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Gene Map of Brain Offers Hope for Alzheimer’s, Autism

November 29, 2006 at 10:24 AM EST
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MARGUERITE KIRST-COLSTON, Mother of Autistic Child: Focus, focus. This one or this one? Hey, why don’t we hold it back here. OK, good choice.

SUSAN DENTZER, NewsHour Health Correspondent: Marguerite Kirst-Colston works hard with her 6-year-old son, Camden, trying as best as possible to get inside his brain.

Camden was born with a condition called Noonan Syndrome, and also with autism. The first explains his short stature and wide-set eyes; the second, his difficulties in communicating and in social interaction.

MARGUERITE KIRST-COLSTON: The middle part of his brain, the corpus callosum, which they think is the cable system of the brain, is there, but it’s small and it’s thin. And so Noonan’s has a big element of problems with growing, and so they wonder if the Noonan’s caused the autism or if it’s separate.

SUSAN DENTZER: Both conditions are triggered by genetic changes or mutations that affect the brain. The hope that Camden and children like him might one day be spared these diseases is why Kirst-Colston is excited about a major new tool in brain research.

The tool is the Allen Brain Atlas, a three-dimensional catalog of all the genes active in the brain. It came about because of this man: Microsoft co-founder and philanthropist Paul Allen.

PAUL ALLEN, Founder, Allen Institute for Brain Science: What we’ve got is really a general purpose tool for anyone that wants to do any kind of brain research, if they want to look at one gene, if they want to look at a set of scenes correlated together, maybe in some disease that might end up having a genetic base.

And in the brain, we only understand things, you know, at a small-scale and at a very large scale. You know, 95 percent of how the brain works is unknown.

The concepts behind the Brain Atlas

SUSAN DENTZER: The Brain Atlas is the first product of a new brain research institute that Allen created in Seattle. He says he spent $100 million of his own funds to launch it, partly because he'd watched aging relatives battle degenerative brain diseases.

PAUL ALLEN: I think anybody that's been familiar with a family member who's had Alzheimer's or Parkinson's or Lou Gehrig's disease, these are all very, very tough diseases. And so anything that could be done that would accelerate the development of drugs or other treatments for these diseases, it would be a fantastic thing.

SUSAN DENTZER: All diseases, including brain diseases, stem from mutations or other changes in the estimated 21,000 genes that make up human DNA. To help understand these processes better, top scientists assembled by Allen advised him to create a roadmap of genes active in the brain. Allan Jones is scientific director of the Allen Brain Institute.

ALLAN JONES, Chief Scientific Officer, Allen Institute: Genes, when they are turned on -- the lingo that we use is, we call them, they're "expressed." And when they get turned on, they actually take that information and they eventually tell the cell what proteins to make.

And so the proteins are the things that go about and do the business of a cell. And what gives the cell its unique character, what makes a bone cell different from a skin cell from an eye cell from a brain cell, is what genes are turned on, of those 21,000, what genes are turned on, and at what level those genes are turned on.

DAVID ANDERSON, California Institute of Technology: It's a great source of satisfaction today to see this vision realized.

SUSAN DENTZER: Scientist Dave Anderson of Caltech is one of the scientists who advised Allen. He told him that knowing which genes turned on and off in different brain regions would provide unparalleled insights into how the brain worked.

DAVID ANDERSON: It's like looking at a map of Africa. And in the old days, you would just look at the borders between the different countries. Now what you can see instead is all the domains where the different animals live, where the different plants are, where the different human tribes and populations are. And that's what you see, irrespective of the borders between countries.

ALLAN JONES: You can really see the advantage of being able to see this in 3-D.

How the Atlas was created

SUSAN DENTZER: The ideal would be to have an atlas of genes expressed throughout the entire human brain, but that would require dissecting a live brain, an ethical and physical impossibility.

So scientists at the Allen Institute settled for the next best thing: an atlas of the brains of special laboratory-bred, genetically identical mice. It may be surprising, but 90 percent of a mouse's genes are identical to a human's. Assembling the Atlas required the work of nearly 100 scientists, engineers, mathematicians and information experts.

ALLAN JONES: We've got individual microscope slides. Each one of them is bar-coded so we can track all of the information. And there, as you can see here, there are very thin slices of mouse brain on each of these slides.

SUSAN DENTZER: They began by literally slicing apart the brains of several thousand mice. Each slice, just 25 microns thick, or about one-sixth of a human hair, was subjected to special chemical probes to detect the presence of specific genes.

Under sophisticated microscopes, the mouse brain cells with specific genes switched on look like this. Special cameras captured thousands of these images.

ALLAN JONES: We've generated over 600 terabytes of raw data, raw picture data. To put that in context, that would fill over 20,000 iPods.

SUSAN DENTZER: The digital images of the mouse brain cells with genes switched on were assembled into a giant database.

ALLAN JONES: We've assembled a large cluster of computers, which simply grind away and process this information and put it into this three-dimensional framework.

SUSAN DENTZER: The end product is this 3-D catalog. It's freely accessible to all on the Web site AllenBrainAtlas.org. Users can easily click on a brain section and see which genes are active there.

DR. SUSAN SWEDO, National Institute of Mental Health: It is exactly like having a Google for the mouse brain now.

SUSAN DENTZER: One researcher who's used the Allen Brain Atlas is Dr. Susan Swedo. She oversees autism research at the National Institute of Mental Health.

DR. SUSAN SWEDO: To be able to go online and just map various areas of the brain and what genes are being expressed in that area is phenomenal. I, in five minutes, was able to do what used to take a graduate student four years for one tiny, little nerve cell connection, and now they have it for the entire brain.

Using the map in modern medicine

SUSAN DENTZER: Neurosurgeon Gregory Foltz of the Swedish Medical Center in Seattle hopes his work with the Brain Atlas will lead to new treatments for patients. Foltz treats glioblastomas, the most malignant form of brain cancer that kills about 17,000 Americans each year.

DR. GREGORY FOLTZ, Neurosurgeon, Swedish Medical Center: One of the central questions we have is, how does your tumor compare to the normal brain?

SUSAN DENTZER: Foltz recently showed the Atlas to one of his patients, 64-year-old Dorothy Harper, who was diagnosed with glioblastoma last spring. He told her that her tumor was linked to changes in one particular gene, called BEX1. That's a finding he and fellow researchers made with the help of the Atlas.

DR. GREGORY FOLTZ: We went to the Allen Brain Atlas to see whether or not this gene was normally turned on or turned off. Now, what we found, if you take a look at the screen, is that this gene is normally turned on. Now, you can see that everywhere that the gene is turned on, there's a little dot. And this is a picture of the normal brain. What do you see there?

PATIENT: I still see a lot of dots on the brain.

DR. GREGORY FOLTZ: There is a lot of dots in that brain. That's because the gene is normally turned on throughout the brain. But in a tumor, in your tumor, it's turned off. So it turns out this gene is very important to keep cells from growing. And when you turn it off, cells grow out of control and can form tumors.

SUSAN DENTZER: These genomic findings have not yet translated into effective therapies for patients like Harper. But Foltz is confident that, one day soon, they will.

Implications on neurologic diseases

DR. GREGORY FOLTZ: I'm not sure what to compare it to in the history of medicine, but I can tell you that it's going to be something that we will look back on decades from now and say that we were there when this was discovered. I believe it'll have widespread impact on all patients who have neurologic disease.

SUSAN DENTZER: The Allen Brain Atlas is also providing new insight into the brain's overall complexity. One of its findings is that 80 percent of all the genes expressed elsewhere in the body are also expressed in the brain. That sheds light on how the human species found new uses for the body's genes as our brains evolved.

Another unexpected finding is that most genes active in the brain are turned on in multiple regions, not just one. Anderson of Caltech says that underscores how complex it will be to treat many brain diseases. He cites the example of autism.

MARGUERITE KIRST-COLSTON: More, OK. Go get it. You can get it.

SUSAN DENTZER: Some scientists think autism may stem from changes in genes expressed in a brain region known as the amygdala. That's a part associated with emotions and social interaction.

DAVID ANDERSON: Most of these genes that are expressed in the amygdala will be expressed in other regions of the brain. If they show changes in expression in the amygdala, we'll also want to know whether their expressions change in other regions of the brain, such as the cortex, and that might lead us to clues about the involvement of other brain regions in autism that we didn't necessarily expect.

SUSAN DENTZER: Swedo of NIMH told us she hopes to use the Allen Atlas, along with tools her institute has developed, to better understand the causes of autism.

DR. SUSAN SWEDO: I think that we have reason to hope that, within our lifetime, we're going to know what causes autism, and we're going to have meaningful treatments and prevention strategies. The value of the Brain Atlas is it has just leapfrogged us to the next level of understanding.

SUSAN DENTZER: That's gratifying news to parents like Kirst-Colston.

MARGUERITE KIRST-COLSTON: If someone like Paul Allen is going to spend his time and money looking into something that affects so many people, then that may have an effect where other people get more interested in it, and we may actually get treatments and potentially cures or diagnosis which we just don't have now.

PAUL ALLEN: The world will develop new treatments for these diseases over the next few decades, I believe. So if what we did was a key to making any of that happen, that will be just incredibly rewarding for everyone involved.

SUSAN DENTZER: The Allen Institute's next project will be making a genetic atlas of the human cortex, the part of the brain associated with higher functions, such as thinking.