Will the novel CRISPR/Cas9 technology for the generation of genetically modified animals increase the number of animals used and lead to a shift in the species used? Statement of the ISTT’s 3Rs Committee

The CRISPR/Cas9 technology emerged only recently. Still it is already obvious, that it makes the generation of genetically modified organisms more efficient than with conventional techniques. Moreover, species that were recalcitrant to those manipulations in the past are now amenable to genome editing.

What we initially saw in the rodent, especially the mouse research community, was a rush into the technique, where many scientists wanted to employ the new technology (me too). While there were a number of reports on off-target effects, it is now clear that off-target genome alterations are rarely found in an in vivo situation (Seruggia et al., 2015; Shen et al., 2014). Moreover modified nucleases are meanwhile available with no detectable off-target effects (Kleinstiver et al. 2016).

In the most widely used model organism in biomedical research, the mouse, the number of animals needed to generate a genetically modified line remains approximately the same with CRISPR/Cas9 as compared to conventional techniques. However, the ease at which new mutations are generated with the new system might lead to increased numbers of novel lines being produced (Williams et al., 2016). Moreover, numbers are also increasing for other species, especially zebrafish and rats (Auer and Del Bene, 2014; Hwang et al., 2013; Wang et al., 2015). As with all novel genetically modified lines, after their generation CRISPR/Cas9 generated animals need to be bred for experiments and are kept on the shelf for considerable time. Thereby, the increase in the number of lines generated will translate into larger numbers of additional animals bred.

At this time, conventional techniques still have their justification in the lab since precise modification of DNA via homologous recombination, especially with large constructs, is not as robust as necessary via CRISPR/Cas9. However, one has to take into account that this is a very recent technology, whilst work to improve the generation of genetically modified mice via homologous recombination in embryonic stem cells has been ongoing for more than 25 years. We therefore may see extensive improvements over the coming years once we gain a better understanding of the underlying mechanisms. With improvements in targeting efficiencies there could be opportunities for further reductions in the number of mice used for the generation of the animal model to be studied: In many cases mutations are still introduced into ES cells that are used for the generation of live mice. Even though culture conditions have been improved over the years, cell clones show a fairly high degree of aneuploidy so that multiple clones have to be injected to generate chimeric offspring that transmit the mutation to their progeny. Due to the non-chimeric nature of CRISPR/Cas9, mutated individuals will in most cases transmit. Therefore an improved ratio of mutant to wildtype offspring could directly reduce the number of animals produced. However, the degree of mosaicism could counteract this reduction. CRISPR/Cas9 technology has the potential that several mutations can be introduced on different alleles at the same time, even homozygously, once the mosaicism issue is solved. Alternatively, complex mutations can be generated by adding additional mutations in pronuclear stage embryos of mutant backgrounds. With a sufficient increase in efficiency, this promise does appear realistic (Williams et al., 2016). This would mean that instead of producing a plethora of unwanted mice with unwanted genotypes in the process of breeding compound mutants, one could proceed right to the desired combination of mutated alleles.

We expect to see an increase in the number of species that will undergo complex targeted genetic manipulation. Still, a significant increase in laboratory animal numbers is not expected. The research infrastructure has been developed and is still being developed for large scale mouse breeding. The breeding of rats takes up much more space and only a few centers have the infrastructure for larger animals. The applicability of the technology to non- human primates means they are also more often nowadays used for transgenic animal research, especially in countries where such research is not strictly regulated. This is another issue of public concern and will require an ethical evaluation process beyond the scope of the 3R approach. CRISPR/Cas9 technology is widely used to genetically manipulate zebrafish. An increase in zebrafish numbers similar to what is foreseen in the mouse can be expected. On the other hand there will be projects where the zebrafish is now amenable to the introduction of complex targeted genetic manipulation and can therefore replace the mouse as a model – a clear refinement in accordance with the 3Rs.

In summary, the ISTT’s 3Rs Committee acknowledges that the advent of the CRISPR/Cas9 technology has the potential to significantly increase the number of animals used and range of species genetically modified. However the committee believes that existing limits on space and other associated resources will inhibit the realization of this at the current time. In the long run, after the technology has been developed further and improved, the Committee is hopeful that opportunities for reducing the number of animals that are bred but not used will be realized.

Boris Jerchow, Chair
On behalf of the ISTT’s 3Rs Committee Berlin in March 2016

Auer, T.O., and Del Bene, F. (2014). CRISPR/Cas9 and TALEN-mediated knock-in approaches in zebrafish. Methods 69, 142-150.
Hwang, W.Y., Fu, Y., Reyon, D., Maeder, M.L., Tsai, S.Q., Sander, J.D., Peterson, R.T., Yeh, J.R., and Joung, J.K. (2013). Efficient genome editing in zebrafish using a CRISPR-Cas system. Nat Biotechnol 31, 227-229.

Kleinstiver, B.P., Pattanayak, V., Prew, M.S., Tsai, S.Q., Nguyen, N.T., Zheng, Z., and Joung, J.K. (2016). High-fidelity CRISPR–Cas9 nucleases with no detectable genome-wide off- target effects. Nature, 529, 490-495.
Seruggia, D., Fernandez, A., Cantero, M., Pelczar, P., and Montoliu, L. (2015). Functional validation of mouse tyrosinase non-coding regulatory DNA elements by CRISPR-Cas9- mediated mutagenesis. Nucleic acids research 43, 4855-4867.

Shen, B., Zhang, W., Zhang, J., Zhou, J., Wang, J., Chen, L., Wang, L., Hodgkins, A., Iyer, V., Huang, X., et al. (2014). Efficient genome modification by CRISPR-Cas9 nickase with minimal off-target effects. Nature methods 11, 399-402.

Wang, L., Shao, Y., Guan, Y., Li, L., Wu, L., Chen, F., Liu, M., Chen, H., Ma, Y., Ma, X., et al. (2015). Large genomic fragment deletion and functional gene cassette knock-in via Cas9 protein mediated genome editing in one-cell rodent embryos. Scientific reports 5, 17517. Williams, A., Henao-Mejia, J., and Flavell, R.A. (2016). Editing the Mouse Genome Using the CRISPR-Cas9 System. Cold Spring Harbor protocols 2016, pdb top087536

Genetic Engineering of Human Embryos- for discussion

Commentary by Ernst-Martin Füchtbauer

The new and accelerating technical development of the CRISPR/Cas9 system opens up for the possibility of targeted genetic modifications in germline competent human embryos. This is an avenue, which until very recently has been regarded as absolutely off limits. To cross the border between genetic modifications of somatic cells and germline cells was simply not conceivable, at least in most Western countries. Indeed, the border has not yet been crossed, but we are getting closer.

In two recent papers Chinese scientists used triploid human embryos as a ‘model’ to either treat ß-thalassemia [1] or to recapitulate a spontaneous mutation in the CCR5 gene [2], which results in resistance against HIV infections. Both targets are clearly chosen due to their potential for future therapeutic application.

Shortly after the first of the two papers was published, the Board of Directors of the ISTT posted a statement [3], which among other arguments contains the following sentence:

Uses of genetic engineering in human embryos should be limited to disease mitigation for those diseases where no other option is available; we reject the idea of “designer babies”.

This raises the question whether there are at all diseases where there are no other options (now or in the future). Hereditary diseases are rarely transmitted by homozygous parents, which makes preimplantation diagnostics (PID) an obvious safer and ethically far less disputed alternative. The example, ß-thalassemia reaches in very limited populations, like the Maldives, a frequency that puts about 1% of couples at risk to be double homozygous. But still, is not a CRISPR/Cas9 based hematopoietic stem cell therapy the obvious and much easier developed therapy?

However, the case of targeting CCR5 is fundamentally different. As no one can claim that being wild type for CCR5 is a disease, this is a clear designer approach. Given that we know relatively little about the function of CCR5, one might wonder how we can be sure that it is beneficial to mutate it in a world of ever changing microbial threats. It seems that developing a CCR5 blocking drug or somatic mutations of CCR5 in HIV patients is the obvious way forward.

It is my feeling that many colleagues, some of whom I greatly admire, are beginning to accept experiments with the obvious goal to modify the human germline ‘if it is the only cure for severe diseases’. However, I have not heard one convincing example of such disease that is not in principle “treatable” or “avoidable”. Finally we should keep in mind that the Hardy-Weinberg equation ridicules all eugenic attempts to clean the population from ‘disease’ alleles.

I am increasingly concerned because the discussion in our community has, within a few months, taken an almost purely technical turn about off target risks and efficiency. We neglect many decades of thorough philosophical and ethical literature on the issue. There is more at stake than the possible treatment of a few rare diseases.

These questions are too important to just wait and see. We as ISTT members are so close to the topic that we need to have an honest and open discussion about our opinions. This blog could be a starting point and I invite/encourage you to add to this discussion.

[1] Liang, P. et al. Protein Cell (2015) http://dx.doi.org/10.1007/s13238-015-0153-5

[2] Kang, X. et al. J. Assist. Reprod. Genet. (2016) http://link.springer.com/article/10.1007%2Fs10815-016-0710-8

[3] http://www.montonerin.es/isttlegacy/isttblog/?p=1581

TT2016 – President’s Synopsis

The opening night of TT2016 was momentous promising subsequent days filled with good friends and good science. We welcomed more than 700 delegates who attended, and then proceeded to hear a wonderful talk from Andras Nagy (2005 ISTT Prize winner). Andras’ talk was followed by a delicious buffet with wine, friends, colleagues and music. The opening proved to be an excellent portent of what was to come. Over the next three days, we heard many excellent talks—talks that encompassed the use of transgenic technologies, and especially CRISPR/Cas9 technology.

Charles Gersbach presents CRISPR/Cas9 modification of the dystrophin gene
Charles Gersbach presents CRISPR/Cas9 modification of the dystrophin gene

We heard about methods to ameliorate muscular dystrophy, to humanize large animals for xenotransplantation, to make swine resistant to an endemic disease, and to examine infertility in humans. We discussed technologies that would use epigenome to target the “regulome”, that would examine non-coding areas of the genome, that would recapitulate immune syndromes in ES cells, and that would allow us to assess phenotypic changes in embryonic lethal mutant mice using imaging. We learned both the history behind the CRISPR/Cas9 system, and newer CRISPR systems that are in development. We discussed ethics, gene drive, non-injection technologies, new injection technologies, and methods of generating many more oocytes in mice. There were seventeen abstracts chosen for full presentation, examining technological developments, large CRISPR/Cas9 initiatives, and transposon-mediated transgenesis. The remainder of the more than 125 abstract submssions were displayed throughout the meeting in the spacious poster room. Three were chosen as Poster Award winners, including Vera Jansen (Optogenetic tools to study cAMP signaling in cilia and flagella), Charles-Etienne Dumeau (Efficient method for the isolation of functional single cell from the ICM of mouse blastocyst), and Hiromi Miura (Generation of knockdown mice by CRISPR/Cas9-based targeted insertion of artificial miRNA sequence). On the last day, the ISTT Young Investigator Award (sponsored by inGenious Targeting Laboratory) was given to Pablo Ross based on his work developing ES cells in farm animals.

Charles River Representative, Iva Morse, and Jan Parker-Thornburg and Elizabeth Williams (ISTT, Inc.) present the Best Poster Awards to Vera Jansen (absent), Charlie
Iva Morse (Charles River), and Jan Parker-Thornburg and Elizabeth Williams (ISTT, Inc.) present the Best Poster Awards to Vera Jansen (absent), Charles-Etienne Dumeau, and Hiromi Miura (represented by Masato Ohtsuka).
Thomas Zeyda (inGenious Targeting Laboratory) and Jan Parker-Thornburg (ISTT President) present the Young Investigator Award to Dr. Pablo Ross, UC Davis.
Thomas Zeyda (inGenious Targeting Laboratory) and Jan Parker-Thornburg (ISTT President) present the Young Investigator Award to Dr. Pablo Ross, UC Davis.
TT2016 - Cryopreservation Workshop presentation by Lluis Montoliu.
TT2016 – Cryopreservation Workshop presentation by Lluis Montoliu.

The meeting was preceded by two workshops—one on programmable nucleases (headed by Radislav Sedlacek) and one on cryopreservation (led by Martin Fray, INFRAFRONTIER). Those who attended the workshops were very pleased with the learning opportunities that were afforded them. In addition, immediately following the meeting was one additional workshop on zebrafish transgenesis (Leads: Petr Bartunek, Zbynek Kozmik, Christian Mosimann and Graham Lieschke). All of the workshops were well-attended and greatly appreciated!

First Orbis pictus lecture given by Richard Behringer.
First Orbis pictus lecture given by Richard Behringer.

There were a number of new initiatives at TT2016. We had Orbis pictus lectures—lectures designed to use pictures and clear descriptions to demonstrate answers to a problem. Richard Behringer gave an excellent, encyclopedic presentation of methods of producing genetically modified animals in a vast variety of species. Later, Thomas Boehm described how lymphoid organs developed throughout evolution to the point where vertebrates now have a thymus. Also, for the first time, we had concurrent sessions. Delegates needed to choose whether to hear about ethics in animal use, or new injection and superovulation technologies. Overall, the scientific program was exceptional!

Departing Board members
Presentation of thank-you gifts to departing ISTT Board members – Wojtek Auerbach (absent), Boris Jerchow, and Tom Fielder.

The ISTT, Inc. held its third General Assembly just prior to the Gala Dinner. During that meeting, we sadly said goodbye to three departing Board members: Tom Fielder, Boris Jerchow and Wojtek Auerbach. We also reviewed ISTT finances, membership, committee activities, and interactions with our affiliated organizations. One new ISTT initiative that was presented was an outreach committee to our members (and non-members) who perform transgenic technologies in non-rodent (generally large-animal) species. The ISTT large animal group will be headed by Martina Crispo and Bruce Whitelaw. The meeting ended with a presentation inviting membership to attend TT2017 in Salt Lake City, Utah, USA, hosted by Susan Tamowski.

A wonderful time at the Zofin Palace.
A wonderful time at the Zofin Palace.

The social program prepared by our Czech colleagues was also amazing. Delegates enjoyed the opening buffet with traditional Czech music. However, it was the Gala Dinner that proved to be the high point of the social program. The Zofin Palace was full with partygoers. The wine flowed freely, the food was wonderful, and the string quartet (plus clarinet) fantastic as well. Overall, TT2016 can be considered as one of the best TT meetings ever, and I am proud, as ISTT President, that we helped to host such a wonderful meeting. Thanks so very much to the organizers—Radislav Sedlacek, Inken Beck and Nicole Chambers. Due to their amazing work, the ISTT has again had a successful TT meeting!

TT2016 Deadlines and Poster

TT2016, to be held in Prague in late March, should prove to be an exciting meeting. The scientific portion of the meeting will be from 20-23 March. In addition, there are three hands-on workshops that are available, including a Mouse Cryopreservation Workshop (16-18 March), a course on CRISPR/Cas9 programmable nucleases (16-18 March) and a Fish Transgenesis Course (23-25 March).

Early registration will close on 15 December, 2015, so register soon! Please note that ISTT members have discounted registrations, and can apply for a limited number of registration and travel awards (as detailed in e-mails sent to ISTT members). Applications and documentation for these awards must be sent in by 15 December, 2015 to istt@transtechsociety.org.

We also encourage you to submit an abstract for the poster session. A number of poster abstracts will be chosen for oral presentation, so this is an excellent opportunity to share your science. Poster submissions are also eligible for the TT2016 Poster awards. Abstracts are due by 15 December, 2015

Please note that a printable poster has been appended to this blog post. Feel free to print and post widely! Looking forward to seeing you at TT2016!

TT2016_poster A3w workshops

LASA Winter Meeting – Genome Editing Session

Meeting Report by Mary-Ann Haskings, 25 November, 2015

It was a cold, sunny day in Brighton, UK for the LASA Winter meeting and we were pleased to see several ISTT members attending the meeting. The talks reflected on recent work involving genome editing across a breadth of species: mouse, zebrafish, opossum and discussion of use in humans.

There were some common themes across the talks and some newer approaches such as testis electroporation highlighted. The occurrence of mosaicism was discussed lengthily. The use of the NHEJ inhibitor SCR7 was another hot topic, with multiple speakers reporting that their experience suggested that there was little gain in using it. Comparisons were shown between Cas9 mRNA and protein; also the use of transgenic mice overexpressing Cas9 was reported. The possibility of reproducing better models of multi locus disease was recognised by several presenters.

The afternoon session focused on the ethical considerations of the technology, with the reminder that while it may well cause a reduction in numbers as we refine the production of genetically altered animals, the ease and efficiency of the technology may actually lead to a rise in the numbers of animals being used.

We closed with a round table discussion giving the audience the opportunity to ask any questions of our speakers. We need to thank all our speakers and our fantastic chairs Brendan Doe and Sarah Hart Johnson who helped the day to run so smoothly.

IMM2015-Leiden, June 11-12, 2015-A Short Meeting Report

IMM2015-Leiden, June 11-12, 2015-A Short Meeting Report
IMM2015-Leiden, June 11-12, 2015-A Short Meeting Report

On June 11-12, the 8th Workshop on Innovative Mouse Models (IMM2015) was held in the Leiden University Medical Center, Leiden, Netherlands. This biannual meeting brings together a diverse group of researchers interested in developing and exploiting mouse models to study fundamental developmental processes and to mimic human disease. Featuring the most recent advances on transgenic animal technology, this meeting encourages in-depth discussions in a very open way, accessible for young and senior scientists. The local organizers proposed a very attractive program composed of 11 keynote lectures, 10 oral selected presentations and a forum discussion on the impact of new transgenic technology advances. About 150 scientists shared data, frustrations and promising future designs of recent transgenic approaches, particularly exploring the future and limits of the extremely powerful CRISPR/Cas9 system for genome editing. Also discussed were improved mouse reproductive technologies (sperm cryopreservation, embryo production…), novel imaging-technologies and a new and very efficient way of delivering native proteins.
Sjef Verbeek, initiator of the IMM worshops, opened the workshop with a warm welcome for all participants and expressed his gratitude to all the sponsors: Innoser, the International Society for Transgenic Technologies (ISTT), Leiden University Medical Center (LUMC) and The Netherlands Cancer Institute (NKI).
While we were proud to notice that many participants were already ISTT members, we believe that our presence there as a sponsor with a booth could convince many more to take THE step forward and join our society, as well as join us at our next TTMeeting in Prague (TT2016, 20-23 March 2016)! Yes, the ISTT booth attracted many scientists interested in our role and activities and has definitely been a central meeting point of IMM2015!
Benoît Kanzler

ISTT Board of Directors: STATEMENT ON GENETIC ENGINEERING OF HUMAN EMBRYOS

ISTT Board of Directors

STATEMENT ON GENETIC ENGINEERING OF HUMAN EMBRYOS

June 10, 2015

Genetic engineering in animals is a process that has engendered great excitement as well as great anxiety. The technology is used to study developmental processes (using small animals such as the mouse, zebra fish, fruit fly, worm, etc.), determine gene function, and mimic human and animal disease processes. Perhaps the greatest promises of this technology are to develop and test drugs and to perform gene therapy, both of which are intended to prevent or cure disease.

Until recently, a variety of limitations made the technology impractical for all but a few species of animals (primarily mice). However, with the advent of new gene-editing systems, where components are inexpensive, readily generated in the laboratory, and applicable to virtually any species, it is now feasible to perform genetic engineering in the human embryo. Changes made in an embryo brought to term would no longer be confined to that individual, but could be passed through the germline to affect future generations.

A recent publication [Liang, P. et al. Protein Cellhttp://dx.doi.org/10.1007/s13238-015-0153-5 (2015)] brought this reality squarely into the public consciousness. In this study, the CRISPR/Cas9 system was used to edit the genome of human embryos. To their credit, the authors were careful to use only non-viable embryos. Furthermore, their detailed examination of the engineered embryos revealed both the intended and unintended modifications that resulted. This study clearly demonstrates that the CRISPR/Cas9 system is currently too imprecise and inefficient for genetic engineering of human embryos for implantation, gestation and birth.

Members of the ISTT use CRISPR/Cas9 technology, as well as other gene-editing technologies, routinely. Many of our members have had integral roles in the development of these technologies and therefore recognize the power of these systems. It is with that knowledge and foresight that the ISTT Board of Directors issues this statement (while understanding that more nuanced discussions and decisions will be needed as the technology improves):

  • Genetic engineering technology, in its current state, is error-prone and must not be used in human embryos intended for implantation.
  • Studies to test new genetic engineering technology in human embryos should be postponed until proven completely safe and effective in other species.
  • New methods of genetic engineering must be carefully assessed to ensure that risk to the human population is negligible.
  • Uses of genetic engineering in human embryos should be limited to disease mitigation for those diseases where no other option is available; we reject the idea of “designer babies.”
  • We strongly urge worldwide agreement on minimum standards for gene editing experiments in human embryos, and will promote such measures with our members. Until such standards have been established, we remain opposed to making any genetic alterations in human embryos that could be inherited by future generations.

 

Meet the ISTT at the 8th Workshop on Innovative Mouse Models (IMM2015)

Meet the ISTT at the 8th Workshop on Innovative Mouse Models (IMM2015), 11-12 June 2015, in Leiden, the Netherlands
Meet the ISTT at the 8th Workshop on Innovative Mouse Models (IMM2015), 11-12 June 2015, in Leiden, the Netherlands

Meet the ISTT at the 8th Workshop on Innovative Mouse Models (IMM2015) that will be held on 11-12 June 2015, in Leiden, the Netherlands. The popular biannual “Workshop on Innovative Mouse Models” brings together a diverse group of scientists interested in developing and exploiting mouse models to study fundamental developmental processes and to mimic human disease. Keynote speakers from leading laboratories present the latest developments on advanced genome alteration protocols, this year specifically focusing on the use of CRISPR/Cas9-assisted gene modification. Also novel imaging-technologies will be presented. The two-day workshop format combines keynote lectures and presentations of selected abstracts in order to encourage in-depth and unvarnished discussions of novel technologies.
For more information, scientific programme with confirmed speakers and registration, please visit: http://research.nki.nl/immworkshop/
Looking forward to meet many of you at IMM2015 in Leiden!

Advances in the Generation of Genetically Modified Animal Models: International Course & Symposium, Institut Pasteur de Montevideo (Uruguay), 7-18 September 2015

Advances in the Generation of Genetically Modified Animal Models: International Course & Symposium, Institut Pasteur de Montevideo (Uruguay), 7-18 September 2015
Advances in the Generation of Genetically Modified Animal Models: International Course & Symposium, Institut Pasteur de Montevideo (Uruguay), 7-18 September 2015

The International Society for Trangenic Technologies (ISTT) proudly co-sponsors the International Course & Symposium on Advances in the Generation of Genetically Modified Animal Models, to be held at the Institut Pasteur de Montevideo (Uruguay), organized by ISTT Members Martina Crispo (Unidad de Animales Transgénicos y Experimentación, UATE, Institut Pasteur de Montevideo) and Alejo Menchaca (Instituto de Reproducción Animal de Uruguay, IRAUy), on 8-15 September 2015.

The aim is to offer a training course of excellence for researchers and technicians working in animal transgenic field. The topics will be focused on both the basic knowledge and the latest advances in transgenic technologies. The course consists of a 1st week of lectures sessions and a 2nd week of practical sessions. In addition, a mini symposium (11-12 September) is organized in order to extend the impact of the presence of the professors to other researchers, technicians and posgraduate students. Current programs for the COURSE and MINI-SYMPOSIUM.

Confirmed speakers attending this Course and mini-Symposium include:

  • Michel Cohen-Tannoudji, IPParis, France
  • Francina Langa, IP Paris, France, ISTT member
  • Ignacio Anegón, INSERM, Nantes, France, ISTT member
  • Lluis Montoliu, CNB, Spain, ISTT member
  • Jorge Sztein, consultant, Spain
  • Sylva Haralambous, HPI, Greece, ISTT member
  • Naomi Nakagata, CARD, Kumamoto U, Japan, ISTT member
  • Charles Long, Texas A&M University, USA
  • Daniel Salamone, Fagro, UBA, Argentina
  • Adrian Mutto, UNSM, Argentina
  • Marcelo Rubinstein, INGEBI, Argentina, ISTT member
  • Marcelo Bertolini, UNIFOR, Brazil

Local professors and instructors include:

  • Magdalena Cárdenas, IP Montevideo, Uruguay
  • Ana Paula Mulet, IP Montevideo, Uruguay
  • Geraldine Schlapp, IP Montevideo, Uruguay, ISTT member
  • María Noel Meikle, IP Montevideo, Uruguay, ISTT member
  • Gabriel Fernández, IP Montevideo, Uruguay
  • Ana Paula Arévalo, IP Montevideo, Uruguay
  • Martina Crispo, IP Montevideo, Uruguay, ISTT member
  • Pedro C. dos Santos, IRAUy, Uruguay
  • Natalibeth Barrera, IRAUy, Uruguay
  • Federico Cuadro, IRAUy, Uruguay
  • Alejo Menchaca, IRAUy, Montevideo, Uruguay, ISTT member

People interested in participating in this COURSE must send the COURSE Application Form to tgcourse2015@pasteur.edu.uy
A maximum of 20 students will be accepted for the COURSE taking into account personal qualifications.
There is no registration fee for the COURSE. Support for accommodation, per diem and local transportation will be provided to all participants from abroad. Travel expenses are not included.
People interested in participating in the MINI SYMPOSIUM must send the SYMPOSIUM Registration Form to tgcourse2015@pasteur.edu.uy
SYMPOSIUM fee is U$S 100.

SAVE THE DATES!
Deadline for COURSE applications is June 28th
Deadline for SYMPOSIUM registrations is July 19th
For any further information contact: tgcourse2015@pasteur.edu.uy
www.pasteur.edu.uy/index.php/en/futurecourses

 

SALAAM kick-off meeting in Munich: thinking big (the important role of large animal models)

SALAAM kick-off meeting in Munich: 15-17 December 2014
SALAAM kick-off meeting in Munich: 15-17 December 2014

About a month ago, shortly before the season break, and very timely to enjoy its Christmas Market (Weihnachtsmarkt), the kick-off meeting of the Project SALAAM (Sharing Advances on Large Animal Models) took place in Munich (Germany), 15-17 December 2014, beautifully organized by Eckhard Wolf and Pascale Chavatte-Palmer, Chair and Co-Chair of this EU-COST Action BM1308. This conference, open to any interested researcher in the field, represented the official launch of the SALAAM project, to discuss about the role of large animal models in Translational Medicine, “Bridging the Gap between Basic and Clinical Research”, as indicated in the SALAAM logo. During these three days, about 120 scientists, including researchers not initially associated with SALAAM (including several ISTT members), gathered at the Gene Center, LMU Munich, to share their views about the role of large animal models in biomedicine.

The meeting started with a welcome address by Eckhard Wolf (LMU, Munich, Chair of SALAAM) who set the stage and underlined the need to use appropriate animal models for succeeding in translational research. In the past, large amount of resources have been devoted to rodents, mostly mice, in biomedicine, where mouse models have become instrumental for the current understanding of how most of our genes work and greatly facilitated the progress in the post-genomic era. However, in spite of mice being widely used in Biomedicine to model human diseases, often mice fail to accurately reproduce the features associated with a given human pathology. Therefore there is an urgent need to develop non-rodent animal models that would mimic aspects of human anatomy and human physiology more closely. Pigs, small ruminants and rabbits appear to be excellent candidates to follow up the preliminary discoveries made in mice, and they are the main purpose of the SALAAM initiative, through all the appointed participants, experts in these large animal models. The conference continued for its first day with lectures by A. Aartsma-Rus (NL), and S. Wildhirt (DE), who described examples of use of large animal models for Duchenne muscular dystrophy and for the development of medical devices, respectively. The initial Ethical perspective on the use of large animals was provided by N. Stingelin (CH). This first day concluded with an interesting key-note lecture by M.M. Mohiuddin (USA) on the recent advances in pig-to-primate cardiac xenotransplantation.

On the second day, the conference presented the very large repertoire of methods and techniques that are currently available for Genetic Tailoring of large animal models. Angelika Schnieke (DE) introduced the state of art for the current genetic engineering of large animals, nicely summarizing many years of techniques and developments that have been successfully applied for the production of large genetically modified animal models. This initial talk was followed by a presentation by Lluis Montoliu (ES) on the use of CRISPR-Cas9 approaches to functionally analyze the role of non-coding genomic sequences, illustrated with some examples tested in mice, depicting the important role of rodents in proof-of-concept type of experiments, before undertaking subsequent experiments in larger animal models. B. Grzeskowiak (PL) presented an innovative set of nanomagnetic gene delivery vectors for transgenesis. Two additional talks illustrated the power of genetic engineering of the pig genome, using transposons (W.A. Kues, DE) or very elaborated gene cassettes for regulating and tracing disease genes (J.E. Jakobsen, DK). The session ended with a presentation from goats, where L. Boulanger (FR) reported the role of FOXL2 as a female sex-determining gene.

The SALAAM conference continued with a session devoted to systematic phenotyping initiatives of large animal models. At first, H. Fuchs (DE), presented the experience and phenotyping pipeline of the German Mouse Clinic, operating within the Infrafrontier consortium, and a good example of successful systematic phenotyping in mice. Next, Pascale Chavatte-Palmer (FR) discussed the achievements and challenges of imaging techniques in large animal models, through her studies on reproduction and fetal development. J. Tibau (ES) presented his interesting studies using pigs to analyze human obesity and to validate the effect of diets on the evolution of fat deposition using tomography approaches. A. Blutke (DE) introduced the impressive Munich MIDY-PIG Biobank initiative, as a unique resource for translational diabetes research. The two last talks presented the use of pigs as models for respiratory infections (K. Skovgaard, DK) or cystic fibrosis (I. Caballero, FR).

The last standard session of this SALAAM conference was devoted to discuss how to select the best animal model. This session began with an interesting presentation by J. Langermans (NL), who shared their initiative of non-human primate biobanking for translational medicine, a collaborative consortium where most of the nonhuman primate research centres in Europe were represented. He also discussed the unique features of non-human primates to investigate devastating diseases affecting us, such as the new infections (i.e. Ebola) or neurodegenerative diseases (i.e. Alzheimer, Parkinson) , often very challenging to be reproduced in non-primate animal models. Next, Antonio Gonzalez-Bulnes (ES) discussed the advantages and challenges of using pigs and sheep animal models, whereas L. Hiripi (HU) presented the unique features of the rabbit models. V. Huygelen (BE) discussed the use of piglets to investigate the human low birth weight cases , and A. Navarrete Santos (DE) further presented rabbits as ideal models for investigating diabetes during pregnancy. Diabetes research was also the focus of the last speaker of the session, G. Pennarossa (IT), whose experimental dessigns are focused on the use of dogs to explore cell therapy-based treatments.

The SALAAM first public conference ended with an excellent and very motivating talk by Karin Blumer (CH) on the ethical aspects of using large animals. She challenged the audience with the question whether “size did matter?” when it comes to Ethics and Animal Models. Her presentation nicely illustrated the different Ethical perspectives existing in the field and, most importantly, the relevant parameters that should be taken into account in order to properly address this question. She presented the “size” of an animal as an accidental attribute, not an intrinsic value, that must not determine its moral status. This presentation triggered an interesting and live discussion among the participants.

On the third and last day, the different working groups of SALAAM gathered first independently to discuss the next initiatives and eventually shared their conclusions in a combined general session. The planned initiatives will include the organization of practical workshops on CRISPR-Cas9 and transposon technologies, the generation of specific pig Cre-transgenic lines for the production of conditional pig mutant animal models, the need to standardize phenotyping protocols associated with additional specific training courses, the preparation of biobanks and associated databases for archiving and sharing tissues from large animal models, and the creation of a group to analyze the implementation of the 2010/63/EU Directive across Europe, the public perception and ethical issues of animal research, and the need for training to adequately communicate results to the public.

Information about future plans, initiatives and activities of the SALAAM EU-COST action will be available from its dedicated web site.