins, or being lax about solanine formation.
Potatoes are also a significant source of natural nitrates and nitrites. A serving of potato contains as much nitrate as one slice of bacon. Nitrates can also upset some failsafer’s stomachs, so be wary if you know you respond badly to nitrates.
Some (crazy) paeleo people think you shouldn’t eat potatoes because “we haven’t evolved to eat them.” Wrong! We evolved eating meat and tuberous roots. You don’t evolve to eat specific foods, you evolve to eat specific food chemicals, micronutrients, and macronutrients. Potatoes, when handled and prepared properly, contain very little in the way of harmful food chemicals. You do not need to challenge the human race to evolve to eat a food when the food contains no challenges.
This is another thought-provoking article from the New Scientist magazine (go out and get a subscription today!).
FOR some reason, it’s always called the “humble” potato. But the tasty tuber from the Andes is poised to take over the world. As the food crisis bites, the land area planted with potatoes is increasing faster than for any other staple crop. Developing countries now grow and eat more of them than the traditional potato-eaters of the rich countries: today, the world’s biggest potato producer is China, and India produces twice as much by weight each year as the US.
Yet behind this success story lies a problem. The blight that wiped out Ireland’s potato crop in the 1840s is becoming more virulent and is increasingly resistant to the fungicides used to control it. Without a new weapon against blight, we could be setting ourselves up for a replay of the famine wherever the disease strikes. And this time even more people could suffer.
There are good reasons why the world is turning to potatoes. Much of the world’s food comes either from grain or animals fed on grain, but rising populations and increasing demand for meat, dairy products and biofuel means that global demand for grain is outstripping supply. Grain yields must ultimately increase to meet this demand but cranking up the global food system will take time, and yields won’t increase overnight. In many places potatoes can plug the gap, providing food and income for the people who need them most. “Worldwide we see an overlap between where the poorest live and where people grow potatoes,” says Pamela Anderson, head of the International Potato Center (CIP) in Lima, Peru, part of the Consultative Group on International Agricultural Research, which works on crop improvement for poor countries.
Potatoes can squeeze in between grain crops, which means a field yields three harvests a year instead of two. Since there is little international trade in potatoes, their prices tend to be more stable than those of grain. All these things have led the UN to dub 2008 the International Year of the Potato and to hail it as the “food of the future”.
In fact, listen to a potato enthusiast, and you may wonder why people bother with grain at all. Potatoes are more nutritious, faster growing, need less land and water and can thrive in worse growing conditions than any other major crop. They provide up to four times as much complex carbohydrate per hectare as grain, better quality protein and several vitamins – a medium-size potato boiled in its skin has half an adult’s daily dose of vitamin C, for example. They also contain B vitamins, plus many of the trace elements poor people, and grain, lack. And, unless you douse them with it, potatoes have almost no fat (see table).
Potatoes do have their downsides, of course. They are more perishable than grain and because they are heavier and bulkier, they are more expensive to transport – one reason why there is little international trade. Their main weakness, though, is disease.
Potatoes are rolling in genetic diversity – there are some 150 species in the potato family and countless varieties. The problem is, almost all potatoes grown outside the Andes are of a single subspecies, Solanum tuberosum tuberosum, first cultivated 8000 years ago in the highlands around Lake Titicaca. Keeping all our potatoes in one basket leaves the world’s crop vulnerable to being wiped out.
The most likely candidate to do this is late blight, which is what destroyed the potato crops in Ireland and other parts of Europe in the mid-19th century. It is caused by Phytophthora infestans, a fungus-like organism called an oomycete, which spreads by producing spores. The disease originated in Mexico, where it infects wild potatoes, and spread north as American agriculture expanded in the 19th century. In 1845, it arrived in Belgium on seed potatoes imported from the US.
The blight quickly spread across Europe, wiping out crops and causing catastrophe in Ireland, where the damp, cool soils and climate, plus the fact that the colonial landowners took the best land to grow grain for export to England, made the Irish poor more reliant on potatoes than other Europeans. Breeders eventually found potatoes that partially resisted the blight, but the crop’s future was only secured when fungicides were invented in the 1880s. Now potatoes are more dependent on chemical treatment than any other crop. The potato industry in the European Union is worth ¬6 billion a year; farmers spend a sixth of that on fungicide.
Farmers in developing countries can rarely afford to buy fungicide, a big reason, along with the pervasive lack of fertiliser and water, why average potato yields in African countries are half those in China or Peru, which are in turn half those of rich countries.
Giving farmers in the developing world access to fungicides would certainly increase yields, but it may not be enough to protect them from blight, as the disease is becoming ever more resistant to fungicides. “Last year I had to spray 12 times, the most ever,” says Jim Godfrey, a potato farmer and former head of the Scottish Crop Research Institute in Invergowrie. In the tropics, where both potato and pathogen grow faster, farmers may need to spray every few days.
What’s more, the blight is becoming more aggressive – P. infestans has two “genders”, only one of which came over in 1845, so it was only able to reproduce asexually. Though it has spread in this way through Europe and much of the world, the asexual spores can persist only on susceptible plants. Then, in the drought of 1976, Europe’s crop failed and it imported tonnes of potatoes from Mexico. With them came the other “gender” of the blight. Now it can breed sexually, which means it can adapt more quickly to both fungicides and resistant potatoes. Sexually produced spores can also survive in soil, making the disease even more difficult to control.
Sexually reproducing blight and increasing fungicide resistance mean more, and worse, outbreaks of the disease around the world. It may not cause starvation on the same scale as the Irish famine – food aid exists now, and few places are as exclusively reliant on potatoes as the Irish were in 1845 – but even so, the potato’s potential for disaster is worrying.
That, says Anderson, is why we need to develop new varieties of blight-resistant potatoes. This won’t be easy. Potatoes are a notoriously difficult crop to breed, thanks to their unusually complex genetics. The common spud carries four copies of each of its chromosomes where most organisms carry two. That means the potato plant carries a possible four variations for each gene, so when two plants are crossed, thousands of different combinations emerge. That makes it an enormous task to select the best ones.
In other crops that have more than two pairs of chromosomes breeders have found ways around the problem. Most wheat has six copies, but wheat breeders start with plants that are already inbred so that for most genes, all six copies are identical. That way they can predict the outcome of crosses. Attempts to do this with potatoes, and also to engineer potato plants with only two-copy genomes, have been disappointing, says Shelley Jansky of the US Department of Agriculture’s potato lab in Madison, Wisconsin. The genetically impoverished potatoes are spindly and weak. “Potatoes just need all that internal genetic diversity to thrive,” she says.
That means potato breeders are forced to take a broad approach when looking for useful new varieties. First, they cross genetically diverse parent plants to create up to 100,000 genetically different progeny. Then, they “walk across the field and choose the potatoes they think look promising, and get it down to a manageable number, say a thousand”, says Jansky, and examine those plants for the qualities they want.
This kind of classical breeding has given us all the potato varieties we have today, but it is very difficult to use this method to breed a single desired trait into an existing commercial potato variety. Recent efforts to cross commercial varieties with Solanum bulbocastanum, a wild Mexican potato which has two genes for resistance to all known strains of blight, did indeed result in blight-resistant potatoes – but they had other, unwanted wild genes as well, and lower yields.
Breeding these hybrids back with the original commercial potato will produce tubers more similar to the original, but they will never be quite the same. This is a problem for the potato industry, says Jansky. Processing companies take a third of the crop in rich countries, and the machines and processes are designed for potatoes of particular shapes, sizes and chemical properties. They know their King Edwards and their Russet Burbanks and they want nothing else – and because potatoes are propagated vegetatively by tuber, they can have exactly the same potato again and again, says Jansky.
Genetic engineering could be the answer to this problem, says Anton Haverkort of Wageningen University in the Netherlands. He is running a 10-year programme to find more genes for resistance to late blight in several wild potato species – and then put them, and nothing else, into three popular varieties of eating potato. Haverkort uses a relatively new method of genetic engineering that doesn’t require an antibiotic resistance marker gene – a common tool in creating engineered plants – to be introduced along with the desired genes. So far he has isolated eight genes and the first of his genetically modified plants are now in field trials.
“We call them cisgenic, instead of transgenic,” he says. “They contain no genes except what they could have acquired naturally by breeding with other potatoes – except it hasn’t taken decades.” He hopes EU law will take account of the development and lighten restrictions on such plants, and that Europe’s anti-GM public will accept them. “The only genes in there are from potatoes,” he says.
Whether consumers accept cisgenic potatoes remains to be seen. Meanwhile, genetically engineered blight-resistant potatoes created by the German chemical giant BASF are already in their third year of field trials. The company has put the two resistance genes from Solanum bulbocastanum into commercial potato varieties along with an antibiotic resistance marker. BASF says the plants seem to have durable resistance to blight strains circulating in Europe, and it is hoping to start selling them by the middle of next decade.
The antibiotic resistance gene could be a problem, however. Its presence is central to objections to GM food; opponents say the gene could be taken up by bacteria in the environment, creating superbugs. BASF has another genetically engineered potato that yields more uniform starch for the paper and fabrics industries, which the European Commission declared safe last year, but as countries such as Austria harden their resistance to GM crops, it is holding back on the go-ahead for release. The same fate may await the company’s GM food potatoes.
Developing countries, having had the potato for less time, seem to be more open to non-traditional varieties, and in some places GM food is less unpopular. China, for example, is rumoured to have developed varieties similar to BASF’s.
In Peru, CIP plans to keep studying how potatoes resist blight, and using its potato gene bank – the world’s largest – to find genes that confer resistance. CIP is using GM to develop late-blight-resistant strains for Asia and is also breeding potatoes conventionally. This is partly because CIP has imposed a moratorium on releasing GM potatoes in South America, where most governments are opposed to GM and where most of the potato’s wild relatives exist, until more is known about whether introduced genes might escape into wild potatoes. But it is also, she says, because “GM is one tool, it doesn’t do everything.” Resistance to blight, for instance, might be achievable by implanting one or two genes at a time, but eventually, the blight will adapt to those few genes. And other, more complex traits like nutritional quality and yield depend on many genes, few of which are known, and can only be bred into farmed varieties the old-fashioned way, says Anderson.
However we come by new varieties, as the humble potato spreads around the world, and more and more people depend on it for sustenance, the need to win the battle against disease becomes more urgent. Blight is a disaster waiting to happen, and this time we have no alternative but to fight back.
The plant that changed the world
The Spanish brought the potato from South America to Europe in 1536. Most histories say it was then ignored for 200 years, but according to University of Chicago historian William McNeil, peasants knew all about it, and quietly took to growing potatoes as insurance against the frequent loss of their grain stores to marauding armies.
When Prussia then other European governments realised in the mid-1700s that potatoes could slash the cost of warfare, they made peasants grow them. Potato-pushers such as nutritionist Antoine Parmentier, whose name still graces French potato dishes, and Austrian empress Maria Theresa, were in fact pushing civil defence. The empress’s daughter, French queen Marie Antoinette, is best known for suggesting peasants eat cake, but she wore potato flowers to promote another alternative to bread.
In the 1800s potatoes moved into the mainstream. Before then, half of Europe’s farmland lay fallow between grain crops. As the population rose, people planted potatoes on this ground instead. The crop needed weeding, but produced more than enough to feed the labour-force.
Then, in 1845, late blight hit Europe. It is remembered as the Irish potato famine, but hundreds of thousands died in the rest of Europe too. In the early 1850s, yields recovered, and Europe’s potato fields continued to feed the population explosion and booming cities of the 19th century. By fuelling the industrial revolution and the economic and military rise of Europeans, says McNeil, potatoes changed the world.
Now history is repeating itself. Asian farmers are feeding a growing population with scarce land and abundant labour by squeezing potatoes between crops of grain. If suitable varieties allow Africans to do the same, the potato may once again be a lifeline for growing, urbanising and war-torn populations. But only if – this time – we can keep blight at bay. How the humble potato could feed the world, 01 August 2008, New Scientist
I highly recommend a subscription to the excellent New Scientist magazine. Every week there’s something great in there. Here are two articles about the differing male and female perception of pain, very interesting, if, like me, most of your symptoms are chronic pain symptoms.
JON LEVINE was just testing painkillers on people who’d had a wisdom tooth extracted, when he uncovered rather more than he’d bargained for. The women in his study group found that strong painkillers related to morphine, called kappa-opioids, were most effective at numbing pain. But the same drugs didn’t work for the men at all. “In fact, the doses used in the clinical trial made pain worse for men,” says Levine, a clinical neuroscientist from the University of California in San Francisco.
He was shocked. “The idea that a therapy that had been around for decades could affect women and men in such dramatically different ways was anathema,” he says. “It was such an incredible mindset in the field of pain, missing what had clearly gone on in front of their eyes for years.”
It’s not an effect specific to opioids, either. Another recent study showed that ibuprofen, a widely used anti-inflammatory drug, can be much less effective for women than for men. Researchers at the University of New South Wales found that when they used mild electric shocks to induce pain in healthy young people, only the men got any relief with ibuprofen. It was only a small study, but still worrying, as the drug is often marketed with women in mind.
It’s been five years now since Levine first spotted a sex difference, yet we still don’t really understand why it exists. And when it comes to testing or prescribing painkillers, or studying pain, nothing much has changed. Remarkably, even many of those involved in pain research are unaware of these findings. “I myself have never been able to get relief from ibuprofen and now I understand why,” says Marietta Anthony, a pharmacologist at Georgetown General Clinical Research Center. “This is very dramatic, and has a direct impact for the clinic.”
There have always been playful stereotypes of how men and women suffer pain differently. Women are more delicate—but endure childbirth. Men are stoical—until they see a dentist’s chair. But these few studies show there’s more to the caricatures than meets the eye. Real differences in the underlying biochemistry of male and female pain are revealing themselves. The differences are also starting to suggest some surprising strategies for sex-specific painkillers.
It’s perhaps no surprise that the differences have eluded scientists for so long. Pain is multidimensional and highly subjective, and therefore very difficult to study. It varies with the time of day, age, diet, stress, genetic background, location, past and present injuries, and in women, reproductive status and the menstrual cycle.
But not only that. Only 10 years ago, pharmaceutical compounds were tested almost exclusively on men. Women were left out of tests in case their inconveniently fluctuating hormones messed up the analysis. The testers also feared harming a pregnant woman’s fetus, while ignoring the obvious safeguard of a pregnancy test and contraceptives.
Only in 1993 did the US make it a legal requirement for women to be included in clinical trials. According to a recent report, on average, 52 per cent of subjects in large-scale trials are women. This looks like progress—but it’s not. This figure includes women-only studies such as those investigating hormone therapies or drugs to treat breast cancer. And when testing medications for diseases common to both sexes, women’s and men’s results are often still lumped together, burying any differences in a statistical quagmire.
In Britain, things are not much better. The Department of Health advises that gender should be taken into account when determining whether a medicinal product is safe and effective. But how strictly this advice is heeded is anyone’s guess.
To Marietta Anthony, who was previously acting deputy director of the Office of Women’s Health at the FDA, change is imperative. If a drug works differently in men and women, this information should be displayed clearly on the label. “Side effects and efficacy really are different in men and women,” says Anthony, “[and] there may be a very fundamental biological reason.”
One of the more obvious biological reasons is that men and women tend to suffer from different disorders, mostly the result of a complex bag of hormones, reproductive status and anatomy (see Diagram). So differences in how women and men report feeling pain have often been dismissed as being solely down to the pain’s different origins. But origins aside, there’s growing evidence that even when the source is the same, the biochemical signals, nerve connections and the way the brain handles pain are all quite different in the two sexes.
Sex hormones are one reason for the differences in pain perception. Women always cry “ouch” first. Whether it’s in the clinic or the lab, using the heat of a small laser, the pressure of a tourniquet or electrodes placed on the skin, women are less tolerant of pain. But women’s pain sensitivity also yo-yos throughout the menstrual cycle, and just before a period, pain thresholds take a dive. “There is a view that oestrogen is excitatory and could enhance pain transmission in the peripheral nervous system, the spinal cord and in the brain,” explains Roger Fillingim from the University of Florida at Gainsville.
Progesterone has quite the opposite effect: it dampens the nervous system’s response to any nasty stimulus. And it’s most obvious during pregnancy. When progesterone levels rocket in the third trimester, they induce a state of profound analgesia in preparation for labour. Indeed, these hormonal influences are being turned to medical advantage (see “Make your own Valium”). The rest of the time—when not pregnant—women’s tolerance generally remains below that of men.
Levine was one of the first to get an inkling of how sex hormones might be setting men’s and women’s pain thresholds at different levels. His team found that women consistently reported more severe pain than men after removal of a wisdom tooth. Since inflammation is known to underlie most aches and pains, Levine decided to investigate whether inflammatory signals differed between sexes. He gave oestrogen to castrated male rats, and found their pain tolerance plummeted to female levels. And giving testosterone to sterilised females gives them masculine tolerance. In other words, if you switch the sex hormones around, you switch their pain sensitivity around too.
Looking deeper into the biochemical pathways, he has recently found that sex hormones alter the chemical signals involved in inflammation and tissue repair. The female hormone oestrogen quenches the production of bradykinin—a potent inflammatory mediator that protects injured tissues. He believes these differences might account for the different responses to opioids seen in his trial. “As difficult as it is for many of us to acknowledge differences other than in reproductive function, there really are differences between men and women,” says Levine.
Another curious difference caused by our distinct physiology is that—especially in women—the visceral organs “talk” to each other, so that pain in one internal organ can be triggered or enhanced by pain in another. Maria Adele Giamberardino at the University of Chieti, Italy, first noticed this effect in women with kidney stones. She has found that when women have painful periods—a condition called dysmenorrhoea—the typical searing back pain from the urinary tract caused by the stones is much more vicious.
Giamberardino’s findings ring true to pain specialists. In the clinic, both men and women who suffer from chronic conditions such as irritable bowel syndrome often also experience fibromyalgia, headaches and chronic pelvic pain. But this coexistence of painful disorders is greater in females than in males. Giamberardino’s hypothesis is that the female reproductive organs are highly interconnected with the other organs, and that pain in one organ may trigger painful conditions in others that have linked nerve supplies. The flipside is that these links could become new avenues for treating pain. By tapping into the same communication channels, treating period pains, for example, might help to alleviate other aches.
Our different reproductive organs can also lead to differences in how our diet affects pain ratings, says Beverly Whipple, a neurophysiologist and obstetric nurse from Rutgers University in New Jersey. She noticed that Hispanic women seemed to experience more pain during labour, and at first she attributed this to culture. “I told my students that these women were just more comfortable expressing their pain.” Then she became aware of studies in which neonatal rats injected with capsaicin—the chemical that gives chilli its hot bite—did not experience a certain pain-blocking effect that females normally get when pressure is applied to the cervix. Could a diet rich in hot peppers be interfering with the Hispanic women’s natural analgesia?
To find out, Whipple set up a study with Mexican women whose consumption of chillies ranged from one or two a week to three a day. “We found that the women who ate a diet high in hot chilli peppers do not get the pain-blocking effect,” she says.
The physiological differences don’t stop at our reproductive organs and hormones, however. They run all the way to the brain. In a study soon to be published, Anthony Jones, director of the human pain research group at the University of Manchester, has scanned the brains of people experiencing pain from a variety of natural causes. Although many parts of the brain are engaged when a person is in pain, Jones pinpointed one main area of disparity between the sexes. “Women tend to process pain more in one part of the brain concerned with attention and emotion,” he says. He suggests that the experience of pain is bound to differ between men and women. “Women tend to process things in a more affective way,” he says. For women, pain depends on how much attention they pay to a tender spot. So when it comes to treatment, for women it may be as important to provide them with distractions, coping mechanisms and psychological care as painkilling drugs.
Distractions may work in a different way for men. It seems to be important for men to act tough in public. In experiments performed at the State University of New York, Fredric Levine and Laura Lee De Simone found that men’s pain thresholds soared if an attractive female technician was conducting the tests. Women, however, seemed immune to the charms of hunky men. And according to Knox Todd, a specialist in the assessment and treatment of pain at Emory University in Atlanta, Georgia, the differences make their way into the clinic. “What we see in the emergency department is that males make a public display of stoicism, ask for no pain medication, and keep up a good public front.” But their stoicism evaporates as soon as men leave the hospital to go home, he says.
But who wins out in the end? Is having a higher pain threshold good or bad? To women, pain is a wake-up call to sort out the problem before it gets too big. Men, who can put up with more, postpone asking for help until it’s too late. Women’s prompt action could be at least part of the key to their longer life expectancy. In the meantime, a message to dithering males: stop procrastinating, make that dental appointment, and your niggling shoulder pain might get sorted into the bargain. And to overdue pregnant women: ignore the advice that a curry will bring on labour. Chillies are the last thing you need when the contractions kick in.
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Make your own Valium
Sex hormones might complicate our understanding of pain, but one day they might help us beat it, too. Locked inside your brain is the most powerful sedative, anti-anxiety drug and painkiller rolled into one. This magical compound derives from the sex hormone progesterone and, if medicinal chemists get it right, it may soon lead to an analgesic to rival morphine.
Scientists have known since the 1940s that progesterone—the female hormone we usually associate with the Pill and making babies—is also an incredibly potent sedative. Now researchers have found that it is the breakdown products of progesterone that have such a potent anaesthetic and analgesic effect. “During pregnancy, for example, as a woman comes close to term, the levels of these breakdown products of progesterone are extremely high,” says Jeremy Lambert, a neuropharmacologist at the University of Dundee in Scotland. Only the natural hormone will do—the synthetic compounds used in contraceptive pills do not work in the same way.
Fortunately, this natural analgesia and anxiolysis is not exclusive to women. There are enzymes in the brain and spinal cord of both men and women that produce similar breakdown compounds, known as neurosteroids, from cholesterol or progesterone. In mounting doses, they may act as analgesics, anticonvulsants and even anaesthetics.
Researchers are now intent on harnessing these effects. The trick is to untangle one neurosteroid action from another: to induce pain relief without knocking you unconscious and without affecting fertility. Colin Goodchild, an anaesthesiologist at Monash University in Victoria, Australia, may have already hit on a compound—alphadolone—that can do exactly that. “It can work as a pain-relieving drug without causing sedation,” says Goodchild.
Goodchild hopes that alphadolone may eventually replace opioids such as morphine, or at least reduce their usage. Progesterone metabolites might also lead to an “all-natural” sleeping pill and antiepileptic with few, if any, side effects. “I think neurosteroids are going to be the pharmaceuticals of the future,” says Goodchild. His pain, her pain, 19 January 2002, New Scientist
ANYONE in a long-term relationship will tell you that, at times, men are indeed from Mars, and women are almost certainly from Venus. It’s common knowledge that the sexes often think very differently, but until recently these differences were explained by the action of adult sex hormones or by social pressures which encouraged males and females to behave in a certain way. For the most part, the basic architecture of the brain, and its fundamental workings, were thought to be the same for both sexes.
Increasingly, though, those assumptions are being challenged. Research is revealing that male and female brains are built from markedly different genetic blueprints, which create numerous anatomical differences. There are also differences in the circuitry that wires them up and the chemicals that transmit messages between neurons. All this is pointing towards the conclusion that there is not just one kind of human brain, but two.
It’s giving neuroscientists something of a headache. Most of what we know about the brain comes from studies of male animals and male human volunteers. If even a small proportion of what has been inferred from these studies does not apply to females, it means a huge body of research has been built on shaky foundations. Working out exactly how women are different could explain some long-running mysteries, such as why men and women are prone to different mental health problems and why some drugs work well for one sex but have little effect on the other.
It has long been known that some differences exist between male and female brains, but they were widely believed to be restricted to the hypothalamus, which is involved in regulating food intake and controlling sex drive, among other things. Unless they were studying the hypothalamus, researchers generally avoided using female animals in their experiments because the ups and downs of oestrogen and progesterone during the female menstrual cycle made interpreting results more complicated. So, hypothalamus aside, neuroscientists continued to believe that male and female brains were the same.
But it’s becoming obvious that the hypothalamus is only the beginning of the story. For a start, the relative sizes of many of the structures inside female brains are different from those of males. In a 2001 study, Jill Goldstein of Harvard Medical School and colleagues measured and compared 45 brain regions in healthy men and women. They found that parts of the frontal lobe, which houses decision-making and problem-solving functions, were proportionally larger in women, as was the limbic cortex, which regulates emotions. Other studies have found that the hippocampus, involved in short-term memory and spatial navigation, is proportionally larger in women than in men, perhaps surprisingly given women’s reputation as bad map-readers. In men, proportionally larger areas include the parietal cortex, which processes signals from the sensory organs and is involved in space perception, and the amygdala, which controls emotions and social and sexual behaviour. “The mere fact that a structure is different in size suggests a difference in functional organisation,” says neurobiologist Larry Cahill at the University of California, Irvine.
Cahill has found evidence that sex also influences how some brain regions are used. In brain-imaging experiments, he asked groups of men and women to recall emotionally charged images they had been shown earlier. Both men and women consistently recruited the amygdala – a pair of almond-sized bundles of neurons which make up part of the limbic system – for the task. However, the men enlisted the right side of it, whereas women used the left. What’s more, each group recalled different aspects of the image. The men recalled the gist of the situation whereas the women concentrated on the details. This suggests men and women process information from emotional events in very different ways, using different mechanisms, says Cahill.
The same may be true for the brain circuits used to dampen pain. It is well known that women are more likely to seek help for chronic pain than men. Some of this can be chalked up to the fact that women use healthcare services more than men, but even taking this into account, there’s strong evidence that women – and female animals – experience more pain than males. Not all studies show sex differences but, when they do, it’s always the females that feel more pain.
Anne Murphy at the University of Georgia in Athens is trying to find out why chronic pain affects women more than men. She is particularly interested in a pain-suppressing circuit that links two parts of the brain – the periaqueductal grey (PAG) and the rostral ventromedialRVM) – with the spinal cord. When this circuit is activated by a pain signal it can dampen pain by setting off a chain reaction that leads to the release of endorphins, which bind to opioid receptors and inhibit the pain signal. medulla ( “This circuit is the Mecca of pain modulation in humans and all vertebrates, yet no one has asked how it is organised in females,” says Murphy.
There is no clear answer yet, but Murphy’s investigations have yielded some intriguing results. Females have a denser connection between PAG and RVM than males, yet Murphy’s work suggests that this pathway is not activated in females to suppress pain. “This pathway is obviously not being used for pain in females, so what’s the function for it and why is it so much bigger?” she asks.
That question remains unanswered for now, but Jeff Mogil at McGill University in Montreal, Canada, thinks he may have found at least part of the female pain circuitry. In experiments in mice, he chemically blocked a particular receptor found on neurons in the mouse PAG and spinal cord. Mogil discovered that male mice use these N-methyl-D-aspartate (NMDA) receptors to dampen pain, but that blocking this pathway had little impact on females’ ability to deal with pain. “It suggests that females have a separate pathway that doesn’t involved the NMDA receptor,” he says.
Genetic experiments in mice have since led him to suspect that female pain inhibition may be linked to sex-specific variations in the gene for the melanocortin-1 receptor (Mc1r), which regulates hair and skin colour in humans and is also expressed in the PAG. Female mice that lacked a functional version of these genes were less able to block pain, as were female human volunteers with red hair, who also lack functional Mc1r genes. Male redheads had no problems blocking pain, presumably because they were using the NMDA circuit instead.
It’s early days, but if women do have a different pain-damping circuit to men, it could explain why there are sex differences in responses to opioid painkillers. Women get more relief from the opioid painkiller nalbuphine compared to morphine, whereas in men morphine is more effective and nalbuphine actually increases the pain intensity. The findings could eventually lead to new painkillers tailored to be more effective in women, but Mogil isn’t holding his breath. “For now there isn’t a big enough and uncontroversial enough literature in any of these differences to justify drug development of any single one of them,” he says.
Similar difficulties have blighted developments in mental health – another area where there are known to be sex differences. Women are diagnosed with depression twice as often as men, for example, and their brains typically produce about half as much serotonin – a neurotransmitter linked to depression. Earlier this year, Anna-Lena Nordström, from the Karolinska Institute in Stockholm, Sweden, found that healthy women have more of the most common type of serotonin receptor than men but fewer serotonin transporters, which are needed to recycle serotonin. It hasn’t been shown that variations of this set-up make some women more prone to depression, but Nordström points out that transporter differences between men and women are of particular interest because this is where antidepressants like Prozac act, and because there is evidence that women respond better to such drugs than antidepressants that act on neurotransmitters other than serotonin.
Males may be less likely to suffer depression, but that doesn’t mean they get an easy ride. Boys are more likely to be diagnosed with autism, Tourette’s syndrome, dyslexia, stuttering, attention-deficit disorder and early-onset schizophrenia. Margaret McCarthy of the University of Maryland in Baltimore believes that hormone-like substances called prostaglandins, which help masculinise the male brain shortly before or after birth may be at least partly to blame. Prostaglandins are also known to cause inflammation, so McCarthy is investigating whether their action, if altered by infection or certain drugs, could cause inflammation and damage to the developing brain.
The ways in which men and women abuse drugs is another area that could reveal brain differences. While men are almost twice as likely as women to use cocaine, possibly due to social factors, when women take it they get addicted more quickly and have a more severe habit when they seek treatment.
Jane Taylor from Yale University suggested in 2007 that genetic differences may help to explain why. She compared mice that were engineered to either be genetically male with testes, genetically male with ovaries, genetically female with testes or genetically female with ovaries. She found that genetically female mice formed drug habits more quickly than the genetically male mice, regardless of which gonads they carried (Nature Neuroscience, vol 10, p 1398).
Jill Becker at the University of Michigan, Ann Arbor, has found something similar. She trained rats to poke their noses into a hole to get a dose of cocaine and compared the cocaine intake of female rats which had had their ovaries removed with castrated male rats. The females were bigger bingers. But when these females were given oestrogen, their total intake nearly tripled. That means that a genetic vulnerablility plus circulating sex hormones can add up to a crippling addiction.
Several studies have since found that women report that cocaine has a bigger positive effect when their oestrogen levels are high and their progesterone levels low. Suzette Evans at the Columbia University College of Physicians and Surgeons in New York City is running a clinical trial to test whether cocaine-dependent women can be treated by increasing their progesterone levels.
There’s much left to learn, but as the evidence mounts for sex-related influences on brain structure and function, the development of medicines better suited to a woman’s biology may yet take off. Before that can occur, however, more work is needed to uncover the differences between the brains of male and female animals. Despite recent progress, such work is very much in the minority.
Mogil, who has demonstrated big differences in pain processing in males and females, is astonished that so many researchers have failed to include female animals in their studies, especially when it comes to pain research. “It’s scandalous,” he says. “Women are the most common pain sufferers, and yet our model for basic pain research is the male rat.” On the flip side, it’s also an area ripe for exploration: “Every year or two we write a paper that says that something someone reported earlier is actually only true in males. We keep making people look bad. They are missing stuff completely.”
Myths and misconceptions
DON’T ASK A WOMAN FOR DIRECTIONS
Give a man a sheet of paper printed with tangled streets and he can tell you where you need to go. But don’t be afraid to ask a woman for directions. Chances are she’ll get you there, too, but using a different technique. Drawing on her hippocampus, she’ll offer you physical cues like the bakery, the post office and the Chinese restaurant.
MEN AREN’T EMOTIONALLY TUNED-IN
He might not remember the details of the big blow-up you had during your honeymoon, ladies, but just because you can it doesn’t mean he’s insensitive. Women are simply better at remembering the details surrounding emotional events, because their amygdala is tuned to capture them.
WOMEN ARE MORE TALKATIVE THAN MEN
Modern folklore claims women speak nearly three times as many words as men. Don’t believe the hype. Women and men both say 16,000 words a day, on average.
OESTROGEN IS THE FEMALE HORMONE
While it’s true that males mainly secrete testosterone from the testes, oestrogen is important to male brain development in the womb. In the male brain, testosterone is converted into oestradiol, which acts on oestrogen receptors and sets the hypothalamus to “male”. Brains apart: The real difference between the sexes, 16 July 2008, New Scientist
Good old Chris from Conditioning Research always comes up with the goods. This is a story he sent me last month. My sister and I both have AD(H)D. She has the hyperactive variety. We’re both somewhat bipolar too.
A genetic change in the dopamine transporter — one of the brain’s dopamine-handling proteins — makes it behave as if amphetamine is present and “run backward,” Vanderbilt University Medical Center investigators report this week in The Journal of Neuroscience.
The altered function of the transporter gene variant, discovered in two brothers with attention deficit hyperactivity disorder (ADHD), supports a role for dopamine signaling in the disease. ADHD is one of the most common mental health disorders in children and adolescents, affecting up to 5 percent of school-age children in the United States.
“We believe that this is important evidence that ADHD can be caused by a functional deficit in the brain’s dopamine signaling pathway,” said Randy Blakely, Ph.D., director of the Center for Molecular Neuroscience.
The researchers propose that because the altered transporter runs backward and pushes dopamine out into the space between neurons — like normal transporters do when amphetamine, or ‘speed,’ is present — it alters dopamine signaling and contributes to the symptoms of ADHD.
“It’s like these kids are on amphetamine all the time,” said Aurelio Galli, Ph.D., an investigator in the center. Amphetamine causes hyperactivity, paranoia and psychosis in normal subjects.
Variations in brain dopamine signaling have long been suspected to participate in the development ADHD and other neuropsychiatric disorders. Dopamine has roles in brain circuits linked to attention, motor function, reward and cognition, and drugs that target dopamine transporters and receptors are used to treat ADHD, bipolar disorder and schizophrenia.
Because the dopamine transporter is a key member of the dopamine-signaling network, Blakely and colleagues searched for changes in this protein in patients with ADHD. They found a single “letter” change in the transporter gene in two brothers. The particular mutation had been reported once before in a patient with bipolar disorder, which also has connections to dopamine signaling, but the functional impact of the mutation had not been pursued, Blakely said.
In initial studies of the variant transporter in cultured cells, the group found no differences in function compared to the normal transporter — the mutant transporter moved dopamine into the cell and was appropriately regulated by dopamine transporter blockers and cellular signaling pathways.
Turning to a sensitive technology called amperometry that uses a small carbon fiber to “listen in” on how single cells release or transport dopamine, the Galli and Blakely laboratories discovered that the altered transporters were running backward at an exaggerated rate, literally pushing dopamine out of the cell.
“We think this activity would short circuit the normal synaptic transmission process,” Blakely said. “Instead of the precise ‘pop-pop-pop’ of dopamine being released from vesicles (tiny packets of neurotransmitter), there’s a cloud of dopamine bleeding out, and the dopamine signaling system is not as sharp as it should be.”
To their surprise, the investigators also found that amphetamine blocks the leak of dopamine through variant transporter. Normally, amphetamine does just what the mutation does — it causes the dopamine transporter to run in the reverse direction.
The findings offer a new perspective on a conundrum in the ADHD field — the fact that two of the medications that successfully treat the disease have opposing effects on their molecular target, the dopamine transporter. With the normal dopamine transporter, methylphenidate (Ritalin) blocks the ability of amphetamine (Adderall) to make the transporter run backward, yet both drugs are equally beneficial to patients with ADHD.
But when the transporter runs backward of its own accord — as it does with this rare mutant version — both agents act as blockers and stop the leak of dopamine.
“This observation unifies the action of these drugs and strongly suggests that backward-running transporters may be an important mechanism in ADHD, even for those who do not have this particular mutation,” Blakely said.
Researchers studying the dopamine transporter have found that there are multiple ways to cause the transporter to run backward, Galli pointed out, and the team is now screening other genes in the “network of signaling pathways that target the transporter and reverse dopamine flow” as potential contributors to ADHD risk.
The investigators also speculate that backward-running transporters may represent a more general phenomenon, giving rise to multiple types of neuropsychiatric disorders.
“Millions of patients have taken drugs that block transporter proteins, such as those that handle brain norepinephrine and serotonin, to treat anxiety and depression,” Blakely said. “We used to think that the only thing these drugs could do is block uptake — now we wonder if reducing the backward leak of neurotransmitter is a key component of their utility.”
M. Mazei-Robison, Ph.D., and E. Bowton at Vanderbilt, and collaborators at the Medical University Vienna contributed to the current study. The National Institutes of Health supported the research. Galli is an associate professor of Molecular Physiology & Biophysics. Blakely is the Allan D. Bass Professor of Pharmacology and Professor of Psychiatry. Protein On ‘Speed’ Linked To ADHD
I did a B12 trial earlier this year. I found that B12 seemed to be useful in helping me recover from food chemical reactions (particularly amine hangovers), but the B12 gave me insomnia, irritability, palpitations, and caused weight gain, which are as bad in their own way as eating the amines in the first place.
B12 seems to have glutamate-agonist properties. I wondered whether taking it with a glutamate-antagonist might help neutralise some of the negative side effects. B6, K2, glycine, glutamine, theanine, and just being in ketosis are all potential options. I know from past experience that some of these have side effects too. B6 just gives me brain fog. Glycine makes me depressed. Glutamine doesn’t do much of anything apart from being very good at neutralising sugar cravings. Theanine had an effect but wore off very quickly, probably because the body breaks down theanine into glutamate. Ketosis makes me calm, but it isn’t strong enough to counteract the effects of the B12.
The last remaining option is vitamin K. I’ve been led to believe that vitamin K is supposed to protect against glutamate toxicity (if only I could find a pubmed study showing that I’d feel more confident about saying it). Vitamin K certainly makes me feel calm. The effect is like being in ketosis, but different. Vitamin K makes me feel drugged, like I’m on Valium. I find it hard to get worked up about anything. It also makes me feel stupid and I get very forgetful. It does not help me to control my weight, if anything, I’ve felt in the past that I’ve gained weight while taking it, though my hunger and blood sugar regulation feels under better control. K2 is supposed to help produce energy so WAPF members have blamed chronic fatigue syndrome on K2 deficiency. K2 has never made me feel more energetic. Pantothenic acid was always much better at that.
I can’t take vitamin K2 regularly because I had deep vein thrombosis a few years ago, and when I take vitamin K2 for more than a few days, the site of my DVT starts hurting and swelling. Vitamin K is involved in clotting, and old DVT sites usually have some fibrin still stuck to the inside of the leg vein just waiting to cause trouble. The only other thing that does that to me is calcium carbonate supplements. I’ve never managed to induce it with vitamin K1, but then, vitamin K1 is very hard for the body to absorb.
During this trial I took between 500mcg and 1.5mg of the Vitamin Research Products brand of vitamin K, which is largely the K2 MK4 variant, along with the adenosylcobalamin I was already using. I did not take the supplements every day, only when I had eaten something I knew I would react to.
What happens when I take B12 and K2 together?
Well, I feel calm. It doesn’t negate the positive effects of the B12 on amine hangovers, but it stops the slightly manic, overstimulated feeling and the insomnia. It doesn’t stop the weight gain. I also managed to pick up a couple of veruccas after years of not having any, possibly something to do with a K2/A antagonism (vitamin A arrests the growth of Human Papilloma Virus and was thought to help that poor tree root man who was in the news a while ago).
But I fall asleep.
I literally can’t keep my eyes open. It takes a couple of hours to kick in. At first, I couldn’t figure out what was going on, so I just thought I must have slept badly or I was just tired. But that’s not the case. I’ve been trying this one out for a couple of months now, and every single time it’s knocked me out. Great at bedtime, not so great on a Sunday morning when you want to recover from Saturday’s cheating.
Vitamin K, along with glutamate, help to form a protein called gamma-carboxyglutamate protein, or Gla protein for short. Gla protein is involved in bone formation. The only suggestion I can find in pubmed that Gla might have anything to do with sleep is this abstract:
The venom of a fish-hunting cone snail (Conus geographus) contains a novel toxin, the “sleeper” peptide, which induces a sleep-like state in mice when injected intracerebrally. We demonstrate that this peptide contains 5 mol of gamma-carboxyglutamate (Gla) in 17 amino acids. The amino acid sequence of the sleeper peptide is Gly-Glu-Gla-Gla-Leu-Gln-Gla-Asn-Gln-Gla-Leu-Ile-Arg-Gla-Lys-Ser-Asn-NH2. Gamma-carboxyglutamate in a neuroactive toxin
The effect is quite different from the effects of GABA and melatonin – they send me into light dream sleep. Melatonin is particularly awful, as it induces a hypnotic not-quite-asleep state in me with vivid dream/hallucinations and a big hangover the following morning. The B12/K2 combo doesn’t do this. The sleep is proper, deep sleep. My partner has problems getting into deep sleep, and he also reported feeling like he got deeper sleep after taking K2. He’s usually very skeptical of vitamins, but he seemed quite impressed in this case.
Yippee, I discovered something unknown to science. A phenomenal new sleep drug. Are there any researchers who would like to take this up?
Unfortunately unless I plan on giving up all my IQ points and turning into a sloth, I think I may have to pass on taking B12/K2 regularly. I went on a five day food chemical binge recently, and B12/K2 failed to stop me feeling awful, though they limited my symptoms. I spent far too much time asleep. But at least I have a backup plan for those days when my diet slips.