High-risk initiative aims to develop ‘Time-Tolerant Biostasis Therapeutics’ that slow down critical processes in the human body to gain time to repair life-threatening injuries
By Benjamin Boettner
(BOSTON) — Known for pursuing seemingly impossible goals and thereby opening up opportunities that have not been thought possible, the Defense Advanced Research Projects Agency (DARPA) has signed a contract worth up to $23 million over 5 years with the Wyss Institute for Biologically Inspired Engineering at Harvard University to help create the future of medicine in scenarios where necessary surgical and therapeutic interventions are not immediately available.
By identifying strategies that can rapidly and reversibly slow down central metabolic processes in the body without actively lowering its temperature, the project’s goal of a chemically inducible state of biostasis (suspended animation) could help civilians or soldiers suffering from life-threatening traumas and infections buy time that they otherwise would not have in order to survive. Additional technology fallout along the way could lead to new ways to stabilize therapeutics and vaccines without a cold chain, or to protect living cells and organs for transplantation.
1/4 To identify key molecules, pathways, and potential drug targets, the team will mine available ‘omics’ data from animals that hibernate or enter a state of torpor for changes in gene and protein expression, and metabolic activities using new machine learning computational methods. Credit: Wyss Institute at Harvard University. 
2/4 With the help of computational molecular simulations and drug design methodologies, new chemical compounds will be created that may bind to identified targets with the potential to induce a state of suspended animation in organisms and cells. Credit: Wyss Institute at Harvard University. 
3/4 The potential biostasis-inducing compounds will be investigated in a highly multiplexed Xenopus platform for their effects in a living organism. This enables the researchers to generate new sets of ‘omics’ data that, again, can be analyzed using their computational suite to create new or improved chemical compounds. Credit: Wyss Institute at Harvard University. 
4/4 In parallel, novel potential biostasis-inducers will be investigated in human in vitro Organs-on-Chips microfluidic systems as a first entry point into human biology; and ‘omics’ data obtained in this approach, like the ones from the Xenopus platform, will be used to inform the next level of computational analyzes and drug design. Credit: Wyss Institute at Harvard University.
“Vastly ambitious, interdisciplinary, high-risk projects like this are what the Wyss Institute was designed to do. We propose to leverage various innovative capabilities we have developed in past efforts to explore a medical problem that has not been approached before, nor can it be approached with any single technology alone. Up to now, it has essentially been limited to the realm of science fiction,” said Wyss Founding Director Donald Ingber, M.D., Ph.D., the Principal Investigator on the project. He is also the Judah Folkman Professor of Vascular Biology at HMS and the Vascular Biology Program at Boston Children’s Hospital, and Professor of Bioengineering at SEAS. “Our end goal – development of Time-Tolerant Biostasis Therapeutics that can intervene to stabilize molecules, cells, organs, and metabolic state of humans in the most profound way – could one day rescue lives in a broad range of situations and environments, if we are successful.”
However, the researchers expect strategies developed in the project to be applicable not only to the entire human body, but across biological systems at multiple scales where these biostasis inducers might stabilize single molecules, such as vaccines or protein therapeutics, as well as cellular therapies, engineered tissues, or whole organ transplants. Importantly, because of their temperature-independent mechanisms, such strategies could eliminate the need for an uninterrupted cold chain in under-resourced regions.
To start developing Time-Tolerant Biostasis Therapeutics, the team will leverage computational molecular discovery tools previously developed by Wyss Staff Scientist Charles Reilly, Ph.D., and Ingber to design new chemicals that slow molecular activities and cellular metabolism without injuring them, much in the way that cryoprotectants and molecular chaperones do when cells are frozen or as in cryptobiotic animals that can tolerate extremely cold temperatures. The team also will take cues from biostasis studies on organisms that enter states of hibernation or torpor in which their metabolism slows down and body temperature drops, like in the Arctic ground squirrel and American black bear, allowing them to survive extreme environmental stresses.
Applying new machine learning-enabled computational tools developed by Wyss Senior Bioinformatics Scientist Diogo Camacho, Ph.D., and Core Faculty member James Collins, Ph.D., they will mine available “omics” data for biostasis-specific changes in gene and protein expression, as well as changes in critical metabolic activities these organisms undergo when they enter, maintain, and leave those natural states. This can identify leads that then will be further translated into a first series of candidate chemical biostasis inducers with the help of computational molecular simulation and drug design methodologies and actual chemical synthesis. Collins, who is a Co-Investigator on this project, is also the Termeer Professor of Medical Engineering & Science and Professor of Biological Engineering at the Massachusetts Institute of Technology’s Department of Biological Engineering.
The team will go on and evaluate these candidates for biostasis effects in Xenopus frog in vivo and human Organ-on-Chip in vitro systems, analyzing resulting gene expression and metabolic changes, and then, based on their findings, design a next generation of improved or entirely new candidate biostasis inducers using their proven suite of computational approaches.
Our end goal – development of Time-Tolerant Biostasis Therapeutics that can intervene to stabilize molecules, cells, organs, and metabolic state of humans in the most profound way – could one day rescue lives in a broad range of situations and environments, if we are successful.
Frogs are an ideal early-stage test bed for such candidates because their development is understood well, happens fast and is easy to monitor and manipulate. Moreover, the group of Mike Levin, Ph.D., an Associate Faculty member of the Wyss Institute and a Co-Investigator on the project, has previously shown that altering the bioelectric communication among cells in the body can in turn alter many aspects of development, which otherwise proceed in a very precise temporal sequence. This effort will be augmented by a highly multiplexed Xenopus analytical platform that was developed by Wyss Senior Staff Engineer and Co-Principal Investigator on this project, Richard Novak, Ph.D., working with Ingber and Levin, which enables real-time analysis of up to 700 frog embryos simultaneously.
“It is going to be extremely interesting to find out how biological timekeeping can be altered by chemical or biophysical manipulation, and how that relates to the computations being performed by cells within a living organism. Developing frogs give us the opportunity to manipulate everything from molecules to behavior, and thus learn about new system-level control mechanisms, which will help drive the project forward,” said Levin. He is also the Vannevar Bush Professor and Director of the Allen Discovery Center at Tufts and the Tufts University Center for Regenerative and Developmental Biology.
This in vivo analysis will be combined with human organs-on-chips (Organ Chips) technology pioneered by Ingber’s group, which involves interfacing multiple tissues in microfluidic devices to recapitulate human-relevant physiology and disease states, study drug efficacies and toxicities, and identify new therapeutic targets. Organ Chip technology will allow the team to address how human engineered tissues, respond to potential biostasis inducers and regulate the process on the level of functional tissues, in a first step toward emulating the complete human body with all its complexity.
By iterating the entire discovery process, the team hopes to gain deeper and deeper understanding of how biostasis can be achieved. It can also help develop refined chemical structures that eventually can be further optimized pharmacologically and tested for their ability to trigger biostasis and thus open up possibilities for rescue in animal models lethally infected with pathogens or injured with radiation.
In addition to the work performed by the Ingber, Levin and Collins groups, the CFD Research Corporation will collaborate with the team to help optimize the pharmacological properties of biostasis inducers in animal studies.