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Mouse pups — and even the offspring's offspring — can inherit a fearful association of a certain smell with pain, even if they have not experienced the pain themselves, and without the need for genetic mutations.

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Certain fears can be inherited through the generations, a provocative study of mice reports¹. The authors suggest that a similar phenomenon could influence anxiety and addiction in humans. But some researchers are sceptical of the findings because a biological mechanism that explains the phenomenon has not been identified.

According to convention, the genetic sequences contained in DNA are the only way to transmit biological information across generations. Random DNA mutations, when beneficial, enable organisms to adapt to changing conditions, but this process typically occurs slowly over many generations.

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Yet some studies have hinted that environmental factors can influence biology more rapidly through 'epigenetic' modifications, which alter the expression of genes, but not their actual nucleotide sequence. For instance, children who were conceived during a harsh wartime famine in the Netherlands in the 1940s are at increased risk of diabetes, heart disease and other conditions — possibly because of epigenetic alterations to genes involved in these diseases². Yet although epigenetic modifications are known to be important for processes such as development and the inactivation of one copy of the X-chromsome in females, their role in the inheritance of behaviour is still controversial.

Kerry Ressler, a neurobiologist and psychiatrist at Emory University in Atlanta, Georgia, and a co-author of the latest study, became interested in epigenetic inheritance after working with poor people living in inner cities, where cycles of drug addiction, neuropsychiatric illness and other problems often seem to recur in parents and their children. “There are a lot of anecdotes to suggest that there’s intergenerational transfer of risk, and that it’s hard to break that cycle,” he says.

Heritable traits

Studying the biological basis for those effects in humans would be difficult. So Ressler and his colleague Brian Dias opted to study epigenetic inheritance in laboratory mice trained to fear the smell of acetophenone, a chemical the scent of which has been compared to those of cherries and almonds. He and Dias wafted the scent around a small chamber, while giving small electric shocks to male mice. The animals eventually learned to associate the scent with pain, shuddering in the presence of acetophenone even without a shock.

This reaction was passed on to their pups, Dias and Ressler report today in Nature Neuroscience¹. Despite never having encountered acetophenone in their lives, the offspring exhibited increased sensitivity when introduced to its smell, shuddering more markedly in its presence compared with the descendants of mice that had been conditioned to be startled by a different smell or that had gone through no such conditioning. A third generation of mice — the 'grandchildren' — also inherited this reaction, as did mice conceived through in vitro fertilization with sperm from males sensitized to acetophenone. Similar experiments showed that the response can also be transmitted down from the mother.

These responses were paired with changes to the brain structures that process odours. The mice sensitized to acetophenone, as well as their descendants, had more neurons that produce a receptor protein known to detect the odour compared with control mice and their progeny. Structures that receive signals from the acetophenone-detecting neurons and send smell signals to other parts of the brain (such as those involved in processing fear) were also bigger.

The researchers propose that DNA methylation — a reversible chemical modification to DNA that typically blocks transcription of a gene without altering its sequence — explains the inherited effect. In the fearful mice, the acetophenone-sensing gene of sperm cells had fewer methylation marks, which could have led to greater expression of the odorant-receptor gene during development.

But how the association of smell with pain influences sperm remains a mystery. Ressler notes that sperm cells themselves express odorant receptor proteins, and that some odorants find their way into the bloodstream, offering a potential mechanism, as do small, blood-borne fragments of RNA known as microRNAs, that control gene expression.

Contentious findings

Predictably, the study has divided researchers. “The overwhelming response has been 'Wow! But how the hell is it happening?' says Dias. David Sweatt, a neurobiologist at the University of Alabama at Birmingham who was not involved in the work, calls it “the most rigorous and convincing set of studies published to date demonstrating acquired transgenerational epigenetic effects in a laboratory model'.

However, Timothy Bestor, a molecular biologist at Columbia University in New York who studies epigenetic modifications, is incredulous. DNA methylation is unlikely to influence the production of the protein that detects acetophenone, he says. Most genes known to be controlled by methylation have these modifications in a region called the promoter, which precedes the gene in the DNA sequence. But the acetophenone-detecting gene does not contain nucleotides in this region that can be methylated, Bestor says. 'The claims they make are so extreme they kind of violate the principle that extraordinary claims require extraordinary proof,” he adds.

Tracy Bale, a neuroscientist at the University of Pennsylvania in Philadelphia, says that researchers need to “determine the piece that links Dad's experience with specific signals capable of producing changes in epigenetic marks in the germ cell, and how these are maintained”.

“It's pretty unnerving to think that our germ cells could be so plastic and dynamic in response to changes in the environment,” she says.

Humans inherit epigenetic alterations that influence behaviour, too, Ressler suspects. A parent’s anxiety, he speculates, could influence later generations through epigenetic modifications to receptors for stress hormones. But Ressler and Dias are not sure how to prove the case, and they plan to focus on lab animals for the time being.

The researchers now want to determine for how many generations the sensitivity to acetophenone lasts, and whether that response can be eliminated. Scepticism that the inheritance mechanism is real will likely persist, Ressler says, “until someone can really explain it in a molecular way”, says Ressler. “Unfortunately, it’s probably going to be complicated and it’s probably going to take a while.”

Nearly 40 years after surgeons first operated on fetuses to cure devastating abnormalities, researchers have taken the first step toward curing genetic disease before birth via genome editing: scientists reported on Monday that they used the genome editing technique CRISPR to alter the DNA of laboratory mice in the womb, eliminating an often-fatal liver disease before the animals had even been born.

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The research, by a team at the University of Pennsylvania and the Children’s Hospital of Philadelphia (CHOP), is a very early proof of concept. But while CRISPRing human fetuses is years away, at best, the success in mice bolsters what Dr. William Peranteau, who co-led the study, calls his dream of curing genetic diseases before birth.

“A lot more animal work needs to be done before we can even think about applying this [fetal genome editing] clinically,” said Peranteau, a pediatric and fetal surgeon at CHOP. “But I think fetal genome editing may be where fetal surgery [which is now routine] once was, and that one day we’ll use it to treat diseases that cause significant morbidity and mortality.”

Simon Waddington of University College London, a leader in research to develop fetal gene therapy who was not involved in the new study, called the CRISPR approach “an elegant refinement of the brute-force technology” that’s been the focus of animal studies of fetal genetic therapy.

The success in mouse fetuses raises the possibility that, even before traditional gene therapy is ready to treat inherited disorders in utero, genome editing might emerge as a safer, more effective approach. In traditional gene therapy, an entire healthy gene is ferried, typically by a virus, into cells containing a disease-causing gene. With CRISPR, only the mutated bit of a defective gene is changed. It’s the difference between retyping a whole 5,000 word document and using Word’s “find and replace” to correct a typo.

“We think this represents a safer and more precise way to make changes in the genome,” said Dr. Kiran Musunuru of Penn and a co-leader of the study. “It’s is the better way forward if you want to take CRISPR into the clinic.”

The rationale for fetal genetic therapy is simple: it could halt a disease before it causes irreversible and even fatal damage. In people, the inherited liver disease that the scientists targeted in mice, called hereditary tyrosinemia type 1, starts damaging the liver months before birth. Another rationale: because a fetus’s immune system is immature, it is less likely than even a newborn’s to attack the alien CRISPR molecules.

For their study, published in Nature Medicine, Musunuru and his colleagues gently opened the uterus of a pregnant mouse, removed the fetus from the amniotic sac, and injected CRISPR into the vitelline vein, which is near the surface of the sac and connects to the liver. “We wanted to make sure we got the genome editor into the liver rather than everywhere else,” Musunuru said. The fetus was then replaced in the uterus and was born normally.

Instead of using the original form of CRISPR, which cuts DNA where a gene is mutated and inserts a replacement string of A’s, T’s, C’s, and G’s, the scientists used the form of CRISPR called base editing. Invented just two years ago, base editing changes an incorrect DNA letter, or base, to the correct one, such as a C to a T or a G to an A. Its advantage is that it doesn’t need to cut DNA to do this, as CRISPR 1.0 does; those cuts can wreak genetic havoc, with unknown consequences for CRISPR’d cells.

For a dry run, the scientists first made a CRISPR base editor that changes a gene called PCSK9, which makes a protein that helps regulate the amount of cholesterol in the bloodstream, into a super-cholesterol-lowering form. When injected into mouse fetuses, the base editor changed liver cells as intended and left other organs alone. Crucially, the mouse mother showed no effects of the CRISPR treatment. After birth, the baby mice had ultra-low cholesterol levels, showing that the CRISPR base editor had worked. Only about 15 percent of the liver cells of the baby mice had been edited, but that fraction remained stable through the animals’ adulthood.

The amount of genetic havoc from the base editing was low: about 2 percent, compared to 40 percent for many uses of traditional CRISPR. And none of the likely spots for “off target” effects — DNA sites that resemble the target and so might be inadvertently edited — showed any sign of being altered.

The Philadelphia scientists then tried their technique on hereditary tyrosinemia type 1. HT1, which strikes 1 in 100,000 newborns worldwide, is caused by any of several mutations in a gene called FAH. All the mutations cause the build-up of toxic breakdown products of the amino acid tyrosine, a component of protein, and ultimately destroy the liver. Treatment with the drug nitisinone and a strict tyrosine-free diet is not always effective, with the result that children sometimes develop fatal liver failure or liver cancer.

The scientists used their base editor on a gene related to the disease-causing one. If this gene, called HPD, is disabled, then no toxic metabolites of tyrosine ever get to where FAH is unable to handle them.

Changing a C to a T in the HPD gene disabled it. No toxic molecules built up in the livers of the fetal mice. No other organs showed signs of editing, no off-target effects were detected, and having only 15 percent of their liver cells edited was enough to cure the mice and keep them cured into adulthood. “We weren’t expecting it, but the genome-edited mice did much better” than mice treated with nitisinone, Musunuru said. “They survived longer and gained more weight.”

The scientists hope to study fetal base editing for other severe congenital diseases. It remains to be seen whether this technique or conventional gene therapy, which provides an entire replacement gene, will work better.

“I’d consider that CRISPR isn’t a replacement” for the latter, Waddington said, “but will be an additional tool” for curing genetic diseases in the womb.

Republished with permission from STAT. This article originally appeared on October 8, 2018