During pregnancy, the baby is mostly protected from harmful microorganisms by the amniotic sac, but recent research suggests the baby could be exposed to small quantities of microbes from the placenta, amniotic fluid, umbilical cord blood and fetal membranes. One theory is that any possible prenatal exposure could ‘pre-seed’ the infant microbiome. In other words, to set the right conditions for the ‘main seeding event’ for founding the infant microbiome.
When a mother gives birth vaginally and if she breastfeeds, she passes on colonies of essential microbes to her baby. This continues a chain of maternal heritage that stretches through female ancestry for thousands of generations, if all have been vaginally born and breastfed. This means a child’s microbiome, that is the trillions of microorganisms that live on and in him or her, will resemble the microbiome of his/her mother, the grandmother, the great-grandmother and so on, if all have been vaginally born and breastfed.
As soon as the mother’s waters break, suddenly the baby is exposed to a wave of the mother’s vaginal microbes that wash over the baby in the birth canal. They coat the baby’s skin, and enter the baby’s eyes, ears, nose and some are swallowed to be sent down into the gut. More microbes form of the mother’s gut microbes join the colonization through contact with the mother’s faecal matter. Many more microbes come from every breath, from every touch including skin-to-skin contact with the mother and of course, from breastfeeding.
With formula feeding, the baby won’t receive the 700 species of microbes found in breast milk. Inside breast milk, there are special sugars called human milk oligosaccharides (HMO’s) that are indigestible by the baby. These sugars are designed to feed the mother’s microbes newly arrived in the baby’s gut. By multiplying quickly, the ‘good’ bacteria crowd out any potentially harmful pathogens. These ‘good’ bacteria help train the baby’s naive immune system, teaching it to identify what is to be tolerated and what is pathogen to be attacked. This leads to the optimal training of the infant immune system resulting in a child’s best possible lifelong health.
With C-section birth and formula feeding, the baby is not likely to acquire the full complement of the mother’s vaginal, gut and breast milk microbes. Therefore, the baby’s microbiome is not likely to closely resemble the mother’s microbiome. A baby born by C-section is likely to have a different microbiome from its mother, its grandmother, its great-grandmother and so on. C-section breaks the chain of maternal heritage and this break can never be restored.
The long term effect of an altered microbiome for a child’s lifelong health is still to be proven, but many studies link C-section with a significantly increased risk for developing asthma, Type 1 diabetes, celiac disease and obesity. Scientists might not yet have all the answers, but the picture that is forming is that C-section and formula feeding could be significantly impacting the health of the next generation. Through the transgenerational aspect to birth, it could even be impacting the health of future generations.
FDA cleared Clever Culture Systems’ artificial intelligence tech for automated imaging, analysis and interpretation of microbiology culture plates speeding up Diagnostics
Reporter: Aviva Lev-Ari, PhD, RN
FDA clears automated imaging AI that speeds up infectious disease Dx
The FDA cleared Clever Culture Systems’ artificial intelligence tech for automated imaging, analysis and interpretation of microbiology culture plates, which can accelerate the diagnosis and reporting of infectious diseases.
Switzerland-based Clever Culture Systems is a joint venture between Hettich AG and Australia’s LBT Innovations. The de novo submission of the Automated Plate Assessment System, or APAS, earned 510(k) clearance, and will be regulated as a Class II medical device, according to a statement.
“It’s a very sophisticated set of algorithms and microbiology decision support system that thinks about the culture plate the same way as a microbiologist does,” said former LBT Innovations CEO Lusia Guthrie in a video. APAS can read a culture plate in about 20 seconds, compared with the minute it would take a microbiologist, the company said. The quicker diagnosis will result in the appropriate antibiotic being prescribed up to 6 hours earlier than with current best practices, LBT said.
The FDA nod comes on the strength of a series of clinical trials that used a manual version of APAS to test 10,000 patients over a 12-month period. The trials took place in Australia and the U.S.
Clever Culture Systems is in discussions with diagnostics companies for the licensing of its APAS products.
On its way for an IPO: mRNA platform, Moderna, Immune Oncology is recruiting 100 new Life Scientists in Cambridge, MA
Curator: Aviva Lev-Ari, PhD, RN
Moderna has now raised $1.9 billion from investors like AstraZeneca – 9% stack [AstraZeneca’s Pascal Soriot helped get that all started with a whopping $240 million upfront in its 2013 deal, which was tied to $180 million in milestones.], with another $230 million on the table from grants. In addition to the financing announcement this morning, Moderna is also unveiling a pact to develop a new Zika vaccine, with BARDA putting up $8 million to get the program started while offering an option on $117 million more to get through a successful development program.
Novel Strategy in Biotech:
in biotech. Instead of grabbing one or two new drugs and setting out to gather proof-of-concept data to help establish its scientific credibility, the company has harvested a huge windfall of cash and built a large organization before even entering the clinic. And it did that without turning to an IPO.
The deal with AstraZeneca covers new drugs for cardiovascular, metabolic and renal diseases as well as cancer.
partners filed a European application to start a Phase I study of AZD8601, an investigational mRNA-based therapy that encodes for vascular endothelial growth factor-A (VEGF-A)
Moderna CEO spelled out plans to get the first 6 new drugs in the clinic by the end of 2016.
The first human study was arranged for the infectious disease drug mRNA 1440, which began an early stage study in 2015.
Moderna built up a range of big preclinical partnerships.
CEO Bancel says the number of drugs in development has swelled to 11, with the first set of data slated to be released in 2017.
Moderna also plans to add about 10 drugs to the clinic by next summer,
UPDATED: Booming Moderna is raising $600M while ramping up manufacturing and clinical studies
Melbourne researchers have uncovered genes responsible for the way the body fights infection at the point of ‘invasion’ – whether it’s the skin, liver, lungs or the gut.
Research led by Dr Axel Kalliesand Dr Klaas van Gisbergen at the Walter and Eliza Hall Institute of Medical Research, and Dr Laura Mackay from the University of Melbourne at the Peter Doherty Institute for Infection and Immunity has identified the genes Hobit andBlimp1 and found that they control a universal molecular program responsible for placing immune cells at the ‘front lines’ of the body to fight infection and cancer.
The presence of these organ-residing cells, which differ strikingly from their counterparts circulating in the blood stream, is key to local protection against viruses and bacteria.
Walter and Eliza Hall Institute’s Dr Kallies said the human body was fighting disease-causing pathogens every minute of its life. Dr Kallies said identifying how immune cells remain in the part of the body where they are needed most was critical to developing better ways to protect us from infections such as malaria orHIV.
“Discovering these ‘local heroes’ and knowing how the localised immune response is established allows us to find ways to ensure the required cells are positioned where they are needed most,” Dr Kallies said.
“This research will help us understand how immune cells adapt, survive and respond within the organs they protect. This is critical to rid the body of pathogens even before they are established and may also have implications for understanding how the spread of cancer could be prevented.”
The Doherty Institute’s Dr Laura Mackay, who is also an associate investigator with the Australian Research Council Centre of Excellence in Advanced Molecular Imaging, said the factors that control the ‘tissue-residency’ of immune cells – their ability to locally reside in different organs of the body – was previously unknown.
“These results have major implications for developing strategies to induce immune cells in tissues that protect against infectious diseases,” Dr Mackay said.
“It’s a crucial discovery for future vaccine strategies – Hobit and Blimp1 would be key to placing immune cells in the tissues, which we know are really important for protection.”
The findings have just been published in the journal Science.
This research was supported by the Victorian State Government Operational Infrastructure Support and the Australian Government National Health and Medical Research Council Independent Research Institute Infrastructure Support Scheme.
Immune cell ‘survival’ gene key to better myeloma treatments
4 February 2013
Scientists have identified the gene essential for survival of antibody-producing cells, a finding that could lead to better treatments for diseases where these cells are out of control, such as myeloma and chronic immune disorders.
The discovery that a gene calledMcl1 is critical for keeping this vital immune cell population alive was made by researchers at Melbourne’s Walter and Eliza Hall Institute. Associate Professor David Tarlinton, Dr Victor Peperzak and Dr Ingela Vikstrom from the institute’s Immunology division led the research, which was published today in Nature Immunology.
Antibody-producing cells, also known as plasma cells, live in the bone marrow and make antibodies that provide a person with long-term protection from viruses and bacteria, Associate Professor Tarlinton said. “Plasma cells are produced after vaccination or infection and are responsible for the immune ‘memory’ that can persist in humans for 70 or 80 years. In this study, we found that plasma cells critically rely on Mcl1 for their continued survival and, without it, they die within two days,” he said.
Dr Peperzak said the team was surprised to find that plasma cells used this as a ‘failsafe’ mechanism in controlling their survival. “One of the interesting things we found is that because plasma cells rapidly destroy Mcl-1 proteins within the cell yet depend on it for their survival, they need continuous external signals to tell them to produce more Mcl-1 protein,” Dr Peperzak said. “This keeps the plasma cells under tight control, with Mcl-1 acting like a timer that constantly counts down and, if not reset, instructs the cell to die.”
Plasma cells are vital to the immune response, but can be dangerous if not properly controlled, Associate Professor Tarlinton said. “As with any immune cell, plasma cells are really quite dangerous in many respects and need to be tightly controlled,” he said. “When they are out of control they continue to make antibodies that can be very damaging if there are too many. This happens in conditions such as myeloma – a cancer of plasma cells – and various forms of autoimmunity, such as systemic lupus erythamatosus or rheumatoid arthritis, where there are excessive levels of antibodies.”
Myeloma is a blood cancer that affects more than 1200 Australians each year, and is more common in people over 60. It is caused by the uncontrolled production of abnormal plasma cells in the bone marrow and the build up of damaging antibodies in the blood. Rheumatoid arthritis and lupus are autoimmune diseases in which the antibodies produced by plasma cells attack and destroy the body’s own tissues.
Associate Professor Tarlinton said that his hope was that the discovery could be used to develop new treatments for these conditions. “Myeloma in particular has a very poor prognosis, and is generally considered incurable,” Associate Professor Tarlinton said. “Now that we know Mcl1 is the one essential gene needed to keep plasma cells alive, we have begun ‘working backwards’ to identify all the critical molecules and signals needed to switch on Mcl1 and keep the cells alive. Our hope is that we will identify some point in the internal cell signalling pathway, or a critical external molecule, that could be blocked to stop Mcl-1 being produced by the cell. This would be an important new platform for diseases that currently have no specific or effective treatment, such as myeloma, or offer new treatment options for people who don’t respond well to existing treatments for diseases such as lupus or rheumatoid arthritis.”
TONY EASTLEY: For want of a better description we all apparently have an immune system ‘kill switch’.
Melbourne researchers have discovered why the body reacts the way it does when under stress from a severe infection.
They’ve found that the immune system switch destroys blood stem cells, and they’ve also discovered how to turn it off.
The discovery could mean a faster recovery rates from blood infections and from bouts of chemotherapy.
Martin Cuddihy reports.
MARTIN CUDDIHY: Worldwide, sepsis or blood poisoning is one of the leading causes of death in the intensive care units of hospitals.
When someone develops the condition the body goes into shock and blood stem cells start dying.
SETH MASTERS: You can think about it like suicide. The cells know that they should die to try and get rid of the infection but if the infection is overwhelming as it is with sepsis, then we need them to stay alive to help fight any infection.
MARTIN CUDDIHY: Dr Seth Masters from the Walter and Eliza Hall Institute in Melbourne is part of a research team that’s discovered the kill switch that tells cells when they should die.
Normally that’s a good thing, except when there’s a massive infection.
SETH MASTERS: You have to repopulate those immune cells somehow and these come from progenitor cells in the bone marrow and we think that this cell death pathway is something we can block to try and help the new cells regenerate to fight the infections better.
MARTIN CUDDIHY: So what does this cell receptor normally do?
SETH MASTERS: We are not entirely clear about that. We think that when a progenitor cell gets infected it’d be really bad if it stayed alive for too long cause it would pass that infection along to all of its daughters and sons.
So instead of staying infected, it just commits suicide and dies via this new pathway.
MARTIN CUDDIHY: Dr Masters is part of an international research team that’s found blocking a certain cell receptor stops blood cells from dying.
The researchers hope the discovery could lead to a treatment for sepsis and a way to help boost the immune system of cancer patients undergoing chemotherapy.
SETH MASTERS: I think that probably the most likely avenue where it could be of use is in trying to help recovery from chemotherapy. That’s a period during which we really need as many cells to mobilise out of the bone marrow into the periphery as possible to try and fight any potential infections that might be coming along.
And so we think that this cell death pathway might be stopping that from happening quickly and if we can inhibit it, we can make it go faster.
MARTIN CUDDIHY: Does that mean then that someone could be subjected to a more intense round of chemotherapy if this was to work and therefore you could boost their immune system following that round of chemo?
SETH MASTERS: Yeah, that does seem like a relatively attractive proposal. It is not something we have actually validated just yet but that would have to be on the cards if we can do some more research down those lines.
MARTIN CUDDIHY: The findings are published today in the medical journal Immunity.
New Class of Immune System Stimulants: Cyclic Di-Nucleotides (CDN): Shrink Tumors and bolster Vaccines, re-arm the Immune System’s Natural Killer Cells, which attack Cancer Cells and Virus-infected Cells
Reporter: Aviva Lev-Ari, PhD, RN
The Immunotherapeutics and Vaccine Research Initiative (IVRI), a UC Berkeley effort funded by Aduro Biotech, Inc.
UC Berkeley cancer immunologists are teaming up with colleagues working on infectious disease to create a new Immunotherapeutics and Vaccine Research Initiative, fueled by $7.5 million in funding from Aduro Biotech Inc., a Berkeley company that develops immunotherapies for cancer and other diseases.
The Immunotherapeutics and Vaccine Research Initiative (IVRI), a UC Berkeley effort funded by Aduro Biotech, Inc.
Aduro’s three years of funding, with the potential for three more, will support work on some of today’s most promising techniques for stimulating the immune system to fight off cancer and infections. These may include investigating a new class of immune system stimulants called cyclic di-nucleotides, which have shown promise in shrinking tumors and bolstering vaccines against tuberculosis, and research that could help re-arm the immune system’s natural killer cells, which normally attack cancer cells and virus-infected cells, to better fight tumors.
“We’re increasingly finding that immune stimulants associated with disease-causing microbes work as cancer therapies, and conversely, that immunotherapies for cancer may have application in fighting infectious disease,” said IVRI director David Raulet, a professor and co-chair of the Department of Molecular and Cell Biology. “Bringing infectious disease and cancer researchers together in a synergistic research effort at UC Berkeley and Aduro Biotech is an exciting and unique idea, and could be where the next generation of therapies will come from.”
Aduro already uses some of UC Berkeley’s technology, including attenuated Listeria monocytogenes mutants and methods to engineer these bacteria to stimulate the immune system as vaccines for immunotherapy. This technology, pioneered by Dan Portnoy, a UC Berkeley professor who has joint appointments in the Department of Molecular and Cell Biology and the infectious diseases and vaccinology division of the School of Public Health, has been further refined by Aduro scientists and is now being employed in Phase IIB clinical trials for vaccines against pancreatic cancer and mesothelioma.
Stephen Isaacs, CEO of Aduro Biotech, at the launch of the IVRI on March 23. (Peg Skorpinski photos)
“Through this unique collaboration, there is tremendous opportunity to improve our understanding of the immune system’s potential to serve as an important weapon in treating cancer and infectious disease,” said Stephen T. Isaacs, chairman, president and CEO of Aduro Biotech. “By combining UC Berkeley’s leading research and academic resources with innovative technology platforms, such as those developed by Aduro, we are confident that this initiative will lead to an improved understanding of, and potential treatments for, some of the most devastating diseases.”
The initiative was officially launched at an evening reception on March 24, the eve of aone-day symposium at UC Berkeley titled “Harnessing the Immune System to Fight Cancer and Infectious Diseases.” The symposium was jointly sponsored by UC Berkeley’s Henry Wheeler Center for Emerging and Neglected Diseases and Cancer Research Laboratory.
Berkeley research revived cancer immunotherapy
Much of the excitement around combining these two areas — the immunology of cancer and the immunology of infectious disease — comes from the amazing success of immunotherapy against cancer, which started with the work of James Allison when he was a professor of immunology at UC Berkeley and director of the Cancer Research Laboratory from 1985 to 2004. Allison, now at the University of Texas MD Anderson Cancer Center, discovered a way to release a brake on the body’s immune response to cancer that has proved highly successful at unleashing the immune system to attack melanoma and is being tried against other types of cancer.
James Allison, whose UC Berkeley work led to the renaissance of cancer immunotherapy.
Allison’s work revived attempts to rev up the immune system to fight cancer, and has led to many new avenues for creating cancer immune-therapies. In addition to Allison’s technique, which uses an antibody that blocks an immune suppressor called CTLA4, antibodies that block another immune suppressor, PD1, have been successful in treating melanoma, renal cancer and a type of lung cancer. Both CTLA4 and PD1 antibodies are now FDA-approved as cancer therapies.
Another promising avenue involves a protein in cells that responds to foreign DNA to launch an innate immune response — the first response of the body’s immune system. The protein, dubbed STING, is triggered by small molecules called cyclic di-nucleotides (CDN), and makes immune cells release interferon and other cytokines that activate disease-fighting T cells and stimulate the production of antibodies that together kill invading pathogens and destroy cancer cells. Listeria bacteria, for example, secrete a CDN directly into infected cells that activates STING.
Russell Vance, a UC Berkeley professor of molecular and cell biology and current head of the Cancer Research Laboratory, discovered several years ago that the chemical structure of these di-nucleotides is critical to their ability to work in humans. Aduro has since developed a CDN designed to work in humans and found that injecting it directly into a tumor in mice caused the tumor to shrink.
“It’s amazing how these discoveries made by infectious disease researchers have given us an exciting new approach to treat cancer,” Raulet said. “These really are areas that have a lot to say to each other.”
Another IVRI-affiliated researcher, Sarah Stanley, an assistant professor of public health, has found evidence that CDNs can help improve the imperfect vaccines we have today against tuberculosis.
Researchers at UC Berkeley will have access to Aduro’s novel technology platforms for research use, including its STING pathway activators, proprietary monoclonal antibodies and the engineered listeria bacteria, referred to as LADD (listeria attenuated double-deleted).
David Raulet, professor of molecular and cell biology and director of IVRI.
Raulet’s own research on natural killer or NK cells of the immune system has contributed to making these cells a new focus of cancer research. Revving up T cells is the goal of most immunotherapies today, but other immune cells, including NK cells, also attack tumors. As tumors advance, NK cells inside the tumors appear to become desensitized, he said. Recent research shows that some cytokines and other immune mediators Raulet discovered are able to “wake them up” and get them to resume their elimination of cancer cells.
“NK cell immunotherapies are very likely to be the next generation to complement T cell immunotherapies,” he predicted.
By focusing on fundamental scientific research to understand the immune system’s biochemical tools and signaling pathways, how the immune system recognizes invaders and how immune cells talk to one another, the IVRI has the potential to discover new ways to selectively target and cure many human diseases.
“The IVRI is a marriage of cancer immunotherapy and infectious disease immunology, where therapies in one area can be effective in the other, and observations in one can be applied to the other,” Raulet said. “It’s exciting to think that drugs tested first in diseases like cancer might have an impact on neglected diseases in the developing world, and that it can work in the other direction too.”