Brand new mutations are helping scientists figure out what is going on in autism.

Autism is incredibly frustrating from a genetic point of view. Every study clearly shows that genetics plays an important role in this disease. But when these studies try to find a cause, they keep coming up short.

And this isn’t because scientists aren’t trying hard. They are. In most of the recent studies they are comparing thousands of people’s DNA at millions of different spots. If there was a simple explanation, they would have found it.

One thing they have managed to find from all of these studies is that a minority of cases result from brand new mutations that most likely happen in either the sperm or the egg before fertilization. While these are not going to be that useful as a diagnostic test, they may prove useful as a way of figuring out which genes to focus on. And maybe even for coming up with new ways to treat autism.

With that in mind, a whole slew of researchers set out to find more of these sorts of de novo mutations (as they are called). They reported their findings in the following three back to back to back reports in the journal Nature:

Study 1
Study 2
Study 3

These researchers took on the herculean task of looking at every letter of every gene of over two thousand people. Basically they compared the genes of parents to the genes of their autistic children (and a few of their unaffected siblings). They were able to confirm that some previously identified genes were important in autism and they identified a few new ones.

They were also able to confirm that older dads pass on more of these sorts of mutations than younger dads or moms of any age. Which makes sense if you think about sperm production.

Each time a sperm is made, its DNA needs to get copied. And each time DNA is copied, there is a chance for a mistake to creep in. So it makes sense that the older the dad, the more mutations he’ll have in his sperm.

Frustratingly, this was the most solid finding in the study. But fret not. They also learned some important things about how autism happens too.

The most important thing they found was that many children with autism shared mutations in related genes. Their mutations affected different genes that all impacted the same or related biochemical pathways.

An fMRI scan of an autistic brain.

This is what we might expect from something as complicated as brain development. To pull off something like this, various genes are going to need to fire off at the right time in the right order. If any one of the genes in a similar pathway misfires, you can end up with similar problems. And this is undoubtedly happening in some cases of autism.

This is a very important finding for identifying where to focus research so new treatments can be found for this disease. Isolated genes can be hard to target because sometimes scientists don’t know what they are doing or how they fit into the grand scheme of things. But researchers can identify a pathway, then they can identify chemicals that can tweak that pathway that can one day become medicines.

These studies also highlight yet again what a hideously complex disease autism is. Your risk depends on what versions of lots of different genes you have. Some versions will increase your risk and some will decrease it. Your chances are a summation of all of these risks.

As if this wasn’t complicated enough, autism is more than genes. Something in the environment has to trigger the disease and we know very little about these triggers (except that vaccines aren’t one). Now add to this the fact that different genetic combinations are going to be susceptible to different triggers and you begin to see why this has been such a challenge to geneticists.

Figuring out why a particular person ended up with autism is really hard. But even if we can’t figure it out for a particular person, these studies are important for finding what is happening in the brains of people with autism. And hopefully by knowing that, we can find new treatments.

A long video about the biology of autism. Well worth your time.

Vincent van Gogh's Sunflowers (1889)

Most admirers of van Gogh's iconic "Sunflower" paintings gaze upon the golden inflorescences without any awareness of the scientific conundrum they pose. But researchers from the University of Georgia have finally cracked the case with a paper published in PLoS Genetics.

Buttercup taken at Tilden Park in Berkeley, California by Calibas

Orchid taken by Alex Tievsky SaveThePoint

The puzzle begins with the fact that all flowers are either radially or bilaterally symmetrical. A buttercup is an example of radial symmetry; it looks the same no matter how you rotate it. An orchid, on the other hand, has bilateral symmetry, like a human face–the left and right sides look the same, but you can tell whether it's right side up or upside down.

Here's the sneaky thing: a lot of seemingly radially symmetrical flowers are actually clusters of tiny bilaterally symmetrical flowers, or florets. In fact, this is true of one of the biggest flower families, Asteraceae, which includes such familiar friends as dandelions, daisies and, yes, sunflowers.

Then the sunflower makes things extra complicated by building its cluster out of two kinds of florets: bilaterally symmetrical ray florets, and radially symmetrical disk florets. This may sound confusing, but it's obvious as soon as you look for it: the classic sunflower is a ring of petals (ray florets) surrounding a big disk that will become filled with seeds (fertilized disk florets). The ray florets are infertile–they're just there to help attract pollinators.

Now at last we can consider van Gogh, and his double-flowered sunflowers. They're mutants.

A double-flowered mutant has no true disk florets, only concentric rings of ray florets–a profusion of petals. Consequently, the plant loses a lot of its fertility. You might wonder, can the opposite occur? Indeed, in tubular-rayed mutants ray florets are replaced with radialized, fertile disk florets.

Mark Chapman and his colleagues have just discovered that one particular gene, called HaCYC2c, causes both mutations. If HaCYC2c is over-expressed, it creates double-flowered van Goghs. If the gene's function is lost, however, you get tubular-rayed flowers.

I particularly love this study because at least the first part of their methods is totally accessible to anyone who's studied Mendelian crosses in high school biology. See:

Okay, maybe it's a bit tricky. If you want to puzzle it out but you're rusty on Mendel, here's a primer.

Of course, you don't need to understand Mendelian crosses–or the super-sophisticated genetic mapping that Chapman et al. use later–to appreciate van Gogh's art. Nor do you need to be an Impressionist fan to appreciate sunflower genetics.

But I think we can all appreciate that it's not often a famous painting is included in Figure 1 of a scientific paper.

Figure 1. Entire inflorescences (A, C, E) and individual florets (B, D, F) from wildtype (A, B), double-flowered (C, D) and tubular (E, F) sunflower individuals. Florets are arranged left to right from the inner florets to the outer florets. (G) “Sunflowers (Still Life: Vase with Fifteen Sunflowers)” by Vincent van Gogh (1888) with double-flowered heads pointed out with arrows. Panel G was obtained from Steve Dorrington on flickr (available at http://flic.kr/p/8SsPYb) and is distributed under the terms of the Creative Commons Attribution 2.0 Generic (CC BY 2.0) License.

It'll be a long time before scientists figure out why this branch is white.
And even longer before the public finds out.

Is there any place to check in for updates on this research?

Timothy Jordan asked this question on Chris Bauer’s blog about figuring out the genetics of redwood albinism. Unfortunately, the answer is that there really isn’t any place to see how the research is going.

This is because science is this weird combination of secrecy and openness. Research projects start out as proprietary but once finished, they become open source.

What this means is that no results will be released until a good chunk of the research is done and it has been published in a peer-reviewed journal. This usually takes a year or more and albino redwoods will probably take even longer.

Part of the reason for this is simple caution on the part of scientists. No one wants to release results so early that that they have to retract them later. Like everyone else, scientists don’t like to be proven wrong in public.

But this only explains not communicating preliminary results. Once a result is pretty solid, it should be OK to broadcast publicly. Except that it still isn’t.

This isn’t the fault of many of the scientists doing the research. I remember wanting to shout my latest results from the mountaintops as soon as I got them. Lots of scientists I have talked to feel the same way.

The problem has more to do with how science is funded. It simply isn’t designed to allow incremental progress to become public.

Scientists rely on the federal government for most of their funding. The NIH, NSF, DOE, and a few other agencies supply the lion’s share of research dollars.

Labs are awarded these grants based on the work they have done. There is absolutely no incentive for sharing their work early. In fact, sharing work too soon can cost you grant money and maybe even (eventually) your lab.

The graveyard of the scientific careers of those scientists who released their data too soon. Photo by Corpse Reviver.

To be credible, scientific results must be published in a peer-reviewed journal. This is the “coin of the realm” in the scientific world. To succeed as a scientist, you need lots of these in the top journals and of course, successful scientists are the ones who get funded.

These journals frown on releasing data before that data can make a big splash for their journal. This forces scientists to not release information to the general public (although they can talk about it at some point at scientific meetings). To keep from perishing, scientists need to keep their results under wraps.

Not only that, but scientists are not above stealing someone’s data and using it to get to the full story first. Smaller labs in particular are vulnerable to this sort of predation. Again, this forces scientists to keep their results to themselves rather than broadcasting it far and wide. Otherwise, they’ll have nothing to show for their work and they won’t get funded.

The only way to overcome these barriers and get results presented to the public in a more timely manner would be to change how science gets funded. Make it so there is lots of money to go around so that scientists will get money whether their lab makes the breakthrough or someone else uses your preliminary results to make the breakthrough.

Of course this won’t happen. For one thing, you wouldn’t be able to screen out the bad and/or lazy scientists nor reward the true go-getters. And besides, there are already way too many labs chasing way too few grants. Given that our government is sliding into insolvency, it is very unlikely that they will throw any more money at science so the public can get information any sooner.

A new way to fund science also wouldn’t change other aspects that keep our current system in place. For example, many scientists like to get a result first and beat the other guys. No funding tweaks are going to change this competitiveness.

Looks like we’ll have to stick with the current way that science is set up. It has done a great job of explaining our world and how it works. We just need to be patient and wait for the findings to eventually be released. As soon as they are, I’ll update you right here.

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This redwood, in Henry Cowell Redwoods State Park near Santa Cruz, might be genetically identical to some of its neighbors. Photo: kqedquest.

QUEST has an inordinate fondness for albino redwoods. It all started with the Science on the SPOT video Albino Redwoods, Ghosts of the Forest. Then there was a radio story, and a few blog posts. And last week QUEST revisited the research in two new Science on the SPOT videos about the ghosts of the forest. The video Revisiting Albino Redwoods, Cracking the Code focuses on QUEST blogger Barry Star and Stanford professor Ghia Euskirchen’s research on how the albinos are genetically different from “normal” coast redwoods. In Revisiting Albino Redwoods, Biological Mystery, Santa Cruz Professor Jarmila Pitterman wonders how albino redwoods’ total lack of chlorophyll affects their physiology and ecology. After producing all these videos, QUEST Producer Chris Bauer still had questions.

Chris saw three albino redwoods, arranged in a straight line, a short distance from one another. He wondered if these three redwoods, yards apart, might be genetically identical. Maybe they sprung from the same individual. To understand how this is even possible, you need to know about the numerous ways that redwoods can reproduce—some of which involve cloning themselves.

New redwood trees can come about in four ways: through seeds, cuttings, stump sprouts, and root sprouts.

QUEST on KQED Public Media.

Like all plants, redwoods can grow from seeds. Redwood seeds come from those tiny, inch-long redwood cones that fall from the branches in autumn. Each cone contains one to two dozen tiny seeds. These seeds were fertilized with redwood pollen; they are mix of genetic material from the parent that made the seed and the parent that made the pollen. However, redwood seeds have a notoriously low germination rate. Hardly any of them will grow into a plant. Which brings us to the next method of redwood tree generation: cuttings.

Redwood trees that you buy from a nursery probably began as cuttings—branches that were cut from a tree. To make a good redwood cutting, horticulturists will cut a branch from a young tree, or sapling, because cuttings from young trees tend to survive better. They treat the cutting with hormones to encourage growth, and plant the cutting in a special blend of soils. After a few months, about 25-35% of the cuttings have formed roots; the others do not survive. Once the cuttings have established, they can grow quite quickly—up to 7 feet in height in a single growing season. Regeneration from existing branches doesn’t just happen in the nursery—it happens in nature too. When a branch falls off a redwood tree, say in a storm, the branch can come in contact with the soil and develop roots. These provide the branch with nutrients and water, and before long the branch has grown into a tree. Trees grown from cuttings or from branches are genetically identical of the tree that donated the branch. (For the same reason, California’s vineyards are very low in genetic diversity; see this article in the New York Times.)

Stump sprouts on a coast redwood. Photo: kqedquest.

Many a majestic redwood tree began as a stump sprout. Stump sprouts are tiny growths from the base of existing trees. They can grow out of a healthy tree, or a tree that has been logged or damaged by fire. Redwoods have extensive underground root systems, which are impervious to trifling things like lumberjacks’ axes and fire. Trees that grow from stumps grow quickly and have a good chance of success, because the trees are automatically connected to a large root system. Multiple stump sprouts from a single trunk form what is called a fairy ring: a ring of trees, with a circular clearing in the middle, because the original tree breaks down. Stump sprouts are generally genetic clones of the original tree. However, the albino redwoods are stump sprouts with a mutation (or two, or three…). The genomic research happening Stanford will hopefully shed some light on how this mutation happens.

A fairy ring. The ring of trees has sprouted from the moss-covered trunk in the middle. Photo: Swiv.

Redwoods don’t just sprout from stumps; they can also sprout new growth from their roots. Redwood roots extend horizontally under the soil. Many redwoods live in flood-prone ecosystems, on the banks of rivers. When redwood forests become flooded, sediment piles up on the surface of the soil, burying the roots a bit deeper than they were before. Redwoods will grow another set of horizontal roots, a little closer to the surface. By digging deep into the ground and counting the horizontal layers of roots, people can tell how many floods a redwood has endured. When new growth sprouts from the surface roots, the original tree soon has a neighbor that is basically an identical twin. This is what Chris thinks is going on with the three albino redwoods, all in a row.

Hopefully Chris can test his hypothesis in a year or two, when the redwood genome is sequenced and we know what mutation (or mutations) cause albinism. Are the three neighboring albino redwoods mutants that sprung from genetically identical trees? Maybe that tree’s genotype is just a little different from that of an albino—and the mutation that causes albinism is very likely to occur. Or maybe the three albinos are a series of chlorophyll-free coincidences. We’ll have to wait patiently for the genome data. But, for a coast redwood that can live for 2,000 years, the wait won’t be long at all.

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If he drinks a lot, he can be up to 56 times more likely to
end up with esophageal cancer compared to a nondrinker.

Many people of East Asian descent react to alcohol with a red face, a racing heartbeat and a slight sick feeling in their stomach. This “Asian glow” is more than just annoying though. If they keep drinking anyway, it can be downright dangerous.

In addition to its obvious charms, drinking alcohol definitely has some drawbacks (besides beer goggles and nasty hangovers). One of these is an increased risk for getting cancer of the esophagus. One study I saw claimed that heavy drinkers are 18 times more likely to end up with esophageal cancer compared to teetotalers.

The risk is even higher for blushers. They are 56 times more likely to end up with this particular cancer if they are heavy drinkers. And even if they just have a couple of drinks a day, they are still at a 5 times higher risk.

Unfortunately, the alcohol flushing response is pretty common. Scientists estimate that 36% of people of East Asian descent respond to alcohol this way. That’s over 500 million people worldwide.

All of these statistics are especially scary because esophageal cancer is so common. For example, it is the 7th leading cause of cancer death worldwide and the 7th most common cancer in men in the U.S. In some parts of Russia and China, the rates of this cancer range from 30-800 cases per 100,000 people. The rate in the U.S is 3-6 per 100,000.

Many if not most of these cancers happen because the patients drank too much alcohol and smoked too many cigarettes. One review article estimated that if heavy drinking blushers from Japan switched to just two drinks per day, the number of cases of esophageal cancer there would be cut in half. Undoubtedly the same thing is true elsewhere.

Everyone is at a higher risk for esophageal cancer when they drink because of how alcohol is broken down in the body. On the way to converting alcohol to the safer acetic acid, our bodies first turn it into acetaldehyde. And that is some nasty stuff!

Acetaldehyde likes to stick to and damage our DNA. Not only that, it also keeps our cells from repairing the damage. Since cancer happens because of DNA damage, it isn’t surprising that alcohol causes an increased risk for cancer.

People who blush from alcohol have a certain version of the ALDH2 gene that has trouble converting alcohol into acetaldehyde. The end result is a build up of acetaldehyde that can damage DNA and so cause esophageal cancer.

Again, there is no increased risk if they don’t drink. In the absence of alcohol, they are just like anyone else. They just need to lay off the liquor.

Maybe these people need to find a new social lubricant. I guess it's too bad Prop 19 didn’t pass…

A fun activity to learn more about the genetics and biology of the alcohol flushing response.

A review article that raises an alarm about the risks of drinking alcohol as a blusher.

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Who ya gonna call? Stanford Genetics.

I know, I know…hokey title, hokey caption. But in many ways it's true.

Albino redwoods have been called the ghosts of the forest. And scientists from Stanford’s Department of Genetics are on the trail to figure out why these trees have white leaves instead of green.

This all started with a Science on the SPOT story about the albino redwoods by Chris Bauer right here on QUEST. In his accompanying blog post about these "ghost trees", he wondered aloud if any geneticists might be interested in trying to figure out what was going on genetically with these pale trees.

I was intrigued enough that I decided to ask the chair of the Department of Genetics, Dr. Mike Snyder, if he was interested in tackling the problem. By chance, he knew of a scientist in the department, Dr. Ghia Euskirchen, who was also interested in the redwood genome.

In the old days, figuring out what exactly was going on at the DNA level of something as complicated as a redwood would have cost way too much time and money to make a study like this worthwhile (if it was even possible at all). Nowadays things are simpler but still no walk in the park. Instead of elegant, time consuming experiments to pinpoint where the problem might be, scientists will use a more brute force method. They will simply sequence all of the DNA of albino and normal redwoods and compare them.

Sequencing is cheaper, simpler, and less time consuming than the old ways but this isn’t CSI. We’re not going to have answers right after this commercial break. It could still take a couple of years to figure this out. Or, if the biology doesn’t cooperate, even longer.

And the only reason we have a chance to do this so “quickly” is because redwoods can reproduce asexually. In other words, they can throw off clones of themselves.

It just so happens that occasionally, a few of these clones end up albino. What this means is that there shouldn’t be a whole lot of differences between the albino and wild type clones. This should make finding the change that caused the albinism relatively easy. That’s the hope anyway…

I am sure you’ve already started to think how weird it is that a clone ended up different from the original. After all, by definition, clones should be the same.

One letter change turns this watch into a cheap knock
off. The same thing may be going on with albino
redwoods but with DNA letters.In real life, though, clones are not the same as the original. They are more like subtle knock-offs. For example, cloned cats look similar but have different personalities. Same thing with garden variety human clones—identical twins.

So how does a clone end up different from the original? There are many possibilities, here are two:

1. The DNA is different. Even though a clone is really just a copy of the original, cells aren’t perfect at making copies of themselves. You try copying the 30 billion letters of redwood DNA and see how well you do! Most of these changes don’t matter but if one happens to hit and damage one of the hundreds of genes involved in making a redwood green, then you’ll get a white tree.

2. The DNA is used differently. All the cells in a redwood have the same DNA but a root is very different from a leaf. These differences come about because each cell uses its DNA differently. The environment can also affect which gene a cell chooses to turn on and to what level. This is often done with differences in something called methylation which scientists can detect. It may be that methylation has shut off a key gene involved in turning redwood leaves green.

Watch out for at least one more blog on this topic from me dealing with bits of DNA outside of the nucleus that may be involved. And for Chris’ upcoming story on how Stanford scientists are going about solving this albino mystery.

QUEST on KQED Public Media.

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Animal viruses can be more deadly than their human
counterparts

Over those two years, at least three waves of flu struck killing over 600,000 people in the U.S. and a staggering 30-50 million people worldwide.  People died at such a high rate that cities ran out of caskets and dead bodies were stacked on porches and in the streets.

Governments have been concerned that history might repeat itself because the two flues share one thing in common–they both started out as animal viruses.  And our bodies are not particularly good at fighting off viruses new to humans.

Each year a new flock of flu strains kicks off the flu season.  Almost always these strains are variations of human flues from previous years.  What this means is that we have seen cousins of these viruses in the past and so have a leg up on mounting an attack and defeating them.

We do not have this same leg up on animal viruses.  Our immune systems haven't seen anything like them and so can't mount a quick attack.  The end result is that the percentage of people who die from animal flues tends to be much higher than from run of the mill human flues.

In any flu season, the CDC estimates that 5-20% of the U.S. population ends up with the flu.  And that 36,000 of these people die.  The numbers of deaths would be much higher if a truly deadly animal flu virus like the bird flu from a few years back were to emerge and gain the ability to spread from person to person.  (The bird flu was never more than a few isolated cases since it never gained this ability.)

At first blush, this is what the swine flu looked like.  The disease spread easily among people and, in Mexico at least, appeared to be more deadly than normal flues.  So governments around the world sprang into action.  Since flu is spread through contact, governments tried to keep people away from each other.

They closed schools at the fist sign of trouble.  Mexico closed restaurants, theaters and museums too.  All of this was done in an attempt to prevent the spread of a disease like the flu of 1918.

At least outside of Mexico, this flu does not seem to be too much worse than other flues.  So it may be that governments overreacted this time.  But I would prefer that they overreact like this as opposed to ignoring a deadly pandemic.  We don't want another 1918 on our hands.

More info on The 1918 Flu in San Francisco

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