Scientists from Fred Hutch and St. Jude Children’s Research Hospital have developed an algorithm that functions like a Rosetta Stone to help decipher how the immune system recognizes and binds antigens. The study, published online Wednesday in the journal Nature, should aid development of more personalized cancer immunotherapy, and advance diagnosis and treatment of infectious diseases.
The immune system depends on molecules called T-cell receptors on the surface of T cells to recognize and respond to foreign antigens from virus-infected cells, tumors and other threats. Genomic rearrangement means that a large number of different T-cell receptors are possible. Each person can have about 100 million different receptors, referred to as their T-cell repertoire, with little overlap even in identical twins. Each receptor in the repertoire is capable of recognizing a different antigen and rallying the immune response to address that threat.
“Our immune repertoires contain detailed information on pathogen exposures, autoimmune diseases and cancer, but this information is encoded in the protein sequences of immune receptors and we don't currently have the ability to interpret these sequences, said Fred Hutch computational biologist Dr. Philip Bradley, co-corresponding author on the study along with St. Jude immunologist Dr. Paul Thomas. “Our study is aimed at developing tools that would allow us to decode T-cell receptor sequences, which could improve diagnosis and treatment of a variety of human diseases and cancers.”
The algorithm was built using tools the researchers developed to define how T-cell receptors recognize a part of the antigen called the epitope. Epitopes are displayed on the surface of circulating immune cells and are where T cells bind antigens to fuel the immune response. Multiple epitopes are produced from the same virus, tumor or other threat. Each epitope is targeted by a pool of T cells bearing different, but specific, T-cell receptors to recognize and respond.
“These analytical tools helped us to understand the T-cell repertoire against a particular antigen in a more coherent way than we have been able to do before. Grouping T-cell receptors for a given epitope revealed underlying common features that characterized the bulk of the repertoire,” said first author Dr. Pradyot Dash, a staff scientist in Thomas’ laboratory.
Like the Rosetta Stone that scholars used to decode hieroglyphics, researchers trained the algorithm with more than 4,600 T-cell receptors and then used it to correctly assign 81 percent of the human T cells and 78 percent of mouse T cells to one of 10 different viral epitopes. The “training data” were generated from 78 mice infected with influenza or cytomegalovirus (CMV) and 32 humans infected with flu, CMV or Epstein-Barr virus. The epitope of each T cell had been determined previously using a different, more labor-intensive method.
Researchers tested the algorithm on three flu-infected mice without knowledge of the epitope-receptor recognition. The algorithm was able to predict with up to 90 percent accuracy the flu epitopes recognized by these cells.
— Adapted from a St. Jude Children’s Research Hospital press release
In the largest study so far of the vaginal microbiome of menopausal women, researchers found that women who reported vaginal itching or pain were more likely to have a particular “bad” strain of bacteria. However, contrary to expectations, the presence of “good” bacteria was not associated with fewer genitourinary menopause symptoms.
“We were expecting to see that Lactobacillus would be associated with fewer vaginal symptoms, but we didn’t see that,” said Fred Hutch’s Dr. David Fredricks, an expert on the vaginal microbiota and senior author of the paper, published online ahead of print June 19 in the journal Menopause. “But we did find that BV-Associated Bacterium 1 is associated with itching and irritation. That’s a completely novel finding and something we’ll need to follow up on in a later study.”
If it turns out that the above-mentioned bacterium, BVAB1, plays a role in the symptoms rather than merely serving as a marker of a woman who is prone to pain and itching, then “we may be able to intervene,” said Fredricks, whose lab was the first to identify the troublesome strain in 2005. The bacterium can be eradicated with a topical antibiotic, he said.
The study used molecular methods to analyze the vaginal bacterial community in 88 menopausal women. It was conducted via MsFLASH, a research network funded by the National Institute on Aging to test various interventions for hot flashes, insomnia, and other menopausal symptoms.
Much of the previous research on the vaginal microbiome has focused on premenopausal women, in large part because of its potential influence on childbirth and other age-related health outcomes. A combination of BV-associated bacteria are behind a sometimes symptomless condition called bacterial vaginosis, or BV, best known for causing local irritation and a foul odor. In premenopausal women, it is also associated with premature delivery and miscarriage, pelvic inflammatory disease, and an increased risk of sexually transmitted infections such as HIV, gonorrhea, and chlamydia.
Healthy vaginas, at least in premenopausal women, are dominated by a species of the genus Lactobacillus. These bacteria produce lactic acid, and researchers believe that lactic acid makes the vagina inhospitable to the overgrowth of bad-guy species such as BV-associated bacteria.
The food source for lactobacillus is a sugar called glycogen. But here, the new study again challenged the prevailing dogma. Estrogen was long believed to drive the production of glycogen in the vagina, Fredricks said. Yet an earlier, smaller study had found that while all postmenopausal women experience a drop in estrogen as well as a change in the microbiota mix, not all lose vaginal Lactobacilli. The new study, which included women just heading into menopause as well as those several years beyond, with varying estrogen levels, confirmed that there may not be direct links between serum estrogen, glycogen, and Lactobacillus colonization, Fredricks said.
The new study piggybacked on an earlier MsFLASH clinical trial comparing the effectiveness of interventions for hot flashes. The main trial had nothing to do with vaginal symptoms. However, researchers, knowing they wanted to investigate such symptoms in the future, carved out a “pilot study” in part “to see whether we could get women to do vaginal swabbing in the clinic and at home on a regular basis,” said Fred Hutch’s Dr. Katherine A. Guthrie, a biostatistician who serves as principal investigator of the Fred Hutch-based MsFLASH Data Coordinating Center.
Yes, they could. MsFLASH is now wrapping up a multicenter clinical trial comparing two common treatments — a vaginal hormonal pill (Vagifem) and an over-the-counter gel (Replens) with placebos to evaluate their effects on menopause-related vaginal symptoms. She expects the results to be published in about six months.
The trial, which involved 300 women between the ages of 45 and 70, recruited much more quickly than the researchers expected.
“People were clamoring to come in,” Guthrie said.
Vaginal symptoms ranging from dryness and atrophy (thinning and shrinking of the tissues) to itching, irritation and painful intercourse occurs in between 40 percent to 77 percent of menopausal women, according to researchers, yet scientists don’t really understand why they occur. For women — and their partners — they can cause significant distress.
“I’m a biostatistician, but working with our clinical investigators, it’s clear that a lot of women don’t realize this is a normal part of aging,” Guthrie said. “They think there’s something wrong with them, or maybe their husbands think they should be able to have sex more easily. It’s quite impactful on a marriage or partnership. But it’s not always easy to bring up to a doctor.”
“There’s a huge amount of interest,” he said. “It reflects that we’re ignoring this important area in women’s health. We need more studies.”
— Mary Engel / Fred Hutch News Service
For 20 years, Jennifer Griffith has been a highly regarded Washington, D.C., insider. She was chief of staff for a U.S. senator. She planned and managed the Capitol Hill ceremonies of President Obama’s first Inauguration Day. She worked the halls of Congress as a lobbyist. Now she has moved to Seattle with a story to tell: the story of Fred Hutch.
On June 1, Griffith started as the Hutch’s vice president of Government & Community Relations, a new role created in recognition of the increasing importance of such relationships to the future of cancer research.
“Jennifer brings a wealth of experience,” said President and Director Dr. Gary Gilliland. “And there is no time where her experience, relationships and strategic input will be more important than now, as we face proposed budget cuts to the National Institutes of Health.”
Griffith said her charter in her new position is to “make sure everyone else — the scientists, the researchers, the postdocs — can get their jobs done.”
Executive Vice President and Chief Operating Officer Steve Stadum noted that Griffith joins the Hutch when it is rapidly growing and its medical research thriving, but that this is also a time of constant change at all levels of government. “We need a well-qualified, highly respected leader like her to help us build and maintain strong partnerships with federal, state and local agencies,” he said.
Griffith will manage strategies to increase support for the Hutch and its mission, including coordinating policy regarding federal, state and local legislation, and regulations that affect research on cancer and related illnesses. In her community relations role, she will work with Seattle-area civic, business and neighborhood notables and help raise the Hutch’s profile as a thought leader in research and health care, a progressive employer and a responsible corporate citizen.
Griffith first caught the political bug in 1999 when she signed on as a legislative assistant to Olympia Snowe, Maine’s former Republican senator. She went on to serve as a legislative assistant, legislative director and deputy chief of staff for Washington’s Sen. Maria Cantwell from 2001–2007. After a stint working for Sen. Diane Feinstein, where she took on the duties of coordinator for the Obama inauguration, Griffith returned to work for Sen. Cantwell, serving as chief of staff for three years.
Now back in her home state, she said there was no doubt she would “hit the ground running” at Fred Hutch.
“I believe in what we are doing,” she said. “I absolutely love it when you come to work in the morning and think you can make a difference in real people’s lives.”
— Sabin Russell / Fred Hutch News Service