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Developing a New Picture of the Nuclear Structure
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| Discovery of a nucleus beyond the existing nucleus model | |||
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"A nucleus behaves like an egg," said Dr. Motobayashi in reply to the question as to the recent achievements of his Laboratory. However, what does he mean by saying that a nucleus is "like an egg"? All matter is made up of atoms, and an atom is made of a nucleus and electrons, and the nucleus is made up of protons and neutrons. Nuclear physics has been progressing at full steam in various ways since about 1950, and this has contributed to deepening our understanding of the atomic nucleus. "In the 1970s while I was a college student, a picture of the nucleus had already been established. It is assumed that protons and neutrons are firmly bound together by the nuclear force discovered by Dr. Hideki Yukawa, and that they move as one unit. It goes without saying that even if the number of protons is different from the number of neutrons, they have the same distribution in the nucleus. However, our research on 16C (an unstable nucleus of carbon) revealed some aspects of the nucleus that depart from the conventional wisdom of nuclear physics. It is true that in the core of the nucleus, protons and neutrons are bound together and form the shape of a ball, moving as one unit. At the periphery, however, neutrons spread out elliptically from the center, and only neutrons are observed to stay in motion, which allows us to imagine an egg with a yolk in the center and egg white at the periphery." Does this challenge the conventional picture of the nucleus? "The conventional picture is not wrong," says Dr. Motobayashi firmly. "A little while ago, our knowledge was limited only to stable nuclei. We have obtained some means of investigating unstable nuclei. Thus, new data has been found that cannot be explained by the conventional picture of the nucleus. We should say that our knowledge of the atomic nucleus has been widened." A natural nucleus does not decay into another nucleus with time. Such a "stable" nucleus is composed of almost equivalent numbers of protons and neutrons. In contrast, some nuclei emit radiations and decay into other kinds of nuclei. This nucleus is called a radioisotope (RI), or an unstable nucleus in nuclear physics. In the unstable nucleus, the numbers of protons and neutrons are weighted extremely toward one or the other. For example, 16C is composed of 6 protons and 10 neutrons. Thus 16C is an unstable nucleus with four more neutrons than protons. "It has been considered that the unstable nucleus has a different structure from that of the stable nucleus and hence it exhibits different phenomena. At that time, however, there was no means to confirm the fact. It was in the 1980s that RI beam appeared as a useful tool to study the unstable nucleus." When target nuclei are bombarded with a beam of stable nuclei accelerated to 40% of the speed of light or faster, various unstable nuclei can be produced because the beam strips off a part of the nuclei. Some of these unstable nuclei can be separated to form a special beam called an 'RI beam.' The RI beam can be used to study the structures and properties of the unstable nucleus by bombarding familiar nuclei with the beam and investigating the responses. So far, a dozen unstable nuclei have been newly discovered with the RIKEN heavy ion accelerator Ring Cyclotron. The structures and properties of many unstable nuclei have also been studied. Some abnormal nuclei structures, other than 16C, that can challenge the conventional picture of nuclear structure have been found (Figure 1). "Some nuclei with their neutrons spreading peripherally have been found; the ones with widely-distributed neutrons are said to have a 'neutron-halo,' and the ones with surrounding neutrons like a skin are said to have a 'neutron-skin.' The nucleus 16C was found as an extension of such unstable nuclei. The discovery of 16C, however, has a very significant meaning in that it was clarified that unstable nuclei with more neutrons show singular phenomena not only in their distribution but also in shape and motion." Dr. Motobayashi thinks that there must be some other mysterious phenomena occurring at the periphery of unstable nuclei with widely-distributed neutrons. "We know that a special phenomenon like superconductivity is occurring in the nucleus, although its scale is different. Just as two electrons form a Cooper pair in the state of superconductivity, two protons or two neutrons form a pair in a larger volume, and move in relation to each other. However, at the periphery of the nucleus, it seems that the neutron pair moves as a compact pair. We would like to clarify this fact."
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| Completion of the RI beam factory in 2006 | |||
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"We may have found only a small part of the nucleus. If we generate many more unstable nuclei with extremely large numbers of neutrons and take a survey of them from every angle, we may be able to develop a new picture of the nuclear structure, and that is our research target. We believe that the RI Beam Factory (RIBF), which is under construction at the RIKEN Wako Laboratory, will help us fulfill our object. The RIBF will be completed in 2006. At the end of the year, the first beam will be generated. Dr. Motobayashi says, "The RIBF Heavy Ion Accelerator is capable of providing the world's strongest heavy ion beams of all elements from hydrogen to heavy elements such as uranium. Thus, we will be able to obtain many more kinds of unstable nuclei. Theoretically, about 10,000 kinds of nuclei are predicted. The RIBF is capable of producing 3,000 or more kinds of unstable nuclei (Figure 2). The wider the domain we can cover, the more accurate the nuclear picture we can develop." Widening the kinds of nuclei generated will surely contribute to clearing up the mystery of the origins of elements. First of all, just after the Big Bang, hydrogen and helium, and lithium were created. Then, more elements were created inside fixed stars that were made up of these elements. However, what are the processes by which the elements heavier than iron were created? The question still remains a mystery. So far, the hypothesis of uranium synthesis is popular, which says that in only one second after the supernova explosion, the unstable nuclei indicated by the green arrows in Figure 2 were created, and that the unstable nuclei then beta-decayed into elements up to uranium. "We human beings have never created even a single unstable nucleus that can be considered to be synthesized by the supernova explosion. Under such circumstances, nothing definite can be said." The RIBF is capable of producing a beam of uranium nuclei. Thus, it is capable of producing the unstable nuclei that are considered to be generated by the supernova explosion. With the RIBF, we can study the properties of unstable nuclei such as life-time, mass, and the processes through which they decay into stable nuclei. The unstable nuclei are expected to serve to ascertain the truth of the hypothesis of uranium synthesis. Inquiring into the origins of elements is one of the major challenges with the RIBF.
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| Exploring nuclear reactions in astronomical objects by Coulomb dissociation | |||
In space, there is what we call neutron stars that are composed of only neutrons. What kind of nuclear reaction is taking place on the surface of neutron stars? This is another major challenge to the Laboratory. "Using the RI beam, we successfully observed nuclear reaction processes occurring in such astronomical objects for the first time in the world," says Dr. Motobayashi. On the surface of neutron stars, a nuclear reaction is occurring, in which unstable nuclei combine with protons to emit gamma rays. To study the reaction, Dr. Motobayashi selected a unique method, which is referred to as "Coulomb dissociation." Coulomb dissociation happens when the RI beam passes very close to a heavy nucleus such as lead, and the nuclei of the RI beam disintegrate after absorbing virtual photons, or gamma rays, radiated from the heavy nucleus (Figure 3). This nuclear reaction, however, is the opposite of what is occurring on the surface of neutron stars. "In physics, we know the principle of time reversal invariance. We can tell what happened by reversing time," explains Dr. Motobayashi. "The possibility of Coulomb dissociation was propounded in the 1930s by Dr. Enrico Fermi, who won the Nobel Prize in 1938, and since by other scientists. For the first time in the world, we succeeded in putting this theory into actual practice in the nuclear reaction occurring in astronomical objects. This kind of pioneering work is really exciting." In his Laboratory, the Coulomb dissociation technique is also used to carry out investigations into the solar-neutrino-creating nuclear reactions. This method can also be used to slightly increase the internal energy of a nucleus, to the extent that the nucleus does not disintegrate. This is what we call 'Coulomb excitation.' Since the excited nucleus vibrates or rotates, we can tell its nuclear structure by investigating its motion in detail. It is by this Coulomb excitation that we succeeded in clarifying the fact that 16C has an egg-like-shaped excited state. "Coulomb dissociation and Coulomb excitation have also drawn the attention of overseas institutions such as Michigan State University (MSU) in the U.S. and the Heavy Ion Research Laboratory (GSI) in German. They have started experimenting, but our Laboratory is ahead of them. When the RIBF is completed, we will be able to further outdistance competing institutions," says Dr. Motobayashi, with the confidence of the originator. The MOTOBAYASHI Heavy Ion Nuclear Physics Laboratory will become busier and busier to prepare for the first experiment in 2007. "The RIBF is capable of providing the world's best performance. To produce results, however, excellent observational instruments well-adapted to the characteristics of the RIBF are indispensable. For example, we have to renew DALI, which can capture gamma rays radiated from unstable nuclei moving at 60% of the speed of light, and which is used to study nuclear structures. We are now designing a new DALI for the RIBF (upper portion of the cover). It is tough work to develop these devices, but we consider this is the best part of experimental physics." With the launch of the RIBF, the realm of nuclear physics is sure to expand. What will we see from there? We look forward to the year 2007 and later. 
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Using a beam of unstable nuclei (RI beam) generated by the world-top-class RIKEN Heavy Ion Accelerator Research Facility, the Heavy Ion Nuclear Physics Laboratory aims at clearing up the mystery of nuclear structure and origins of elements. "We tend to think that we have understood the atomic nucleus. However, we still have insufficient knowledge of its structure. It is said that half of atomic nuclei heavier than iron (up to uranium) were generated by the supernova explosion. However, nobody has ever confirmed how these nuclei have been generated," says Dr. Motobayashi, Chief Scientist. "We want to understand the true nature of the atomic nuclei and to develop a new picture of the nuclear structure." In 2006, the RI Beam Factory (RIBF), the next generation heavy ion accelerator research facility, will be put into operation. The new nuclear structure is becoming a real possibility. Here, we asked him about the future of the nuclear structure and how the RIBF will serve to develop it.
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Challenging AIDS
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| I want to save the lives of animals! | |||
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Aida talks about her early days: "My father was a technical officer in animal breeding at Japan's Ministry of Agriculture, Forestry, and Fisheries. Before I was born, he retired from the post and opened up a racehorse breeding and yielding in Aomori Prefecture with the aim of giving shape to his long-cherished dream of producing a fast horse. His farm was located in the snowy backcountry, where the horse sledge was the only means of traffic available in winter. I was born and grew up on a farm. Devoting himself to his work, my father often said, 'breeding a fast horse is an art.' I grew up seeing my father working at the risk of his life." After Aida had entered the faculty of veterinary medicine at university, she encountered an event that had a big effect on her. "In 1976, when a racehorse bred by my father won the year's race for the Kikkasho (Chrysanthemum Prize), one of Japan's top horse races, I watched a shocking video film reporting on the outbreak of foot-and-mouth disease in the UK. Foot-and-mouth disease is a dreadful viral infection, which is transmitted to even-toed ungulates such as cattle and sheep at the greatest speeds, resulting in major economic losses. Not only the infected animals, but also all animals that might be infected with the pathogen within a radius of several tens of kilometers of the point of outbreak were slaughtered and their carcasses burnt. Until then, I had been ready to take over from my father, whom I had great respect for, but I wept tears of sadness on seeing the animals being burnt one after another, and I decided to become a veterinary virologist and work to save the lives of animals." |
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| Aiming at producing disease-resistant livestock | |||
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Aida has been engaged in research into bovine leukemia virus (BLV) since she was a graduate school student. BLV remains latent for about 10 years after infecting cattle. The virus then transforms B lymphocytes, a type of immune cells, into cancer cells, which in turn cause enzootic bovine leukosis. BLV is prevalent all over the world. In Japan as well, many cattle have been infected with the virus. After onset, BLV-induced leukemia is always fatal to the infected animal because of a lack of a therapy, causing vast economic damage and ensuing social concern. It should be noted, however, that the ratio of BLV-infected cattle that develop leukemia is about two to three per 100 animals. "I began studying this virus with the expectation that predicting which cattle would develop the disease would be enormously helpful to livestock farmers." Aida discovered a protein appearing in BLV-transformed cells (tumor-associated antigen = tumor marker) and succeeded in preparing an antibody that recognizes the protein. She also demonstrated that infected cattle with an antibody reactivity exceeding a particular level are highly likely to experience leukemia in the space of several years. Additionally, she showed experimentally that it is possible to save their lives by using this antibody to deliver a therapeutic drug to the cancer cells, and to destroy the cells. For this work, Aida received her doctoral degree in veterinary medicine. Later, Aida became a research fellow at RIKEN and restarted her research into BLV around 1989. She identified the tumor-associated antigen she discovered to be a protein called major histocompatibility complex (MHC) class IIDR. Upon entry into the body, the virus is engulfed by antigen-presenting cells (APC), processed and then parts of virus are displayed on surface of APC together with MHC. As a result, the immune system is activated to eliminate the virus and infected cells. As such, MHC has genetic variation of genes that differ with the individual and is termed 'polymorphism'. Aida and others determined polymorphism in the genes for bovine MHC molecules using their own method, and demonstrated the presence of not only alleles that were associated with susceptibility to development of BLV-induced leukemogenesis, but also alleles associated with resistance. It is postulated that this type of MHC presents the particular peptides derived from BLV to the immune system and induces a strong immune response to significantly eliminate BLV, thus preventing leukemogenesis. Furthermore, Aida and others are willing to develop this work to produce disease-resistant livestock. "If an allele of MHC gene of high reactivity not only to BLV but also commonly to bacteria and viruses that cause major infectious diseases is discovered, it would be possible to breed disease-resistant livestock retaining such a gene which would exhibit excellent immune potential. The achievement should contribute to the creation of a safe secure environment without the need for vaccination or the administration of antibiotics." |
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| Vpr, a key to AIDS pathogenesis | |||
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BLV is classified as a 'retrovirus' because it is an RNA virus having reverse transcriptase. In 1980, the human adult T cell leukemia virus (HTLV) was discovered as the first human retrovirus. BLV is the virus most closely related to HTLV. Human immunodeficiency virus type 1 (HIV-1), an AIDS-causing virus discovered in 1983, is also a retrovirus. "With my long career in research into BLV and other animal-infecting retroviruses, I was willing to concentrate my energy on my research to conquer AIDS" says Aida looking back on the past. She commenced her research into HIV-1 in 1996. Currently, there are about 42 million people infected with HIV-1 worldwide, with about five million newly infected and about three million dying from AIDS every year. The number of orphans who have lost their parents due to AIDS is estimated to be about fifteen million. The majority of the damage occurs in African countries south of the Sahara Desert. The loss of the main supporter in many families and society due to AIDS is aggravating Africa's issues of poverty. Conquering AIDS is mankind's most important issue. HIV-1 infects particular types of cells in the immune system. Subsequently, the virus is replicated in numerous copies in the infected cells; the infection expands increasingly and destroys the immune system, resulting in the onset of AIDS. At present, even if an HIV-1 infection occurs, it is possible to inhibit the virus' replication using highly active anti-retroviral therapy (HAART) to delay the progression of AIDS. However, there are some cases in which the drug soon becomes ineffective due to the rapid mutation of the virus, or adverse drug reactions appear. AIDS cannot be conquered unless the unknown replication mechanism of HIV-1 is clarified and a drug with a new action point is developed. Aida focused on a group of genes of HIV-1 known as "accessory genes." Accessory genes had been considered to be literally "accessories" and unnecessary for viral replication. "We introduced various accessory genes to cells one after another and cultured the cells in Petri dishes for two weeks, then examined them using a microscope. Cells were transfected with the accessory gene vpr were found to have transformed into giant cells several times as large as ordinary cells (Figure 1). I cried in spite of myself, "I did it!" At that moment, I realized intuitively that the thing that causes the most dramatic change to the host cells parasited by the virus would lead to a great discovery." Each HIV-1 is an enveloped virus with a viral core containing two identical RNA (Figure 2). Vpr protein, produced by the vpr gene, is contained in HIV-1 particles along with RNA and reverse transcriptase. Upon adsorption and entry into cells, HIV-1 puts off its protein coat to become naked RNA. This is followed by production of DNA from the RNA by the action of reverse transcriptase. The resulting DNA enters the nucleus (nuclear localization) and is integrated in the cell's DNA. Based on the DNA of viral origin, RNA is transcribed, followed by splicing and translation, resulting in the production of RNA and protein HIV-1, which constitute the virus. Subsequently, these components assemble, and numerous HIV-1 particles are replicated at one time, released outside the cells (budding), and infect other cells one after another. Cells grow through the cell cycle that proceeds in the order of G1 phase in preparation for DNA replication, S phase for DNA replication, G2 phase for checking prior to cell division, and M phase for cell division, and the expression of the HIV-1 genome is maximal during the G2 phase of the host cell cycle. In 1998, a research group released a paper showing that Vpr inhibits cell proliferation by arresting the cell cycle at the G2 phase, suggesting Vpr to be a key to AIDS pathogenesis. "We had realized that the giant cells produced by Vpr are also a result of the arrest of the cell cycle at the G2 phase by Vpr, but we lagged behind them," says Aida regretfully. Aida and others continued exploring unknown functions of Vpr.
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| Success in experiments for AIDS gene therapy | |||
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Aida and others discovered a phenomenon in which Vpr inhibits the cell cycle at the G1 phase and causes apoptosis (programmed cell death) in mouse cells. "To verify the occurrence of this phenomenon in human cells, we produced various mutants of Vpr and performed experiments for their expression in human cells. As a result of a vast amount of laboratory work, including all-night experiments, we found that the mutant C81 can induce cell cycle arrest at the G1 phase in human cells, thus inducing apoptosis (lower panel on the cover)." As such, C81 may be specifically expressed in HIV-1-infected cells to induce apoptosis and completely eliminate the virus from the infectee's body, in order to prevent the pathogenesis of AIDS. "We developed a vector (carrier) capable of introducing C81 selectively to HIV-1-infected cells and administered it to monkeys in a gene therapy experiment. The level of viral load decreased until zero. Now, we are working to find applications for humans." |
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| The fight against emerging viruses | |||
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Currently, about 30% of mortalities worldwide are associated with infections, and it is feared that the ratio may rise abruptly to an extent that threatens the survival of humankind in the future. This is because what are called emerging viruses, such as HIV-1, the Ebola virus, and SARS coronavirus, have recently emerged one after another, and also because development of traffic networks may promote the rapid expansion of affected areas. Are there any means available of fighting against these emerging viruses? "It is extremely difficult to fight against individual emerging viruses. Different viruses have different replication mechanisms, which, however, should share an unknown portion. The common mechanism must be the target of the research." At present, Aida and others are focusing on the splicing and nuclear import processes in the common mechanism. Although some viruses do not show nuclear import, all DNA viruses except for poxviruses such as the hepatitis B virus, and several RNA viruses such as retrovirus and influenza virus, show nuclear import. Aida and others discovered that the binding of Vpr to the nuclear envelope and then to intracellular protein (importin a) is essential to the nuclear import of HIV-1. They also confirmed that when the binding is inhibited, HIV-1 is no longer capable of infecting a type of immune system cells known as a macrophage. Furthermore, Aida and others discovered that Vpr could inhibit the splicing of cellular pre-mRNA and the HIV-1 genome by binding to the intracellular protein SAP145. It should be possible to prevent HIV-1 replication using the inhibition of its function. "With the reliance of viral growth on the host cells in mind, I am planning to develop an AIDS remedy based on my own idea for targeting the interaction between viral and host proteins. In the future, I want to further investigate the mechanisms, including nuclear import and splicing, and to clarify the replication mechanism commonly found in many viruses, and create a drug targeting this point of action to combat emerging viruses." Aida and others are continuing to work at the frontiers of the fight against viruses.
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"The 21st century must be the century in which man fights the viruses that threaten our fate," says Yoko Aida, Unit Leader of the Retrovirus Research Unit at Discovery Research Institute. Currently, infections account for about 30% of annual mortalities worldwide, and it is feared that the ratio may rise abruptly in the future. This is because new viral infections have recently emerged one after another. One representative of such infections is AIDS, which kills about three million people every year. As a virologist with a long career in research into bovine leukemia virus (BLV) and other viruses, Aida is concentrating her energy on her research to conquer AIDS. Furthermore, in preparation for the coming threats from newly-emerging viruses, she is willing to develop a new drug targeting a replication mechanism shared by many viruses.
