Duplicate Systems May Be Part of Brain Design
If you’re building an automobile, redundancy is a key design concern. When the brakes fail, it’s nice to have a backup. But what about when building a brain? While neuroscientists know many things about how neurons propagate signals, they do not know how much brain circuitry carries duplicate signals and, when it does, they do not always know why.
Eavesdropping on Neural Neighbors
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New work from the lab of Rachel Wilson, HMS associate professor of neurobiology, provides new insight into the mechanisms and functions of redundancy in the brain. The work, accomplished using novel and meticulously precise techniques (see sidebar), suggests a new twist to a longstanding theory that the brain tends to minimize redundancy in the way information is processed and stored. “Biological systems are not so different from systems designed by humans,” said Wilson. “Some redundancy is useful. It’s a tradeoff between efficiency and robustness.”
Wilson and first author research fellow Hokto Kazama recorded neural signals between pairs of neurons in the olfactory system of the fruit fly Drosophila. Because the fly brain contains only 100,000 neurons (the human brain contains 100 billion), it is a useful test bed for investigating neural circuits. Moreover, unique genetic tools available in the fly olfactory system allow researchers to label certain types of neurons with fluorescent markers so they can specifically record from those cells. Recording multiple neurons at once allowed Wilson and Kazama to measure whether the electrical signals in these brain cells are independent or redundant.
They found, surprisingly, that many pairs of neurons carry highly redundant signals about the olfactory environment. In addition, neurons carrying redundant signals send this information to two distinct higher brain regions. In one of these regions, the redundant signals converge onto neurons that may exploit the replication for error checking. For instance, if the same faint signal comes in on multiple inputs, it is likely to reflect a real odor, not merely electrical noise.
Redundancy might be a useful safety factor,” said Wilson. “We think this brain region is very good at detecting weak signals in an ambiguous environment.”
In a second brain region, the redundant signals appear to be distributed to distinct destinations. “Instead of error correction, this may help propagate the signal to a bunch of different places,” said Wilson.
These findings, described in the September Nature Neuroscience, are reminiscent of results seen in the retina, where signals are initially received and integrated for vision, suggesting that redundancy might be a fundamental design principle for the earliest stages of sensory processing.
Students may contact Rachel Wilson at rachel_wilson@hms.harvard.edu for more information.
Conflict Disclosure: The authors declare no conflicts.
Funding Sources: The National Institutes of Health, a Pew Scholar Award, a McKnight Scholar Award, a Sloan Foundation Research Fellowship, and a Beckman Young Investigator Award.
Cancer Gets Taste of Own Medicine
Researchers at Children’s Hospital Boston have identified a potent suppressor of tumor metastasis. The compound, a protein called prosaposin, is itself produced by tumors and triggers the body to cut off nourishment to other, newly formed tumors.
The findings, published in the July 21 Proceedings of the National Academy of Sciences, could lead to drugs that render a tumor harmless by preventing its spread, thereby blocking a key step in the progression toward malignancy.
Senior author Randolph Watnick, an HMS assistant professor of surgery in the Vascular Biology Program at Children’s, was initially motivated by the age-old puzzle of metastasis. Why do certain patients survive after a tumor is surgically removed, while other, similar patients die after surgery because tumors invade all parts of their body?
An answer began to emerge when Watnick, collaborating with first author Soo-Young Kang, a research fellow in the Vascular Biology Program, discovered in mice elevated levels of the protein thrombospondin-1 (Tsp-1) in the tissue around tumors known to be non-metastatic. Conversely, mice containing metastatic tumors displayed low levels of Tsp-1. Realizing that this pattern could be explained by the presence of an unknown molecule secreted by the tumors, the researchers applied a combination of chromatography and short hairpin RNA to isolate the mystery compound from the tumors. They found prosaposin.
What is remarkable about prosaposin, according to the researchers, is the novel mechanism behind its cancer-fighting powers. Instead of targeting tumors directly, the protein coaxes cells in the stroma, a type of connective tissue that is abundant throughout the body, to produce Tsp-1. In turn, Tsp-1 blocks angiogenesis, or blood vessel formation, in budding tumors. Without nutrients carried by the blood, the growth of new tumors is stunted or forestalled completely. The effect on metastasis is dramatic. In lab tests, mice injected with prosaposin exhibited 20 times fewer tumors than untreated control mice.
“Other proteins have been found to inhibit metastasis, but they directly prevent migration of tumor cells or act on nearby tissue to prevent blood vessel growth,” said Watnick. “Prosaposin is the first protein that fights metastasis by indirectly blocking angiogenesis.”
Children’s Hospital has filed a patent on prosaposin with the intent of licensing the compound for commercial development. Watnick and his collaborators are currently working to identify the specific regions responsible for the anti-metastatic effects. They have also isolated a compound that performs the opposite function of prosaposin in a set of experiments pending publication.
Students may contact Randolph Watnick at randy.watnick@childrens.harvard.edu for more information.
Conflict Disclosure: The authors declare no conflicts of interest.
Funding Sources: Gackstatter Foundation, National Aeronautics and Space Administration,
Department of Defense; the content of the work is the responsibility solely of
the authors.
Know Thy Enemy: Probing How Immune Cells Identify Pathogens
The immune system is engaged in a constant war, protecting us from armies of invading pathogens. Being able to respond quickly and effectively to these attacks means the difference between health and disease. Scientists have now deciphered key molecular circuits that enable the body to distinguish among viruses, bacteria and other microbes, elucidating how mammalian immune cells identify and fend off a host of invaders.
The underlying biological question is simple: What mechanism do immune cells use to mount pathogen-specific responses? Senior author Nir Hacohen, an HMS assistant professor at Massachusetts General Hospital and at the Broad Institute, first observed differential responses in primary mouse dendritic cells while working as a Whitehead Institute fellow.
In the current study, Ido Amit, a joint postdoctoral fellow in Hacohen’s lab and the lab of senior author Aviv Regev at the Broad, MIT and Howard Hughes Medical Institute, used a blend of gene expression arrays, RNA interference technologies and bioinformatics to identify genes that activate or repress the response to pathogens. Their work was accomplished remarkably quickly, within two years from start to accepted publication.
The investigation began by acquiring profiles of gene expression at different time points across the entire genome in mouse dendritic cells exposed to different stimuli. Expression levels were then analyzed to identify potential regulator genes that are themselves regulated by gene transcription and also predict the activation of other gene modules. Additionally, signature target genes that represented the entire genetic activation profile were selected.
From there, the team generated a validated library of short hairpin RNA (shRNA) complementary to all candidate regulators, with more than 100 genes selected for the study. This library was used to knock down each candidate independently in the mouse immune cells. Following shRNA treatment, the cells were stimulated with lipopolysaccharide (LPS), a major component of Gram-negative bacteria. Analysis of the signature target genes’ mRNA levels in treated cells revealed a regulatory network of associated regulators with individual targets as well as overall cellular responses.
While many expected regulators were found, many other regulators identified by the screen were not originally suspected to be involved in such direct immune responses. Moreover, the researchers pinpointed a remarkable number of connections between regulators and additional system components; some regulators provided coarse adjustments to the immune response while others fine-tuned and tailored responses as needed. One intriguing “coarse tuner” is called Timeless, a circadian clock protein in fruit flies. In mammalian dendritic cells, Timeless is a chief regulator of antiviral responses, controlling more than 200 genes.
Though these findings are primarily mechanistic in nature, they possess important medical implications by advancing the understanding of immune-response networks. In addition, the methods employed in the study could be readily adapted toward studies of other regulatory networks in other cell types in a relatively cheap, fast, yet effective way.
The study appears in the Sept. 3 online edition of Science.
Students may contact Nir Hacohen at nhacohen@partners.org for
more information.
Conflict Disclosure: The authors declare no conflicts of interest.
Funding sources: The Human Frontier Science Program Organization; the American
Physicians
Fellowship for Medicine in Israel; National Institutes of Health; the Burroughs
Wellcome Fund; and the Sloan Foundation; the content of the work is the responsibility
solely of the authors.
Diabetes Drug Targets Cancer Stem Cells
A familiar diabetes drug, in combination with cancer therapy, reduced tumors faster and prolonged remission longer than chemotherapy alone, apparently by knocking out cancer stem cells. The findings, in cell culture and mice, were reported by HMS researchers on Sept. 14 in the online Cancer Research.
“We have found a compound selective for cancer stem cells,” said senior author Kevin Struhl, the David Wesley Gaiser professor of biological chemistry and molecular pharmacology at HMS. “What’s different is that metformin is a first-line diabetes drug.”
In mouse experiments led by postdoctoral fellows Heather Hirsch and Dimitrios Iliopoulos, pretreatment with metformin prevented the otherwise marked ability of cancerous stem cells to form tumors. In another group of mice, in which tumors were allowed to take hold for 10 days, the drug in combination with the anticancer agent doxorubicin reduced tumor mass more quickly and prevented relapse for longer than doxorubicin alone. In contrast, once the tumors took hold, metformin alone had no effect against the deadly mass, composed mostly of non-stem cancer cells.
The discovery adds to a growing body of preliminary evidence in cells, mice, and people that metformin may improve breast cancer outcomes in people. In this study, the diabetes drug seemed to work independently of its ability to improve insulin sensitivity and lower blood sugar and insulin levels, all of which are associated with better breast cancer outcomes.
The results fit within the cancer stem cell hypothesis, an intensely studied idea that a small subset of cancer cells have a special power to initiate tumors, fuel tumor growth, and promote recurrence of cancer. Cancer stem cells appear to resist conventional chemotherapies, which kill the bulk of the tumor.
“This is really the first study that shows that metformin may have an effect on these very resistant cancer cells,” said Jennifer Ligibel, a medical oncologist at Dana-Farber Cancer Institute and an HMS instructor in medicine, who was not involved in the study. Ligibel is collaborating with colleagues at the University of Toronto and the National Cancer Institute of Canada Clinical Trials Group to develop a large-scale trial to study metformin’s impact on recurrence in women after they are treated for early stage breast cancer. The study may start next year.
Struhl hopes the results will encourage additional clinical trials of metformin in combination with a reduced dose of chemotherapy and to prevent recurrence in treated people for breast cancer and other forms of the disease.
Students may contact Kevin Struhl at kstruhl@hms.harvard.edu for more information.
Funding Sources: The research was funded by the National Institutes of Health and the American Cancer Society.
Conflict Disclosure: HMS has applied for a patent for a combined therapy of metformin and a lower dose of chemotherapy, which is being tested in animals