Until the late 1960s the museum was the pathology department of the Central Indiana Hospital for the Insane. The bits of brain in the jars were collected during patient autopsies performed between 1896 and 1938. Most of the jars sat on a shelf until the summer of 2010, when Indiana University School of Medicine pathologist George Sandusky began popping off the lids.

Frustrated by a dearth of postmortem brain donations from people with mental illness, Sandusky—who is on the board of directors at the museum—seized the chance to search this neglected collection for genes that contribute to mental disorders.

Sandusky is not alone. Several research groups are now seeking ways to mine genetic and other information hidden in old, often forgotten tissue archives—a handful of which can be found in the U.S., along with many more in Europe. Several technical hurdles stand in the way, but if these can be overcome, the archives would offer several advantages. Beyond supplying tissues that can be hard to acquire at a time when autopsies are on the decline, the vintage brains are untainted by modern psychiatric drugs and are often paired with detailed clinical notes that help researchers make more accurate post hoc diagnoses.

“There are probably a fair number of these collections around the country that grew out of state hospitals,” says John Allman, professor of biology at the California Institute of Technology. “It is an untapped resource. If it were carefully planned and reasonably funded, it could become quite a valuable thing.”

Read more at…

Scientific American, January 2012.

Ten years later, a journalist at a big newspaper pointed out that, well, no, the $3 billion we spent on the human genome — a dollar for each pair of DNA letters — had not bought us the ability to diagnose, prevent or treat common diseases. The genome had revolutionized basic biology, sure, but done little for human health.

The newspaper article made a lot of scientists angry. (Some of them are still sputtering about it at conferences.) It also launched a broader discussion about science communication and hype. A month ago, I went to a public event at the American Museum of Natural History, in Manhattan, called “The Human Genome and Human Health: Will the Promise Be Fulfilled?” Four experts on genetics, medicine, ethics and law discussed whether the promises of that 2000 announcement would ever come true. The general consensus was that the White House hoopla had raised expectations much too high, inevitably leading to disappointment. Pride goeth before the fall.

As a journalist, I hate hype, and I will never argue that journalists should be anything but skeptical of scientific advancements. But I recently learned that, like all of the Seven Deadly Sins, pride is necessary for survival. So I wonder, does science need hubris?

Read more at…

The Last Word on Nothing, December 2011.

The findings, published December 15, 2011, in Cell Reports, could pave the way to new therapies for more common forms of seizures and dyskinesias, or abnormal movements, the researchers say.

“There are a lot of dyskinesias for which we don’t have good treatments and they are a big problem, such as in Huntington’s disease and Parkinson’s disease,” says Howard Hughes Medical Institute investigator Louis Ptáček, professor of neurology at the University of California San Francisco, who led the new study. “If we can understand the pathways in the brain that regulate dyskinesia, then it’s my hope that we’ll be able to target better drugs.”

Ptáček’s interest in dyskinesia dates to 1985 when, as a third-year medical student at the University of Wisconsin, Madison, he met a 16-year-old boy who was having bizarre spasms. Every time the boy switched from one movement to another, like from sitting to standing or walking to running, his limbs would inexplicably flail or twist, as if performing an odd dance.”Nobody knew what the heck was going on,” Ptáček recalls.

One night around 2 a.m., after scouring the library’s medical databases, Ptáček figured out the diagnosis: paroxysmal kinesigenic dyskinesia, or PKD, which had been reported in just a handful of other cases. He knew from those papers that PKD could be treated with a low dose of a common anticonvulsant medication. When doctors gave the boy the drug, carbamazepine, he quickly improved.

“He had been having attacks hundreds of times per day. A few weeks after treatment, he was essentially having zero attacks,” Ptáček says. “It felt so satisfying to have gotten it right.”

Read more at…

HHMI News, December 2011.

For most researchers, the rise of whole-genome sequencing is old news, and so are its potential pitfalls. The sheer volume of data will be difficult to store and, at least for a while, impossible to interpret. Then there are those frightening scenarios of how your genetic information might be used against you that routinely make it into headlines and Hollywood blockbusters.

But one aspect that is rarely discussed is that the rise of whole-genome sequencing may well result in a deluge of lawsuits against doctors. That’s the sobering prediction by two lawyers in an essay published 25 November in the online magazine Slate.

Read more at…

SFARI, December 2011.

Using a mix of chemicals in a dish, the researchers reprogrammed skin cells from individuals with Timothy syndrome into so-called induced pluripotent stem (iPS) cells and then coaxed these cells to differentiate into neural precursor cells and neurons.

The cells derived from individuals with Timothy syndrome show a host of defects, including abnormal calcium signaling and low numbers of cells that can form long-range connections. Notably, Timothy neurons produce more catecholamines, a class of chemical messengers, compared with neurons reprogrammed from healthy individuals. These chemicals have been linked to autism and, more often, to bipolar disorder and depression.

This chemical excess is largely reversed when researchers expose the cells to a drug called roscovitine, which blocks the flow of calcium across the cell membrane.

The Timothy syndrome gene, CACNA1C, makes a protein needed for a certain type of calcium channel. Mutations in the gene, reported in only a few dozen people, cause heart defects, physical malformations and, usually, autism.

Using the iPS cell approach with rare forms of autism, “you can find things that are interesting potential clinical leads,” says lead investigator Ricardo Dolmetsch, assistant professor of neurobiology at Stanford University in Palo Alto, California. “In a way, it gives you a better preclinical model than we’ve had before.”

Read more at…

SFARI, December 2011.

In the nucleus of every cell, threads of DNA wrap tightly around spools of histones. Methyl and other chemical groups that attach to either the DNA or histones can turn genes on or off. These so-called epigenetic changes add an extra layer of genetic control by tweaking the amount of RNA and protein produced without changing the underlying DNA sequence.

Looking at postmortem brain tissue from 16 individuals with autism and 10 age-matched controls, the researchers found hundreds of places in the genome where histone methylation is different in individuals with autism.

Many of these abnormal epigenetic marks land on or near known autism risk genes, suggesting that the biological pathways involving these genes may be important even in children with autism who do not carry mutations in the genes, the researchers say.

“You could say that the epigenetic risk architecture that’s described is tracking the genetic risk architecture,” says lead investigator Schahram Akbarian, professor of psychiatry at the University of Massachusetts Medical School.

Read more at…

SFARI, December 2011.

The findings suggest that drugs that effectively treat people with one form of autism may not help, and may even harm, individuals with another form, the researchers say.

“One implication is, boy, it’s going to be important to know where you are on this spectrum to devise the right therapy,” says lead investigator Mark Bear, professor of neuroscience at the Massachusetts Institute of Technology.

The work, first presented at the 2010 Society for Neuroscience annual meeting in San Diego, focuses on mouse models of two genetic diseases: fragile X syndrome, the most common inherited cause of autism, and tuberous sclerosis complex (TSC), characterized by benign tumors, seizures and, often, autism.

Autism is notoriously diverse. But the new study suggests that many forms of the disorder stem from a spectrum of disruptions to the same biological pathway, Bear says. “The hope is we’re gaining insights that will be broadly applicable.”

Read more at…

SFARI, December 2011.

Progress was slow at first, partly because of money: The first sequencing efforts cost hundreds of millions of dollars. But with the price tag now at less than $5,000 per person, researchers can begin building large collections of DNA data.

In October, for example, the autism science and advocacy organization Autism Speaks announced its plans to sequence whole genomes of 10,000 individuals —children with the disorder and their family members — over the next two years.

Read more at…

SFARI, November 2011.

Sigma Life Science

Six of the rats each lack one autism candidate gene — FMR1, NLGN3, MeCP2, NRXN1, CACNA1C and PTEN — and a seventh lacks mGluR5, which encodes a neuronal signaling receptor that is important in fragile X syndrome.

The impetus for making the rat models is to make autism research more attractive to the pharmaceutical industry. The standard approach in the industry is to test dosage and toxicology in rats, not in mice.

“Unless there’s investment, it doesn’t matter how many great ideas — which tend to be risky — you generate, they will not proceed forward,” says Robert Ring, vice president of translational research at the advocacy organization Autism Speaks. The idea is not to replace mice, Ring adds, but “to begin creating complementary animal models that help facilitate translational research.”

Over the past few months, Richard Paylor at Baylor College of Medicine in Houston, Texas, has done behavioral testing on young rats missing FMR1 — mutations in which lead to fragile X syndrome — and NLGN3, one of the first genes implicated in non-syndromic autism.

Unexpectedly, some of the rat behaviors are the opposite of what’s seen in their mouse counterparts: The FMR1-deficient rats engage in social play less than controls do, for example, whereas some strains of mice lacking FMR1 have more social interactions than controls.

Rats missing either FMR1 or NLGN3 also show some unexpected new characteristics, such as severe female aggression and compulsive chewing on water bottles.

Read more at…

SFARI, November 2011.

Her lab, headed by Northwestern University neurologist Teepu Siddique, has been all over the news recently for a study published in August in Naturereporting a new gene associated with the disease formally known as amyotrophic lateral sclerosis (ALS). “Breakthrough could lead to effective treatment for Lou Gehrig’s disease,” read the LA Times‘s headline; “Cause of ALS is found, Northwestern team says,” wrote theChicago Tribune. In honor of the study, in fact, the event’s organizers asked Siddique to lead the walkathon. Countless people approached Caliendo that day with the same questions: Does this mean there’s a cure? Is there a blood test for ALS? Is there a drug to treat it?

The answer to all these inquiries was ‘no’. “It’s not a cure, but people read into it what they want to hear,” Caliendo says. “I don’t think they were disappointed, though, because it’s still very good news. It’s huge.”

The study, some two decades in the making, was certainly newsworthy: it uncovered mutations in a gene called UBQLN2 that seemed to cause ALS in a handful of individuals with hereditary forms of the disease. But, according to Siddique, that’s not even the exciting part. In the new paper, his team analyzed postmortem spinal cord tissue from dozens of people with different forms of the disease, including those who developed ALS spontaneously and didn’t carry UBQLN2 mutations. To their surprise, Siddique and his colleagues found abnormal blobs of the ubiquilin-2 protein encoded by UBQLN2 in the neurons of every single individual they looked at.

In Siddique’s view, his study proves that all forms of ALS converge on a glitch in protein recycling that results in the accumulation of many types of proteins and the death of motor neurons. It’s similar, he says, to the discovery decades ago that people with a genetic disease called familial hypercholesterolemia carry mutations in a receptor for ‘bad’ cholesterol. On the basis of those data, researchers designed drugs—statins—that are now taken not only by those affected by the rare disorder but also by the majority of people with all forms of heart disease in the developed world.

“What we’re showing here is a direct functional mechanism that causes disease,” Siddique says. “It’s not just another cause; it’s not just another pathology; it’s a game changer.”

However, many of Siddique’s colleagues worry that his statements extend beyond what the data show. “To those of us who live in this world, it’s great that there’s another new gene,” says Jeffrey Rothstein, director of the Robert Packard Center for ALS Research at Johns Hopkins University in Baltimore. “But it’s been way overblown.”

Because of the media frenzy, the study ended up overshadowing two papers published exactly one month later that many ALS researchers find more significant but that didn’t receive as much press coverage. The studies, published back to back on 29 September in Neuron, reported mutations in a region of chromosome 9 called C9ORF72 that crop up in as many as one-third of all familial cases of ALS. In contrast, mutations in all of the other ALS-associated genes combined—including UBQLN2—only account for about 25% of all familial cases.

The Neuron studies, one of which included Rothstein as an author, bring the number of genes linked to familial forms of ALS up to 18, depending on how you count them. Yet most experts say the field is still far from understanding how any of these genes cause the disease—let alone how these genes relate to sporadic forms of ALS, which make up about 90% of all diagnoses. Plus, none of the genetic culprits are easy targets for drug development.

“There is a lot of excitement about [these discoveries], and nobody is more excited than I am,” says Lewis Rowland, a neurologist at Columbia University Medical Center in New York. “But then there is this horrible fact that knowing the genetics of the disease doesn’t help you treat the patients—either the genetic ones or the sporadic ones. ALS is just brutal as hell.”

Read more at…

Nature Medicine, November 2011.