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The Technology
Add2X Biosciences’ proprietary technology port folio is based on the
research in the Hooykaas group at Leiden University on the soil
bacterium and plant pathogen Agrobacterium tumefaciens. Previously, as
part of the MOLBAS group headed by Prof. Rob Schilperoort, this research
has led to the discovery and development of the Binary Vector System (BVS).
The BVS technology comprises the use of Agrobacterium tumefaciens as
efficient transporter of DNA to eukaryotic cells, and has become one of
the central technologies in plant biotechnology. Over the past 20 years,
the BVS technology has allowed for the convenient and reliable
introduction of a variety of new genetic traits into commercially
interesting eukaryotic organisms such as plants, yeast, and filamentous
fungi.
More recent research in the Hooykaas group has led to important new
discoveries that form the basis of the platformtechnologies of Add2X
Biosciences BV:
1. Efficient gene targeting in eukaryotes
2. Bacterial translocation of heterologous proteins
3. Induction of somatic embryogenesis
Gene targeting
Introducing desired genetic traits into eukaryotic host organisms is a
powerful tool often used to enhance production processes (e.g. the
production of antibiotics or industrial enzymes) or to improve crops.
However, in most eukaryotes the predominant route of DNA integration is
via random integration, making it very difficult to exactly predict the
position of the introduced genetic trait in the genome of the host cell.
Such random integration of DNA could cause potentially harmful, unwanted
side effects. To prevent such side effects, the preferred method of DNA
integration is therefore predictable integration, commonly referred to
as gene targeting. Gene targeting is considered to be "the holy grail"
of plant biotechnology, as it should lead to a better acceptance of
genetically modified crops by environmental organizations and consumers.
Research in the Hooykaas group led to the identification of key factors
involved in random integration of DNA in the bakers yeast Saccharomyces
cerevisiae. Inactivating these factors was immediately recognized as a
possibility of increasing gene targeting efficiencies in a wide variety
of eukaryotes, and was therefore patent protected as a method for
efficient gene targeting by Leiden University. An exclusive license on
gene targeting technology has been granted to Add2X.
In a strategic alliance with DSM, the gene targeting technology has been
applied to the major antibiotic producing fungus Penicillium chrysogenum.
During this ongoing project, proof of principle (POP) was already
obtained in 2005, and several enhancements of the technology have been
developed as well. Currently, experiments are in progress within Add2X
Biosciences, in close collaboration with the Hooykaas group and
strategic partner Keygene NV in Wageningen, to obtain POP in plants.
Protein translocation
Another major breakthrough by the Hooykaas group was the discovery that
Agrobacterium not only transfers DNA, but simultaneously injects
proteins into plant cells to assist DNA integration and tumor formation.
This ‘injection’ of DNA and proteins is performed by Agrobacterium's
so-called nano-injection needle (see adjacent figure). The fact that the
genetic components that form the needle are known, opens up the
possibility to use Agrobacterium and other bacteria possessing a similar
protein injection system for protein therapy in eukaryotic host cells,
i.e. (temporarily) inducing changes in eukaryotic host cells by
injecting proteins, without modifying the genetic material of the host
cells. Again, the Hooykaas group has protected the use of the bacterial
protein translocation technology in a patent application, and an
exclusive license ensures the addition of a highly valuable tool to
Add2X’s portfolio.
Embryogenesis
A different research program in the Hooykaas group recently revealed the
existence of a class of plant proteins, the so-called At-Hook protein
family, whose members stimulate the spontaneous formation of embryos
from vegetative plant cells (plant cells that do not participate in the
production of gametes). This process of asexual plant reproduction, in
which vegetative plant cells are induced to form embryos in tissue
culture, is referred to as somatic embryogenesis. Expression of one of
the members of the At-Hook protein family has been shown to result in
spontaneous somatic embryo formation on Arabidopsis cotyledons (the
first leaves of a germinating seed) and to result in increased plant
regeneration in general. Based on these characteristics, the
introduction of AT-Hook proteins in plants should enable the in vitro
propagation of a wide range of plant species that is difficult to
reproduce asexually under standard conditions. Another application of
the AtT-Hook technology is for molecular breeding of commercial crop
species that until now have been recalcitrant to genetic modification.
Having obtained an exclusive license on the patent of the Hooykaas group,
Add2X is currently performing experiments to obtain proof of concept for
this exciting At-Hook technology in economically important plant species
such as rice and Chinese kale.
Integrated approach
Add2X Biosciences' platform technologies stand well on their own, but
they clearly have the potential to be combined into integrated
technologies or products. For example, by using the
Agrobacterium-mediated protein translocation technology to introduce a
protein or peptide that transiently inhibits the random integration
pathway, gene targeting may be enhanced. Furthermore, the
Agrobacterium-mediated protein translocation technology can be used for
transient introduction of At-Hook proteins to induce somatic
embryogenesis. This would allow efficient large scale asexual
propagation of crop species without the need of making and marketing
transgenic plants!
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