Category Archives: Neuroscience

Stem Cells for Central Neurotrauma

BY SAM WU, BS, KEVIN T. FITZGERALD, SJ, PhD, and JAMES GIORDANO, PhD

Central neurotrauma: epidemiological and social impacts

Central neurotrauma – or insult to the central nervous system that results in disturbance or loss of neural circuitry, axonal pathways, or neural cells – such as, spinal cord injury (SCI) traumatic brain injury (TBI), and stroke can incur significant impact on patients’ quality of life (Struzyna, et al., 2017; Wu, FitzGerald, and Giordano, 2018). The National Spinal Cord Injury Statistical Center estimates that in 2017, 285,000 persons in the U.S. were living with spinal cord injury (SCI) (National Spinal Cord Injury Database, 2017). In addition, TBI affects approximately 1.5-2 million persons annually in the U.S., with 75,000 to 100,000 of these cases being severe (Johnson, Stewart, and Smith, 2013; Bose, Hou, and Thompson, 2015), while stroke causes 1 out of every 20 deaths in the US annually (Yang, et al., 2017).

The impact of central neurotrauma can be both short- and long-term, with neurological damage and accompanying symptoms lasting for months, years, or even for the remainder of a person’s life. In part, this is because the adult nervous system has only limited ability to regenerate neurons and repair itself following major injury (Struzyna, et al., 2017; Wu, FitzGerald, and Giordano, 2018). Signs and symptoms vary with the type and severity of neurotrauma, and can include sensory, motor and autonomic impairment (Johnson, Stewart, and Smith, 2013; Bose, Hou, and Thompson, 2015; Tsintou, Dalamagkas, and Seifalian, 2015). While pharmacological and surgical interventions can provide some value in managing certain symptoms, these approaches are often of only limited benefit, and do not repair structural damage or lead to replacement of lost tissue (Kabu, et al., 2016; Diaz-Arrastia, et al., 2014; Bansal, et al., 2014; Cramer, 2015).

 

The potential of regenerative therapies

In light of this situation, there are considerable clinical and socioeconomic incentives to develop more effective regenerative treatments for central neurotrauma.  Among these are cell-based approaches, intended for use either singularly or in combination with pharmacological and/or structural treatments (Fouad, et al., 2005; Oraee-Yazdani, et al., 2016; Bento, et al., 2017). Therapies currently being explored for neuro-regenerative and reparative properties involve the use of pluripotent cells derived from embryonic stem cells, fetal stem cells, mesenchymal stem cells, adult neural stem cells (NSCs), induced pluripotent stem cells (iPSCs), Schwann cells, or olfactory ensheathing cells (Wu, FitzGerald, Giordano, 2018).

Preclinical trials of some of these cell-based therapies have had promising outcomes, and are facilitating the possible use of certain types of stem cell interventions for central neurotrauma in human clinical applications. For example, transplanted NSCs have provided neuroprotection, neurotrophic support, immunomodulation, and cell replacement – all of which enable neuroregeneration in the injured CNS (Martino and Pluchino, 2006; Jin, et al., 2011; Pluchino, et al., 2005; Bonner, et al., 2011). Furthermore, mesenchymal stem cells, which are relatively easy to obtain from multiple allogeneic and autologous sources, have been widely used in SCI clinical trials (Wu, FitzGerald, Giordano, 2018). In contrast, translation of other stem cell-based therapies, such as those involving embryonic stem cells or fetal stem cells, have been hindered by technical and ethical challenges related to procurement, transplantation (Nakamura and Okano, 2013; Hockemeyer and Jaenisch, 2016), and safety (Sadowski, et al, 2010; Webowetski-Ogilvie, et al., 2009).

Reprogramming strategies open the door for new possibilities

Improved techniques for cellular reprogramming have enabled the use of other autologous cell sources to be induced to become pluri- or multi-potent stem cells. These reprogrammed cells can alleviate concerns about incompatibility and rejection when transplanted. Combinations of specific transcription factors can be used to generate iPSCs or NSCs from autologous somatic cells (such as fibroblasts, melanocytes, adipocytes, mesenchymal stem cells, cord blood, and others) (Yamanaka, Ralston, and Stephenson, 2006; Kim, et al., 2009; Sun, et al., 2009). Additionally, reprogramming techniques can be used to convert somatic cells directly into neural precursor cells (NPCs) or NSCs, without having to go through intermediate pluripotent stages that may increase the risk of mutagenesis and tumorigenicity (Kelaini, Cochrane and Margariti, 2014; Lujan, et al., 2012; Shahbazi, et al., 2016; Wu, FitzGerald, Giordano, 2018).

Persistent concerns

While research suggests the potential of these innovative stem cell-based therapies for neuro-regeneration and repair, ongoing technical, ethical, legal, and social issues remain and must be addressed. These issues include the validity of patient informed consent given for a particular procedure (in part due to the relative lack of information about the long-term characteristics of reprogrammed cells), the provision and distribution of stem cell resources (inclusive of possible venues for medical tourism), and the importance – if not necessity – of continuing studies of, and clinical care for, those patients receiving reprogrammed neural stem cells (Giordano, 2011; Giordano, 2017; Giordano, 2015; Wu, FitzGerald, and Giordano, 2018).

With reflection upon the past, engagement in the present, and a keen and prudent eye toward the future, it is likely that the most viable regenerative approach to treating central neurotrauma will involve a combination of customizable interventions, inclusive of the use of current and newly developed stem cell technologies. A priority toward realizing these treatments will be the time- and cost-efficient development of high-quality cells that can be translated into safe, affordable and accessible clinical therapies. To achieve this goal will require the increased and ongoing cooperation and collaboration of science, medicine, economics, and policy to ensure that the most valuable therapies are pursued and provided to patients in need.

See On the Viability and Potential Value of Stem Cells for Repair and Treatment of Central Neurotrauma: Overview and Speculations for a more comprehensive review of current and emerging stem cell technologies for central neurotrauma.

 

ABOUT THE AUTHORS


 

Sam Wu, BS is Program Manager and Research Assistant at the Pellegrino Center for Clinical Bioethics.  Sam is completing a MS in Clinical and Translational Research at Georgetown University. 

 

 

Kevin T. FitzGerald, SJ, PhD is the John A. Creighton University Chair and Professor in the Creighton University School of Medicine, Department of Medical Education.  He joins Creighton from Georgetown University, where he was the Dr. David Lauler Chair of Catholic Health Care Ethics in the Pellegrino Center for Clinical Bioethics.  

 

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James Giordano, PhD, MPhil is Chief of the Neuroethics Studies Program and Scholar-in-Residence at the Pellegrino Center for Clinical Bioethics, Professor in the Departments of Neurology and Biochemistry at Georgetown University Medical Center.  He is also Distinguished Visiting Professor of Brain Science, Health Promotions and Ethics at the Coburg University of Applied Sciences, Health Promotions and Ethics at the Coburg University of Applied Sciences, Coburg, Germany.  He currently serves as an appointed member of the US Department of Health and Human Services Secretary’s Advisory Council on Human Research Protections.

 

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“Philosophy and ethics in the frontiers of brain science”

“With large scale international programs entering new phases, upcoming meetings and a growing debate, new discoveries in brain science always keep fostering ethical and social questions. Philosophy matters, in this field more than in any other, because it reminds us that science sometimes is not only obtaining new facts, but also engaging new ways of thinking about them.”

New Post from Dr. James Giordano on BioMed Central Blog.

The Dangers and Challenges of Weaponizable Neuroscience: A Call for Renewed Engagement

Photo Source: This Image was released by the United States Navy with the ID 021015-N-6996M-109 (http://bit.ly/2oQFUdh)

 

BY DR. DIANE DIEULIIS and DR. JAMES GIORDANO

The chemical weapon attack in Syria that has killed at least 70 people employed the nerve gas sarin. And, it is believed that it was the nerve agent VX that was used to assassinate Kim Jong-nam in a public airport. These uses of nerve agents violate the international Chemical Weapons Convention (CWC). While the Syrian government signed the CWC in 2013, it was never ratified, and of course, signatory agreement does not guarantee compliance. Nor do such treaties among nation states necessarily provide any security against the development and use of biological and chemical weapons by non-state actors. These events are disturbing and, we believe, portend a larger, and ever growing issue of how such neurological agents could be used, altered and/or developed anew as weapons.

International advances in brain science over the past decade are enabling ever greater capabilities to control neurological processes of thought, emotion and behavior. So, while the CWC and Biological Toxin and Weapons Convention (BTWC) prohibit development of drugs, microbes and toxins that can be made into weapons, these prohibitions are not absolute – many of these substances can be – and are – used in basic neuroscience research, or in research programs that seek to develop defenses against biochemical weapons. What’s more, new tools and methods with which to edit genes, such as CRISPR/Cas9, can make it easier to modify bacteria, viruses or certain toxins to be weaponized. Until recently, these approaches were regarded as not yet ready for human applications; but the use of CRISPR-modified cells in humans by scientists in China has established both a new timetable and a new level of risk for such possibilities. Gene editing kits are commercially available and not excessively expensive. Thus, real concerns arise about the ability of both state and non-state actors to bio-engineer agents, including those that act on the nervous system. In light of this, last year, then Director of National Intelligence James Clapper identified the very real potential to use gene editing to create lethal or highly disruptive biological agents; a warning that was seconded by the President’s Council of Advisors on Science and Technology (PCAST).

In its military response to the events in Syria, the United States government has strongly communicated that continued use of these agents ‘…crosses a line’.   Indeed it has. The time to “wait and see” if neuroweapons will be developed and used has passed. The specter of available agents has been realized, and with it, should be recognition that the tools that make science easier to execute, and more accessible, should also prompt revision of the ways such methods and products are regarded and regulated. Indeed, recognizing the risk and growing threat of neuroweapons is important; but we believe insufficient. There is profound ethical obligation to acknowledge that science and technology can be used to harm as well as heal. As we further make strides to explore and affect the brain, it is critical to pay close attention to the directions that each and every step may lead. Thus, it will be essential to pursue and obtain a deeper and fuller understanding of the ways brain science can be harnessed to create weapons, and to establish more comprehensive, ethical guidelines and oversight policies.

A working group of the European Union’s Human Brain Project (HBP) is focusing efforts on a thorough review of what constitutes ‘dual use’ applications of brain science, both within the HBP programs, and more broadly; recommending more stringent policies for regulation of neuroscientific research that can be employed in such ways. This is laudable and noteworthy, even if only as a first step. But perhaps the more imposing issues remain: such research will still likely be conducted by individuals and groups that do need heed proposed guidelines or policies; and while it may be possible to regulate research (at least to some extent), the use of neuroweapons by state and non- state actors is far more difficult to address and control. Let these challenges serve as opportunities for action. We suggest that the scientific executive committees of both the BTWC and CWC could be utilized as forums for acknowledging and assessing the potential risks and threats posed by current and near-term capabilities in brain science, and that the international community of brain scientists and ethicists further proactive discourse and engagement toward informing and developing policies and regulations to govern dual-use neuroscientific research and its applications. We believe that such action would represent a necessary response to a real and growing danger.

Diane DiEuliis

James Giordano

 


ABOUT THE AUTHORS

dieuliis-diane

Dr. Diane DiEuliis is Professor at National Defense University, in the Center for the Study of Weapons of Mass Destruction. Her research areas focus on emerging biological technologies, biodefense, and preparedness for biothreats. Dr. DiEuliis also studies issues related to dual use research, disaster recovery research, and behavioral, cognitive, and social science as it relates to important aspects of deterrence and preparedness.

giordano-2017Dr. James Giordano is Professor in the Departments of Neurology and Biochemistry, Chief of the Neuroethics Studies Program in the Pellegrino Center for Clinical Bioethics, and Co-director of the O’Neill-Pellegrino Program for Brain Sciences and Global Health Law and Policy at the Georgetown University Medical Center. He serves as a Task Leader and Researcher of the EU Human Brain Project’s Working Group on Dual-Use, and is an appointed member of the US Department of Health and Human Services Secretary’s Advisory Council for Human Research Protections.

 

The views expressed in this blog do not necessarily represent those of the EU Human Brain Project, the US Department of Health and Human Services, or the United States Department of Defense.


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