Frameworks

We have some ideas that may help guide where our research goes. These aren’t set in stone – they’re outlines that explore a variety of reasonable possibilities for accomplishing morphological freedom. They include, in no particular order (1) neuroprosthetics, (2) genetic modifications, (3) bioprinting, and/or (4) remodeling.

Please note:

(1) While these methods are presented separately, it’s likely that they’ll be mixed and matched for strategies ultimately arising from our research.
(2) We provide very broad strategic views of several research fields representing the collective work of thousands of scientists. These are necessarily less detailed than review articles in journals, to give context for our overall directions.
(3) As with most grant-giving research organizations, most research is performed by scientists we fund. Our strategic guide is largely intended to be a flexible source of inspiration for them.

We’ve also prepared an in-depth white paper (PDF) that covers the below topics in more detail.

 

Neuroprosthetics:

A “neuroprosthetic” is simply any prosthetic, a synthetic device on (or in) the body, that has a neural interface with the user, communicating with sensory and motor information, via nerves or the brain. Neuroprosthetics can take many forms, and provide a huge diversity of motor and sensory functions throughout the body. They have been an area of research for decades. Motorized limbs (e.g. arms) have been demonstrated, with various strategies of neural/motor interfacing that includes peripheral nerve electrodes, EEG electrodes, and electrodes placed in nearby muscles. Sensory prosthetics have also been demonstrated, such as for feeling touch and pressure, and even for tasks as complicated as invoking visual “phosphenes”, on the path to full image-forming vision.

Some of the most striking demonstrations of the power of neuroprosthetics include neural interfaces for thought-controlled usage of motorized robotics in paralyzed individuals. These include clinical trials of BrainGate, and the kick-off by a paralyzed individual of the 2014 World Cup led by the Nicolelis lab at Duke (NIH NINDS, 2012; Smith, 2014). Equally as important, recent developments in tactile perception and proprioceptive feedback suggest that fully functional neuroprosthetics are nearing reality (Graczyk et al., 2016; Marasco et al., 2018; Park et al., 2015; Tabot et al., 2013; Tee et al., 2015).

We can say that if neuroprosthetics could be properly harnessed, they would allow for significant customization of one’s appearance and capabilities. Motorized neuroprosthetics could even permit the creation of wings and tails, while neural-interfaced synthetic skin could accommodate changes in skin texture, visual patterns, fur, scales, feathers, and so forth.

Even so, we would love to see additional work on these areas to see neuroprosthetics brought to their full potential:

  1. Improved integration of biocompatible materials in simultaneously recording and simulation-capable neural interfaces.
  2. Increased resolution and signal processing of neural interfaces.
  3. Attempts to use technological solutions from consumer electronics, such as digital cameras, for high-resolution, low-voltage sensing and processing.
  4. Modularity of design, and attempts to standardize integration between neural interfaces and neuroprosthetics.
  5. Development of customizeable closed-loop neuroprosthetics.

 

Genetic modifications:

Genetic modifications are some of the most frequent ideas mentioned in our discussions with people who want to bring about morphological freedom. And for good reason – there’s tremendous potential even in current gene therapy strategies. With the broadening deployment of CRISPR, there’s ample substance behind the excitement to say that genetic modifications may be useful for attaining morphological freedom.

Gene therapy strategies involve the introduction of new, engineered DNA (or RNA) to cells, whether those cells are inside a patient, or outside the body with in vitro culture. A vector is used to deliver this new information. Commonly, the vector is derived from a virus. The viral ‘coat’ is taken, but not the rest of the virus – this takes advantage of the virus as a delivery vehicle, but doesn’t allow it to produce more of itself. There’s countless examples of vector usage in literature, with exciting results in both basic science and clinical translation. Many are now in the middle of human clinical trials (ClinicalTrials.gov, 2018) while approvals for clinical usage are starting to trickle in, including Luxturna (AAV), Glybera (AAV), and Strimvelis (a retrovirus) (FDA, 2017; Gallagher, 2012; Pollack, 2012; Regalado, 2016; Spark Therapeutics Inc, 2017).

What might the genetic modifications entail? They might deliver regulators of metabolism and cell growth, they might manipulate developmental morphogen signaling, they might regulate cell adhesion or structural properties (e.g. through adhesion and cytoskeletal genes), or they might control transcription factor networks to manipulate the differentiation status of cells, just to name a few possibilities. The possibilities are nearly endless.

The fundamentals of genetic modifications are well established, but we want to see researchers in the field push boundaries, especially in these areas:

  1. Develop high-content genetic modifications (> 100 genes), through either large single payloads or mixtures of small viral particles.
  2. Improve efficiency and distribution of vector delivery.
  3. Incorporate quantitative modeling to predict optimal genetic strategies.

 

Bioprinting:

3D printed cartilage, held up close by a nitrile glove-covered finger. Peter Apelgren, Matteo Amoroso, Anders Lindahl, Camilla Brantsing, Nicole Rotter, Paul Gatenholm, Lars Kölby. “Chondrocytes and stem cells in 3D-bioprinted structures create human cartilage in vivo”. PLoS ONE. 2017. License: CC-BY.

Bioprinting is a massive new development in the capabilities of tissue engineering, involving the precise 3D arrangement of biological materials to form desired tissues for an organ. Further development and usage of this technology will let us construct new limbs, tails, organs, and any other new body part with exceptional precision and customizability while integrating seamlessly into the body.

Generally, bioprinting technologies involve deposition of a scaffold and/or stem cells. Several examples exist of this working as a method to grow organs in vitro (Murphy and Atala, 2014) and in vivo (Pan et al., 2016). Scaffolds are typically made from decellularized collagen matrices or other biocompatible, 3D printable materials such as hydrogels (Hinton et al., 2015) and perhaps even silicone rubber composites (O’Bryan et al., 2017). Dental repair and regrowth using a dentin-derived hydrogel ‘bio-ink’ to make ‘cell-laden scaffolds’ now allows teeth to be regrown (Athirasala et al., 2018).

Bioprinting is currently a very active area of research and development, with a lively mix of new biotech startups and involvement of larger, more developed companies. The importance and practical applications of bioprinting can’t be overstated.

Even so, we would like to see additional development, including (but not limited to) the following areas:

  1. Production and placement of irregularly-shaped cells such as muscle fibers and neurons.
  2. Increasingly precise control of heterogenous and polymeric extracellular biomolecule structures like collagen and proteoglycans.
  3. Printing morphogens, axon guidance factors, and other signaling molecules.
  4. Assembly of bioprinted tissues into larger, complex systems.
  5. Improved software and hardware integration and control.

 

Remodeling:

Biological tissue adapts to loads placed upon it. Dental braces are a common example of a way to guide this remodeling process. Bones, and the soft tissues around them, grow and shrink as needed to equalize stress channeled through the teeth into the maxilla and mandible.

Likewise, distraction osteogenesis (bone growth) is a surgical technique used to produce large morphological changes in bones (e.g., craniofacial bones and leg bones) and their surrounding soft tissues (Wikipedia, 2018). The surgery is usually an outpatient procedure, and is associated with discomfort but generally not pain (Quitmeyer, 2018; Wikipedia, 2018). Conceptually, it involves the partial or complete separation of bone into two parts, and gradual separation of those halves as new osteogenesis takes place. Gradual separation may involve steps, or continuous tension from a spring (Wikipedia, 2018). Outcomes of distraction osteogenesis are at least on par with, and are likely superior to, those of conventional acute surgeries (Kloukos et al., 2016).

It’s easy to suppose, then, that with careful application of remodeling technologies, it would be possible to substantially alter someone’s body shape gradually, through self-regulating and self-limiting processes, while preserving their musculoskeletal, neurological, and other functions. Therefore, we want to support the investigation and development of technology and surgical techniques that exploit these principles to yield desired morphological changes.

We would like to see additional developments in these areas:

  1. Improved directional control of remodeling in 3D, across several tissue types in an area.
  2. Development of higher-resolution remodeling.
  3. Explore implementations of an active meshwork of motorized agents (e.g., on the scale of centimeters or millimeters) supporting the above.
  4. Methods, including software and manufacturing, to make results of remodeling more customizable.

 

References:

Athirasala, A., Tahayeri, A., Thrivikraman, G., França, C.M., Nelson Monteiro, Tran, V., Ferracane, J., and Bertassoni, L.E. (2018). A dentin-derived hydrogel bioink for 3D bioprinting of cell laden scaffolds for regenerative dentistry. Biofabrication 10, 024101.

ClinicalTrials.gov (2018). Home – ClinicalTrials.gov.

FDA (2017). Press Announcements – FDA approves novel gene therapy to treat patients with a rare form of inherited vision loss.

Gallagher, J. (2012). Europe backs first gene therapy. BBC News.

Graczyk, E.L., Schiefer, M.A., Saal, H.P., Delhaye, B.P., Bensmaia, S.J., and Tyler, D.J. (2016). The neural basis of perceived intensity in natural and artificial touch. Sci. Transl. Med. 8, 362ra142-362ra142.

Hinton, T.J., Jallerat, Q., Palchesko, R.N., Park, J.H., Grodzicki, M.S., Shue, H.-J., Ramadan, M.H., Hudson, A.R., and Feinberg, A.W. (2015). Three-dimensional printing of complex biological structures by freeform reversible embedding of suspended hydrogels. Sci. Adv. 1, e1500758.

Kloukos, D., Fudalej, P., Sequeira-Byron, P., and Katsaros, C. (2016). Maxillary distraction osteogenesis versus orthognathic surgery for cleft lip and palate patients. Cochrane Database Syst. Rev. 9, CD010403.

Marasco, P.D., Hebert, J.S., Sensinger, J.W., Shell, C.E., Schofield, J.S., Thumser, Z.C., Nataraj, R., Beckler, D.T., Dawson, M.R., Blustein, D.H., et al. (2018). Illusory movement perception improves motor control for prosthetic hands. Sci. Transl. Med. 10, eaao6990.

Murphy, S.V., and Atala, A. (2014). 3D bioprinting of tissues and organs. Nat. Biotechnol. 32, 773–785.

NIH NINDS (2012). Thought control of robotic arms using the BrainGate system.

O’Bryan, C.S., Bhattacharjee, T., Hart, S., Kabb, C.P., Schulze, K.D., Chilakala, I., Sumerlin, B.S., Sawyer, W.G., and Angelini, T.E. (2017). Self-assembled micro-organogels for 3D printing silicone structures. Sci. Adv. 3, e1602800.

Pan, J., Yan, S., Gao, J., Wang, Y., Lu, Z., Cui, C., Zhang, Y., Wang, Y., Meng, X., Zhou, L., et al. (2016). In-vivo organ engineering: Perfusion of hepatocytes in a single liver lobe scaffold of living rats. Int. J. Biochem. Cell Biol. 80, 124–131.

Park, J., Kim, M., Lee, Y., Lee, H.S., and Ko, H. (2015). Fingertip skin–inspired microstructured ferroelectric skins discriminate static/dynamic pressure and temperature stimuli. Sci. Adv. 1, e1500661.

Pollack, A. (2012). European Agency Recommends Approval of a Gene Therapy. N. Y. Times.

Quitmeyer, A. (2018). Distraction Osteogenesis Rockingham VA.

Regalado, A. (2016). Gene-therapy treatment for “bubble boy” syndrome finally moves from concept to cure.

Smith, S. (2014). Mind-controlled exoskeleton kicks off World Cup.

Spark Therapeutics Inc (2017). BLA Clinical Review Memorandum for LUXTURNA. Clin. Rev. FDA STN 1256100 Clin. Rev. Yao-Yao Zhu MD PhD.

Tabot, G.A., Dammann, J.F., Berg, J.A., Tenore, F.V., Boback, J.L., Vogelstein, R.J., and Bensmaia, S.J. (2013). Restoring the sense of touch with a prosthetic hand through a brain interface. Proc. Natl. Acad. Sci. 110, 18279–18284.

Tee, B.C.-K., Chortos, A., Berndt, A., Nguyen, A.K., Tom, A., McGuire, A., Lin, Z.C., Tien, K., Bae, W.-G., Wang, H., et al. (2015). A skin-inspired organic digital mechanoreceptor. Science 350, 313–316.

Wikipedia (2018). Distraction osteogenesis.