Dr Joakim Larsson

TEDx-lecture by Joakim Larsson 2011 on “Our Drugs in Their Water”

Summary of funded projects

Pharmaceutical pollution – antibiotic resistance development and mode-of-action based test strategies

Senior scientist position for Joakim Larsson 2009-2015 within the field of Translational Pharmacology including a startup-grant from the Swedish Research Council (Medicine).
This grant covers research on several aspects on environmental effects of pharmaceuticals where there currently are major knowledge gaps. My group will focus on three areas:

1. assess risks (including resistance development) associated with the extaordinary large releases of antibiotics and other pharmaceuticals from bulk drug producers in India
2. identify drugs likely to cause environmental effects and contribute to a scientifically founded framework for mode-of-action based environmental risk assessments of human pharmaceuticals
3. evaluate effluent treatment technologies to reduce the environmental impact of pharmaceuticals

MistraPharma - Identification and reduction of environmental risks caused by human pharmaceuticals (phase II).

Research program supported by the Swedish Foundation for Strategic Environmental Research (MISTRA) 2012-2015 with 52 MSEK. The program involves partners at the Sahlgrenska Academy at University of Gothenburg, Chalmers University of Technology, the Royal Institute of Technology, Uppsala University, Stockholm University, Umeå University, Brunel University (UK) and Stella Futura. Program website: www.mistrapharma.se

The major aims of this interdisciplinary research program are to:

(1) Identify high risk APIs
By generating new data with high relevance in environmental risk management
(2) Understand promotion of antibiotic resistance in the environment
By determining antibiotic resistance factors in contaminated environments and assessing different selection pressures
(3) Evaluate removal of high risk APIs through wastewater treatment
By assessing the feasibility of ozonation and/or activated carbon in wastewater treatment
(4) Contribute to the development of improved risk management
By improving the scientific basis for environmental classification, risk assessment and substitution
(5) Provide state-of-the-art analyses of APIs of environmental concern
By developing and quality assuring analytical methods
(6) Provide decision support to stakeholders
By communicating generated knowledge to ensure that it can be put to practical use.
 

Antibiotic resistance in marine bacteria - the role of biocides and metals in the marine environment for promoting and maintaining antibiotic resistance

Funding for two PhD student from the Gothenburg Centre for Marine Research 2012-2015 to Joakim Larsson and Hans Blanck
One of the primary goals for Gothenburg Centre for Marine Research is to coordinate marine environmental research in Gothenburg and to bring together scientists from different disciplines. This interdisciplinary project combines competence from the Health Faculty and the Natural Science Faculty to address potential drivers for the development of antibiotic resistance, one of the most urgent threats to human health globally. Bacteria often carry resistance elements to metals and biocides together with resistance elements to antibiotics. Thus, a selection pressure from metals and biocides may select also for antibiotic resistance. By combining our competences in large-scale DNA sequencing and bacterial biofilm ecology, this project will address the risks for the promotion of antibiotic resistant bacteria, through indirect selection pressures, in the marine environment.

NICE – Novel Instruments for effect-based assessment of Chemical pollution in coastal Ecosystems

Strong Research Environment funded by the Swedish Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS) 2012-2016 with 25 MSEK. The program, coordinated by Dr Thomas Backhaus, involves 12 partners from the Gothenburg region. The JL group is mainly involved in work on bacterial metagenomics.

Mixtures of toxic chemicals regularly occur in our coastal ecosystems. NICE develops instruments for monitoring their ecological effects, as required by the Water Framework Directive and needed for identification of the relevant pollutants in the field. The NICE tools will be evaluated in field studies. We will suggest options for environmental regulation of chemical mixtures, thus providing input to the water management in Västra Götaland. Reference and contaminated sites mainly on the Swedish coast will be selected in co-operation with stakeholder authorities and subjected to deeper ecotoxicological investigations. Chemical monitoring data will initially be used for pinpointing the pollutants at each site. These will be ranked according to their expected environmental impact and then further investigated by extended chemical analysis. Ecotoxicological effect profiles ("fingerprints") of the priority pollutants will be recorded for microbial communities, invertebrates and fish, using classic biomarkers, population level endpoints, ecological effect indicators (PICT) and advanced fingerprints based on (gen-)OMICs. The fingerprints will be used to detect effects in the environment, providing causal links between the mere presence of pollutants and their ecological impact of a site. The effect profiles will be aggregated into models for site-specific ecological impacts, which will be amended, if needed, to take into account the presence of unknown pollutants and interactions.
 

Characterization of antibiotic resistance in bacterial communities: novel methods using next generation
sequencing

Project grant from the Swedish Research Council (VR-NT) 2012-2015 to Erik Kristiansson (DGJ Larsson, ERB Moore and G Kemp are co-applicants).

The accelerated development of antibiotic resistance is one of the most urgent threats to human health. Bacteria become resistant to antibiotics by acquiring resistance genes through the process of horizontal gene transfer. Since antibiotics are naturally produced by many organisms, environmental bacterial communities contain a particular high diversity of resistance genes. Understanding the role of the environment as a reservoir for resistance genes and their routes of transfer is therefore vital. In this project we will develop novel tools for explorative analysis of resistance genes in bacterial communities. The tools are based on data generated by the next generation DNA sequencing and have therefore a high sensitivity and precision, even for less abundant genes. We will also develop tools for culture-independent characterization of resistance plasmids, which are the main vehicles for transmission of resistance genes between bacterial cells. The methods will be used to analyze data from environmental bacterial communities, both with and without antibiotic selection pressure, and the human microbiome. The project will generate novel insights into the development, promotion and spread of antibiotic resistance. The methods will have a great applicability in both basic and clinical microbiology as well as in metagenomics in general.
 

Multi-drug-resistant Gram-negative infectious bacteria: new genotypic and phenotypic developments for diagnostics and epidemiological control within the clinical environment

ALF-LUA grant to Ed Moore and several co-applicants (including DGJ Larsson) 2012-2013.

A primary focus of the project is the use of an unusually well-defined epidemiological out-break situation to establish the basis for how we should conduct continuous monitoring of ESBL-producing bacteria and other multi drug resistant gram negatives in an efficient and cost effective manner. A range of different typing strategies, including MALDI-TOF, will be assessed and evaluated. My group’s primary involvement and interest in this project involve evaluations with sequencing-based technologies.
 

Antibiotic resistance in the external environment - the role of antibiotic pollution in the selection of resistance and subsequent gene transfer to the human microbiome

Project grant from the Swedish Research Council (VR-MH) 2011-2013
 

Does a high level of antibiotic pollution increase risks for mobilization of resistance genes from the environment to the human microflora - exploratory studies including deep sequencing

Project grant funded by the Swedish Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS) 2011-2013.
 

Increasing frequencies of multiresistant pathogens is a global problem accelerated by our heavy use of antibiotics. As bacteria and bacterial genes often are mobile, the external environmental may serve as a reservoir of resistance genes to human pathogens. We have recently demonstrated unprecedented pollution with broad-spectrum antibiotics in India with potential implications for resistance development. The main questions to answer within the VR and FORMAS projects are ¹⁾ How does a high and persistent environmental antibiotic selection pressure affect the abundance of resistance genes and genetic elements promoting their mobility? ²⁾ Can we find evidence for a role of environmental antibiotic pollution in the transfer of resistance genes to the human microflora? ³⁾ Can we explore the environmental microbiome to identify novel resistance genes that we may face in the clinic tomorrow? High-throughput DNA sequencing of isolates and complex bacterial communities, in parallel with traditional microbiology, will be used to genetically and functionally characterize resistance factors in bacteria from river sediment, soil, drinking water and human faeces from highly antibiotic-polluted Indian environments and reference sites. Science-based evidence of the consequences of antibiotic pollution, as those generated here, could provide strong incentives to reduce antibiotic selection pressure on environmental bacteria in order to protect public health. Click here for a 15 minute presentation (in Swedish) on the challenges with antibiotics in the environment.
 

Resistance in environmental bacteria evolving under extreme antibiotic selection pressure – characterization of the resistance genes we may face tomorrow

PhD student project 2010-2013 (Anna Johnning) co-financed by the Sahlgrenska Academy
The heavy use of antibiotics in human and veterinary medicine is a major driving force behind the development of multi-resistant bacteria. Antibiotics find their way to the environment through excretion and via effluents from manufacturers. This promotes the development of resistant bacteria, which can serve as a recruitment pool for resistance genes to human pathogens through horizontal gene transfer.
The aim of this project is to assess risks of extreme antibiotic contamination in the environment. Environmental samples from areas heavily contaminated with antibiotics will be analyzed using large-scale gene-sequencing techniques, and resistant bacteria and their resistance factors investigated. Meta-genomic analysis will provide culture-independent information on a community level and whole-genome sequencing will identify important genetic alterations. Experimental work will be undertaken to identify novel resistance factors and the presence of transfer mechanisms. A clinical study is proposed to establish links between environmental exposure to antibiotics and resistance factors in the human microbiome.
 

Microbial diversity and development of antibiotic resistance associated with industrial wastewater treatment

Swedish Research Link programme funded 2009-2011 by SIDA.

The Swedish Research Links programme from SIDA aims to stimulate research cooperation between researchers in Sweden and researchers in Asia, the Middle East and North Africa (MENA) region and South Africa. One important focus is to stimulate the mobility for the involved scientists. Within this collaborative project between the University of Gothenburg and Indian scientists, we intend to analyze the impact of extraordinary high levels of antibiotic pollution from pharmaceutical manufacturing near Hyderabad, India, on bacterial diversity and the development of antibiotic resistance. We will also study the potential impact on the emergence of antibiotic-resistant bacterial pathogens as well as the genetic background to their resistance. This research will provide insights into the relationships between selection processes due to antibiotic pollution and subsequent development of resistance.
 

Consumption of inexpensive medicines – increased risks for resistance development and environmental effects?

PhD-student project (Carolin Rutgersson) funded by the Research School for Environment and Health in Göteborg 2008-2012.

Pharmaceuticals are thought to reach the aquatic environment primarily via sewage effluents, where for example estrogens can feminize fish. Antibiotics in normal treated sewage effluents are not believed to cause resistance or affect microbial diversity. However, we recently showed that treated effluent from 90 production sites in India contains extremely high, toxic levels of antibiotics, with ciprofloxacin up to 1 million times the levels normally found in sewage effluents. We will start to address the environmental impact of the release of pharmaceuticals at this centre for the global bulk-drug market. This will also include the impact on species diversity and resistance development of bacterial communities. The project will also address different possibilities of how the situation can be improved. We believe the project will provide new knowledge on antibiotic pollution and the subsequent development of resistance, of urgent importance for improving regulatory standards for production units world-wide. The project will be performed in collaboration with several other research groups, both in Sweden and India.
 

Endocrine disruption of non-genomic progesterone signalling – consequences for gamete transport and sex ratios

Research program funded by the Swedish Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS) 2008-2010 to Joakim Larsson. Anna Bylander is a PhD student within this program.

The aim of this project is to investigate how progesterone and various endocrine disrupters affect membrane progesterone receptor expression, oviductal ciliary activity, gamete transport and male to female ratios among the offspring in a mouse model. Within the project, the development and application of ciliary activity analysis together with Dr Mattias Goksör (Physics, GU) is particularly important. We believe our research will contribute both to our understanding of the gamete transport and the physiological control of sex in mammals as well as to better understand the interference by pollutants in these processes. In the future, this research could potentially pave the way for drugs or other treatments to reduce the risks for ectopic pregnancies in women.
 

BALCOFISH - Integration of pollutant gene responses and fish ecology in Baltic coastal fisheries and management

Research project funded by the European BONUS program 2008-2012. Joakim Larsson, Erik Kristiansson and Noomi Asker (postdoctoral fellows) are active within BALCOFISH.

The overall objective of the BALCOFISH project is to provide science-based input to foster the development of appropriate measures in the management of the Baltic Sea environment to protect it against anthropogenic chemical pollution. For this purpose it is important to unravel causal links between the current pollution situation and effects observed in the field. To establish such links we will develop novel toxicogenomics approaches and integrate these with existing early effects biomarkers. These responses will be anchored to effects relevant to the sustainability of coastal fish populations of the Baltic Sea, such as impaired reproduction. We will systematically test strengths of evidences supporting causal linkages between contaminants and effects on Baltic fish by using a formal weight-of-evidence approach. The BALCOFISH project is coordinated by Gothenburg University (Lars Förlin, Zoology) and involves partners from the Sahlgrenska Academy (our group), University of Aarhus (Denmark), Swedish Board of Fisheries, Institute for Applied Ecology (Germany) Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences (Sweden) and the Swedish Museum of Natural History, Sweden. In total 16 BONUS projects were funded in June 2008 (out of 149 application), with a total budget of 22 Million Euro.
 

MistraPharma - Identification and reduction of environmental risk caused by the use of human pharmaceuticals.

Research program supported by the Swedish Foundation for Strategic Environmental Research (MISTRA) 2008-2011 with 44.2 MSEK. Joakim Larsson, Filip Cuklev (PhD student), Lina Gunnarsson, Bethanie Carnie Almroth, Bart Adriaenssens, Erik Kristiansson (postdoctoral fellows) and other members of the group are involved in this program.

This research program will take a comprehensive approach for prioritizing environmental research on the majority of the human drugs used in Sweden in order to facilitate possible mitigations. Bioconcentration into fish blood plasma will be assessed for about 100 substances using fish exposed to various sewage effluents. For the drugs showing the highest fish blood plasma levels in comparison with human therapeutic levels, comprehensive biological effect studies will be performed. Other strategies for prioritization will be applied as well. The effect studies include both directed, mechanism-of action-based analyses as well as different exploratory approaches using for example microarrays and histology. Rainbow trout and Daphnia will be the primary test models. The efficacy of a range of different treatment technologies will be evaluated with particular respect to the most highly ranked drugs. Different test strategies will be evaluated which will be used to improve existing risk assessment procedures. MistraPharma has been developed and will be performed in close collaboration with the water treatment companies, the health care sector, representatives for industries, environmental agencies and the Medical Products Agency.

Involved partners are in addition to our research group at the Sahlgrenska Academy at Göteborg University: the Royal Institute of Technology, Uppsala University, Stockholm University, Umeå University, LundUniversity/Denmarks Technical University and Kemi&Miljö. The program director will be Dr Christina Rudén at the Royal Institute of Technology.

Our research on environmental effects of pharmaceuticals is one example of how Göteborg University and the Sahlgrenska Academy work proactively with environmental issues. Sustainable development is emphasized in many courses for students as well. Click on this link to view a short presentation (in Swedish).

Ecotoxicology – from gene to ocean

Interdisciplinary research platform (Joakim Larsson co-applicant together with L Förlin, H Blanck, G Dave and M Celander) funded by the Science faculty at Göteborg University 2007 – 2012.

In this platform we intend use a set of genome-wide approaches to identify responses and mechanisms of action of individual chemicals and their mixtures. The platform encompasses different subprojects dealing with ecotoxicological effects of marine antifouling paints and pharmaceuticals to mention a couple of examples. We will extend our approach from single species and single chemicals to complex, contaminated ecosystems. The platform brings together scientists from complementing disciplines in molecular genetics, cell biology, physiological, organismic and community ecotoxicology and mode of action research. This interdisciplinary team will integrate current individual research efforts in genomics and ecotoxicology at Göteborg University. Or vision is to consolidate, renew and strengthen ongoing research, as well as providing the critical mass for future research applications on a national as well as international level.
 

Metabolic processes underlying seasonal growth patterns in fish

Research project funded by the Science Faculty at Göteborg University within the larger GRIP-platform (Göteborg Research on Integrative Physiology: http://www.grip.science.gu.se/ ). 2006-2011. The project is jointly coordinated between departments of Zoophysiology (Elisabeth Jönsson, Thrandur Björnsson), Zooecology (Jörgen Johnsson) and the Sahlgrenska Academy (Joakim Larsson)

The project objective is to improve the understanding of the metabolic processes underlying seasonal growth patterns in fish, and link this to ecological questions. Focus will be on the influence of food availability, temperature, and population density on the endocrine regulation of growth patterns and associated metabolic processes in whole animals, in the lab and field. The research aim to advance the understanding of physiological mechanisms behind seasonal adaptations, thus increasing our ability to predict consequences of climatic changes on fish populations.