Losing Money, Emotions, and Evolution; Kill the Messenger; Living Microprocessor Tunes in to Feedback

Losing Money, Emotions, and Evolution

Financial loss can lead to irrational behavior. Now, research by Weizmann Institute scientists reveals that the effects of loss go even deeper: loss can compromise our early perception and interfere with our grasp of the true situation. The findings, which recently appeared in the Journal of Neuroscience, may also have implications for our understanding of the neurological mechanisms underlying post-traumatic stress disorder (PTSD).

The experiment was conducted by Dr. Rony Paz and research student Offir Laufer of the Department of Neurobiology. Subjects underwent a learning process, based on classic conditioning, that involved money. They were asked to listen to a series of tones composed of three different notes. After hearing one note, they were told they had earned a certain sum; after a second note, they were informed that they had lost some of their money; and a third note was followed by the message that their bankroll would remain the same. According to the findings, when a note was tied to gain, or at least to no loss, the subjects improved over time in a learned task – distinguishing that note from other, similar notes. But when they heard the “lose money” note, they actually got worse at telling one from the other.

Functional MRI (fMRI) scans of the brain areas involved in the learning process revealed an emotional aspect: the amygdala, which is tied to emotions and reward, was strongly involved. The researchers also noted activity in another area in the front of the brain, which functions to moderate the emotional response. Subjects who exhibited stronger activity in this area showed less of a drop in their abilities to distinguish between tones.

According to Dr. Paz, “The evolutionary origins of that blurring of our ability to discriminate are positive: if the best response to the growl of a lion is to run quickly, it would be counterproductive to distinguish between different pitches of growl. Any similar sound should make us flee without thinking. Unfortunately, that same blurring mechanism can be activated today in stress-inducing situations that are not life-threatening – like losing money – and this can harm us.”

That harm may even be quite serious; for instance, it may be involved in PTSD. If sufferers are unable to distinguish between a stimulus that should cause a panic response and similar, but non-threatening, stimuli, they may experience strong emotional reactions in inappropriate situations. This perceptional blurring may even expand over time to encompass a larger range of stimuli. Dr. Paz intends to investigate this possibility in future research.

Dr. Rony Paz’s research is supported by the Sylvia Schaefer Alzheimer’s Research Fund; the Ruth and Herman Albert Scholars Program for New Scientists; Pascal and Ilana Mantoux, Israel; the Nella and Leon Benoziyo Center for Neurological Diseases; Katy and Gary Leff, Calabasas, CA; the European Research Council; and Dr. and Mrs. Alan I. Leshner. Dr. Paz is the incumbent of the Beracha Foundation Career Development Chair.

Kill the Messenger

What’s good news in one setting might spell disaster in another. In cancer for instance, when a certain cell is commanded to grow and divide without restraint, it’s a welcome message for the cell itself but a tragedy for the person who harbors this cell in his or her body. Weizmann Institute scientists have managed to decipher and block one type of molecular message that prompts unbridled cellular growth.

The molecular message first arrives at the cell’s membrane, but its ultimate destination is the cell’s nucleus, which contains the DNA. It’s a huge distance for the message to cross, equivalent to 50 kilometers (about 31 miles) for a human being. To reach the nucleus quickly, the message is relayed by a chain of chemical messengers, from one molecule to another. More than two decades ago, Prof. Rony Seger of the Weizmann Institute’s Department of Biological Regulation took part in the discovery of one such chain – one that participates in the induction of numerous types of cancer. Among other molecules, it includes the enzymes MEK1, MEK2, ERK1, and ERK2.

At first, Prof. Seger studied the transmission of molecular messages by these enzymes in the cell’s cytoplasm. Just four years ago, he and his team succeeded in revealing the details of the later, most crucial step: the entry of the message into the cell’s nucleus. The scientists identified a segment called NTS in the enzymes. NTS undergoes a change, through the addition of phosphorus molecules, which makes the enzymes’ entry into the nucleus possible. When the team created a small peptide mimicking NTS, the message was blocked and failed to reach the nucleus. As a result, the cell stopped growing: Apparently, the peptide had intercepted the “enter the nucleus!” command. In experiments with mice, the peptide effectively blocked the development of several types of cancer, particularly melanoma; in fact, not only did the tumors stop growing, they disappeared entirely.

Prof. Seger’s findings are currently being considered for future biotechnological applications.

Prof. Rony Seger’s research is supported by the M.D. Moross Institute for Cancer Research; the Phyllis and Joseph Gurwin Fund for Scientific Advancement; and Katy and Gary Leff, Calabasas, CA. Prof. Seger is the incumbent of the Yale S. Lewine and Ella Miller Lewine Professorial Chair for Cancer Research.

Living Microprocessor Tunes in to Feedback

MicroRNAs (miRNAs) – tiny strands of non-protein-coding RNAs – start off as long strands of precursor miRNAs. These long strands get chopped up by a special kind of machinery, the “Microprocessor” complex, to transform them into their shorter functional form. The resulting miRNAs bind to messenger RNA (mRNA) molecules, inhibiting their protein production capacity and thus regulating the levels of hundreds of different proteins.

But the Microprocessor complex can also cut up other forms of RNA, including mRNAs, which sometimes generate a transient structure that resembles the target site of miRNAs. Cleaving the wrong RNAs could prove disastrous for the organism.

In a paper recently published in Nature Structural and Molecular Biology, Dr. Eran Hornstein, Prof. Naama Barkai, and former PhD students Dr. Omer Barad and Dr. Mati Mann of the Weizmann Institute’s Department of Molecular Genetics focus on understanding how the Microprocessor machinery balances the interplay between efficiency and specificity in the production of miRNAs. “On the one hand, it should not be overly efficient, as this may come at the cost of also cleaving unwanted nonspecific RNA substrates. On the other hand, it should not be too ‘picky’ because exaggerated specificity comes with the risk of not sufficiently processing genuine miRNAs,” says Dr. Hornstein.

In an interdisciplinary project, the scientists used mathematical modeling to characterize the Microprocessor system, and then tested their theories in cells. They predicted that the balance between efficiency and specificity would be maintained via a feedback loop in which the Microprocessor detects the amount of precursor miRNA available in the cell and alters its own production accordingly.

Checking this premise in mouse and human tissue, the researchers were able to show that the Microprocessor is indeed attuned to levels of precursor miRNA, upping its own production if the cell is inundated with precursor miRNA, or halting production in response to a decrease in the flow of precursors. This is achieved by the digestion of Dgcr8 mRNA, which structurally mimics miRNA. By keeping levels in line with precursor miRNAs, the Microprocessor thus reduces its chances of chopping off-target RNAs.

Since small RNAs are produced synthetically as possible new therapies for a number of diseases, this research may direct efforts to efficiently produce such therapies in the future. In addition, many other biological systems need to balance efficiency with specificity, and the team’s findings suggest that many may do so in a similar way.

Dr. Eran Hornstein’s research is supported by Dr. Sidney Brenner and Friends; the Carolito Stiftung; the Nella and Leon Benoziyo Center for Neurological Diseases; the Y. Leon Benoziyo Institute for Molecular Medicine; the Nathan, Shirley, Philip and Charlene Vener New Scientist Fund; the estate of Fannie Sherr; the estate of Lola Asseof; Maria Halphen, France; the Julius and Ray Charlestein Foundation; the Legacy Heritage Fund; the Kekst Family Institute for Medical Genetics; the David and Fela Shapell Family Center for Genetic Disorders Research; the Helen and Martin Kimmel Institute for Stem Cell Research; the Crown Human Genome Center; the Celia Benattar Memorial Fund for Juvenile Diabetes; the Fraida Foundation; and the Wolfson Family Charitable Trust. Dr. Hornstein is the incumbent of the Helen and Milton A. Kimmelman Career Development Chair.

Prof. Naama Barkai’s research is supported by the Helen and Martin Kimmel Award for Innovative Investigation; the Jeanne and Joseph Nissim Foundation for Life Sciences Research; Lorna Greenberg Scherzer, Canada; the Carolito Stiftung; the European Research Council; the estate of Hilda Jacoby-Schaerf; and the estate of John Hunter. Prof. Barkai is the incumbent of the Lorna Greenberg Scherzer Professorial Chair.