The first annual symposium of the Harvard Medical School–Portugal Program, held in mid-December in Lisbon, cast light on key areas of clinical and translational science: aging, cancer, viral infection, the role of adipose tissue, brain disorders, malaria, and others. The event drew doctors, researchers and a large segment of students from Portuguese medical schools. One of the goals was to show students that translational and clinical research is a valuable professional option. Summaries of the talks appear below.
Cancer and AgingThe genetic differences between mice and humans can be exploited to understand some of the deepest mysteries of human cancers, said Ronald DePinho, the first speaker of the conference, whose talk was titled “Telomeres in Cancer and Aging.” To underscore the importance of the topic, DePinho, HMS professor of medicine (genetics) at Dana-Farber Cancer Institute, pointed to the 2009 Nobel Prize in Physiology or Medicine that went to three researchers (one from HMS) who had discovered the way telomeres protect chromosomes. Serving as caps at the chromosome tips, telomeres prevent chromosomes from serious damage when the DNA is copied during cell division.
Yet even when telomeres and the enzyme that maintains them, telomerase, function normally, chromosomes gradually wear down with age. This degradation eventually results in the natural elimination of compromised cells through programmed cell death, senescence and metabolic reprogramming. If the safeguards against telomere damage do not kick in, these cells continue to proliferate and accumulate genomic alterations. The result is cancer, common in aged humans. Such tumors often arise from epithelial cells, which line structural surfaces and cavities in the body, and affect the skin, breast, prostate, lung and colon. On the other hand, when the safeguards do take effect, the result can be equally devastating, giving rise to age-related diseases, organ degeneration and aging.
In mice, DePinho explained, telomeres are longer than in humans, and, unlike humans, the rodents rarely suffer from cancers linked to the shortening of telomeres and faulty chromosomal duplication. Researchers led by DePinho engineered mice without telomeres or with shorter telomeres. The animals still did not develop epithelium-based cancers unless they were crossed with mice that lacked the tumor suppressor protein p53, a trigger for programmed cell death and senescence. Since humans with intact p53 do develop these cancers, the finding suggests that humans are prone to a disease process involving telomere degradation that mice are not.
DePinho’s team also discovered that development of tumors depended on chromosome breakage and amplification of specific genes, aberrations that precede extensive cancer growth and that may hold promise for early detection.
Facets of Immune Cell GrowthIn a mouse study that changed the way she looks at the natural cycle of cell division, Benedita Rocha explored the role of the cell cycle protein cyclin D1 and the two closely related cyclins, D2 and D3. She and her colleagues worked in lymphocytes, immune cells that arise from the blood and replicate dramatically in response to an attack on the body. The team silenced either the complete gene for cyclin D1 or only a portion of it, leaving intact the domains known to regulate the transcription of other genes. The researchers found that the total absence of D1 blocked the formation of blood cells, or hematopoiesis, and most mice died. But the activation of just the regulatory domains of D1 led to an extraordinary amplification of hematopoietic cells. Her talk, “The Role of Cyclin D1 in Lymphopoiesis,” demonstrated the complexity of cyclin D1’s role in hematopoiesis, in general, and in lymphocyte replication, in particular. A Portuguese scientist, Rocha is based at the Necker Institute in the Medical Faculty of Paris.
For the last 20 years, Adriano Aguzzi has been passionate about prions, a group of infectious agents behind mad cow disease and other animal and human disorders. His talk, “Molecular Biology on Prions,” was the result of these two decades of work, which he continues at the Institute of Neuropathology, University Hospital of Zurich. Prion proteins, whose discovery netted a University of California, San Francisco researcher the 1997 Nobel Prize in Physiology or Medicine, have been found to have a normal function in yeast and other organisms. Yet abnormal prions are able to cause misfolding of normal prion proteins in the brain, leading to nerve cell damage and death. The latest studies by Aguzzi’s team have aimed at understanding how prions reach the brain. It was already known that B lymphocytes are important to this process. The team discovered that prions pass from this type of immune cell to another—follicular dendritic cells. The only prerequisite is an infection in the body since infection brings these immune-cell types together, allowing prions to be transferred and carried by the follicular dendritic cells to the brain. How disease develops in the brain is a question for further research.
Stress on the BrainBased at the University of Minho in Portugal, Nuno Sousa focuses his research on chronic stress. In his talk, “The Stressed Brain,” he described changes that chronic stress causes in the brain due to increased production of corticosteroids. In humans, the primary stress hormone is cortisol, which binds to glucocorticoid receptors in the hippocampus, a brain center for memory, learning, and spatial navigation. This action leads to a reduction in volume of the hippocampus. Working in rats, the researchers found that among the behavioral changes in animals under stress was a loss of spatial memory. The team determined that the cause of the behavioral changes and volume decline was not cell death but nerve cell atrophy. In this region, the signal-receiving branches of the cells, or dendrites, become smaller and less complex.
The team also studied the effects of stress on other brain regions. The scientists discovered that changes progress from the hippocampus to closely connected areas, particularly the prefrontal cortex and striatum. In these brain regions, however, changes are remarkably distinct: in the prefrontal cortex and dorsomedial striatum, there is decreased volume without loss of neurons; but in the dorsolateral striatum, there is increased volume due to hypertrophy of dendrites. Sousa and his colleagues showed that these modifications in the corticostriatal circuits triggered by chronic stress bias the animals’ decision-making processes toward habitual behavior, a finding relevant to several neurological and psychiatric disorders in humans.
Fortunately, said Sousa, the research also showed that some of the effects of chronic stress can be reversed.
Judy Lieberman works with RNA interference (RNAi), a technology that utilizes small RNA molecules that bind to the messenger RNA of any given gene being translated into protein, preventing completion of this process and thereby turning down expression of the gene. In a talk titled “Silencing Sexual Transmission of HSV-2 and HIV,” she outlined her progress in using this technology against HIV and herpes simplex virus type 2 (HSV-2). Lieberman, an HMS professor of pediatrics in the Program in Cellular and Molecular Medicine and the Immune Disease Institute at Children’s Hospital Boston, applied RNAi to a gene that activates death of liver cells in a mouse model of hepatitis. The mice survived a typically fatal hepatitis challenge, indicating that the RNAi had succeeded in shutting down the cell death mechanism.
Lieberman and her colleagues then aimed at exploiting RNAi in developing a therapy that would prevent vaginal transmission of the AIDS virus. The goal was to silence the gene for a host cell membrane protein, CCR5, used by the virus to infect helper T cells and macrophages of the immune system. Experiments in human cells were encouraging.
To further test the approach, the team again turned to an animal model. Since HIV and herpesvirus have similar routes of infection, the researchers developed and tested a topical treatment based on RNAi in mice challenged with herpesvirus. The researchers targeted two genes, one used by the virus to enter cells, and the other used for replication once inside. The experiments yielded promising results, largely preventing HSV-2 transmission to the animals. Yet the approach that protected mice from herpes turned out not to work for HIV. Lieberman’s laboratory has now developed a new method to silence genes in immune cells that looks very promising—it inhibits HIV transmission to vaginal tissue explants.
Hot Topic in Fat ResearchIn his talk, “Brown Adipose Tissue: Location, Significance and Health Implications,” Aaron Cypess explained the recent discovery of brown fat in healthy adults. Unlike white fat, brown fat burns energy and generates heat. Its name derives from the many iron-rich mitochondria contained in each cell, which function like furnaces to produce the heat while consuming calories. Usually associated with animals and human babies, brown fat was thought to be insignificant in human adults. But Cypess, an HMS instructor in medicine at Joslin Diabetes Center, and others have shown that the tissue is, indeed, present in adults, accumulating near the kidneys, under the collarbones and in the neck. The cold-activated tissue is important for maintaining body temperature and may be more plentiful in people under colder conditions, in women, and in people who are leaner or younger. Interest in brown fat has now turned toward exploring ways to manipulate it for treating obesity and obesity-related diseases.
Malaria’s Big PictureMaria Mota has spent many years investigating malaria, a disease that kills more than a million children annually. In her talk, “Approaching Malaria from Various Angles,” Mota reviewed the last five years of her work, stressing the importance of the different phases of the malaria parasite’s life cycle in the human body. The parasite, of the genus Plasmodium, needs to jump from mosquito to human and back to mosquito to complete its development. In the human host, the plasmodium has multiple states and, until now, researchers have tended to focus on just one. But Mota, who works at the Instituto de Medicina Molecular in Lisbon, has shown that the phases in the human body are interconnected, and it is necessary to study the interactions between phases to understand the disease as a whole.
Studying a mouse model of infection, Mota and her colleagues are concentrating on infection of the liver, the first stop the plasmodium makes after being injected into the skin by a mosquito. The scientists are exploring the molecular steps the parasite takes to replicate at this early stage. Quashing the parasite at this point would be a medical coup since it is in the liver that it undergoes explosive replication—by a factor of 30,000 in 48 hours—in preparation for migration to red blood cells. It is infection of the red cells that leads to serious symptoms of disease.
Breaking Down MalariaMalaria was also the focus of the last talk, “A 21st Century Solution for an Ancient Disease.” Dyann Wirth presented new strategies to fight malaria after first discussing the history of malaria drugs. With each new drug, from quinine to artemisinin, the parasite that causes the disease, of the genus Plasmodium, has gained resistance ever more quickly. Wirth, the chair of the Department of Immunology and Infectious Diseases and the Richard Pearson Strong professor of infectious diseases at Harvard School of Public Health, belongs to a network of researchers that has sequenced the parasite genome and investigates the genetics of malarial infection. She described her recent work in delineating the genetic history of the parasite and the genes that have changed less over the past million years. She advocates developing drugs that attack the proteins coded by these conserved genes, which are involved in basic cellular metabolism, in the belief that they will remain effective for a longer period of time.
