Isaac Cann

Isaac Cann

icann@illinois.edu

3408 Institute for Genomic Biology, 1206 West Gregory Drive | MC-195
Urbana, IL 61801
Office: (217) 333-2090

Mail to: 3408 Institute for Genomic Biology, 1206 West Gregory Drive | MC-195
Urbana, IL 61801

Professor of Animal Sciences, Carl R. Woese Institute for Genomic Biology, and Nutritional Sciences

Affiliate Professor of Microbiology and Center for East Asian Studies

Research Topics

Archaea, Biofuels, Enzymology, Genomics, Host-Pathogen Interactions, Molecular Evolution, Protein Structure, Protein-Nucleic Acid Interactions

Education

B.Sc (Hons) Animal Sciences, University of Ghana 1986
M.S. (Rumen Microbiology), Mie University, Japan, 1991
Ph.D. (Rumen Microbiology), Mie University, Japan, 1994
Postdoctoral (Anaerobic Microbiology), Department of Animal Sciences, University of Illinois, 1994-1997

Molecular biology and biochemistry of archaeal DNA replication; host-microbiome interactions; enzymes of plant cell wall hydrolysis

The research of the Cann lab focuses on three areas: DNA replication in the archaeal domain of life, host-microbiome interactions and their effects on health and disease, and enzymes of importance to biofuel production. Isaac Cann is a member of two themes at the Carl R. Woese Institute for Genomic Biology (IGB), and his research is carried out at the space shared by his affiliated themes [Microbiome Metabolic Engineering (MME) and Biocomplexity (BCXT)] with others at the IGB.

Archaeal DNA replication

The Archaea, Bacteria, and Eukarya constitute the three domains of life, and in each domain, DNA replication is the process by which members transfer genetic information to offspring to ensure continuity of the lineage. DNA replication requires a large number of proteins working in concert to faithfully copy the genome, although a level of mutation that leads to either selective advantage or disadvantage is tolerated.

DNA replication is quite well understood in bacteria, but less understood in eukaryotes, although also in these organisms our knowledge continues to expand. The archaea were only discovered in the 1980’s by Carl R. Woese at University of Illinois; therefore, we know much less of how they replicate their genomes.

The Cann lab is interested in assembling the DNA replication machinery of archaea in vitro to determine how the different components work together to replicate the archaeal genomes in environments that range from close to freezing (deep sea sediments) to those above the boiling point of water (deep sea hydrothermal vents). Our research is further motivated by the fascinating discovery that archaeal organisms contain genes encoding proteins with striking similarities to eukaryotic DNA replication proteins, although the archaeal proteins have simpler architectures compared to their eukaryotic functional homologs. An important conclusion one can draw from this observation is that the archaeal and eukaryotic replication proteins descended from common protein ancestors. Thus, we anticipate that the knowledge gained in our studies on archaeal DNA replication will provide insights into how the simpler forms of the archaeal/eukaryotic DNA replication machineries evolved to the more complex ones in extant eukaryotes, including humans. Furthermore, the microorganisms that produce methane, a potent greenhouse gas, on our planet are members of the archaeal domain of life. Thus, by elucidating the molecular details of archaeal DNA replication, a fundamental process required for their proliferation, we may provide the critical knowledge required to control the growth of methane producing organisms and therefore reduce their contribution to global warming.

We use both the mesophilic archaeon Methanosarcina acetivorans and the hyperthermophilic archaeon Methanopyrus kandleri , an archaeon that grows at an amazing temperature maximum of 112 °C, for our studies. Some of our discoveries include a protein complex that represents an intermediate of the simplest clamp loaders (found in most common in archaea) and the most complex clamp loaders (found in extant eukaryotes). Clamp loaders are protein complexes that switch DNA synthesis from slow to the incredible speeds required to copy the large genomes of extant organisms in order to transfer the genetic material to daughter cells. We have also recently discovered that unlike several archaea investigated to date that have initiation of DNA replication decoupled from cell division, in M. acetivorans initiation of DNA replication is tightly coupled to cell division. We are interested in unraveling the evolutionary determinants that led to this process in M. acetivorans, an archaeon with replication proteins that appear to be intermediates of the very simple ones in the hyperthermophilic archaea and the highly complex ones in eukaryotes.

A schematic representation showing that Archaea and Eukarya share similar replication machineries (A) and Archaea uses different mechanisms for cell division (B).
From: Cann, I.K.O. 2008. Proc Natl Acad Sci USA. 105:18653.

Fiber degradation in the human gut and its impact on health and nutrition

Dr. Abigail Salyers of the Department of Microbiology, UIUC, was one of the fierce champions of the concept that humans are a composite of eukaryotic and microbial cells; however, it took some time before the significance of this association was seriously considered by the scientific community. It is now well accepted that our microbial selves, which some even consider as organs, significantly impact our physiology, especially our health and nutritional status. Collectively the different microbial communities associated with different parts of our bodies are now referred to as microbiomes, leading to the designation of the communities associated with our lungs, mouths, and colons as the lung, oral, and colonic microbiomes, respectively. Importantly, maintenance of a healthy microbiome, whether the skin, vagina, mouth or gut microbiome is critical for good health.

In the Cann lab, we are interested in the function of the colonic microbiome, which is dominate by the two bacterial phyla, the Firmicutes and Bacteroidetes. These bacteria and other colonic microbiome members have adapted to their environment through acquisition of energy from host undegradable dietary components and host-emanating nutrients, such as the mucins in our intestinal mucus layer.

Starch is the main source of energy in most human diets, and our eukaryotic or human intestinal cells are able to degrade it into its unit sugars and derive energy out of starch. Human diets contain many other polysaccharides; however, aside from the starch component, our eukaryotic cells are incapable of depolymerizing and deriving energy from these complex dietary polysaccharides. The polysaccharides, including pectins, arabinoxylans, and mannans escape hydrolysis in the upper gastrointestinal tract (GIT) and flow into the lower GIT where they encounter our microbial cells, a community that has evolved a wide array of enzymes to degrade the polysaccharides, releasing their unit components for fermentation.

The microbial action on the nutrients and polysaccharides flowing into the colon yields metabolites with diverse activities, including neurotransmitters (GABA), potent antioxidants (e.g., ferulic acid), and G-protein coupled receptor ligands (e.g., propionate and butyrate) that modulate immune function, and overall impact the host physiology.

The main thrust of our research on the human colonic microbiome is to unravel the diversity of the polysaccharides uniquely sensed by the human colonic Bacteroidetes and to determine whether depending on the food culture, unique Polysaccharide Sensing and Degradation Signatures (PSDS) have been evolved by the colonic microbiomes. Importantly, we would like to know what are the metabolites associated with the different diets and what are their associated health benefits.

We anticipate that our research approach, which combines bacterial growth and manipulations, transcriptomics, metabolomics, enzymology, biochemistry, germ-free animal studies, bioinformatics and protein structural studies, will unravel the molecular mechanisms underlying complex polysaccharide degradation and fermentation in the human gut. In an era of acute interest in personalized nutrition, we anticipate that the knowledge gained from our research will facilitate rational manipulation of the diet and the microbiome to elicit maximum health and nutritional benefits to individuals.

A model predicting sensing of polysaccharides by the human colonic Bacteroidetes and regulation of the genes in their Polysaccharide Utilization Loci (PULs) for complete enzymatic degradation and fermentation of the unit sugars.
From: Cann and Mackie. 2018. Nat Microbiol. 3:127.

The role of the microbiome in acute lung injury-associated lung diseases

Diseases that cause acute injury of lung tissue represent some of the most intractable illnesses worldwide, with acute exacerbation of Idiopathic Pulmonary Fibrosis (IPF) and Acute Respiratory Distress Syndrome (ARDS) being two of the most pervasive in our societies. Significant efforts by many researchers are devoted to elucidating the mechanisms underlying IPF and ARDS; however, progress has been slow.

Recurrent injury and apoptosis of lung alveolar epithelial cells and aberrant tissue repair, caused by increased secretion of profibrotic factors, play significant roles in the pathogenesis of IPF. While the progression of the disease in patients varies, the life expectancy following diagnosis of IPF could be 2-3 years, and this can be hastened if the patient experiences what is termed Acute Exacerbation (AE) of IPF. Infections and diagnostic or surgical procedures are thought to be triggers of AE; however, the precise mechanisms are unknown. Acute Exacerbation of Idiopathic Pulmonary Fibrosis (AE-IPF) and ARDS share similar pathophysiological characteristics, including diffuse alveolar damage, increased lung tissue concentration of proinflammatory cytokines, enhanced neutrophils recruitment in the lungs, and increased apoptosis of lung parenchymal cells. Patients with AE-IPF or ARDS have a poor prognosis. The mortality rate of AE-IPF patients is 50% within three months, and the mortality rate of ARDS patients is between 30% to 50%.

The lung microbiome has been reported to play a role in IPF; however, most of the research has been based on bacterial community changes at the phylogenetic level. To gain a better understanding of how the lung microbiome contributes to the progression of both IPF and ARDS, the Cann lab, in collaboration with Professor Esteban Gabazza’s group in Japan, has been using microbiological and immunological approaches to determine how the two forms of Acute Lung Injury (ALI) diseases modulate the lung environment to remodel the microbiome and what are the consequences to the host. The research has led to the discovery that lung fibrosis or a lung with pre-existing tissue injury leads to impaired metabolic processes that enrich for halophilic bacteria, including several species of the bacterial genus Staphylococcus.

Importantly, we discovered that a number of the Staphylococcus species produce a polypeptide that is processed into peptides, with one component named corisin and corisin-like peptides being noteworthy in the pathophysiology of the two forms of acute lung injury. The secreted polypeptide, an IsaA-like transglycosylase, and the corisin peptide mimic the story of the “Trojan Horse”. In brief, while the full-length polypeptide appears harmless; its degradation product corisin exacerbates acute tissue injury in a lung with tissue fibrosis or pre-existing tissue injury by inducing extensive apoptosis of lung alveolar epithelial cells, a cardinal feature of both AE-IPF and ARDS.

The Cann and Gabazza groups are collaborating to unravel the mechanisms underlying the newly discovered apoptosis of lung cells induced by peptides from members of the genus Staphylococcus and to develop new approaches to alleviate or treat the two incurable diseases.

Induction of apoptosis of lung alveolar epithelial cells. Morphology of a cell treated with saline and a cell treated with the peptide corisin, a potent proapoptotic factor, hidden in the full-length IsaA-like transglycosylase in some Staphylococcus species.
From: D’Alessandro-Gabazza et al. 2020. Nat Commun. 11: 1539.

Enzymes of plant cell wall hydrolysis for biofuel production

One of the rate-limiting steps in the industrial production of cellulosic ethanol is the capacity to release the sugars locked up in plant cell walls for fermentation by organisms such as the yeast Saccharomyces cerevisiae to ethanol and other value-added products. In the biomass to bioenergy effort aimed at reducing the use of fossil fuels as energy for powering our vehicles, the main strategy is to release the six-carbon sugar glucose and the five-carbon sugar xylose present, respectively, in cellulose and hemicellulose, the major polysaccharides in the plant cell wall.

Industrially, the release of the sugars from cellulose and hemicellulose can be achieved in different ways, including chemical treatments and enzymatic treatment. In the Cann lab, we are interested in the application of enzymes for this purpose, since we find this approach to be environmentally friendly.

Complete depolymerization of the two polysaccharides requires a large number of enzymes working in concert to release the sugars. Our group uses microbial fermentation, transcriptomics, biochemical and structural approaches to discover and assemble enzymes that work in synergy under mesophilic, thermophilic, and hyperthermophlic conditions to release the glucose and xylose from bioenergy feedstocks.

The enzymes we work on, although mostly aimed for biofuel production, are also applicable in many other industrial processes, and patents from our lab based on these enzymes have been commercialized in the animal feed industry, a market projected to exceed $2.3 billion by 2026.

Most importantly, by studying these enzymes at the molecular, biochemical and structural levels, we are able to determine how the microbes (mostly originating from the cow rumen, the human gut and hot springs) access energy from complex plant polysaccharides.

A structural model showing an oligosaccharide of six glucose units (cellohexaose) bound to the Caldanaerobius polysaccharolyticus manno-oligosaccharide degrading enzyme, Man5B.
From: Cann et al. unpublished.

Awards

National Science Foundation CAREER Award 2003
Fellow, Center for Advanced Study 2005
Excellence in Guiding Undergraduate Research Award (UIUC) 2012
Paul A. Funk Award, College of ACES 2014

Representative Publications

Cann, I.K.O. 2008. Cell sorting protein homologs reveal an unusual diversity in archaeal cell division. Proc Natl Acad Sci USA. 105: 18653-18654. PMID: 19033202.

X. Shi, Y. Jung, L.J. Lin, C. Liu, C. Wu, I.K.O. Cann, and T. Ha. 2012. Quantitative, fluorescent labeling of aldehyde-tagged protein (Q-FLAP) for single-molecule imaging. Nat Methods. 9:499-503. PMID: 22466795.

Zhang, M., J.R. Chekan, D. Dodd, P.Y. Hong, L. Radlinski, V. Revindran, S.K. Nair, R.I. Mackie, and I. Cann. 2014. Xylan utilization in the human gut commensal bacteria is orchestrated by unique modular organization of polysaccharide-degrading enzymes. Proc Natl Acad Sci USA. 111: E3708-3717. PMID: 26136124.

Mackie, R.I. and I. Cann. 2018. Let them eat fruit. Nat Microbiol. 3: 127-129: PMID: 29358680.

Pereira, G.V., A.M. Abdel-Hamid, S. Dutta, C.N. D’Alessandro-Gabazza, D. Wefers, J.A. Farris, S. Bajaj, Z. Wawrzak, H. Atomi, R.I. Mackie, E.C. Gabazza, D. Shukla, N.M. Koropatkin, and I. Cann. 2021. Degradation of complex arabinoxylans by human colonic Bacteroidetes. Nat Commun. 12: 459. PMID: 33469030.

D’Alessandro-Gabazza, C.N., C. Mendez-Garcia, O. Hataji, S. Westergaard, F. Watanabe, T. Yasuma, M. Toda, H. Fujimoto. K. Nishihama, K. Fujiwara, O. Taguchi, T. Kobayashi, R.I. Mackie, I. Cann, and E.C. Gabazza. 2018. Identification of halophilic microbes in lung fibrotic tissue by oligotyping. Front. Microbiol. 9:1892. PMID: 30233503.

D’Alessandro-Gabazza, C.N., ………., I. Cann*, and E.C. Gabazza*. 2020. A Staphylococcus pro-apoptotic peptide induces acute exacerbation of pulmonary fibrosis. Nat Commun. 11:1539 PMID: 32210242. (*Co-corresponding authors).

D’Alessandro-Gabazza, C.N., ……….., I. Cann*, and E.C. Gabazza*. 2021. Inhibition of lung microbiota-derived peptide ameliorates Acute Exacerbation of Pulmonary Fibrosis. In review. (*Co-corresponding authors).

D. Dodd, Y. H. Moon, K. Swaminathan, R.I. Mackie, and I.K.O. Cann. 2010. Transcriptomic analyses of xylan degradation by Prevotella bryantii and insights into energy acquisition by xylanolytic Bacteroidetes. J Biol Chem. 285:30261-30273. PMID: 20622018.

Y. Han, V. Agarwal, D. Dodd, J. Kim, B. Bae, R.I. Mackie, S. K. Nair, and I.K.O. Cann. 2012. Biochemical and structural insights into xylan utilization by the thermophilic bacterium Caldanaerobius polysaccharolyticus. J Biol Chem. 287:34946-34960. PMID: 22918832.

Complete Publications List