A team of UC San Francisco and UC Berkeley researchers and other collaborators have identified the rare genetic mutation responsible for a unique case of severe combined immunodeficiency (SCID), a deadly immune system disorder also known as “boy in the bubble” disease. In addition to defining the latest of more than two dozen known genetic causes of SCID, the study — published online Nov. 30, 2016, in the New England Journal of Medicine — revealed an unexpected role for the mutated gene in the normal processes of immune system development.
“We’re entering a new era of genomic medicine,” said Jennifer Puck, MD, UCSF professor of immunology and pediatrics, a pediatric immunologist at UCSF Health and senior author of the new study. “Our technology has progressed to the point that we can learn a great deal about a disease, and even learn important new facts about normal biology, from just a single patient. In this case we were able to unearth the potentially unique underlying genetic cause of one patient’s disease and come away with brand new understanding of how the immune system develops.”
The patient featured in the new study was identified through a population-based neonatal screening approach for SCID that Puck developed in 2005, and which is now widely performed. (Since it was introduced in California in 2010, Puck’s screening method has increased the survival rate of infants with SCID to 94 percent, and by 2017 will be used in 47 US states.) The screening indicated a severely compromised immune system, leaving the patient open to a likely fatal series of infections. However, UCSF doctors performed a bone-marrow transplant, the standard of care for SCID, which provided the infant with a fully functional immune system.
In addition to SCID, however, the infant was also born with a constellation of abnormal features including craniofacial deformities, loose skin, excess body hair, and neurological abnormalities, which suggested that a single rare genetic defect could underlie the patient’s disease. In part to determine whether the infant’s parents were carriers of a genetic mutation that could be passed on to future children, Puck’s group set out to scan the genomes of both infant and parents for mutations that could be responsible for the disease. Working with the lab of computational biologist Steven Brenner of UC Berkeley's Department of Plant & Microbial Biology and with researchers at Tata Consultancy Services, the team used next-generation exome sequencing to identify a single mutation present in the infant but not the parents — referred to as a de novo mutation — in the BCL11B gene, which had previously been associated only with lymphatic cancer.
“This is a gene that had never been associated with SCID before, which required more advanced genome analysis techniques to discover,” said Brenner. “Moreover, unlike variants in every other known SCID gene, this mutation is dominant, which means you only need one copy of this mutation to disrupt multiple aspects of development.”
In order to understand the biological effects of the patient’s mutation, the researchers collaborated with the team of David Wiest, PhD, of the Fox Chase Cancer Center in Philadelphia, to introduce the patient’s mutated form of BCL11B into zebrafish, whose immune systems are similar to those of humans. They found that the mutated form of BCL11B produced abnormalities in the zebrafish that mimicked those observed in the patient, including not only a disabled immune system but also similar craniofacial abnormalities. Blocking the mutated gene and replacing it with the normal human gene in embryonic zebrafish reversed all these symptoms, strongly suggesting that abnormal BCL11B was the cause of the symptoms seen in both zebrafish and the human patient.
The normal BCL11B protein binds to DNA at sites across the genome to activate a wide variety of developmental genes in a precisely orchestrated sequence. Experiments revealed that the BCL11B gene mutation identified in the new study disrupts this protein’s ability to bind to DNA, thereby resulting in the wide array of immunological, neurological, and craniofacial disruptions seen in both the human patient and in zebrafish.
"Mutations do arise on the way from the joining of sperm and eggs to producing a new person,” Puck said. “Everyone has such new mutations, but usually they are silent passengers that don’t do any harm. In this case, however, a mutation in BCL11B turned the protein it produces into a monkey wrench that disrupted many different systems in the body.”
Because zebrafish embryos are transparent, the researchers were able to observe that one key effect of disrupting BCL11B was to block the ability of immature bone marrow stem cells to successfully migrate into the thymus, where these cells are normally “educated” to become mature T lymphocytes, often called ‘T cells’, which are essential for combating infection and are almost completely lacking in patients with SCID.
Further experiments in the lab in which the researchers introduced the BCL11B mutation into normal human bone marrow stem cells and compared them with diseased cells obtained from the patient confirmed that this infant’s mutation impaired its T cells’ ability to migrate and mature.
According to Puck, the findings illustrate the power of deeply studying rare diseases in individual patients: “We may never get another patient just like this one,” she said. “But as a result of studying this one case we were able to learn so much about a critical gene in a critical pathway that hadn’t been appreciated before.”
Divya Punwani, PhD, of UCSF and Yong Zhang, MD, PhD, of the Fox Chase Cancer Center were co-lead authors on the new paper. Additional authors on the paper were Jason Yu, PhD, Morton J. Cowan, MD, Antonia Kwan, MD, PhD, Carlos O. Lizama, PhD, Bryce A. Mendelsohn, MD, and Shawn P. Fahl, PhD, of the Fox Chase Cancer Center; Aashish N. Adhikari, PhD of UC Berkeley; and Sadhna Rana, PhD, Ajithavalli Chellappan, and Rajgopal Srinivasan, PhD of Tata Consultancy Services.Thursday, December 1, 2016 - 14:15byline: Nicholas Weiler, UCSF Public RelationsLegacy: section header item: Date: Thursday, December 1, 2016 - 14:15headline_position: Top Leftheadline_color_style: Normalheadline_width: Longcaption_color_style: Normalcaption_position: Bottom Left
This morning during the Big Give, the Department of Molecular and Cell Biology was one of the winners of a "Random Alumni Donor" drawing. That means that whatever that alumni donated, the university will contribute an additional $2K! Check out the Big Give Leaderboard for more stats.
Tobacco leaves showing transient overexpression of genes involved in nonphotochemical quenching (NPQ), a system that protects plants from light damage. Red and yellow regions represent low NPQ activity, while blue and purple areas show high levels induced by exposure to light. (Credit: Lauriebeth Leonelli and Matthew Brooks/UC Berkeley)
Plant biologists have bumped up crop productivity by increasing the expression of genes that result in more efficient use of light in photosynthesis, a finding that could be used to help address the world’s future food needs.
Scientists at the Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab), UC Berkeley, and the University of Illinois targeted three genes involved in a process plants use to protect themselves from damage when they get more light than they can safely use. By increasing the expression of those genes, the scientists saw increases of 14-20 percent in the productivity of modified tobacco plants in field experiments.
The researchers described their findings in a paper published today in the journal Science.
“Tobacco was used as the model crop plant in this study because it is easy to work with, but we’re working to make the same modifications in rice and other food crops,” said co-senior author Krishna Niyogi, a professor in the Department of Plant and Microbial Biology. “The molecular processes we’re modifying are fundamental to plants that carry out photosynthesis, so we hope to see a similar increase in yield in other crops.”
Niyogi, who is a Howard Hughes Medical Institute investigator and a faculty scientist in Berkeley Lab’s Division of Molecular Biophysics and Integrative Bioimaging, teamed up with Stephen Long, a plant biology and crop sciences professor at the University of Illinois, for the study.
In photosynthesis, plants use the energy in sunlight to take up carbon dioxide from the atmosphere and convert it into biomass, which we use for food, fuel, and fiber. When there is too much sunlight, the photosynthetic machinery in chloroplasts can be damaged, so plants need photoprotection. Inside chloroplasts, plants have a system called NPQ, or nonphotochemical quenching, for this purpose.
Niyogi compared NPQ to a pressure relief valve in a steam engine.
“When there is too much sunlight, it’s like pressure building up,” said Niyogi. “NPQ turns on and gets rid of the excess energy safely. In the shade, the pressure in the engine decreases. NPQ turns off, but not quickly enough. It’s like having a leak in the system with the valve left open. The photosynthetic engine can’t work as efficiently.”
The highly variable levels of light plants receive, particularly in densely planted crop fields, presents a challenge to the efficient use of solar energy. Plants must adapt to intermittent shading from leaves that are higher in the canopy, or from passing clouds.
Niyogi and his postdoctoral research associates Lauriebeth Leonelli, Stéphane Gabilly, and Masakazu Iwai figured out a way to speed up recovery from photoprotection and demonstrated a proof of this concept in the laboratory. They used a new method to rapidly test gene expression in tobacco leaves. By boosting the expression of three genes involved in NPQ, they showed that NPQ turned off more quickly, and the efficiency of photosynthesis in the shade was higher.
Half of crop photosynthesis occurs in the shade, so any improvement in speeding up recovery from photoprotection could have a big benefit, the researchers said.
Illinois postdoctoral researchers Johannes Kromdijk and Katarzyna Glowacka took the trio of genes studied at Berkeley and put them into tobacco plants for further testing in greenhouse and field experiments.
The work to boost crop productivity comes as concerns about food shortages rise with the world’s population. The Food and Agriculture Organization of the United Nations estimates that food production will need to nearly double by 2050 to meet increasing demand. Yields of the world’s major staple crops have not been increasing fast enough to meet this projected need.
“My attitude is that it is very important to have these new technologies on the shelf now because it can take 20 years before such inventions can reach farmer’s fields,” said Long. “If we don’t do it now, we won’t have this solution when we need it.”
This research was supported by the Bill and Melinda Gates Foundation. Any new technology licensed from this work will be made freely available to farmers in poor countries in Africa and South Asia.Thursday, November 17, 2016 - 11:15byline: Sarah Yang, Berkeley LabLegacy: section header item: Date: Thursday, November 17, 2016 - 11:15headline_position: Top Leftheadline_color_style: Normalheadline_width: Longcaption_color_style: Normalcaption_position: Bottom Left
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This election was particularly stressful. More than 50 percent of Americans reported that it was a significant source of stress, and this was true for supporters of both parties. The surprising result certainly stressed many. So, what do we do now?
The stress response is actually crucial for survival. When we get down to the biology of it, we understand that without it an organism will die when it encounters the first challenge in its environment.
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