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Microbe meets cancer

Posted in Bacterial Resistance, Biochemical pathways, Biological Networks, Gene Regulation and Evolution, Cancer - General, Cancer Informatics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Clinical & Translational, Clinical Genomics, Curation, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Gastroenterology, Gene Regulation, Genome Biology, Inflammasome, Liver & Digestive Diseases Research, Metabolism, Methylation, Microbiologial genetics, Microbiology, Molecular Genetics & Pharmaceutical, Oxidative phosphorylation, Warburg effect, tagged Cancer immunology, Cancer immunotherapy, gut microbiome, gut microbiota, Immunotherapy, Microbiology, microbiome on April 10, 2016| Leave a Comment »

Microbe meets cancer

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Microbes Meet Cancer

Understanding cancer’s relationship with the human microbiome could transform immune-modulating therapies.

By Kate Yandell | April 1, 2016  http://www.the-scientist.com/?articles.view/articleNo/45616/title/Microbes-Meet-Cancer

 © ISTOCK.COM/KATEJA_FN; © ISTOCK.COM/FRANK RAMSPOTT  http://www.the-scientist.com/images/April2016/feature1.jpg

In 2013, two independent teams of scientists, one in Maryland and one in France, made a surprising observation: both germ-free mice and mice treated with a heavy dose of antibiotics responded poorly to a variety of cancer therapies typically effective in rodents. The Maryland team, led by Romina Goldszmidand Giorgio Trinchieri of the National Cancer Institute, showed that both an investigational immunotherapy and an approved platinum chemotherapy shrank a variety of implanted tumor types and improved survival to a far greater extent in mice with intact microbiomes.¹ The French group, led by INSERM’s Laurence Zitvogel, got similar results when testing the long-standing chemotherapeutic agent cyclophosphamide in cancer-implanted mice, as well as in mice genetically engineered to develop tumors of the lung.²

The findings incited a flurry of research and speculation about how gut microbes contribute to cancer cell death, even in tumors far from the gastrointestinal tract. The most logical link between the microbiome and cancer is the immune system. Resident microbes can either dial up inflammation or tamp it down, and can modulate immune cells’ vigilance for invaders. Not only does the immune system appear to be at the root of how the microbiome interacts with cancer therapies, it also appears to mediate how our bacteria, fungi, and viruses influence cancer development in the first place.

“We clearly see shifts in the [microbial] community that precede development of tumors,” says microbiologist and immunologist Patrick Schloss, who studies the influence of the microbiome on colon cancer at the University of Michigan.

But the relationship between the microbiome and cancer is complex: while some microbes promote cell proliferation, others appear to protect us against cancerous growth. And in some cases, the conditions that spur one cancer may have the opposite effect in another. “It’s become pretty obvious that the commensal microbiota affect inflammation and, through that or through other mechanisms, affect carcinogenesis,” says Trinchieri. “What we really need is to have a much better understanding of which species, which type of bug, is doing what and try to change the balance.”

Gut feeling

In the late 1970s, pathologist J. Robin Warren of Royal Perth Hospital in Western Australia began to notice that curved bacteria often appeared in stomach tissue biopsies taken from patients with chronic gastritis, an inflammation of the stomach lining that often precedes the development of stomach cancer. He and Barry J. Marshall, a trainee in internal medicine at the hospital, speculated that the bacterium, now called Helicobacter pylori, was somehow causing the gastritis.³ So committed was Marshall to demonstrating the microbe’s causal relationship to the inflammatory condition that he had his own stomach biopsied to show that it contained no H. pylori, then infected himself with the bacterium and documented his subsequent experience of gastritis.⁴ Scientists now accept that H. pylori, a common gut microbe that is present in about 50 percent of the world’s population, is responsible for many cases of gastritis and most stomach ulcers, and is a strong risk factor for stomach cancer.⁵ Marshall and Warren earned the 2005 Nobel Prize in Physiology or Medicine for their work.

H. pylori may be the most clear-cut example of a gut bacterium that influences cancer development, but it is likely not the only one. Researchers who study cancer in mice have long had anecdotal evidence that shifts in the microbiome influence the development of diverse tumor types. “You have a mouse model of carcinogenesis. It works beautifully,” says Trinchieri. “You move to another institution. It works completely differently,” likely because the animals’ microbiomes vary with environment.

IMMUNE INFLUENCE: In recent years, research has demonstrated that microbes living in and on the mammalian body can affect cancer risk, as well as responses to cancer treatment. Although the details of this microbe-cancer link remain unclear, investigators suspect that the microbiome’s ability to modulate inflammation and train immune cells to react to tumors is to blame.
See full infographic: WEB | PDF© AL GRANBERG

Around the turn of the 21st century, cancer researchers began to systematically experiment with the rodent microbiome, and soon had several lines of evidence linking certain gut microbes with a mouse’s risk of colon cancer. In 2001, for example, Shoichi Kado of the Yakult Central Institute for Microbiological Research in Japan and colleagues found that a strain of immunocompromised mice rapidly developed colon tumors, but that germ-free versions of these mice did not.⁶ That same year, an MIT-based group led by the late David Schauer demonstrated that infecting mice with the bacterium Citrobacter rodentium spurred colon tumor development.⁷ And in 2003, MIT’s Susan Erdman and her colleagues found that they could induce colon cancer in immunocompromised mice by infecting them with Helicobacter hepaticus, a relative of? H. pylori that commonly exists within the murine gut microbiome.⁸

More recent work has documented a similar link between colon cancer and the gut microbiome in humans. In 2014, a team led by Schloss sequenced 16S rRNA genes isolated from the stool of 90 people, some with colon cancer, some with precancerous adenomas, and still others with no disease.⁹ The researchers found that the feces of people with cancer tended to have an altered composition of bacteria, with an excess of the common mouth microbes Fusobacterium or Porphyromonas. A few months later, Peer Bork of the European Molecular Biology Laboratory performed metagenomic sequencing of stool samples from 156 people with or without colorectal cancer. Bork and his colleagues found they could predict the presence or absence of cancer using the relative abundance of 22 bacterial species, including Porphyromonas andFusobacterium.¹⁰ They could also use the method to predict colorectal cancer with about the same accuracy as a blood test, correctly identifying about 50 percent of cancers while yielding false positives less than 10 percent of the time. When the two tests were combined, they caught more than 70 percent of cancers.

Whether changes in the microbiota in colon cancer patients are harbingers of the disease or a consequence of tumor development remained unclear. “What comes first, the change in the microbiome or tumor development?” asks Schloss. To investigate this question, he and his colleagues treated mice with microbiome-altering antibiotics before administering a carcinogen and an inflammatory agent, then compared the outcomes in those animals and in mice that had received only the carcinogenic and inflammatory treatments, no antibiotics. The antibiotic-treated animals had significantly fewer and smaller colon tumors than the animals with an undisturbed microbiome, suggesting that resident bacteria were in some way promoting cancer development. And when the researchers transferred microbiota from healthy mice to antibiotic-treated or germ-free mice, the animals developed more tumors following carcinogen exposure. Sterile mice that received microbiota from mice already bearing malignancies developed the most tumors of all.¹¹

Most recently, Schloss and his colleagues showed that treating mice with seven unique combinations of antibiotics prior to exposing them to carcinogens yielded variable but predictable levels of tumor formation. The researchers determined that the number of tumors corresponded to the unique ways that each antibiotic cocktail modulated the microbiome.¹²

“We’ve kind of proven to ourselves, at least, that the microbiome is involved in colon cancer,” says Schloss, who hypothesizes that gut bacteria–driven inflammation is to blame for creating an environment that is hospitable to tumor development and growth. Gain or loss of certain components of the resident bacterial community could lead to the release of reactive oxygen species, damaging cells and their genetic material. Inflammation also involves increased release of growth factors and blood vessel proliferation, potentially supporting the growth of tumors. (See illustration above.)

Recent research has also yielded evidence that the gut microbiota impact the development of cancer in sites far removed from the intestinal tract, likely through similar immune-modulating mechanisms.

Systemic effects

In the mid-2000s, MIT’s Erdman began infecting a strain of mice predisposed to intestinal tumors withH. hepaticus and observing the subsequent development of colon cancer in some of the animals. To her surprise, one of the mice developed a mammary tumor. Then, more of the mice went on to develop mammary tumors. “This told us that something really interesting was going on,” Erdman recalls. Sure enough, she and her colleagues found that mice infected with H. hepaticus were more likely to develop mammary tumors than mice not exposed to the bacterium.¹³The researchers showed that systemic immune activation and inflammation could contribute to mammary tumors in other, less cancer-prone mouse models, as well as to the development of prostate cancer.

MICROBIAL STOWAWAYS: Bacteria of the human gut microbiome are intimately involved in cancer development and progression, thanks to their interactions with the immune system. Some microbes, such as Helicobacter pylori, increase the risk of cancer in their immediate vicinity (stomach), while others, such as some Bacteroides species, help protect against tumors by boosting T-cell infiltration.© EYE OF SCIENCE/SCIENCE SOURCE
http://www.the-scientist.com/images/April2016/immune_2.jpg

 

 

© DR. GARY GAUGLER/SCIENCE SOURCE  http://www.the-scientist.com/images/April2016/immune3.jpg

At the University of Chicago, Thomas Gajewski and his colleagues have taken a slightly different approach to studying the role of the microbiome in cancer development. By comparing Black 6 mice coming from different vendors—Taconic Biosciences (formerly Taconic Farms) and the Jackson Laboratory—Gajewski takes advantage of the fact that the animals’ different origins result in different gut microbiomes. “We deliberately stayed away from antibiotics, because we had a desire to model how intersubject heterogeneity [in cancer development] might be impacted by the commensals they happen to be colonized with,” says Gajewski in an email to The Scientist.

Last year, the researchers published the results of a study comparing the progression of melanoma tumors implanted under the mice’s skin, finding that tumors in the Taconic mice grew more aggressively than those in the Jackson mice. When the researchers housed the different types of mice together before their tumors were implanted, however, these differences disappeared. And transferring fecal material from the Jackson mice into the Taconic mice altered the latter’s tumor progression.¹⁴

Instead of promoting cancer, in these experiments the gut microbiome appeared to slow tumor growth. Specifically, the reduced tumor growth in the Jackson mice correlated with the presence of Bifidobacterium, which led to the greater buildup of T?cells in the Jackson mice’s tumors. Bifidobacteriaactivate dendritic cells, which present antigens from bacteria or cancer cells to T?cells, training them to hunt down and kill these invaders. Feeding Taconic mice bifidobacteria improved their response to the implanted melanoma cells.

“One hypothesis going into the experiments was that we might identify immune-suppressive bacteria, or commensals that shift the immune response towards a character that was unfavorable for tumor control,” says Gajewski.  “But in fact, we found that even a single type of bacteria could boost the antitumor immune response.”

http://www.the-scientist.com/images/April2016/immune4.jpg

 

Drug interactions

Ideally, the immune system should recognize cancer as invasive and nip tumor growth in the bud. But cancer cells display “self” molecules that can inhibit immune attack. A new type of immunotherapy, dubbed checkpoint inhibition or blockade, spurs the immune system to attack cancer by blocking either the tumor cells’ surface molecules or the receptors on T?cells that bind to them.

CANCER THERAPY AND THE MICROBIOME In addition to influencing the development and progression of cancer by regulating inflammation and other immune pathways, resident gut bacteria appear to influence the effectiveness of many cancer therapies that are intended to work in concert with host immunity to eliminate tumors. Some cancer drugs, such as oxaliplatin chemotherapy and CpG-oligonucleotide immunotherapy, work by boosting inflammation. If the microbiome is altered in such a way that inflammation is reduced, these therapeutic agents are less effective. Cancer-cell surface proteins bind to receptors on T cells to prevent them from killing cancer cells. Checkpoint inhibitors that block this binding of activated T cells to cancer cells are influenced by members of the microbiota that mediate these same cell interactions. Cyclophosphamide chemotherapy disrupts the gut epithelial barrier, causing the gut to leak certain bacteria. Bacteria gather in lymphoid tissue just outside the gut and spur generation of T helper 1 and T helper 17 cells that migrate to the tumor and kill it.

As part of their comparison of Jackson and Taconic mice, Gajewski and his colleagues decided to test a type of investigational checkpoint inhibitor that targets PD-L1, a ligand found in high quantities on the surface of multiple types of cancer cells. Monoclonal antibodies that bind to PD-L1 block the PD-1 receptors on T?cells from doing so, allowing an immune response to proceed against the tumor cells. While treating Taconic mice with PD-L1–targeting antibodies did improve their tumor responses, they did even better when that treatment was combined with fecal transfers from Jackson mice, indicating that the microbiome and the immunotherapy can work together to take down cancer. And when the researchers combined the anti-PD-L1 therapy with a bifidobacteria-enriched diet, the mice’s tumors virtually disappeared.¹⁴

Gajewski’s group is now surveying the gut microbiota in humans undergoing therapy with checkpoint inhibitors to better understand which bacterial species are linked to positive outcomes. The researchers are also devising a clinical trial in which they will give Bifidobacterium supplements to cancer patients being treated with the approved anti-PD-1 therapy pembrolizumab (Keytruda), which targets the immune receptor PD-1 on T?cells, instead of the cancer-cell ligand PD-L1.

Meanwhile, Zitvogel’s group at INSERM is investigating interactions between the microbiome and another class of checkpoint inhibitors called CTLA-4 inhibitors, which includes the breakthrough melanoma treatment ipilimumab (Yervoy). The researchers found that tumors in antibiotic-treated and germ-free mice had poorer responses to a CTLA-4–targeting antibody compared with mice harboring unaltered microbiomes.¹⁵ Particular Bacteroides species were associated with T-cell infiltration of tumors, and feedingBacteroides fragilis to antibiotic-treated or germ-free mice improved the animals’ responses to the immunotherapy. As an added bonus, treatment with these “immunogenic” Bacteroides species decreased signs of colitis, an intestinal inflammatory condition that is a dangerous side effect in patients using checkpoint inhibitors. Moreover, Zitvogel and her colleagues showed that human metastatic melanoma patients treated with ipilimumab tended to have elevated levels of B. fragilis in their microbiomes. Mice transplanted with feces from patients who showed particularly strong B. fragilis gains did better on anti-CTLA-4 treatment than did mice transplanted with feces from patients with normal levels of B. fragilis.

“There are bugs that allow the therapy to work, and at the same time, they protect against colitis,” says Trinchieri. “That is very exciting, because not only [can] we do something to improve the therapy, but we can also, at the same time, try to reduce the side effect.”

And these checkpoint inhibitors aren’t the only cancer therapies whose effects are modulated by the microbiome. Trinchieri has also found that an immunotherapy that combines antibodies against interleukin-10 receptors with CpG oligonucleotides is more effective in mice with unaltered microbiomes.¹He and his NCI colleague Goldszmid further found that the platinum chemotherapy oxaliplatin (Eloxatin) was more effective in mice with intact microbiomes, and Zitvogel’s group has shown that the chemotherapeutic agent cyclophosphamide is dependent on the microbiota for its proper function.

Although the mechanisms by which the microbiome influences the effectiveness of such therapies remains incompletely understood, researchers once again speculate that the immune system is the key link. Cyclophosphamide, for example, spurs the body to generate two types of T?helper cells, T?helper 1 cells and a subtype of T?helper 17 cells referred to as “pathogenic,” both of which destroy tumor cells. Zitvogel and her colleagues found that, in mice with unaltered microbiomes, treatment with cyclophosphamide works by disrupting the intestinal mucosa, allowing bacteria to escape into the lymphoid tissues just outside the gut. There, the bacteria spur the body to generate T?helper 1 and T?helper 17 cells, which translocate to the tumor. When the researchers transferred the “pathogenic” T?helper 17 cells into antibiotic-treated mice, the mice’s response to chemotherapy was partly restored.

Microbiome modification

As the link between the microbiome and cancer becomes clearer, researchers are thinking about how they can manipulate a patient’s resident microbial communities to improve their prognosis and treatment outcomes. “Once you figure out exactly what is happening at the molecular level, if there is something promising there, I would be shocked if people don’t then go in and try to modulate the microbiome, either by using pharmaceuticals or using probiotics,” says Michael Burns, a postdoc in the lab of University of Minnesota genomicist Ran Blekhman.

Even if researchers succeed in identifying specific, beneficial alterations to the microbiome, however, molding the microbiome is not simple. “It’s a messy, complicated system that we don’t understand,” says Schloss.

So far, studies of the gut microbiome and colon cancer have turned up few consistent differences between cancer patients and healthy controls. And the few bacterial groups that have repeatedly shown up are not present in every cancer patient. “We should move away from saying, ‘This is a causal species of bacteria,’” says Blekhman. “It’s more the function of a community instead of just a single bacterium.”

But the study of the microbiome in cancer is young. If simply adding one type of microbe into a person’s gut is not enough, researchers may learn how to dose people with patient-specific combinations of microbes or antibiotics. In February 2016, a team based in Finland and China showed that a probiotic mixture dubbed Prohep could reduce liver tumor size by 40 percent in mice, likely by promoting an anti-inflammatory environment in the gut.¹⁶

“If it is true that, in humans, we can alter the course of the disease by modulating the composition of the microbiota,” says José Conejo-Garcia of the Wistar Institute in Philadelphia, “that’s going to be very impactful.”

Kate Yandell has been a freelance writer living Philadelphia, Pennsylvania. In February she became an associate editor at Cancer Today.

GENETIC CONNECTION The microbiome doesn’t act in isolation; a patient’s genetic background can also greatly influence response to therapy. Last year, for example, the Wistar Institute’s José Garcia-Conejo and Melanie Rutkowski, now an assistant professor at the University of Virginia, showed that a dominant polymorphism of the gene for the innate immune protein toll-like receptor 5 (TLR5) influences clinical outcomes in cancer patients by changing how the patients’ immune cells interact with their gut microbes (Cancer Cell, 27:27-40, 2015). More than 7 percent of people carry a specific mutation in TLR5 that prevents them from mounting a full immune response when exposed to bacterial flagellin. Analyzing both genetic and survival data from the Cancer Genome Atlas, Conejo-Garcia, Rutkowski, and their colleagues found that estrogen receptor–positive breast cancer patients who carry the TLR5 mutation, called the R392X polymorphism, have worse outcomes than patients without the mutation. Among patients with ovarian cancer, on the other hand, those with the TLR5 mutation were more likely to live at least six years after diagnosis than patients who don’t carry the mutation. Investigating the mutation’s contradictory effects, the researchers found that mice with normal TLR5produce higher levels of the cytokine interleukin 6 (IL-6) than those carrying the mutant version, which have higher levels of a different cytokine called interleukin 17 (IL-17). But when the researchers knocked out the animals’ microbiomes, these differences in cytokine production disappeared, as did the differences in cancer progression between mutant and wild-type animals. “The effectiveness of depleting specific populations or modulating the composition of the microbiome is going to affect very differently people who are TLR5-positive or TLR5-negative,” says Conejo-Garcia. And Rutkowski speculates that many more polymorphisms linked to cancer prognosis may act via microbiome–immune system interactions. “I think that our paper is just the tip of the iceberg.”

References

1. N. Iida et al., “Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment,” Science, 342:967-70, 2013.
2. S. Viaud et al., “The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide,” Science, 342:971-76, 2013.
3. J.R. Warren, B. Marshall, “Unidentified curved bacilli on gastric epithelium in active chronic gastritis,”Lancet, 321:1273-75, 1983.
4. B.J. Marshall et al., “Attempt to fulfil Koch’s postulates for pyloric Campylobacter,” Med J Aust, 142:436-39, 1985.
5. J. Parsonnet et al., “Helicobacter pylori infection and the risk of gastric carcinoma,” N Engl J Med, 325:1127-31, 1991.
6. S. Kado et al., “Intestinal microflora are necessary for development of spontaneous adenocarcinoma of the large intestine in T-cell receptor β chain and p53 double-knockout mice,” Cancer Res, 61:2395-98, 2001.
7. J.V. Newman et al., “Bacterial infection promotes colon tumorigenesis in ApcMin/+ mice,” J Infect Dis, 184:227-30, 2001.
8. S.E. Erdman et al., “CD4+ CD25+ regulatory T lymphocytes inhibit microbially induced colon cancer in Rag2-deficient mice,” Am J Pathol, 162:691-702, 2003.
9. J.P. Zackular et al., “The human gut microbiome as a screening tool for colorectal cancer,” Cancer Prev Res, 7:1112-21, 2014.
10. G. Zeller et al., “Potential of fecal microbiota for early-stage detection of colorectal cancer,” Mol Syst Biol, 10:766, 2014.
11. J.P. Zackular et al., “The gut microbiome modulates colon tumorigenesis,” mBio, 4:e00692-13, 2013.
12. J.P. Zackular et al., “Manipulation of the gut microbiota reveals role in colon tumorigenesis,”mSphere, doi:10.1128/mSphere.00001-15, 2015.
13. V.P. Rao et al., “Innate immune inflammatory response against enteric bacteria Helicobacter hepaticus induces mammary adenocarcinoma in mice,” Cancer Res, 66:7395, 2006.
14. A. Sivan et al., “Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy,” Science, 350:1084-89, 2015.
15. M. Vétizou et al., “Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota,”Science, 350:1079-84, 2015.

……..

 

Th17 Cell Induction by Adhesion of Microbes to Intestinal Epithelial Cells

Koji Atarashi · Takeshi Tanoue · Minoru Ando ·Nobuhiko Kamada ·….. · Yoshinori Umesaki · Kenya Honda ·

ABSTRACT: Intestinal Th17 cells are induced and accumulate in response to colonization with a subgroup of intestinal microbes such as segmented filamentous bacteria (SFB) and certain extracellular pathogens. Here, we show that adhesion of microbes to intestinal epithelial cells (ECs) is a critical cue for Th17 induction. Upon monocolonization of germ-free mice or rats with SFB indigenous to mice (M-SFB) or rats (R-SFB), M-SFB and R-SFB showed host-specific adhesion to small intestinal ECs, accompanied by host-specific induction of Th17 cells. Citrobacter rodentium and Escherichia coli O157 triggered similar Th17 responses, whereas adhesion-defective mutants of these microbes failed to do so. Moreover, a mixture of 20 bacterial strains, which were selected and isolated from fecal samples of a patient with ulcerative colitis on the basis of their ability to cause a robust induction of Th17 cells in the mouse colon, also exhibited EC-adhesive characteristics….. · Sep 2015 · Cell 163(2)    https://www.researchgate.net/profile/Shoichi_Kado     http://dx.doi.org:/10.1016/j.cell.2015.08.058

MIT Faculty Newsletter     Vol. XXII No. 2  Nov / Dec 2009  Memorial Resolution for David B. Schauer

We regretfully acknowledge the sudden death of our friend and colleague, Dr. David Schauer, on June 7, 2009 – one day after his 48th birthday. David Schauer was known not only for his keen scientific mind, but also as a friend whose empathy and compassion touched countless individuals.

David’s research was supported on a continuous basis by the National Institutes of Health throughout his career at MIT. His studies on microbial pathogenesis of gastrointestinal pathogenic bacteria, particularly Citrobacter rodentium, a murine model of enteropathogenic Escherichia coli, and enterohepatic helicobacter are widely known and respected.

David’s research provided important insights into the molecular mechanisms evoked by enteric pathogens and how the infections caused by these bacteria perturb the gastrointestinal barrier, elicit inflammation, and produce clinically relevant disease.

Susan Erdman is a Principal Research Scientist and Assistant Director in the Division of Comparative Medicine at MIT.

• Invited Speaker. National Cancer Institute (NCI) Mucosal, Immunosurveillance, Inflammation and Cancer Workshop.  April, 2005.
• Invited reviewer. National Cancer Institute (NCI) RFA-CA-06-014 Tumor Microenvironment Network.  August, 2006.
• Invited speaker. Keystone Symposium on Mechanisms Linking Inflammation and Cancer, February, 2007
• Alumni Fellow, College of Veterinary Medicine, Mississippi State University, 2007
• Invited Speaker. National Cancer Institute (NCI) Changing Concepts in Cancer Etiology: The Role of the Human Microbiome.  November, 2009.
• Invited speaker. Keystone Symposium on Role of Inflammation in Oncogenesis, February, 2010
• Invited reviewer. National Cancer Institute (NCI) Tumor Microenvironment Network.  June, 2011
• Invited Speaker, National Institute of Health (NIH) Human Microbiome Science Conference: Vision for the Future. Wound healing to longevity: Microbe-induced immune proficiency for human health. July, 2013.
• Invited speaker, Wellcome Trust, Human Host-Microbiome Interactions Conference, April 2014.
• Invited speaker, Van Andel Institute, Origins of Cancer Conference, July 2014

Peer Bork

• Current position: senior group leader (bioinformatics) at the EMBL (Heidelberg);
  joint coordinator of the EMBL Structural and Computational Biology unit;
  visiting group leader at the MDC (Berlin-Buch)
• Advisor: Current and former member of various SABs and evaluation panels (academia + industry)
  Cofounder of LION bioscience AG (now SYGNIS Pharma AG), Cellzome AG, Anadys Pharmaceuticals Inc. and biobyte solutions GmbH
• Scientific interests: prediction of protein function at different spatial scales,
  protein and genome evolution (iTOL), protein domain analysis,
  comparative genome and proteome analysis, bridging genotype and phenotype
• Some Projects: genome annotation,
  comparative analysis of protein modules (SMART),
  biochemical pathways and networks (STRING),
  networks of chemicals and proteins (STITCH)
  bioinformatics applications in molecular medicine
  comparative metagenomics
• List of group publications

Microbially Driven TLR5-Dependent Signaling Governs Distal Malignant Progression through Tumor-Promoting Inflammation

Melanie R. Rutkowski, Tom L. Stephen, Nikolaos Svoronos, …., Julia Tchou,  Gabriel A. Rabinovich, Jose R. Conejo-Garcia
Cancer cell    12 Jan 2015; Volume 27, Issue 1, p27–40  http://dx.doi.org/10.1016/j.ccell.2014.11.009

http://www.cell.com/cms/attachment/2023542033/2043769432/fx1.jpg

• •TLR5-dependent IL-6 mobilizes MDSCs that drive galectin-1 production by γδ T cells
• •IL-17 drives malignant progression in IL-6-unresponsive tumors
• •TLR5-dependent differences in tumor growth are abrogated upon microbiota depletion
• •A common dominant TLR5 polymorphism influences the outcome of human cancers

The dominant TLR5^R392X polymorphism abrogates flagellin responses in >7% of humans. We report that TLR5-dependent commensal bacteria drive malignant progression at extramucosal locations by increasing systemic IL-6, which drives mobilization of myeloid-derived suppressor cells (MDSCs). Mechanistically, expanded granulocytic MDSCs cause γδ lymphocytes in TLR5-responsive tumors to secrete galectin-1, dampening antitumor immunity and accelerating malignant progression. In contrast, IL-17 is consistently upregulated in TLR5-unresponsive tumor-bearing mice but only accelerates malignant progression in IL-6-unresponsive tumors. Importantly, depletion of commensal bacteria abrogates TLR5-dependent differences in tumor growth. Contrasting differences in inflammatory cytokines and malignant evolution are recapitulated in TLR5-responsive/unresponsive ovarian and breast cancer patients. Therefore, inflammation, antitumor immunity, and the clinical outcome of cancer patients are influenced by a common TLR5 polymorphism.

see also… Immune Influence

In recent years, research has demonstrated that microbes living in and on the mammalian body can affect cancer risk, as well as responses to cancer treatment.

By Kate Yandell | April 1, 2016

http://www.the-scientist.com/?articles.view/articleNo/45644/title/Immune-Influence

Although the details of this microbe-cancer link remain unclear, investigators suspect that the microbiome’s ability to modulate inflammation and train immune cells to react to tumors is to blame. Here are some of the hypotheses that have come out of recent research in rodents for how gut bacteria shape immunity and influence cancer.

HOW THE MICROBIOME PROMOTES CANCER

Gut bacteria can dial up inflammation locally in the colon, as well as in other parts of the body, leading to the release of reactive oxygen species, which damage cells and DNA, and of growth factors that spur tumor growth and blood vessel formation.

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Helicobacter pylori can cause inflammation and high cell turnover in the stomach wall, which may lead to cancerous growth.

HOW THE MICROBIOME STEMS CANCER

Gut bacteria can also produce factors that lower inflammation and slow tumor growth.

Some gut bacteria (e.g., Bifidobacterium) appear to activate dendritic cells, which present cancer-cell antigens to T cells that in turn kill the cancer cells.

http://www.the-scientist.com/images/April2016/ImmuneInfluence3_310px1.jpg

http://www.the-scientist.com/images/April2016/ImmuneInfluence4_310px1.jpg

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Signaling of Immune Response in Colon Cancer

Posted in BioIT: BioInformatics, Biological Networks, Biomarkers & Medical Diagnostics, Cancer - General, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Curation, Cytokines, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Gastroenterology, Gene Regulation, Human Immune System in Health and in Disease, Immuno-Oncology & Genomics, Immunology, Metabolism, Metabolomics, Proteomics, tagged Colorectal cancer, protein, STING (innate immune signaling) on January 9, 2016| Leave a Comment »

Signaling of Immune Response in Colon Cancer

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Revised 1/13/2016

STING Protein May Serve as Biomarker for Colorectal and Other Cancers

http://www.genengnews.com/gen-news-highlights/sting-protein-may-serve-as-biomarker-for-colorectal-and-other-cancers/81252165/

 

Scientists at University of Miami Miller School of Medicine’s Sylvester Comprehensive Cancer Center say they have discovered how the stimulator of interferon genes (STING) signaling pathway may play an important role in alerting the immune system to cellular transformation. They believe their finding will shed further light on the immune system’s response to cancer development.

In 2008, Glen N. Barber, Ph.D., leader of the viral oncology program at Sylvester, and professor and chairman of cell biology at the Miller School of Medicine, and colleagues published in Nature (“STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling”) the discovery of STING as a new cellular molecule that recognizes virus and bacteria infection to initiate host defense and immune responses. In the new study, published in Cell Reports (“Deregulation of STING Signaling in Colorectal Carcinoma Constrains DNA Damage Responses and Correlates With Tumorigenesis”), they describe STING’s role in the potential suppression of colorectal cancer.

“Since 2008 we’ve known that STING is crucial for antiviral and antibacterial responses,” said Dr. Barber. “But until now, little had been known about its function in human tumors. In this study we show, for the first time, that STING signaling is repressed in colorectal carcinoma and other cancers, an event which may enable transformed cells to evade the immune system.”

Colorectal cancer currently affects around 1.2 million people in the U.S. and 150,000 new cases are diagnosed every year, making it the third most common cancer in both men and women. Since most colon cancers develop from benign polyps, they can be treated successfully when detected early. However, if the tumor has already spread, survival rates are generally low.

Using disease models of colorectal cancer, the team of Sylvester scientists showed that loss of STING signaling negatively affected the body’s ability to recognize DNA-damaged cells. In particular, certain cytokines that facilitate tissue repair and antitumor priming of the immune system were not sufficiently produced to initiate a significant immune response to eradicate the colorectal cancer.

“We were able to show that impaired STING responses may enable damaged cells to elude the immune system,” continued Dr. Barber. “And if the body doesn’t recognize and attack cancer cells, they will multiply and, ultimately, spread to other parts of the body.”

He and his colleagues suggest evaluating STING signaling as a prognostic marker for the treatment of colorectal as well as other cancers. For example, Dr. Barber’s study showed that cancer cells with defective STING signaling were particularly prone to attack by oncolytic viruses presently being used as cancer therapies.

“Impaired STING responses may enable damaged cells to evade host immunosurveillance processes, although they provide a critical prognostic measurement that could help predict the outcome of effective oncoviral therapy,” wrote the investigators.

STING Protein Could be Used for Cancer Diagnosis

http://www.technologynetworks.com/Proteomics/news.aspx?ID=186674

 

This is the first detailed examination of how the stimulator of interferon genes (STING) signaling pathway, discovered by Glen N. Barber, Ph.D., Leader of the Viral Oncology Program at Sylvester Comprehensive Cancer Center, may play an important role in alerting the immune system to cellular transformation.

In 2008, Barber, who is also Professor and Chairman of Cell Biology at the University of Miami Miller School of Medicine, and colleagues published in Nature the discovery of STINGas a new cellular molecule that recognizes virus and bacteria infection to initiate host defense and immune responses. In the new study they describe STING’s role in the potential suppression of colorectal cancer.

“Since 2008 we’ve known that STING is crucial for antiviral and antibacterial responses,” said Barber. “But until now, little had been known about its function in human tumors. In this study we show, for the first time, that STING signaling is repressed in colorectal carcinoma and other cancers, an event which may enable transformed cells to evade the immune system.”

Colorectal cancer currently affects around 1.2 million people in the United States and 150.000 new cases are diagnosed every year, making it the third most common cancer in both men and women. Since most colon cancers develop from benign polyps, they can be treated successfully when detected early. However, if the tumor has already spread, survival rates are generally low.

Using disease models of colorectal cancer, the team of Sylvester scientists showed that loss of STING signaling negatively affected the body’s ability to recognize DNA-damaged cells. In particular, certain cytokines – small proteins important for cell signaling – that facilitate tissue repair and anti-tumor priming of the immune system were not sufficiently produced to initiate a significant immune response to eradicate the colorectal cancer.

“We were able to show that impaired STING responses may enable damaged cells to elude the immune system,” added Barber. “And if the body doesn’t recognize and attack cancer cells, they will multiply and, ultimately, spread to other parts of the body.”

Barber and his colleagues suggest evaluating STING signaling as a prognostic marker for the treatment of colorectal as well as other cancers. For example, Barber’s study showed that cancer cells with defective STING signaling were particularly prone to attack by oncolytic viruses presently being used as cancer therapies. Alternate studies with colleagues have also shown that activators of STING signaling are potent stimulators of anti-tumor immune responses. Collectively, the control of STING signaling may have important implications for cancer development as well as cancer treatment.

 

Every step you take: STING pathway key to tumor immunity

http://sciencelife.uchospitals.edu/2014/11/20/every-step-you-take-sting-pathway-key-to-tumor-immunity/

A recently discovered protein complex known as STING plays a crucial role in detecting the presence of tumor cells and promoting an aggressive anti-tumor response by the body’s innate immune system, according to two separate studies published in the Nov. 20 issue of the journal Immunity.

The studies, both from University of Chicago-based research teams, have major implications for the growing field of cancer immunotherapy. The findings show that when activated, the STING pathway triggers a natural immune response against the tumor. This includes production of chemical signals that help the immune system identify tumor cells and generate specific killer T cells. The research also found that targeted high-dose radiation therapy dials up the activation of this pathway, which promotes immune-mediated tumor control.

These findings could “enlarge the fraction of patients who respond to immunotherapy with prolonged control of the tumor,” according to a commentary on the papers by the University of Verona’s Vincenzo Bronte, MD. “Enhancing the immunogenicity of their cancers might expand the lymphocyte repertoire that is then unleashed by interference with checkpoint blockade pathways,” such as anti-PD-1.

STING, short for STimulator of INterferon Genes complex, is a crucial part of the process the immune system relies on to detect threats — such as infections or cancer cells — that are marked by the presence of DNA that is damaged or in the wrong place, inside the cell but outside the nucleus.

Detection of such “cytosolic” DNA initiates a series of interactions that lead to the STING pathway. Activating the pathway triggers the production of interferon-beta, which in turn alerts the immune system to the threat, helps the system detect cancerous or infected cells, and ultimately sends activated T cells into the battle.

“We have learned

“Innate immune sensing via the host STING pathway is critical for tumor control by checkpoint blockade,” Gajewski’s team noted in their paper. They found promising drugs known as checkpoint inhibitors — such as anti PD-1 or anti PD-L1, which can take the brakes off of an immune response — were not effective in STING-deficient mice. New agents that stimulate the STING pathway are being developed as potential cancer therapeutics.

A second University of Chicago team, led by cancer biologistYang-Xin Fu, MD, PhD, professor of pathology, and Ralph Weichselbaum, MD, chairman of radiation and cellular oncology and co-director of the Ludwig Center for Metastasis Research, found that high-dose radiation therapy not only kills targeted cancer cells but the resulting DNA damage drives a systemic immune response.

a great deal recently about what we call checkpoints, the stumbling blocks that prevent the immune system from ultimately destroying cancers,” said Thomas Gajewski, MD, PhD, professor of medicine and pathology at the University of Chicago and senior author of one of the studies. “Blockade of immune checkpoints, such as with anti-PD-1, is therapeutic in a subset of patients, but many individuals still don’t respond. Understanding the role of the STING pathway provides insights into how we can ‘wake up’ the immune response against tumors. This can be further boosted by checkpoint therapies.”

The two published studies, he said, help move this approach forward.

In a series of experiments in mice, both research teams found tumor cell-derived DNA could initiate an immune response against cancers. But when tested in mice that lacked a functional gene for STING, the immune system did not effectively respond.

“This result unifies traditional studies of DNA damage with newly identified DNA sensing of immune responses,” Fu said.

“This is a previously unknown mechanism,” Weichselbaum added.

In mice that lacked STING, however, there was no therapeutic immune response. The induction of interferons by radiation and consequent cancer cell killing, they conclude, depends on STING-pathway signaling.

They did find that combining cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), an earlier step in the STING pathway, with radiation, could greatly enhance the antitumor efficacy of radiation.

“This opens a new avenue to develop STING-related agonists for patients with radiation-resistant cancers,” Fu said.

 

 

STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors

Seng-Ryong Woo¹, Mercedes B. Fuertes¹, Leticia Corrales¹, …., Maria-Luisa Alegre², Thomas F. Gajewski^{1, 2}   

Immunity 20 Nov 2014; 41(5): 830–842    http://dx.doi.org:/10.1016/j.immuni.2014.10.017

 

Highlights

• Spontaneous T cell responses against tumors require the host STING pathway in vivo

• Tumor-derived DNA can induce type I interferon production via STING

• Tumor DNA can be identified in host APCs in the tumor microenvironment in vivo

---

Summary

Spontaneous T cell responses against tumors occur frequently and have prognostic value in patients. The mechanism of innate immune sensing of immunogenic tumors leading to adaptive T cell responses remains undefined, although type I interferons (IFNs) are implicated in this process. We found that spontaneous CD8⁺ T cell priming against tumors was defective in mice lacking stimulator of interferon genes complex (STING), but not other innate signaling pathways, suggesting involvement of a cytosolic DNA sensing pathway. In vitro, IFN-β production and dendritic cell activation were triggered by tumor-cell-derived DNA, via cyclic-GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3). In the tumor microenvironment in vivo, tumor cell DNA was detected within host antigen-presenting cells, which correlated with STING pathway activation and IFN-β production. Our results demonstrate that a major mechanism for innate immune sensing of cancer occurs via the host STING pathway, with major implications for cancer immunotherapy.

 

http://ars.els-cdn.com/content/image/1-s2.0-S1074761314003938-fx1.jpg

 

Immunity Erratum STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors

Seng-Ryong Woo, Mercedes B. Fuertes, Leticia Corrales, Stefani Spranger, Michael J. Furdyna, Michael Y.K. Leung, Ryan Duggan, Ying Wang, Glen N. Barber, Katherine A. Fitzgerald, Maria-Luisa Alegre, and Thomas F. Gajewski* *Correspondence: tgajewsk@medicine.bsd.uchicago.edu http://dx.doi.org/10.1016/j.immuni.2014.12.015 (Immunity 41, 830–842; November 20, 2014)

The original Figure 3C accidentally contained a duplicated panel in the bright-field column, third row down, and this has now been replaced with the correct data. The change does not alter the conclusions of the paper. This mistake has now been corrected online, and the authors regret the error.

 

Cytosolic DNA Sensors (CDSs): a STING in the tail – Review

November 2012   http://www.invivogen.com/review-cds-ligands

The innate immune system provides the first line of defense against infectious pathogens and serves to limit their early proliferation. It is also vital in priming and activating the adaptive immune system.

Innate immune detection of intracellular DNA derived from viruses and invasive bacteria is important to initiate an effective protective response. This crucial step depends on cytosolic DNA sensors (CDSs), which upon activation trigger the production of type I interferons (IFNs) and the induction of IFN-responsive genes and proinflammatory chemokines.
Although the identity of these CDSs is not fully uncovered, much progress has been made in understanding the signaling pathways triggered by these sensors.

Cytosolic DNA-mediated production of type I IFNs (mainly IFN-β) requires the transcription factor IFN regulatory factor 3 (IRF3), which is activated upon phosphorylation by TANK-binding-kinase-1 (TBK1) [1].

STING in DNA sensing

Recently, a new molecule, STING (stimulator of IFN genes), has been shown to be essential for the TBK1-IRF3- dependent induction of IFN-β by transfected DNA ligands and intracellular DNA produced by pathogens after infection [2, 3].
STING (also known as MITA, MPYS and ERIS) is a transmembrane protein that resides in the endoplasmic reticulum (ER) [2-6]. In response to cytosolic DNA, STING forms dimers and translocates from the ER to the Golgi then to punctate cytosolic structures where it colocalizes with TBK-1, leading to the phosphorylation of IRF3.
How STING stimulates TBK1-dependent IRF3 activation was recently elucidated by Tanaka and Chen. They found that, upon cytosolic DNA sensing, the C-terminal tail of STING acts as a scaffold protein to promote the phosphorylation of IRF3 by TBK1 [7].

STING in the host response to intracellular pathogens. Linking type I IFN response and autophagy for better defense

http://www.invivogen.com/images/STING-autophagy.png

 

STING activates the IFN response

Until very recently, STING in addition to its role as an adaptor protein was also thought to function as a sensor of cyclic dinucleotides.
Burdette et al. first demonstrated that STING binds directly to the bacterial molecule cyclic diguanylate monophosphate (c-di-GMP) [8]. This finding was confirmed by several teams who examined the structure of STING bound to c-di-GMP [9-11], including Cheng and colleagues, however their data suggest that STING is not the primary sensor of c-di-GMP [12]. Rather, they indicate that DDX41, an identified CDS, functions as a direct receptor for cyclic dinucleotides upstream of STING. The authors hypothesized that DDX41 binds to c-di-GMP then forms a complex with STING to activate the IFN response.

STING induces autophagy

Exciting new developments reveal that STING participates in another aspect of innate immunity, autophagy.
Autophagy plays a critical role in host defense responses to pathogens by promoting the elimination of microbes that enter into the cytosol by their sequestration into autophagosomes and their delivery to the lysosome.

 

http://www.invivogen.com/images/STING-CDS_pathway_small.jpg

Recent studies have reported that DNA viruses and intracellular bacteria induce autophagy and that this process is dependent on cytosolic genomic DNA and STING [13-15]. Robust induction of autophagy was also observed after transfection of various double stranded (ds) DNA species, such as poly(dA:dT), poly(dG:dC) or plasmid DNA, but not single stranded (ss) DNA, dsRNA or ssRNA [16].

Interestingly, activated STING was shown to relocate to unidentified membrame-bound compartments where it colocalizes with LC3, a hallmark of autophagy, and ATg9a. The latter protein was reported to regulate the interaction between STING and TBK1 after dsDNA stimulation [16]. The E3 ubiquitin ligases TRIM56 and TRIM32
were also found to regulate STING by mediating its dimerization through K63-linked ubiquitination [17, 18].

Several cytosolic DNA sensors upstream of STING have been proposed.
DNA-dependent activator of IRFs (DAI) was the first CDS discovered based on the ability of transfected poly(dA:dT) to induce IFN-β [19]. However, the role of DAI has been shown to be very cell-type specific and cells derived from DAI-deficient mice responded normally to dsDNA ligands [20].

While analyzing immune responses to dsDNA regions derived from vaccinia virus (VACV-70) or Herpes simplex virus 1 (HSV-60) genomes, Unterholzner et al. identified IFI16 as a DNA binding protein mediating IFN-β induction [21]. Interestingly, IFI16 belongs to a new family of pattern recognition receptors that contain the pyrin and HIN domain (PYHIN), termed AIM2-like receptors (ALRs).

AIM2 is a STING-independent cytosolic DNA sensor that forms an inflammasome with ASC to trigger caspase-1 activation and the secretion of the proinflammatory cytokines IL-1β and IL-18 [20].

Members of the DExD/H-box helicase superfamily have also been reported to function as cytosolic DNA sensors. While DHX36 and DHX9 were identified as STING-independent but MyD88-dependent sensors of CpG-containing DNA in plasmacytoid dendritic cells, DDX41 was found to bind various dsDNA ligands and localize with STING to promote IFN-β expression [22]. Other CDSs have been reported to function independently of STING: RNA Pol III, LRRFIP1 and Ku70 [20].

Unlike cytosolic RNA sensors (RIG-I, MDA-5), which detect structural moieties specific to pathogen RNA, such as 5’-triphosphates, it is not clear whether cytosolic DNA sensors can recognize any particular structural motif of DNA that would discriminate between self and non-self. This suggests that CDSs may have a role not only in anti-microbial innate immune responses but also in autoimmunity. A multitude of CDSs have been described but whether they are all true receptors remains an open question.

1. Stetson DB & Medzhitov R. 2006. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity. 24(1):93-103.
2. Ishikawa H. & Barber GN., 2008. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 455(7213):674-8.
3. Ishikawa H. et al., 2009. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature. 461(7265):788-92.
4. Zhong B. et al., 2008. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity. 29(4):538-50.
5. Jin L. et al., 2008. MPYS, a novel membrane tetraspanner, is associated with major histocompatibility complex class II and mediates transduction of apoptotic signals. Mol Cell Biol. 28(16):5014-26.

 

UV Light Potentiates STING (Stimulator of Interferon Genes)-dependent Innate Immune Signaling through Deregulation of ULK1 (Unc51-like Kinase 1).

Kemp MG¹, Lindsey-Boltz LA², Sancar A³. Author information

 J Biol Chem. 2015 May 8;290(19):12184-94.  http://dx.doi.org:/10.1074/jbc.M115.649301. Epub 2015 Mar 19.

The mechanism by which ultraviolet (UV) wavelengths of sunlight trigger or exacerbate the symptoms of the autoimmune disorder lupus erythematosus is not known but may involve a role for the innate immune system. Here we show that UV radiation potentiates STING (stimulator of interferon genes)-dependent activation of the immune signaling transcription factor interferon regulatory factor 3 (IRF3) in response to cytosolic DNA and cyclic dinucleotides in keratinocytes and other human cells. Furthermore, we find that modulation of this innate immune response also occurs with UV-mimetic chemical carcinogens and in a manner that is independent of DNA repair and several DNA damage and cell stress response signaling pathways. Rather, we find that the stimulation of STING-dependent IRF3 activation by UV is due to apoptotic signaling-dependent disruption of ULK1 (Unc51-like kinase 1), a pro-autophagic protein that negatively regulates STING. Thus, deregulation of ULK1 signaling by UV-induced DNA damage may contribute to the negative effects of sunlight UV exposure in patients with autoimmune disorders.

 

 

STING and the innate immune response to nucleic acids in the cytosol

Dara L Burdette & Russell E Vance

https://mcb.berkeley.edu/labs/vance/Resources/Burdette%20(2013)%20review.pdf

Cytosolic detection of pathogen-derived nucleic acids is critical for the initiation of innate immune defense against diverse bacterial, viral and eukaryotic pathogens. Conversely, inappropriate responses to cytosolic nucleic acids can produce severe autoimmune pathology. The host protein STING has been identified as a central signaling molecule in the innate immune response to cytosolic nucleic acids. STING seems to be especially critical for responses to cytosolic DNA and the unique bacterial nucleic acids called ‘cyclic dinucleotides’. Here we discuss advances in the understanding of STING and highlight the many unresolved issues in the field.

The detection of pathogen-derived nucleic acids is a central strategy by which the innate immune system senses microbes to then initiate protective responses1. Conversely, inappropriate recognition of self nucleic acids can result in debilitating autoimmune diseases such as systemic lupus erythematosus2. It is therefore important to understand the molecular basis of the detection of nucleic acids by the innate immune system. Studies have established that nucleic acids derived from extracellular sources are sensed mainly by endosomal Toll-like receptors (TLRs), such as TLR3, TLR7 and TLR9, whereas cytosolic nucleic acids are detected independently of TLRs by a variety of less-well-characterized mechanisms1.

Studies have identified STING (‘stimulator of interferon genes’; also known as TMEM173, MPYS, MITA and ERIS) as a critical signaling molecule in the innate response to cytosolic nucleic-acid ligands. STING was first described as a protein that interacts with major histocompatibility complex class II molecules3, but the relevance of this interaction remains unclear. Subsequent studies have instead focused on the role of STING in the transcriptional induction of type I interferons and coregulated genes in response to nucleic acids in the cytosol. Several groups have independently isolated STING by screening for proteins able to induce interferon-B (IFN-B) when overexpressed4–6. Studies of STING-deficient mice have subsequently confirmed the essential role of STING in innate responses to cytosolic nucleic-acid ligands, particularly double-stranded DNA (dsDNA) and unique bacterial nucleic acids called ‘cyclic dinucleotides’7–9. Several studies have also linked STING to the interferon response to cytosolic RNA5–7, but this has not been found consistently7,8,10,11; thus, we focus here on the role of STING in response to DNA and cyclic dinucleotides.

 

Protein Stimulator of interferon genes protein

Gene TMEM173

Organism Homo sapiens (Human)

Facilitator of innate immune signaling that acts as a sensor of cytosolic DNA from bacteria and viruses and promotes the production of type I interferon (IFN-alpha and IFN-beta). Innate immune response is triggered in response to non-CpG double-stranded DNA from viruses and bacteria delivered to the cytoplasm. Acts by recognizing and binding cyclic di-GMP (c-di-GMP), a second messenger produced by bacteria, and cyclic GMP-AMP (cGAMP), a messenger produced in response to DNA virus in the cytosol: upon binding of c-di-GMP or cGAMP, autoinhibition is alleviated and TMEM173/STING is able to activate both NF-kappa-B and IRF3 transcription pathways to induce expression of type I interferon and exert a potent anti-viral state. May be involved in translocon function, the translocon possibly being able to influence the induction of type I interferons. May be involved in transduction of apoptotic signals via its association with the major histocompatibility complex class II (MHC-II). Mediates death signaling via activation of the extracellular signal-regulated kinase (ERK) pathway. Essential for the induction of IFN-beta in response to human herpes simplex virus 1 (HHV-1) infection. Exhibits 2′,3′ phosphodiester linkage-specific ligand recognition. Can bind both 2′-3′ linked cGAMP and 3′-3′ linked cGAMP but is preferentially activated by 2′-3′ linked cGAMP (PubMed:26300263)

Stimulator of interferon genes protein (IPR029158)

Transmembrane protein 173, also known as stimulator of interferon genes protein (STING) or endoplasmic reticulum interferon stimulator (ERIS), is a transmembrane adaptor protein which is involved in innate immune signalling processes. It induces expression of type I interferons (IFN-alpha and IFN-beta) via the NF-kappa-B and IRF3, pathways in response to non-self cytosolic RNA and dsDNA [PMID: 18724357, PMID: 19776740,PMID: 18818105, PMID: 19433799].

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Contribution to Inflammatory Bowel Disease (IBD) of bacterial overgrowth in gut on a chip

Posted in 3D Printing for Medical Application, Curation, Disease Biology, Gastroenterology, MicroEngineering Cell-Tissue & Systems, Organ-on-a-Chip, Tissue Engineering, tagged antibiotic sensitivities, gut microbiome, inflammatory bowel disease (IBD), organ chip gut model on December 16, 2015| Leave a Comment »

Contribution to Inflammatory Bowel Disease (IBD) of bacterial overgrowth in gut on a chip

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Contributions of microbiome and mechanical deformation to intestinal bacterial overgrowth and inflammation in a 

human gut-on-a-chip 

Hyun Jung Kima,1, Hu Lia,2, James J. Collinsa,b,c,d,e,f,3, and Donald E. Ingbera,g,h,3
Proceedings of the National Academy of the Sciences   http://www.pnas.org/content/early/2015/12/09/1522193112.full.pdf
http://www.rdmag.com/articles/2015/12/gut-chip-holds-clues-treating-inflammatory-bowel-diseases

Gut-On-a-Chip Holds Clues for Treating Inflammatory Bowel Diseases

Greg Watry

http://www.rdmag.com/articles/2015/12/gut-chip-holds-clues-treating-inflammatory-bowel-diseases

http://www.rdmag.com/sites/rdmag.com/files/newsletter-ads/human-intestinal-epithelium-400×181.png

Human intestinal epithelial cells cultured in the Wyss Institute’s human gut-on-a-chip form differentiated intestinal villi when cultured in the presence of lifelike fluid flow and rhythmic, peristalsis-like motions. Here the villi are visible using a traditional microscope (left) or a confocal microscope (right); when the same villi are stained with fluorescent antibodies, it clearly reveals the nuclei in the intestinal cells (blue) and their specialized apical membranes when they contact the intestinal lumen (green). Credit: Wyss Institute at Harvard University

Roughly the size of a computer memory stick and made of clear flexible polymer, the human gut-on-a-chip was created by Harvard Univ.’s Wyss Institute in 2012. Three years later, researchers are utilizing the technology in hopes of creating new therapies for inflammatory bowel diseases (IBD).

The Centers for Disease Control and Prevention estimates that between 1 and 1.3 million people suffer from IBD, including such diseases as ulcerative colitis and Crohn’s disease. With origins still mysterious, IBD is currently incurable.

“It has not been possible to study…human intestinal inflammatory diseases, because it is not possible to independently control these parameters in animal studies or in vitro models,” wrote the researchers in Proceedings of the National Academy of the Sciences. “In particular, given the recent recognition of the central role of the intestinal microbiome in human health and disease, including intestinal disorders, it is critical to incorporate commensal microbes into experimental models, however, this has not been possible using conventional culture systems.”

Additionally, static in vitro methods fail to replicate the pathophysiology of human IBD.

But the hollow-channeled microfluidic gut-on-a-chip successfully simulates the human intestine’s physical structure, microenvironment, peristalsis-like motion, and fluid flow.

“With our human gut-on-a-chip, we can not only culture the normal gut microbiome for extended times, but we can also analyze contributions of pathogens, immune cells, and vascular and lymphatic endothelium, as well as model specific diseases to understand the complex pathophysiological responses of the intestinal tract,” said Donald Ingber, founding director of the Wyss Institute.

The device was “used to co-culture multiple commensal microbes in contact with living human intestinal epithelial cells for more than a week in vitro and to analyze how gut microbiome, inflammatory cells, and peristalsis-associated mechanical deformations independently contribute to intestinal bacterial overgrowth and inflammation,” the researchers wrote.

Thus far, use of the device has yielded two interesting observations.

Four proteins—called cytokines—work together to trigger an inflammatory responses that exacerbate the bowel, the researchers found. Potentially, this new discovery could lead to the development of treatments that block the cytokine interaction.

Another observation, the researchers noted, is that “by ceasing peristalsis-like motions while maintaining luminal flow, lack of epithelial deformation was shown to trigger bacterial overgrowth similar to that observed in patients with ileus and inflammatory bowel disease,” according to the researchers.

The researchers believe the micro-device may one day be applicable to precision medicine. Eventually, a custom treatment may arise from scientists using a patient’s gut microbiota and cells on a human gut-on-a-chip.

 

 

Contributions of microbiome and mechanical deformation to intestinal bacterial overgrowth and inflammation in a human gut-on-a-chip
Hyun Jung Kima,1, Hu Lia,2, James J. Collinsa,b,c,d,e,f,3, and Donald E. Ingbera,g,h,
http://www.pnas.org/content/early/2015/12/09/1522193112.full.pdf

A human gut-on-a-chip microdevice was used to coculture multiple commensal microbes in contact with living human intestinal epithelial cells for more than a week in vitro and to analyze how gut microbiome, inflammatory cells, and peristalsis-associated mechanical deformations independently contribute to intestinal bacterial overgrowth and inflammation. This in vitro model replicated results from past animal and human studies, including demonstration that probiotic and antibiotic therapies can suppress villus injury induced by pathogenic bacteria. By ceasing peristalsis-like motions while maintaining luminal flow, lack of epithelial deformation was shown to trigger bacterial overgrowth similar to that observed in patients with ileus and inflammatory bowel disease. Analysis of intestinal inflammation on-chip revealed that immune cells and lipopolysaccharide endotoxin together stimulate epithelial cells to produce four proinflammatory cytokines (IL-8, IL-6, IL-1β, and TNF-α) that are necessary and sufficient to induce villus injury and compromise intestinal barrier function. Thus, this human gut-on-a-chip can be used to analyze contributions of microbiome to intestinal pathophysiology and dissect disease mechanisms in a controlled manner that is not possible using existing in vitro systems or animal models.

 

Significance The main advance of this study is the development of a microengineered model of human intestinal inflammation and bacterial overgrowth that permits analysis of individual contributors to the pathophysiology of intestinal diseases, such as ileus and inflammatory bowel disease, over a period of weeks in vitro. By studying living human intestinal epithelium, with or without vascular and lymphatic endothelium, immune cells, and mechanical deformation, as well as living microbiome and pathogenic microbes, we identified previously unknown contributions of specific cytokines, mechanical motions, and microbiome to intestinal inflammation, bacterial overgrowth, and control of barrier function. We provide proof-of-principle to show that the microfluidic gut-on-a-chip device can be used to create human intestinal disease models and gain new insights into gut pathophysiology.

 

Various types of inflammatory bowel disease (IBD), such as Crohn’s disease and ulcerative colitis, involve chronic inflammation of human intestine with mucosal injury and villus destruction (1), which is believed to be caused by complex interactions between gut microbiome (including commensal and pathogenic microbes) (2), intestinal mucosa, and immune components (3). Suppression of peristalsis also has been strongly associated with intestinal pathology, inflammation (4, 5), and small intestinal bacterial overgrowth (5, 6) in patients with Crohn’s disease (7) and ileus (8). However, it has not been possible to study the relative contributions of these different potential contributing factors to human intestinal inflammatory diseases, because it is not possible to independently control these parameters in animal studies or in vitro models. In particular, given the recent recognition of the central role of the intestinal microbiome in human health and disease, including intestinal disorders (2), it is critical to incorporate commensal microbes into experimental models; however, this has not been possible using conventional culture systems. Most models of human intestinal inflammatory diseases rely either on culturing an intestinal epithelial cell monolayer in static Transwell culture (9) or maintaining intact explanted human intestinal mucosa ex vivo (10) and then adding live microbes and immune cells to the apical (luminal) or basolateral (mucosal) sides of the cultures, respectively. These static in vitro methods, however, do not effectively recapitulate the pathophysiology of human IBD. For example, intestinal epithelial cells cultured in Transwell plates completely fail to undergo villus differentiation, produce mucus, or form the various specialized cell types of normal intestine. Although higher levels of intestinal differentiation can be obtained using recently developed 3D organoid cultures (11), it is not possible to expose these cells to physiological peristalsis-like motions or living microbiome in long-term culture, because bacterial overgrowth occurs rapidly (within ∼1 d) compromising the epithelium (12). This is a major limitation because establishment of stable symbiosis between the epithelium and resident gut microbiome as observed in the normal intestine is crucial for studying inflammatory disease initiation and progression (13), and rhythmical mechanical deformations driven by peristalsis are required to both maintain normal epithelial differentiation (14) and restrain microbial overgrowth in the intestine in vivo (15).

Thus, we set out to develop an experimental model that would overcome these limitations. To do this, we adapted a recently described human gut-on-a-chip microfluidic device that enables human intestinal epithelial cells (Caco-2) to be cultured in the presence of physiologically relevant luminal flow and peristalsislike mechanical deformations, which promotes formation of intestinal villi lined by all four epithelial cell lineages of the small intestine (absorptive, goblet, enteroendocrine, and Paneth) (12, 16). These villi also have enhanced barrier function, drug-metabolizing cytochrome P450 activity, and apical mucus secretion compared with the same cells grown in conventional Transwell cultures, which made it possible to coculture a probiotic gut microbe (Lactobacillus rhamnosus GG) in direct contact with the intestinal epithelium for more than 2 wk (12), in contrast to static Transwell cultures (17) or organoid cultures (11) that lose viability within hours under similar conditions. In the present study, we leveraged this human gut-on-a-chip to develop a disease model of small intestinal bacterial overgrowth (SIBO) and inflammation. We analyzed how probiotic and pathogenic bacteria, lipopolysaccharide (LPS), immune cells, inflammatory cytokines, vascular endothelial cells and mechanical forces contribute individually, and in combination, to intestinal inflammation, villus injury, and compromise of epithelial barrier function. We also explored whether we could replicate the protective effects of clinical probiotic and antibiotic therapies on-chip to demonstrate its potential use as an in vitro tool for drug development, as well as for dissecting fundamental disease mechanisms.

 

Fig. 1. The human gut-on-a-chip microfluidic device and changes in phenotype resulting from different culture conditions on-chip, as measured using genome-wide gene profiling. (A) A photograph of the device. Blue and red dyes fill the upper and lower microchannels, respectively. (B) A schematic of a 3D cross-section of the device showing how repeated suction to side channels (gray arrows) exerts peristalsis-like cyclic mechanical strain and fluid flow (white arrows) generates a shear stress in the perpendicular direction. (C) A DIC micrograph showing intestinal basal crypt (red arrow) and villi (white arrow) formed by human Caco-2 intestinal epithelial cells grown for ∼100 h in the gut-on-achip under medium flow (30 μL/h) and cyclic mechanical stretching (10%, 0.15 Hz). (Scale bar, 50 μm.) (D) A confocal immunofluorescence image showing a horizontal cross-section of intestinal villi similar to those shown in Fig. 1C, stained for F-actin (green) that labels the apical brush border of these polarized intestinal epithelial cells (nuclei in blue). (Scale bar, 50 μm.) (E) Hierarchical clustering analysis of genome-wide transcriptome profiles (Top) of Caco-2 cells cultured in the static Transwell, the gut-on-a-chip (with fluid flow at 30 μL/h and mechanical deformations at 10%, 0.15 Hz) (Gut Chip), or the mechanically active gut-on-a-chip cocultured with the VSL#3 formulation containing eight probiotic gut microbes (Gut Chip + VSL#3) for 72 h compared with normal human small intestinal tissues (Duodenum, Jejunum, and Ileum; microarray data from the published GEO database). The dendrogram was generated based on the averages calculated across all replicates, and all branches in the cluster have the approximately unbiased (AU) P value equal to 100. The y axis next to the dendrogram represents the metric for Euclidean distance between samples. Corresponding pseudocolored GEDI maps analyzing profiles of 650 metagenes between samples described above (Bottom).

 

Fig. 2. Reconstitution of pathological intestinal injury induced by interplay between nonpathogenic or pathogenic enteroinvasive E. coli bacteria or LPS endotoxin with immune cells. (A) DIC images showing that the normal villus morphology of the intestinal epithelium cultured on-chip (Control) is lost within 24 h after EIEC (serotype O124:NM) are added to the apical channel of the chip (+EIEC; red arrows indicate bacterial colonies). (B) Effects of GFP-EC, LPS (15 μg/mL), EIEC, or no addition (Control) on intestinal barrier function (Left). Right shows the TEER profiles in the presence of human PBMCs (+PBMC). GFP-EC, LPS, and EIEC were added to the apical channel (intestinal lumen) at 4, 12, and 35 h, respectively, and PBMCs were subsequently introduced through the lower capillary channel at 44 h after the onset of experiment (0 h) (n = 4). (C) Morphological analysis of intestinal villus damage in response to addition of GFP-EC, LPS, and EIEC in the absence (−PBMC) or the presence of immune components (+PBMC). Schematics (experimental setup), phase contrast images (horizontal view, taken at 57 h after onset), and fluorescence confocal micrographs (vertical cross-sectional views at 83 h after onset) were sequentially displayed. F-actin and nuclei were coded with magenta and blue, respectively. (D) Quantification of intestinal injury evaluated by measuring changes in lesion area (Top; n = 30) and the height of the villi (Bottom; n = 50) in the absence (white) or the presence (gray) of PBMCs. Intestinal villi were grown in the gut-on-a-chip under trickling flow (30 μL/h) with cyclic deformations (10%, 0.15 Hz) during the preculture period for ∼100 h before stimulation (0 h, onset). Asterisks indicate statistical significance compared with the control at the same time point (*P < 0.001, **P < 0.05). (Scale bars, 50 μm.)

 

Recapitulating Organ-Level Intestinal Inflammatory Responses. During inflammation in the intestine, pathophysiological recruitment of circulating immune cells is regulated via activation of the underlying vascular endothelium. To analyze this organ-level inflammatory response in our in vitro model, a monolayer of human microvascular endothelial cells (Fig. 3 C and D and Fig. S6 A and C) or lymphatic endothelial cells (Fig. S6 B and C) was cultured on the opposite (abluminal) side of the porous ECM-coated membrane in the lower microchannel of the device to effectively create a vascular channel (Fig. 3C). To induce intestinal inflammatory responses, LPS (Fig. 3 C and D) or TNF-α (Fig. S6) was flowed through the upper epithelial channel for 24 h, and then PBMCs were added to the vascular channel for 1 h without flow (Fig. 3 C and D). Treatment with both LPS (or TNF-α) and PBMCs resulted in the activation of intercellular adhesion molecule-1 (ICAM-1) expression on the surface of the endothelium (Fig. 3 C and D, Left, and Fig. S6) and a significant increase (P < 0.001) in the number of PBMCs that adhered to the surface of the capillary endothelium compared with controls (Fig. 3D). These results are consistent with our qPCR results, which also showed up-regulation of genes involved in immune cell trafficking (Fig. S5). Neither addition of LPS nor PBMCs alone was sufficient to induce ICAM-1 expression in these cells (Fig. 3D), which parallels the effects of LPS and PBMCs on epithelial production of inflammatory cytokines (Fig. 3A) as well as on villus injury (Fig. 2 B and D).

Evaluating Antiinflammatory Probiotic and Antibiotic Therapeutics On-Chip. To investigate how the gut microbiome modulates these inflammatory reactions, we cocultured the human intestinal villi with the eight strains of probiotic bacteria in the VSL#3 formulation that significantly enhanced intestinal differentiation (Fig. 1E and Fig. S1B). To mimic the in vivo situation, we colonized our microengineered gut on a chip with the commensal microbes (VSL#3) first and then subsequently added immune cells (PBMCs), pathogenic bacteria (EIEC), or both in combination. The VSL#3 microbial cells inoculated into the germ-free lumen of the epithelial channel primarily grew as discrete microcolonies in the spaces between adjacent villi (Fig. 4A and Movie S3) for more than a week in culture (Fig. S7A), and no planktonic growth was detected. These microbes did not overgrow like the EIEC (Fig. 2A and Movie S2), although occasional microcolonies also appeared at different spatial locations in association with the tips of the villi (Fig. S7 B and C). The presence of these living components of the normal gut microbiome significantly enhanced (P < 0.001) intestinal barrier function, producing more than a 50% increase in TEER relative to control cultures (Fig. 4B) without altering villus morphology (Fig. 4C). This result is consistent with clinical studies suggesting that probiotics, including VSL#3, can significantly enhance intestinal barrier function in vivo (18).

To mimic the effects of antibiotic therapies that are sometimes used clinically in patients with intestinal inflammatory disease (29), we identified a dose and combination of antibiotics (100 units per mL penicillin and 100 μg/mL streptomycin) that produced effective killing of both EIEC and VSL#3 microbes in liquid cultures (Fig. S9) and then injected this drug mixture into the epithelial channel of guton-a-chip devices infected with EIEC. When we added PBMCs to these devices 1 h later, intestinal barrier function (Fig. 4B) and villus morphology (Fig. 4C) were largely protected from injury, and there was a significant reduction in lesion area (Fig. 4D). Thus, the gut-on-a-chip was able to mimic suppression of injury responses previously observed clinically using other antibiotics that produce similar bactericidal effects.

Analyzing Mechanical Contributions to Bacterial Overgrowth. Finally, we used the gut-on-a-chip to analyze whether physical changes in peristalsis or villus motility contribute to intestinal pathologies, such as the small intestinal bacterial overgrowth (SIBO) (5, 6) observed in patients with ileus (8) and IBD (7). When the GFPEC bacteria were cultured on the villus epithelium under normal flow (30 μL/h), but in the absence of the physiological cyclic mechanical deformations, the number of colonized bacteria was significantly higher (P < 0.001) compared with gut chips that experienced mechanical deformations (Fig. 5A). Bacterial cell densities more than doubled within 21 h when cultured under conditions without cyclic stretching compared with gut chips that experienced physiological peristalsis-like mechanical motions, even though luminal flow was maintained constant (Fig. 5B). Thus, cessation of epithelial distortion appears to be sufficient to trigger bacterial overgrowth, and motility-induced luminal fluid flow is not the causative factor as assumed previously (7).

 

Discussion One of the critical prerequisites for mimicking the living human intestine in vitro is to establish a stable ecosystem containing physiologically differentiated intestinal epithelium, gut bacteria, and immune cells that can be cultured for many days to weeks. Here we leveraged a mechanically active gut-on-a-chip microfluidic device to develop an in vitro model of human intestinal inflammation that permits stable long-term coculture of commensal microbes of the gut microbiome with intestinal epithelial cells. The synthetic model of the human living intestine we built recapitulated the minimal set of structures and functions necessary to mimic key features of human intestinal pathophysiology during chronic inflammation and bacterial overgrowth including epithelial and vascular inflammatory processes and destruction of intestinal villi.

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The History and Creators of Total Parenteral Nutrition

Posted in Disease Biology, Gastroenterology, Uncategorized, tagged Amino acids, enteral nutrition, Nutrition, TPN on November 30, 2015| Leave a Comment »

The History and Creators of Total Parenteral Nutrition

Curator: Larry H. Bernstein, MD, FCAP

WordCloud by Daniel Menzin; Article Title: The History and Creators of Total Parenteral Nutrition

The History and Creators of Total Parenteral Nutrition

I am a pathologist who became involved in the measurement of acute and chronic malnutrition in hospitalized patients through my working with a burn surgeon, Walter Pleban, in the mid-1980s.  I had already been interested in this as a clinical pathology issue because the most abundant plasma protein, albumin, is markedly decreased, but that protein has a half-life of disappearance on 21 days.  This was problematic because it was inadequate for early recognition, or for response to feeding.  It became of considerable interest that two rapid turnover proteinhttp://www.ncbi.nlm.nih.gov/pubmed/20150597s – transthyretin (TTR)(then referred to as prealbumin) and retinol binding protein (RBP) that are synthesized by the liver have short half-lifes.  The measurement of TTR was then possible by an immunodiffusion assay on agarose overnight, but was not automated.  This changed with the introduction of an immunoassay for research use, and that offered by Beckman was ideal for the automated clinical laboratory.  One could then follow the level of TTR in the recovery phase.  There was some discussion for years about the fact that TTR might be considered an inverted acute phase protein because of a recognition that the liver decreases synthesis of TTR and produces acute phase proteins in the adaptive inflammatory response.  This is not insignificant, but it is also not quite relevant for reasons that have been addressed by Yves Ingenbleek and collaborators.  TTR is a key determinant of protein sufficiency and of sulfur homeostasis in health and disease.  I shall not say more, as the development of total parenteral (TPN), and also enteral (TEN) nutrition are of specific interest here.  However, the evaluation of patients’ nutritional status has widely been carried out by subjective global assessment, which is insufficient in a large population at risk.

History of parenteral nutrition.

Dudrick SJ¹.  Author information     J Am Coll Nutr. 2009 Jun;28(3):243-51.   http://www.ncbi.nlm.nih.gov/pubmed/20150597

The concept of feeding patients entirely parenterally by injecting nutrient substances or fluids intravenously was advocated and attempted long before the successful practical development of total parenteral nutrition (TPN) four decades ago. Realization of this 400 year old seemingly fanciful dream initially required centuries of fundamental investigation coupled with basic technological advances and judicious clinical applications. Most clinicians in the 1950’s were aware of the negative impact of starvation on morbidity, mortality, and outcomes, but only few understood the necessity for providing adequate nutritional support to malnourished patients if optimal clinical results were to be achieved. The prevailing dogma in the 1960’s was that, “Feeding entirely by vein is impossible; even if it were possible, it would be impractical; and even if it were practical, it would be unaffordable.” Major challenges to the development of TPN included: (1) formulate complete parenteral nutrient solutions (did not exist), (2) concentrate substrate components to 5-6 times isotonicity without precipitation (not easily done), (3) demonstrate utility and safety of long-term central venous catheterization (not looked upon with favor by the medical hierarchy), (4) demonstrate efficacy and safety of long-term infusion of hypertonic nutrient solutions (contrary to clinical practices at the time), (5) maintain asepsis and antisepsis throughout solution preparation and delivery (required a major culture change), and (6) anticipate, avoid, and correct metabolic imbalances or derangements (a monumental challenge and undertaking). This presentation recounts approaches to, and solution of, some of the daunting problems as really occurred in a comprehensive, concise and candid history of parenteral nutrition.

Historical highlights of the development of total parenteral nutrition.

Dudrick SJ¹, Palesty JA.  Author information
Surg Clin North Am. 2011 Jun;91(3):693-717.    http://dx.doi.org:/10.1016/j.suc.2011.02.009.      Epub 2011 Apr 29.

The events and discoveries thought to be the most significant prerequisites to the development of total parenteral nutrition (TPN) dating back to the early 17th century are chronicled. A more detailed description and discussion of the subsequent early modern highlights of the basic and clinical research beginning in the mid-20th century and the advances culminating in the first demonstration of the feasibility and practicality of TPN, and its successful, safe and efficacious applications clinically, are presented. Some of the reasoning, insights, and philosophy of a pioneer clinician-scientist in the field are shared with readers.

The History, Principles, and Practice of Parenteral Nutrition in Preterm Neonates

Stanley J. Dudrick , Alpin D. Malkan
Chapter in:  Nutrition for the Preterm Neonate    27 June 2013   pp 193-213

The history of the successful development of Total Parenteral Nutrition (TPN), first in beagle puppies in the basic science laboratories, and its subsequent clinical translations initially to adults, and shortly thereafter, to a newborn infant, is recounted by the original developer of the techniques, data, and results that have led to its widespread application and acceptance throughout the world. The principles, practices, standards, techniques, observations, technology, and several of the countless details which were so essential in guiding this dream to reality, are woven throughout the narrative. The advances and milestones are traced along this passionate, relentless journey to the present day, when preterm infants are actually expected to live and thrive. The precision and conscientious attention which are essential to the judicious, safe, efficacious use of TPN in preterm neonates throughout all aspects of solution formulation and delivery, together with appropriate monitoring and assessment of outcomes, are described and discussed briefly. The multiple risks and complications associated with this complex life-saving technique are extensively tabulated, with the intention to teach, in order to avoid, prevent, or overcome them. Moreover, attention has been directed toward pointing out many of the persisting shortcomings of the technique which remain to be prevented, overcome, or corrected by future research efforts and experiences. Finally, the costs, philosophy, humanity, and future advancements necessary to apply TPN to the care of preterm infants in developing countries are stated with optimism and hope.

Brief History of Parenteral and Enteral Nutrition in the Hospital in the USA
Bruce R. Bistrian
Clinical Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

Elia M, Bistrian B (eds): The Economic, Medical/Scientifi c and Regulatory Aspects of Clinical Nutrition Practice: What Impacts What?
Nestlé Nutr Inst Workshop Ser Clin Perform Program, vol. 12, pp 127–136, Nestec Ltd., Vevey/S. Karger AG, Basel, © 2009.

The meteoric rise in parenteral and enteral nutrition was largely a consequence of the development of total parenteral nutrition and chemically defined diets in the late 1960s and early 1970s and the recognition of the extensive prevalence of protein calorie malnutrition associated with disease in this same period. The establishment of Nutrition Support Services (NSS) using the novel, multidisciplinary model of physician, clinical nurse specialist, pharmacist, and dietitian, which, at its peak in the 1990s, approached 550 well-established services in about 10% of the US acute care hospitals, also fostered growth. The American Society of Parenteral and Enteral Nutrition, a multidisciplinary society reflecting the interaction of these specialties, was established in 1976 and grew from less than 1,000 members to nearly 8,000 by 1990. Several developments in the 1990s initially slowed and then stopped this growth. A system of payments, called diagnosis-related groups, put extreme cost constraints on hospital finances which often limited financial support for NSS teams, particularly the physician and nurse specialist members. Furthermore, as the concern for the nutritional status of patients spread to other specialties, critical care physicians, trauma surgeons, gastroenterologists, endocrinologists, and nephrologists often took responsibility for nutrition support in their area of expertise with a dwindling of the model of an internist or general surgeon with special skills in nutrition support playing the key MD role across the specialties. Nutrition support of the hospitalized patient has dramatically improved in the US over the past 35 years, but the loss of major benefits possible and unacceptable risks of invasive nutritional support if not delivered when appropriate, delivered without monitoring by nutrition experts, or employed where inappropriate or ineffective will require continued attention by medical authorities, hospitals, funding agencies, and industry in the future.

The rapid ascension of parenteral and enteral nutrition into an important component of clinical care in the hospital setting can be traced to three developments that occurred over an about 5-year period in the late 1960s and early 1970s. First and foremost was the first successful use of total parenteral nutrition (TPN), initially in beagle dogs to show the feasibility, and then its successful extension to 30 patients with chronic, complicated gastrointestinal disease by Dudrick et al. [1] at the University of Pennsylvania. At about the same time chemically defined or elemental diets were developed in normal volunteers to be employed in the US Mercury Space Program [2] where storage space and a low residue made these diets very desirable. These novel formulas were subsequently used in clinical conditions in which digestion and/or absorption was impaired and were provided usually through nasoenteric feeding tubes [3]. Both parenteral and enteral nutrition were initially studied in surgical patients in whom protein calorie malnutrition through gut malfunction had long been an often insurmountable problem. The third and final development was the identification of the extraordinary prevalence of malnutrition in hospitalized patients occurring in up to half of those on both surgical [4] and medical [5] services described in 1974 and 1976 respectively, when defined by simple anthropometric tools of weight, height, and upper arm anthropometry and serum albumin levels.

At this point one can view the glass as half full or half empty. From the optimistic or glass half full standpoint the period from 1975 to 1985 after the above advances could be described as a logarithmic phase of growth in clinical nutrition. Nutrition Support Services (NSS) using the novel, multidisciplinary model of physician, nurse specialist, pharmacist, and dietitian initially began in the early 1970s [6, 7] and at their high point probably approached 550 well-established services [8] in about 10% of America’s acute care hospitals by 1990. A number of studies during this early period demonstrated the ability of such groups to dramatically reduce the risk of catheter-related sepsis and to limit the development of electrolyte and metabolic abnormalities with TPN and to reduce complications and increase the adequacy of enteral nutrition [9]. Financial benefits were less certain in part due to difficulties to fully estimate costs and benefits [9], but at the very least were cost neutral in most circumstances [10].

The American Society of Parenteral and Enteral Nutrition which reflected this unique multidisciplinary membership of the NSS was established and had its first meeting in Chicago in 1976. Membership, initially less than 1,000 grew to nearly 8,000 by 1990 and was composed of approximately 20% physicians, 15% nurses, 15% pharmacists, and 50% dietitians in 1990. The annual ASPEN Clinical Congress, which continues to date, became an important venue to educate and train and provide a forum for the presentation of new research findings.

Finally from a personal perspective when I first became involved with nutrition support during my PhD training in Nutritional Biochemistry and Metabolism at MIT from 1972 to 1975, a period in which we were conducting the early surveys of nutritional status [4, 5], there was a general lack of appreciation for the nutritional status of patients. Protein calorie malnutrition was so widespread and undertreated that we developed a system of measurement of delayed cutaneous hypersensitivity to document cutaneous anergy [11] in order to convince clinicians that their patients required invasive nutritional support to reverse anergy. By 1990 there was a general appreciation that hospital protein calorie malnutrition was common, that invasive feeding could improve outcome, and that lack of feeding for periods of longer than 7–10 days in critically ill patients was an unacceptable practice. During this period from 1975 to 1990 there was a steady increase in the number of converts to better nutritional practices, particularly in surgical patients and in the critically ill in intensive care units, both medical and surgical. Testing for cutaneous anergy was abandoned at our medical center in the mid 1980s [12], principally because prolonged inadequate feeding became so uncommon, and there was little difficulty in convincing the primary physician of the need for invasive feeding when appropriate.

What happened subsequent to 1990? Now we can discuss the glass that is half empty, and this largely relates to medical funding. In the early 1980s the Medicare system in the US began a system of hospital payments based on diagnosis-related groups, where a fixed amount of money was paid according to diagnosis rather than actual costs. Medicare is the government system of reimbursement for patients 65 years or older, the disabled, or those receiving dialysis therapy. But the other source of hospital payments from medical care for the indigent through the government program Medicaid is the joint responsibility of the individual state and the federal government, and private insurance links their payments to government policy. The severe cost-containment pressures brought on by these changes in medical insurance have adversely affected nutrition support team staffing which began to have its greatest impact in the 1990s and was particularly harsh on hyperalimentation nurses and physicians involved in nutrition support. Although there are medical and financial costs associated with the termination of a nutrition support nurse [13], this cost must often be forcefully documented with hospital authorities, and generally can be in terms of unacceptable rates of catheter infection without their presence. With physicians there is no acknowledged medical specialty for clinical nutrition, although there was a split vote of 2–1 against by the American Board of Medical Specialties in the 1990s which would have accomplished this had it passed. Therefore, if the local hospital administrator or chairmen of medicine or surgery cannot be convinced of the value of providing partial financial support to nutrition support physicians for their clinical participation, then either it is done as a free service as an avocation by these individuals or done as a component of their underlying specialty. Thus most intensivists will provide parenteral and enteral nutrition as part of their care, as will many surgical specialists, particularly trauma surgeons, burn surgeons, and general surgeons. Oversight for home parenteral and enteral nutrition is often provided by gastroenterologists. However it is likely in many instances that nutritional care by these specialists is at an acceptable if perhaps not ideal level. For medical patients parenteral and enteral nutritional support is now often delivered under the care of dietitians which is reasonably good vis-à-vis enteral nutrition, but with parenteral nutrition may sometimes be outside their level of clinical competence, particularly for the management of fluid and electrolyte disorders and insulin management in diabetic patients. Dietitians have been less severely impacted by cost considerations, because there is a Joint Commission on Accreditation of Hospital Organizations (JCAHO) requirement that hospitals nutritionally monitor their patients. Pharmacists are also very important in the provision of parenteral nutrition, particularly by determining compatibilities of parenteral nutrition admixtures, checking the stability of orders from day-to-day, and by making certain of the completeness of parenteral regimens. Their continued availability to provide this level of expertise is also mandated by JCAHO as well as by their own professional standards.

There has also been a change in the membership of ASPEN that reflects this trend. After an initial fall of total members through the 1990s, the number has more recently stabilized, but there has been a dramatic decrease in nurses from nearly 1,000 to about 300 in 1999 and less than 200 at present (2006) with a concomitant increase in dietitians to about 60% of a total of 5,000 members, which has been relatively stable for the past 7 years, and a slowly diminishing number of physicians from 1,000 (20%) in 1999 to 735 (15%) in 2006. However both physician and pharmacist numbers have stabilized from 2001 to 2006, at approximately 750 and 620 members. Fellowship opportunities for physicians have also diminished, and there is some concern about what the future holds for physicians principally interested in parenteral and enteral nutrition. The second major American society for clinical nutrition after ASPEN was an independent group of academic physicians and PhD nutritionists interested in this field, the American Society for Clinical Nutrition. Last year by vote of its members it chose to disband and become a component of the American Society of Nutrition. Hopefully this group of individuals will maintain their interest in this field and continue to promote the improvement of parenteral and enteral nutrition for the hospitalized patient. However the likelihood of getting specialty recognition from the American Board of Medical Specialties is dim under the present conditions.

How does this bode for the future? Presumably there will always be some physicians trained in clinical nutrition, but some programs, like the exemplary program at MIT which trained many of the academic clinical nutritionists, have been discontinued and not been replaced. Certainly there is ample evidence for the need for such individuals. For instance one of the most important recent developments in clinical medicine has been the demonstration that tight blood glucose control in the critically ill can dramatically improve the morbidity and mortality of patients [18]. However this was primarily a study in cardiac surgical patients, and a similar study in medical patients by the same group demonstrated that tight blood glucose control improved morbidity but did not affect mortality [19]. In fact in those medical patients who received therapy for less than 3 days, mortality was actually increased. These superb innovative studies were primarily conducted by an endocrinologist who is a specialist in critical care. However an important variable in these two landmark studies, not previously commented on, is that in the surgical study the patients also received hypertonic dextrose initially for the first 24 h and TPN subsequently [18]. The medical patients in the second study received the initial hypertonic dextrose followed by inadequate nasogastric tube feeding for the first 3 days providing substantially less calories and grossly inadequate protein [19]. It may well be that it is the combination with tight glucose control in the setting of adequate feeding that is essential to achieve all the benefits rather than the control of hyperglycemia alone. Similarly a recent study in cardiac surgical patients receiving tight glucose control during their surgery and tight regulation of both treatment and control postoperatively showed no benefit and, in fact, a suggestion of harm in the treatment group [20]. Perhaps lowering blood glucose in cardiac patients not receiving hypertonic dextrose before revascularization may deprive the heart of an essential fuel. Having some physicians thoroughly trained in clinical nutrition to discern these possibilities may be important in the future to design and interpret the results of clinical trials.

For Patients Who Can’t Eat, Dr. Stanley Dudrick’s Intravenous Feeding System Is a Lifeline

By Kent Demaret

People  October 02, 1978; 10(14)    http://www.people.com/people/archive/article/0,,20071854,00.html

O.D. Simons, 57, of Lubbock, Texas has not eaten for two years. Instead, he is nourished by chemicals that are pumped into his bloodstream by an apparatus he wears all his waking hours. The device, invented by Dr. Stanley Dudrick of Houston, is cumbersome, and its menu hardly compares with a steak dinner. But without it, Simons, who has had cancer of the bowel, would almost surely be dead.

Nearly 100 patients at the University of Texas Medical Center are undergoing similar nutritional therapy. Each owes his survival to Dr. Dudrick, who in 1972, at the precocious age of 37, became head of the center’s department of surgery.

Dudrick was turned from a fledgling cardiac surgeon into a pioneer nutritionist one day when he was an intern in Philadelphia. “We had three patients who had gone through successful surgery—but they all died,” he recalls. “I was terribly discouraged. Then the chairman of the surgery department said that, if I analyzed it, I’d see they really died of starvation. They couldn’t eat, and they didn’t have enough reserve tissues to draw on. I was too dumb to make that observation myself.”

Dudrick immersed himself in the study of how to provide food for those who can’t eat. From 10 to 40 percent of hospital deaths are still caused, he believes, by malnutrition. Patients with gastrointestinal cancer are especially vulnerable, as well as those with kidney or liver failure or burn trauma.

Sir Christopher Wren experimented with intravenous feeding of dogs as early as the 17th century. In its modern traditional form (most familiar in the glucose drip bottle), it cannot support life for long, however. Dudrick solved the problem by developing a complete nutritive compound. But he faced another obstacle: “We couldn’t put it in through the arm because the mixture was too thick and produced problems in the small veins. We couldn’t thin it down with water either, because that produced edema, or excess fluid in the connective tissue.

“Then,” Dudrick says, “we hit on the idea of putting it into larger veins, where the blood flow is so great that the nutritional substances would be diluted and rushed throughout the body.” Often the compound is pumped into the superior vena cava, through a catheter threaded through a smaller vein near the collarbone.

Dudrick’s nutrient, specially mixed for each patient, is composed of some 40 substances, including amino acids, glucose, vitamins and minerals. In some cases druggists or patients themselves can prepare the mixture.

Total Parenteral Nutrition (TPN) is Dudrick’s term for his technique. (Parenteral refers to bypassing the intestines.) In 1964 he astounded a medical convention in Germany with the news that he had raised six beagle puppies entirely on TPN for 287 days. In 1966 he first tried it on six humans with apparently terminal illness; all recovered and four are still alive. Since then Dudrick has used TPN on about 6,000 patients and has received two American Medical Association awards.

Eldest of four children of a Nanticoke, Pa. coal miner turned insurance agent, Dudrick decided on a medical career after watching the family doctor pull his mother through a near-fatal illness. Both his sisters are nurses. Still a crusader, he worries that, while half the nation’s doctors are aware of TPN, only five percent are using it. “It takes time,” he says, “for doctors to accept so much responsibility for dealing with such complex advances in human chemistry, metabolism and nutrition.”

Success will depend on campaigning for the technique, while simplifying it. “Someday we’ll have TPN down so that it will commonly be done in a general practitioner’s office,” Dudrick predicts. “That’s what I’m hoping for. I want to leave something better behind when I go, rather than just practice medicine the way it has always been done.”

Dr. Dudrick invented IV feeding (TPN) in the 1960’s and is credited for thousands of lives from premature newborns to post surgical patients with difficulty recovering.

Stanley J. Dudrick, M.D. is widely recognized and respected throughout the scientific, academic and clinical world for his innovative and pioneering research in the development of the specialized central venous feeding technique known as intravenous hyperalimentation (IVH) or total parenteral nutrition (TPN). The basic investigative development and subsequent successful clinical application of this highly effective therapeutic modality has been described as one of the four most significant accomplishments in the history of the development of modern surgery, together with the discovery and development of asepsis and antisepsis, antibiotic therapy and anesthesia (JAMA 239:192, 1978). It has also been acknowledged as one of the three most important advancements in surgery during the past century along with open heart surgery and organ transplantation.

Born in Nanticoke, Pennsylvania, April 9, 1935, Dr. Dudrick received his B.S. in Biology with Honors in 1957 from Franklin and Marshall College in Lancaster, graduating Cum Laude. He was a member of Phi Beta Kappa honor fraternity and was awarded the Williamson Medal as the outstanding member of his graduating class. His M.D. degree was conferred by the University of Pennsylvania School of Medicine in 1961 followed by a rotating internship and residency training in General Surgery at the Hospital of the University of Pennsylvania where he served as Chief Resident in Surgery under Dr. Jonathan E. Rhoads until 1967. After his training, he joined the faculty at Penn and ascended in rank from Instructor to Professor of Surgery at his alma mater within five years. In 1972, he was recruited to Houston as the first Professor and Founding Chairman of the Department of Surgery at the then new University of Texas Medical School at Houston and Chief of Surgical Services at Hermann Hospital/The University Hospital. In 1988, he joined the staff of Pennsylvania Hospital, the nation’s first hospital, in Philadelphia as Chairman of the Department of Surgery, Surgeon to the Hospital, Director of the Residency Training Program in General Surgery and Clinical Professor of Surgery at the University of Pennsylvania. On May 1, 1990, he was appointed Surgeon-in-Chief of the Center for Cardiovascular Disease and Director of the Hermann Nutrition and Human Performance Center, the Nutritional Support Service, and the Nutritional Science Center at Hermann Hospital and Clinical Professor of Surgery at the University of Texas Medical School at Houston.

In November, 1994, he began serving as Associate Chairman of the Department of Surgery and Director of the Program in Surgery at Saint Mary’s Hospital, a Yale Affiliated Teaching Hospital, in Waterbury, Connecticut and as Professor of Surgery at Yale University School of Medicine. In October, 1995, he assumed the additional responsibilities at Saint Mary’s Hospital as Director of Graduate Medical Education. In October, 1996, he was appointed Adjunct Clinical Professor of Surgery on the faculty of Quinnipiac College. Yale University granted him a Master of Arts Honoris Causa Degree in 1999. Between January, 2000 and September, 2002, he served also as Chairman of the Department of Surgery and Director of Surgical Education for the newly integrated Bridgeport Hospital/Yale New Haven Health System. He then returned to serve as Chairman of the Department of Surgery, Director of the Training Program in Surgery and Designated Institutional Official for Graduate Medical Education at Saint Mary’s Hospital/Yale Affiliate in Waterbury, Connecticut and Professor of Surgery at Yale University School of Medicine for more than five years. Dr. Dudrick assumed his current Chairman – Emeritus, Department of Surgery, status in October, 2007, while continuing as Director of the Training Program in Surgery until July, 2008, when he became Director – Emeritus of the Program in Surgery at Saint Mary’s Hospital. He currently continues to be active in both of these positions at Saint Mary’s Hospital and as Professor of Surgery at Yale.

A prolific medical writer, Dr. Dudrick was acknowledged by Current Contents, a publication of the Institute for Scientific Information, as the author or co-author of 2,535 scientific reference citations during a 13 year period, the most for any general surgeon in the literature. His more than 700 published works include a wide variety of topics on the care and management of surgical patients, especially those with complex nutritional, metabolic, critical care and re-operative problems.

Since 1974, he has served on more than fifteen Editorial Boards of scientific journals and professional publications including the prestigious Annals of Surgery. Of the several books he has produced, he is most proud of having served as a Co-Editor of the American College of Surgeons Manual of Surgical Nutrition, and as the Editor of the Manual of Preoperative and Postoperative Care, The Surgical Clinics of North America-Current Strategies in Surgical Nutrition, and The Biology and Practice of Current Nutritional Support.

Dr. Dudrick is a Fellow of the American College of Surgeons, was elected a Director of the American College of Surgeons South Texas Chapter and served as a Governor at Large of the American College of Surgeons from the State of Texas from 1979 – 1985. The Board of Regents selected him as the recipient of the prestigious American College of Surgeons Jacobsen Innovation Award in 2005. In 2008, he received the Distinguished Service Award of the American College of Surgeons Connecticut Chapter.

Among the more than 100 honors and awards which Dr. Dudrick has received are the AMA Joseph B. Goldberger Award in Clinical Nutrition; the AMA Brookdale Award in Medicine; the Seale Harris Medal of the Southern Medical Association; the Ladd Medal of the American Academy of Pediatrics; the American College of Nutrition Goldsmith Award; the Distinguished Alumnus Citation, the Alumni Medal, and The President’s Medal of Franklin and Marshall College; and the American Surgical Association’s First Flance/Karl Award in 1997 for his seminal and lifetime scientific contributions to surgery.

Dr. Khursheed N. Jeejeebhoy
http://jeejeebhoy.ca/library/lifeliner/jeej/

Born in Rangoon, Burma on August 26, 1935, Khursheed N. Jeejeebhoy fled seven years later with his family to India to escape the Japanese invaders. He attended medical school in Vellore, India; trained in London, England; married and had three children; and in 1967, accepted a position at the Toronto General Hospital and the University of Toronto.From the beginning of his career, he was always on the forefront of research: he was one of the first to discover lactose intolerance. In 1970, with a surgical colleague, he was experimenting with TPN on post-surgical patients when Judy Ellis Taylor came into his care.

Dr. Khursheed Jeejeebhoy received his medical degree from the Christian Medical College Hospital in Vellore, India in 1959 and completed residency in India and the UK. He obtained his PhD from London University in 1963. He became division director of gastroenterology at the University of Toronto and the Toronto General Hospital. Currently, he is directs nutrition support and is a staff physician at St. Michael’s Hospital. He is also a professor of medicine, professor in the department of nutritional sciences and professor in the department of physiology, all at the University of Toronto. He has published over 500 peer-reviewed articles, abstracts and book chapters. He has a CIHR funded research program. He is on the editorial boards of nutritional journals and contributes to the Medical Post. He has received numerous awards throughout his career from Canada, USA and UK. He has been elected senior member of the Canadian Medical Association.

This determined young woman intended to live and expected him to save her. He took her up on her challenge and developed first a viable, long-term form of TPN, then a version Judy could use at home.With Judy such a success, Dr. Jeejeebhoy (Jeej to his patients and colleagues) bent his efforts to saving other lives with TPN and to learning more about the nutrients that the human body needs and in what dosages, both orally and intravenously, so that he could better nourish his patients and reduce their suffering. He has written over 350 papers and 100 books and chapters; was made professor of medicine, physiology, and nutrition at the University of Toronto; has lectured in virtually every country; and has taught many graduate students from Europe, North America, Asia, and Australia, as well as the first doctor allowed to leave China to study temporarily after China started opening up to the west.

His patients are intensely loyal to him, for his understanding, listening skills, expertise. In 1990, he moved to St. Michael’s Hospital and built up a TPN program there. He entered the commercial arena when he conducted research in and developed a radical new, nutritional way to improve the function of patients with congestive heart failure. MyLife Requirements “contains a patented combination of three nutrients, which interact synergistically and are needed by the heart to maintain optimal health and to function efficiently.  These nutrients are Coenzyme Q10, and the amino acids Taurine and Carnitine.” Due to the interesting regulation of L-carnitine by Health Canada, this supplement is available only in the US, not here in Canada.

At the end of 2007, he retired, sort of, a few years after becoming Professor Emeritus at the University of Toronto due to mandatory retirement at age 65. He closed his university lab at the end of 2007 when his last grant ran out. That ended a 40-year run of successful research grant applications and groundbreaking research. He embarked on a new role at St. Mike’s at the beginning of 2008, teaching at a Home TPN clinic; he continues to see patients part-time at a private clinic; and he conducts hospital rounds every week. His patients and colleagues would not allow complete retirement! Besides, Jeej is far too curious and interested in exploring new ideas to completely retire either!

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