Observed: The Outburst Before the Blast; Two Antibodies Are Better Than One; A Genetic Device Performs DNA Diagnosis

Observed: The Outburst Before the Blast

Before they go all-out supernova, certain large stars undergo a sort of “mini-explosion,” throwing a good-sized chunk of their material off into space. Though several models predict this behavior and evidence from supernovae points in this direction, actual observations of such pre-explosion outbursts have been rare. In new research led by Dr. Eran Ofek of the Weizmann Institute of Science, scientists found such an outburst taking place a short time — just one month — before a massive star underwent a supernova explosion.

The findings, which recently appeared in Nature, help to clarify the series of events leading up to the supernova, as well as provide insight into the processes taking place in the cores of such massive stars as they progress toward the final stage of their lives.

Dr. Ofek, a member of the Institute’s Department of Particle Physics and Astrophysics, is a participant in the Palomar Transient Factory (PTF) project (led by Prof. Shri Kulkarni of the California Institute of Technology), which searches the skies for supernova events using telescopes at the Palomar Observatory in California. He and a research team from Israel, the UK, and the US decided to investigate whether outbursts could be connected to later supernovae by combing for evidence of them in observations that predated PTF supernova sightings, using tools developed by Dr. Mark Sullivan of the University of Southampton (UK).

The fact that the team found such an outburst occurring just a little over a month before the onset of the supernova explosion was something of a surprise, but the timing and mass of the ejected material helped them to validate a particular model that predicts this type of pre-explosion event. A statistical analysis showed that there was only a 0.1% chance that the outburst and supernova were unrelated occurrences.

The exploding star, known as a type IIn supernova, began as a massive star, at least eight times the mass of our sun. As such a star ages, the internal nuclear fusion that keeps it going produces heavier and heavier elements — until its core is mostly iron. At that point, the weighty core quickly collapses inward and the star explodes.

The violence and mass of the pre-explosion outburst they found, says Dr. Ofek, indicate a source in the star’s core. The material is speedily ejected from the core straight through the star’s surface by the excitation of gravity waves. The researchers believe that continued research in this direction will show such mini-explosions to be the rule for this type of supernova.

Also participating in this research were Prof. Avishay Gal-Yam, Dr. Ofer Yaron, and Iair Arcavi of the Institute’s Department of Particle Physics and Astrophysics, and Prof. Nir Shaviv of the Hebrew University of Jerusalem.

Prof. Avishay Gal-Yam’s research is supported by the Helen and Martin Kimmel Award for Innovative Investigation; the Nella and Leon Benoziyo Center for Astrophysics; and the Lord Sieff of Brimpton Memorial Fund.

Dr. Eran Ofek’s research is supported by the Willner Family Leadership Institute. Dr. Ofek is the incumbent of the Arye and Ido Dissentshik Career Development Chair.

Two Antibodies Are Better Than One

A new approach mimicking the body’s natural defenses could help treat a therapy-resistant breast cancer.

Cancer drugs of the new molecular generation destroy malignant breast tumors in a targeted manner: They block characteristic molecules on tumor cells — receptors for the hormones estrogen or progesterone, or a co-receptor, called HER2, that binds to many growth factors. But about one in every six breast tumors has none of these receptors. Such cancers, called triple-negative, are particularly aggressive and notoriously difficult to treat.

Some of these therapy-resistant cancers have a potential molecular target for cancer drugs, a growth-factor receptor called EGFR, but an EGFR-blocking drug has proved ineffective in treating them. In a study published recently in the Proceedings of the National Academy of Sciences, Weizmann Institute researchers propose a potential solution: to simultaneously treat triple-negative breast cancer with two EGFR-blocking antibodies instead of one. In a study in mice, the scientists showed that a certain combination of two antibodies indeed prevented the growth and spread of triple-negative tumors. The research team, led by Prof. Yosef Yarden of the Department of Biological Regulation and Prof. Michael Sela of the Department of Immunology, included Drs. Daniela Ferraro, Nadège Gaborit, Ruth Maron, Hadas Cohen-Dvashi, Ziv Porat, Fresia Pareja, and Sara Lavi, as well as Dr. Moshit Lindzen and Nir Ben-Chetrit.

Of the different combinations they tried, the scientists found that the approach worked when the two antibodies bound to different parts of the EGFR molecule. The combined action of the antibodies was stronger than would have been expected by simply adding up the separate effects of each. Apparently, the use of the two antibodies created an entirely new anti-cancer mechanism: In addition to blocking the EGFR and recruiting the help of immune cells, the antibodies probably overwhelmed the EGFR by their sheer weight, causing it to collapse inward from the membrane into the tumor cell.

Deprived of EGFR on its surface, the cells were no longer receiving the growth signals, preventing the growth of the tumor. This approach resembles the natural functioning of the immune system, which tends to block essential antigens at several sites by targeting them with multiple antibodies. If supported by further studies, the two-antibody approach, in combination with chemotherapy, might in the future be developed into an effective treatment for triple-negative breast cancer.

Prof. Michael Sela is the incumbent of the W. Garfield Weston Professorial Chair of Immunology.

Prof. Yosef Yarden’s research is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; the M.D. Moross Institute for Cancer Research; the Steven and Beverly Rubenstein Charitable Foundation, Inc.; Julie Charbonneau, Canada; the European Research Council; and the Marvin Tanner Laboratory for Research on Cancer. Prof. Yarden is the incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology.

A Genetic Device Performs DNA Diagnosis

Scientists hope that one day in the distant future, miniature, medically savvy computers will roam our bodies, detecting early-stage diseases and treating them on the spot by releasing a suitable drug, without any outside help. To make this vision a reality, computers must be sufficiently small to fit into the body’s cells. Moreover, they must be able to “talk” to various cellular systems. These challenges can be best addressed by creating computers based on biological molecules such as DNA or proteins. The idea is far from outrageous; after all, biological organisms are capable of receiving and processing information, and of responding accordingly, in a way that resembles a computer.

Researchers at the Weizmann Institute of Science have recently made an important step in this direction: They have succeeded in creating a genetic device that operates independently in bacterial cells. The device has been programmed to identify certain parameters and mount an appropriate response.

The device searches for transcription factors — proteins that control the expression of genes in the cell. A malfunction of these molecules can disrupt gene expression. In cancer cells, for example, the transcription factors regulating cell growth and division do not function properly, leading to increased cell division and the formation of a tumor. The device, composed of a DNA sequence inserted into a bacterium, performs a “roll call” of transcription factors. If the results match preprogrammed parameters, it responds by creating a protein that emits green light — supplying a visible sign of a “positive” diagnosis. In follow-up research, the scientists — Prof. Ehud Shapiro and Dr. Tom Ran of the Department of Biological Chemistry and Computer Science and the Department of Applied Mathematics — plan to replace the light-emitting protein with one that will affect the cell’s fate; for example, a protein that can cause the cell to commit suicide. In this manner, the device will cause only “positively” diagnosed cells to self-destruct.

In the present study, published in Nature’s Scientific Reports, the researchers first created a device that functioned like what is known in computing as an NOR logic gate: It was programmed to check for the presence of two transcription factors and respond by emitting a green light only if both were missing. When the scientists inserted the device into four types of genetically engineered bacteria — those making both transcription factors, those making none of the transcription factors, and two types making one of the transcription factors each — only the appropriate bacteria shone green. Next, the research team — which also included graduate students Yehonatan Douek and Lilach Milo — created more complex genetic devices, corresponding to additional logic gates.

Following the success of the study in bacterial cells, the researchers are planning to test ways of recruiting such bacteria as an efficient system to be conveniently inserted into the human body for medical purposes (which shouldn’t be a problem; recent research reveals there are already 10 times more bacterial cells in the human body than human cells). Yet another research goal is to operate a similar system inside human cells, which are much more complex than bacteria.

Prof. Ehud Shapiro’s research is supported by the Paul Sparr Foundation and the European Research Council. Prof. Shapiro is the incumbent of the Harry Weinrebe Professorial Chair of Computer Science and Biology.