striking shear-thinning that enables easy injection through conventional syringes
[22]. The “injectability” of such gels is potentially useful in cellular transplantation
therapy, a subject that we address briefly in the following section.
2.4 Artificial Extracellular Matrix Proteins
It seems likely that the first practical applications of artificial proteins will be in
surgery or medicine. Polymer chemists have had great success in creating materials
for reconstructive surgery, drug delivery, and other medical procedures [23], and
engineered proteins provide an especially convenient platform for the creation of
new macromolecules with well defined and useful biological properties. Given
recent advances in stem cell biology, the design of protein matrices for cell
transplantation appears to be an exciting and important challenge.
We began working on this problem in the late 1990s by constructing “artificial
extracellular matrix” (aECM) proteins that combine domains drawn from the natural
ECM proteins elastin and fibronectin. Our designs drew heavily on earlier work by
Dan Urry, who showed that many of the most important physical properties of elastin
are retained by simple repeating polypeptides rich in valine, glycine, and proline [24],
and by Erkki Ruoslahti and Jeffrey Hubbell, who demonstrated that short sequences
of fibronectin could be used to induce cells to bind to artificial substrates by engaging
cell-adhesion receptors of the integrin family [25, 26].
Over the past 15 years, we have made many variants of aECM proteins, including
photocrosslinkable versions that contain the photosensitive non-canonical amino acid
p-azidophenylalanine [27]. Our most recent experiments in this area are being done in
collaboration with Teresa Ku and Arthur Riggs at City of Hope, and are directed
toward the development of matrices for maturation and transplantation of human
pancreatic β-cells for treatment of Type 1 diabetes [28].
3 Non-canonical Amino Acids as Probes of Biological
Processes
We realized early in our studies of artificial proteins that some of the things we
wanted to do would require expansion of the set of 20 “canonical” amino acids that
cells normally use to make proteins. We were confident that some expansion would
be possible because translationally active amino acid analogs had been reported as
early as 1951 [29]. As it turns out, the chemistry of cellular protein synthesis is
considerably more permissive than we imagined, and our laboratory and many
others have now developed dozens of new amino acids that can be used to engineer
and probe protein behavior [30–32].
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D.A. Tirrell
[22]. The “injectability” of such gels is potentially useful in cellular transplantation
therapy, a subject that we address briefly in the following section.
2.4 Artificial Extracellular Matrix Proteins
It seems likely that the first practical applications of artificial proteins will be in
surgery or medicine. Polymer chemists have had great success in creating materials
for reconstructive surgery, drug delivery, and other medical procedures [23], and
engineered proteins provide an especially convenient platform for the creation of
new macromolecules with well defined and useful biological properties. Given
recent advances in stem cell biology, the design of protein matrices for cell
transplantation appears to be an exciting and important challenge.
We began working on this problem in the late 1990s by constructing “artificial
extracellular matrix” (aECM) proteins that combine domains drawn from the natural
ECM proteins elastin and fibronectin. Our designs drew heavily on earlier work by
Dan Urry, who showed that many of the most important physical properties of elastin
are retained by simple repeating polypeptides rich in valine, glycine, and proline [24],
and by Erkki Ruoslahti and Jeffrey Hubbell, who demonstrated that short sequences
of fibronectin could be used to induce cells to bind to artificial substrates by engaging
cell-adhesion receptors of the integrin family [25, 26].
Over the past 15 years, we have made many variants of aECM proteins, including
photocrosslinkable versions that contain the photosensitive non-canonical amino acid
p-azidophenylalanine [27]. Our most recent experiments in this area are being done in
collaboration with Teresa Ku and Arthur Riggs at City of Hope, and are directed
toward the development of matrices for maturation and transplantation of human
pancreatic β-cells for treatment of Type 1 diabetes [28].
3 Non-canonical Amino Acids as Probes of Biological
Processes
We realized early in our studies of artificial proteins that some of the things we
wanted to do would require expansion of the set of 20 “canonical” amino acids that
cells normally use to make proteins. We were confident that some expansion would
be possible because translationally active amino acid analogs had been reported as
early as 1951 [29]. As it turns out, the chemistry of cellular protein synthesis is
considerably more permissive than we imagined, and our laboratory and many
others have now developed dozens of new amino acids that can be used to engineer
and probe protein behavior [30–32].
206
D.A. Tirrell