Individual symptoms of psychiatric disorders, such as anxiety, avoidance and a heightened response to stress, can be transmitted from mother to child and even grandchild by multiple non-genetic mechanisms, a new study by investigators at Weill Cornell Medicine and other institutions shows. The pre-clinical findings, published May 13 in Nature Communications, may lead to tools to predict if a child is at risk of developing behavioral problems later in life after exposure to stress signals in the womb.

"Genetic and non-genetic inheritance are different but complementary mechanisms to pass information from one generation to the next," said senior author Dr. Miklos Toth, a professor of pharmacology at Weill Cornell Medicine. "It will be necessary to develop tools to determine if the familial occurrence of a disease is based on a non-genetic, as opposed to genetic, mechanism. On a positive note, non-genetic, in contrast to genetic, inheritance of disease is not inevitable and, if recognized in time, may be prevented.

Studies in humans have previously suggested that mothers can pass down behavioral traits to their children and grandchildren in a non-genetic manner. Grandchildren may be affected because fetuses produce early precursors to sperm and oocytes as they develop in the womb. A well-documented example of this transmission is the increased vulnerability of adult children and grandchildren of Holocaust survivors to psychological stress.

Because it would be unethical to perform controlled experiments on interactions between women and their developing or newborn children, the mechanisms by which these behavioral symptoms are passed on have been difficult to determine. So Dr. Toth and colleagues turned to mice, where they could separate the genetic effects of maternal influence on new generations from those that occur in the womb and after birth. Their strategy was to transfer offspring at various stages of development, for example, when the embryo was 1-day old or immediately after birth, to a surrogate mother.

The group began with female mice missing one copy of a serotonin receptor, one of a family of proteins found on the surface of nerve cells that transmit the message carried by the neurochemical serotonin to the cell's interior. Reduced activity of serotonin or its receptors is associated with anxiety, depression and stress disorders in humans and similar behavioral traits in mice.

The scientists found that mutant females, in addition to their behavioral symptoms, showed signs of inflammation and immune activation during gestation that were transmitted to their fetuses. Newborn mice that didn't inherit the serotonin receptor mutation nevertheless showed similar signs of immune activation, and the males later developed anxiety-like behavior. Studies by others have shown that when high levels of inflammatory cells are present in an individual, some of these cells can enter the brain and lead to psychiatric problems. These studies raise the possibility that one mechanism for the non-genetic transfer of a behavioral trait is through the immune system, Dr. Toth said.

Although some of the grandchildren displayed immune system aberrations and behavioral symptoms, embryo-transfer experiments demonstrated that the transmission was not direct from the grandmother. Instead, the whole process appeared to start anew, passing from the affected mother to her child.

Interestingly, another set of embryo-transfer experiments showed that a different behavioral trait in the mutant mice, a heightened response to stress, was directly transmitted to the grandchildren through non-genetic changes in the fetuses' developing oocytes.

"Our study helps explain why individuals, even within the same family, can display various combinations of anxiety, depression, bipolar disease and schizophrenia symptoms," Dr. Toth said. "We found that, at least in mice, each symptom can be passed on by a distinct mechanism."

The group then asked how an indicator of stress or infection makes its mark on an offspring's brain and persists to adulthood once it has been transferred from the mother. They turned to epigenetics, the study of how a series of chemical modifications to DNA, called methylation, can change how a gene is expressed but not the nature of its informational content. In the affected offspring, the scientists found these modifications on genes that are involved in nerve signaling and linked to behavioral traits.

"This paper begins to reveal what lies beneath the enigmatic and complex pathology of psychiatric disease, which is remarkably prevalent in today's society," said lead author Dr. Emma Mitchell, a former graduate student in Dr. Toth's lab and now a clinical trial associate at Shionogi, Inc.

With clues from the mouse studies, the team is now investigating a bacterial infection that inflames human fetal membranes, called chorioamnionitis. They hope to identify small proteins produced in this condition that lead to immune system effects on the fetal brain. They are also trying to develop a blood test for signs of prenatal exposure to stress in newborns, who may then be periodically assessed and given extra support for any cognitive and behavioral issues that develop as they grow up.

Dr. Toth emphasized that many children are resilient and may never show signs of behavioral problems despite early exposure to adverse conditions. But early intervention can help ameliorate any problems a child may have before they grow more difficult to treat, he said.

Diabetes is a disease in which the pancreas either does not produce enough insulin or cells in the body fail to respond to insulin properly. Diabetic patients experience abnormally high blood sugar levels, which can lead to heart disease, stroke, kidney failure, and eye damage. The disease, which affects more than 29 million Americans, is treated with drugs that help to keep blood sugar within a normal range. Steatosis, or fatty liver, occurs in at least half of all diabetics, though the relationship between the two diseases is not clear. Steatosis can also occur in other patients, such as those with hepatitis. It is a condition in which fat accumulates in the liver, causing inflammation and damage to liver cells. Most patients with fatty liver can only be treated with lifestyle and diet changes.

In a study published in the February issue of Diabetes, Obesity and Metabolism, scientists at Weill Cornell Medicine have identified a new drug that appears to treat both of these diseases at the same time. The drug targets a specific protein, called retinoic acid receptor beta-2 (RARB2), which is critical in the development and functioning of pancreatic cells.

"This is a whole new class of drugs," said senior author Dr. Lorraine Gudas, chair of the Department of Pharmacology and the Revlon Pharmaceutical Professor of Pharmacology and Toxicology at Weill Cornell Medicine. "RARB2 is a new target for diabetes treatment. We are also excited because, currently, there is no medicine that effectively treats fatty liver, so this may be a breakthrough therapy."

The researchers studied mice with diabetes. The mice were given the new drug in their water. "We found that this drug restored normal blood sugar levels in the mice," said Dr. Xiao-Han Tang, an assistant research professor in pharmacology at Weill Cornell Medicine, who is an author on the paper. "And we also found that it reduced fatty liver symptoms."

The new drug, which has not been tested in humans, might have several advantages over current treatments. First, it is able to be taken orally, which makes it appealing for patients when compared to injectable diabetes medications. Second, it does not cause weight gain in mice. This is critical, said first author Dr. Steven Trasino, a postdoctoral fellow in pharmacology at Weill Cornell Medicine. "Some of the most commonly used anti-diabetes drugs cause weight gain, which can eventually make both diabetes and fatty liver worse. Avoiding that is a great advantage."

The ability to treat both of these diseases at once could result in major benefits to patients. "We think that this drug is a potential, potent anti-diabetic drug for humans," Dr. Tang said. "It's very exciting." Dr. Gudas and her team, which also includes Dr. Jose Jessurun, a professor of pathology and laboratory medicine and co-author of the paper, are making plans to bring this discovery to the clinic.

Scientists have long known that diseased cells produce proteins that help them thrive in the body. These proteins sometimes allow the cells to undermine mechanisms that the body uses to rid itself of undesired cells. Now, Weill Cornell Medicine researchers have discovered precisely how this subversion is possible — a finding that may explain how diseases like cancer flourish in the body and could lead to the development of new treatments, an avenue of research this team is now exploring.

Normal cells produce proteins using tiny particles called ribosomes. Ribosomes look for and bind to caps at the end of strand-like molecules called messenger RNA, which are copied from the DNA in the cell nucleus. These caps are recognizable because they are made of a unique nucleotide — the building block that makes up mRNA. After binding to these caps, ribosomes take genetic information from the mRNA and use it to help build proteins that healthy cells need to function, a process called translation.

In diseased cells, ribosomes don't look for these caps. Instead, the ribosomes seem to latch onto a different location on the mRNA strand and achieve translation without binding to the cap — a process called cap-independent translation. These mRNA subsets often contain instructions for making proteins that are important for diseased cells to survive and multiply. This is particularly prominent in cancer and supports the disease's growth.

Cap-independent translation is a phenomenon that scientists have observed for years but have not completely understood. In a new study, published online Oct. 22 in Cell, a team of scientists from Weill Cornell Medicine, Cornell University, and SUNY Downstate Medical Center explains how this form of translation is possible.

"Our team has uncovered a pathway through which cap-independent translation can be turned on and off, raising the possibility that diseased cells might use this mechanism to regulate the translation of specific mRNAs that are important for survival or proliferation," said senior author Dr. Samie Jaffrey, a professor of pharmacology at Weill Cornell Medicine. "This discovery has important clinical ramifications because it identifies a novel pathway that can potentially be targeted therapeutically."

The research team found that cap-independent translation relies on a small alteration in one of the nucleotides within certain mRNAs. Nearly a third of all mRNA molecules have the chemical compound methyl attached to one of the nucleotide building blocks, adenosine — a discovery Dr. Jaffrey and his colleagues made in 2012. In their latest paper, the researchers explain that this modified nucleotide, also called m6A, is responsible for cap-independent translation.

"Nucleotide m6A directly recruits the ribosome, just like the cap does," Dr. Jaffrey said. Specifically, mRNAs that have m6A within a region near the beginning of the transcript, where the translation process starts, no longer require a cap to recruit ribosomes. Additional Weill Cornell Medicine investigators who helped make this discovery include Dr. Kate D. Meyer and Dr. Deepak P. Patil, also of the Department of Pharmacology, and Dr. Olivier Elemento, of the Department of Physiology and Biophysics and the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine.

Normal cells usually contain only a few hundred mRNAs that have these special translation-promoting m6A residues. However, when researchers introduced stress to these cells, this number rapidly increased three-fold. This multiplication process may contribute to the production of proteins essential for disease progression, Dr. Jaffrey said.

"If we could develop strategies to selectively block the function of these m6A, or if we could manipulate their levels in specific mRNAs, we might have a way to halt the progression of certain diseases," added Dr. Meyer, a postdoctoral associate in Dr. Jaffrey's laboratory and the first author of the study.

The researchers are trying to understand how critical m6A-containing mRNA is for cancer survival as well as other diseases. They're also trying to block the activity of m6A to see if tumors better respond to treatment.

"The m6A nucleotide appears to have critical roles in controlling translation for certain cancer subtypes," Dr. Jaffrey said. "Identifying these cancer subtypes and how they use m6A to enable their survival will provide a completely new direction for targeting cancer and other diseases."

Researchers at Weill Cornell Medical College have discovered what they believe may be the first effective drug therapy to prevent tongue cancer, one of the world’s most common cancers. The finding is reported in the June 2 issue of PNAS.

Currently, tongue cancer is treated with radiation and surgery, which can be very disfiguring. Because the cancer is often discovered at later stages — such as when a patient has difficulty swallowing — the five-year survival rates are less than 50 percent.

"Clearly, we need a treatment that can work to help prevent development of the cancer in people at risk, reducing the need for radical surgery," said Dr. Lorraine Gudas, chair of the Department of Pharmacology at Weill Cornell.

"The two drugs we tested showed remarkable benefit in our animal studies and our animal model mirrors development of human tongue cancer. While we have much research yet to do, this is a very exciting discovery," she says.

One of the drugs, Bexarotene, is approved by the FDA to treat T-cell lymphoma. The other, CD1530, is a synthetic derivative of vitamin A, similar to a cousin vitamin A derivative that is currently used as part of a combination chemotherapy for a blood cancer, acute promyelocytic leukemia.

"This is the first time this combination of agents has been used in a solid cancer, and given the impressive results we have seen in this preclinical study, we plan to test this combination in other solid tumors," Dr. Gudas says.

In the study, mice were given a carcinogen that causes the development of tongue cancer. Mice treated with the two drugs developed 75 percent fewer tumors on average than did untreated mice. "We have never seen such a dramatic reduction in cancer that was destined to develop," Dr. Gudas says.

If clinical studies prove successful, individuals at risk for developing tongue cancer — those who smoke and drink alcohol heavily, have a family history of the disease, or develop white "leukoplakia" lesions in the mouth that can signal future development of the cancer — could be treated preventatively, Dr. Gudas says.

She says that there may be a link between the blood cancers treated by vitamin A derivatives and the tongue cancer she has been studying. In both cases their growth likely depends on cancer stem cells — and Bexarotene and CD1530 may modify specific properties of these stem cells.

"This synergistic inhibition may also work on some of the solid cancers in which cancer stem cells play a pivotal role. If the drugs work to prevent tongue cancer, they may also work to treat cancer that has already developed," she adds, "and we are currently doing those studies.

"For the first time, we may be able to develop ways not just to treat, but to prevent, tongue cancer, and that is a remarkable development in this disease."

Other authors on the study are Drs. Xiao-Han Tang, Alison M. Urvalek, Kwame Osei-Sarfo, Tuo Zhang, and Theresa Scognamiglio, all from Weill Cornell. The research was supported by the National Institute of Dental and Craniofacial Research and the National Institute on Alcohol Abuse and Alcoholism.