Like other alpacas, as well as camels and llamas, Bryson (left) and Sanchez produce unusually small antibodies that could have a role in cancer immunotherapy. (PHOTO COURTESY HIDDE PLOEGH / BOSTON CHILDREN’S HOSPITAL)
In 1989, two undergraduate students at the Free University
of Brussels were asked to test frozen blood serum from camels, and stumbled on
a previously unknown kind of antibody. It was a miniaturized version of a human
antibody, made up only of two heavy protein chains, rather than two light and
two heavy chains. As they
eventually reported, the antibodies’ presence was confirmed not only in
camels, but also in llamas and alpacas.
Fast forward 30 years. In the journal PNAS this week, researchers at Boston Children’s Hospital and MIT show that these mini-antibodies, shrunk further to create so-called nanobodies, may help solve a problem in the cancer field: making CAR T-cell therapies work in solid tumors.
Many blood disorders, immune disorders and metabolic disorders can be cured with a transplant of hematopoietic (blood-forming) stem cells, also known as bone marrow transplant. But patients must first receive high-dose, whole-body chemotherapy and/or radiation to deplete their own defective stem cells, providing space for the donor cells to engraft. These “conditioning” regimens are highly toxic: they wipe out the immune system, raising infection risk, and can cause anemia, infertility, other organ damage and cancers. And when the donor isn’t an exact match, patients’ immune systems must be suppressed for prolonged periods to prevent rejection.
As a result, most patients either don’t receive a transplant
or must endure serious side effects. But if two new studies bear out in
clinical trials, a far gentler conditioning treatment could enable stem-cell
transplants for a much wider range of disorders, even possibly from unmatched
donors.
Combined expansion microscopy and lattice light-sheet microscopy allows for highly detailed images to be taken over large sections of the brain. (IMAGES COURTESY SRIGOKUL UPADHYAYULA, RUIXUAN GAO, AND SHOH ASANO)
Decades ago, discoveries about the brain’s intricate anatomy were made with careful dissection and drawings. Today, they’re made with super-resolution imaging and massive computing power capable of handling hundreds of terabytes of data.
In this week’s Science, a team out of the Massachusetts Institute of Technology (MIT), the Janelia Research Campus of the Howard Hughes Medical Institute (HHMI), Harvard Medical School (HMS) and Boston Children’s Hospital, describes a technique capable of imaging whole brains at exquisitely high resolution, allowing scientists to distinguish tiny sub-cellular structures. …
Scientists studying how genetics impact brain disease have long sought a better experimental model. Cultures of genetically-modified cell lines can reveal some clues to how certain genes influence the development of psychiatric disorders and brain cancers. But such models cannot offer the true-to-form look at brain function that can be provided by genetically-modified mice.
Even then, carefully breeding mice to study how genes impact the brain has several drawbacks. The breeding cycles are lengthy and costly, and the desired gene specificity can only be verified — but not guaranteed — when mouse pups are born.
In today’s Nature, scientists from Boston Children’s Hospital and UC San Francisco describe a new way to create customized mouse models for studying the brain. …
A T cell (right) launches an attack on an immature red blood cell (left) infected with a malaria parasite called P. vivax. At the arrow, the T cell breaches the infected cell’s membrane to deliver death-inducing enzymes. Credit: Lieberman lab/Boston Children’s Hospital
Malaria parasite infection, which affects our red blood cells, can be fatal. Currently, there are about 200 million malaria infections in the world each year and more than 400,000 people, mostly children, die of malaria each year.
Now, studying blood samples from patients treated for malaria at a clinical field station in Brazil’s Amazon jungle, a team of Brazilian and American researchers has made a surprising discovery that could open the door to a new vaccine.
“I noticed that white blood cells called killer T cells were activated in response to malaria parasite infection of immature red blood cells,” says Caroline Junqueira, PhD, a visiting scientist at Boston Children’s Hospital and Harvard Medical School (HMS).
For red blood cells, this activity is unusual.
“Infected red blood cells aren’t recognized by our immune system’s T cells in the same way that most other infected cells of the human body are,” says Judy Lieberman, MD, PhD, chair in the Program in Cellular and Molecular Medicine at Boston Children’s Hospital.
Digging deeper, Junqueira, Lieberman and collaborators have found a completely unexpected immune response to malaria parasites that infect immature blood cells called reticulocytes. The revelation could help to design a new vaccine that might be capable of preventing malaria.
Their findings, published today in Nature Medicine, uncover special cellular mechanisms and properties specific to “teenaged” reticulocytes and a strain of malaria called Plasmodium vivax that enable our T cells to recognize and destroy both the infected reticulocytes and the parasites inside them. …
Artist’s rendering of chromatin, which is housed inside the nuclei of mammalian cells. A new discovery about its physical arrangement could pave the way for new therapeutics.
A new discovery about the spatial orientation and physical interactions of our genes provides a promising step forward in our ability to design custom antibodies. This, in turn, could revolutionize the fields of vaccine development and infection control.
Recent years of research by Alt and others in the field of molecular biology have revealed that it’s not just our genes themselves that determine health and disease states. It’s also the three-dimensional arrangement of our genes that plays a role in keeping genetic harmony. Failure of these structures may trigger genetic mutations or genome rearrangements leading to catastrophe.
The importance of genetic loops
Crammed inside the nucleus, chromatin, the chains of DNA and proteins that make up our chromosomes, is arranged in extensive loop arrangements. These loop configurations physically confine segments of genes that ought to work together in a close proximity to one another, increasingly their ability to work in tandem.
“All the genes contained inside one loop have a greater than random chance of coming together,” says Suvi Jain, PhD, a postdoctoral researcher in Alt’s lab and a co-first author on the study.
Meanwhile, genes that ought to stay apart remain blocked from reaching each other, held physically apart inside our chromosomes by the loop structures of our chromatin.
But while many chromatin loops are hardwired into certain formations throughout all our cells, it turns out that some types of cells, such as certain immune cells, are more prone to re-arrangement of these loops. …
A new microscope allows us to see how cells behave in 3D and real time inside living organisms.
Astronomers developed a “guide star” adaptive optics technique to obtain the most crystal-clear and precise telescopic images of distant galaxies, stars and planets. Now a team of scientists, led by Nobel laureate Eric Betzig, PhD, are borrowing the very same trick. They’ve combined it with lattice light-sheet to create a new microscope that’s able to capture real-time, incredibly detailed and accurate images, along with three-dimensional videos of biology on the cellular and sub-cellular level.
The work — a collaboration between researchers at Howard Hughes Medical Institute, Boston Children’s Hospital and Harvard Medical School — is detailed in a new paper just published in Science.
“Every time we’ve done an experiment with this microscope, we’ve observed something novel — and generated new ideas and hypotheses to test,” Kirchhausen said in a news story by HMS. “It can be used to study almost any problem in a biological system or organism I can think of.” …
Ribonucleic acid, or RNA, has long been underappreciated for its role in gene expression. Until recent years, RNA has been thought of merely as a messenger, shuttling DNA’s instructions to the genetic machinery that synthesizes proteins.
But new discoveries of RNA functions, modifications and its ability to transcribe sections of the genome that were previously considered “junk DNA” has led to the discovery of a huge number of new druggable targets.
These new insights into RNA’s complex purposes have largely been uncovered through ever-increasingly sensitive and affordable sequencing methods. As a result, RNA-based drugs now stand to greatly extend our ability to treat diseases beyond the scope of what’s possible with small molecules and biologics.
Although several RND-based drug approaches have already been established, some barriers still prevent these strategies from working broadly. In a review paper for Nature Structural and Molecular Biology, Judy Lieberman, MD, PhD, of the Program in Cellular and Molecular Medicine of Boston Children’s Hospital, lays out where RNA-based drug development currently stands.
Lieberman, who has helped pioneer the RNA-based drug revolution herself, was the first scientist to show in an animal disease model that small, double-stranded RNAs could be used as drugs and leveraged to knock down genes in cells.
Cells throughout the human body are constantly being damaged as a part of natural life, normal cellular processes, UV and chemical exposure and environmental factors — resulting in what are called DNA double-strand breaks. Thankfully, to prevent the accumulation of DNA damage that could eventually lead to cell dysfunction, cancer or death, the healthy human body has developed ways of locating and repairing the damage.
Unfortunately, these DNA repair mechanisms themselves are not impervious to genetic errors. Genetic mutations that disrupt DNA repair can contribute to devastating disease.
Across the early-stage progenitor cells that give rise to the human brain’s 80 billion neuronal cells, genomic alterations impacting DNA repair processes have been linked to neuropsychiatric disorders and the childhood brain cancer medulloblastoma. But until now, it was not known exactly which disruptions in DNA repair were involved.
A Boston Children’s Hospital team led by Frederick Alt, PhD, has finally changed that. …
Viruses have a genetic signature that a human receptor called MDA5 recognizes, causing the immune system to attack. But when MDA5 confuses the body’s own genetic material for that of a virus, disease ensues.
The human body’s innate immune system employs a variety of “sensors” for identifying foreign invaders such as viruses. One such viral sensor is a receptor called MDA5, found in every cell of the body.
Inside each cell, MDA5 constantly scans genetic material, checking if it’s native to the body or not. As soon as MDA5 identifies the genetic signature of a viral invader, it trips a system-wide alarm, triggering a cascade of immune activity to neutralize the threat.
But if a genetic mutation to MDA5 causes it to confuse some of the body’s own genetic material for being foreign, “false alarms” can lead to unchecked inflammation and disease. Scientists from Boston Children’s Hospital have discovered a new link between MDA5’s ability to discriminate between “self” and “non-self” genetic material — called RNA duplexes — and a spectrum of autoimmune disorders. …