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Nanomedicine: Future Legal, Ethical and Policy Considerations SIU School of Medicine and School of Law  Presentation, June 13, 2008 Linda MacDonald Glenn, JD, LLM
The NBIC Report Converging Technologies for Improving Human Performance N anotechnology,  B iotechnology,  I nformation Technology, and  C ognitive Science NSF/DOC-sponsored report June 2002 Arlington, Virginia http://www.technology.gov/reports/2002/NBIC
Scale Canary Island palm  Mosquito Nano-needle penetration  micropenetration nanopenetration Offshore oil rig  macropenetration  0.1 m 0.001 m 0.01 m 10 m
Eight nodes of societal discussion on nanotechnology ,[object Object],[object Object],[object Object],[object Object],[object Object]
Eight nodes, continued ,[object Object],[object Object],[object Object],[object Object]
Three Approaches ,[object Object],[object Object],[object Object]
First, the Promises… 'Nano-needle' operates on cell BBC News, December 15, 2004  - Japanese scientists have performed a delicate surgical operation on a single living cell, using a needle that is just a few billionths of a metre wide.  (200-300 nanometers) The needles used much less force to penetrate the cell than a conventional Atomic Force Microscope probe, causing less damage and deformation to  the  cell.  In one experiment, on a human embryonic kidney cell, the scientists managed to insert the needle accurately into the cell's nucleus, which contains its genetic material.
The humble mosquito http://www.nomorebites.com Malaria Viral encephalitis Dengue fever
Malaria Malaria kills 2 million people each year. Worldwide prevalence of falciparum malaria is half a billion people. The Current Global Picture Malaria is a public health problem today in more than 90 countries, inhabited by a total of some 2,400 million people - 40% of the world's population.   How might nanomedicine help to fight diseases like malaria?
Red blood cells Image taken from "The Microscopic Diagnosis of Tropical Diseases",  Published by BAYER in 1955 (Public Domain).   Each erythrocyte contains 270 million hemoglobin molecules 10,000 nm Plasmodium falciparum
The Future: Nanorobots? Nanomachines are largely in the research-and-development phase, but some primitive devices have been tested. The first useful applications of nanomachines will likely be in medical technology, where they could be used to identify pathogens and toxins from samples of body fluid and destroy them.  (Wikipedia)
                                                                                                                                                                                                                   Optical tweezers stretch a healthy red blood cell (top row of images; left to right, increasing force in the picoNewton range) and a cell in a late stage of infection with the P. falciparum malaria parasite (bottom row; same force levels as above). Note the parasite visible in the bottom three images, and how the cell cannot be easily stretched by the tweezers. Photo courtesy / Suresh et al. http://www.voyle.net/Nano%20Medicine/Medicine%202004-0068.htm MIT professor Subra Suresh, left, and research scientist Ming Dao  Here Now: Optical Tweezers Silica spheres or beads are attached to opposite sides of a red blood cell, and a laser beam is aimed at one bead. Under the right conditions, the laser "traps" the bead, so that the trapped bead can be pulled, stretching or deforming the cell.
Genomics DNA molecule Complete 24 mb genome sequence   of  Plasmodium falciparum  published in Nature [2002 Oct 3; 419(6906): 498-511  Information at the nanoscale 1 nm
Plasmodium falciparum genome CTAAACCTAA ACCTAAACCC TGAACCCTAA ACCCTAAACC CTGAACCCTA AACCCTGAAC CCTGAACCCT AAACCCTGAA CCCTAAACCC TGAACCCTGA ACCCTAAACC CTAAACCCTA AACCCTAAAC CCTAAACCCT AAACCCTGAA CCCTAAACCC TGAACCCTAA ACCCTAAACC CTAAACCCTA AACCCTAAAC CCTGAACCCT AAACCCTGAA CCCTGAACCC TAAAACCTAA ACCCTAAACC CTAAACCCTG AACCCTAAAC CCTGAACCCT AAACCCTAAA CCCTGAACCC TAAACCCTAA ACCCTGAACC CTAAACCCTG AAACCTAAAC CCTGAACCCT AAACCCTGAA CCCTGAACCC TAACCCTAAA CCCTAAACCT AAAACCCTGA ACCCTAAACC CTGAACCCTG AACCCTAAAC CCTGAACCCT AAACCCTAAA CCCTGAACCC TAAACCCTGA ACCCTAAACC CTAAACCCTG AACCCTGAAC CCTAAAACCT AAACCCTAAA CCCTAAACCC TAAACCCTGA ACCTAAACCT AAAACCTAAA ACCTAAAACC CTGAACCCTT ACTTTTCATT TCTTCTTCTT ATCTTCTTAC TTTTCATTCT TTACTCTTAC TTACTTAGTC TTACTTACTT ACTCTTACTT ACTTACTCTT ATCTTCTTAC TTTTCATTTC TTAGTCTTAC TTACTTACTC TTACTTACTT ACTCTTATCT TCTTACTTTT CATTCCTTAC TCTTACTTAC TTACTGTTAT CTTCTTACTT TTCATTCCTT ACTCTTACTT ACTTACTCTT ACTTACTTAC TCTTACTTAC TTACTCTTAT CTTCTTACTT TTCATTCCTT ACTCTTACTT ACTTACTCTT ACTTACTTAC TCTTATCTTC TTACTTTTCA TTCCTTACTT TTCATTTCTT AGTCTTACTT ACTTACTCTT ACTTACTTAC TCTTACTTAC TTACTCTTAC TTTCTTCTTC TTATCTTCTT ACTGTTATCT TCTTACTTTT CATTCCTTAC TCTTACTTAC TTACTCTTAT CTTCTTACTT TTCATTCCTT ACTCTTACTT ACTTACTCTT ATCTTCTTAC TTTTCATTCC TTACTCTTAC TTACTTACTC TTATCTTCTT ACTTTTCATT CCTTACTCTT ACTTACTTAC TCTTACTTAC TTACTCTTAC TTACTTACTG TTATCTTCTT ACTTTTCATT CCTTACTCTT ACTTACTTAC TCTTACTTAC TTACTCTTAC TTACTTACTC TTATCTTCTT ACTTTTCATT TGTTAGTCTT ACTTTCTTCT TCTTAGGTCC TTACTTTTCA TTTCTTAATC ATATATTCTT ACTCATATAG TTCTTGACTT AACTTCTTAT TCTTACTTAC TTACTCTTAT ATTCTTTTTA TCATGTTCAA GGTCTTACTT CTTAAATATT AGGTCCTTAA TCTCATAATT CTACTCTTAC TTTCTTACTT CTAGAACCTT ATTCTTACTT TCTTCATCTT ACATCCTCAG TCTCAAGTCT TTAATCTTAT CTTCTTACTC TTACTTACTT ACTCTTATCT TCTTACTTCT CATTTCTTAC TCTTACATAC CTTCTCTTCA TTCTTCAATC ATCAATTCTC ACTCTTCATT CCTTGGTCTT ACTTCTTTCT TCTTAATGTC ATACTTTTAT CCCCTATTAT CATCTACTTA GTCTTCATTT ACTCTTCTAA CTTCTTCATC TATCACTTTT CATCATCATT CATGCTTACT TAACTTACTT TCATATACTT ACTTCTACTA CATCTTCACC AAATCCGGAC TTAGCTTAAC TTTTCTCTCT TTATTCTTAC CTTACTTAGC TCTTACATAC TTAGGATCTA CTTCTTACTT ACTACTACCT TACTTACCTC TTATTTCACT TACATCTAGG TACTTATCCT ACTTTACTTC TCTTATCTTA CTTCTTTATT CTCAGATTCC GGACTTAGCT TAACTTTTTT GTGTTTGTTC TTATCTTACT TAGCTCTTAC ATACTTAGGA TCTACTTCTT TACTTACTTT CTTCTTACTT ATGTGGTAAT AAGCTACTCG GTTGGGCACT AAGGTTAGGT TTAGCTGTTC TTTAGTTCTT AAAGGGTAAG AATTTAAGGT TTGTATTGAA TTATTATTAC TATTTCATTA CTATTGTTGC TATTAAGGAC TTATAATGTT ATGTTTTCTA TCCATTTTGT TCTTTTATGT TACTAAATTC ATTGTAGATT CCGGATTTAG CTCATTAACT ATGCTTCTTA CTTCTTCTTT TACTCTTTTT AGGTCTTATG TTGTATTTAG AGTAGTAATG TTACTTAATT AGTACTTAGG ATTCATCTCA TGTAGGTTAT ATGTTCTTAT AAGGTGCACC TACATGCATA ATATCATCCA ATATATCTCA TTTAGTACTA CTATGATGAC TTATATTATC ATTATCTTAC  etc. etc. nucleoside diphosphate kinase B
Proteomics and drug targeting Pfal007254AAA Plasmodium falciparum/ Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key glycolytic enzyme.  This target has been an exploratory target for drug design by the MMV (Medicines for Malaria Venture:  http://www.mmv.org ).
Nanomedicine frontiers ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Nanopore  immuno-isolation devices Nanoporous membrane with 24.5-nm pores.   S.L. Tao and T.A. Desai, Microfabricated drug delivery systems: from particles to pores,  Adv Drug Delivery Rev   55  (2003), pp. 315–328
Nanoshells   Metal “nanoshells” are 100 nm diameter spheres of gold-coated silica. Molecular conjugates can be designed to recognize and bind to tumor cells. Nanoshells have size-dependent tunable optical properties. When they come into contact with cancer-specific membrane biomarkers, their absorption peak shifts to the near-infrared spectrum. Light passing harmlessly through normal tissue causes cancer cells to heat up and be destroyed. Drezek and West, Rice University
Nanofiber scaffolds Stupp, Kessler, et al., Northwestern University Self-assembling nanofiber scaffold Mouse neurons growing within scaffold
Self-aggregating structure Beta-amyloid plaque of Alzheimer’s disease Beta-amyloid fibril aggregates have been used as templates for growing metal nanowires.
Nanoencapsulation   Lambda cyhalothrin capsules attach to the mosquito’s hairs when it comes into contact with a treated net.  This insecticide is highly effective at low doses against many insects that vector human diseases.  Syngenta has developed a water-based, capsule suspension formulation for the treatment of bednetting and is exploring nanoencapsulation methods.
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Some anticipated NIBC payoffs  (pp. ix-xi)
The Perils… ,[object Object],[object Object],[object Object],[object Object]
Chances are, you have recently been monitored by this optical surveillance structure: 1 mm
Practical Concerns ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Ecological effects need further study Water concentration of 500 ppb led to a 17-fold increase in lipid peroxidation in largemouth bass brain tissue.  Eva Oberdorster of Southern Methodist University Buckyballs cause brain damage in fish New Scientist, 29 March 2004
Protecting Our Borders: The Blood-Brain Barrier Experiments by University of Rochester toxicologist Gunter Oberdoerster showed that nanoparticles can make their way from a rat's throat into its brain, apparently via the nasal cavities and olfactory bulb.  “ Who knows how they interact with cells there?” Oberdoerster asked.  “Maybe they do something bad and lead to brain diseases.” For Science, Nanotech Poses Big Unknowns   Rick Weiss, Washington Post  Sunday, February 1, 2004; Page A01
Nanotech ‘borg’ dystopia? “ The twenty-first century could end in world peace, universal prosperity, and evolution to a higher level of compassion and accomplishment. . . .  It may be that humanity would become like a single, distributed and interconnected ‘brain’ based in new core pathways of society.”  (NBIC, p. 6)
Could nanotechnology achieve a symbiosis of brain and computer?  And should we hope for that? ,[object Object],“ Hive mind. . . . Think Vulcan mind-meld.  We would perhaps become more of a hive mind – an enormous, single, intelligent entity.”  (NBIC p. 169)
Concern ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Some technologies ,[object Object],[object Object],What can our knowledge of infectious agents teach us about conceiving precautionary standards for biologically active self-replicating nanodevices? Killer flu recreated in the lab BBC News, October 7, 2004 Genetically modified Yersinia pestis Antibiotic resistant anthrax
A Double Edged Sword ,[object Object],[object Object]
Some Ethical/legal Issues Nanomedicine is likely to  face over the next 25 years   ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Humans and Persons   ,[object Object],[object Object]
Criteria for Personhood? ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Joseph Fletcher’s 15 Propositions for Personhood ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
What Beings Should be Considered Persons? ,[object Object],[object Object],[object Object],[object Object],[object Object]
What the Courts have said… ,[object Object],[object Object],[object Object],[object Object]
Identity and Rights ,[object Object],[object Object],[object Object],[object Object]
Legal and Ethical Considerations ,[object Object],[object Object]
Legal and Ethical Considerations ,[object Object],[object Object],[object Object]
Legal and Ethical Considerations ,[object Object],[object Object],[object Object]
Recommendations and Conclusions   ,[object Object],[object Object],[object Object],[object Object]
Thank you for your attention! ,[object Object],[object Object]

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Siu School Of Medicine And School Of Law June 13 2008

  • 1. Nanomedicine: Future Legal, Ethical and Policy Considerations SIU School of Medicine and School of Law Presentation, June 13, 2008 Linda MacDonald Glenn, JD, LLM
  • 2. The NBIC Report Converging Technologies for Improving Human Performance N anotechnology, B iotechnology, I nformation Technology, and C ognitive Science NSF/DOC-sponsored report June 2002 Arlington, Virginia http://www.technology.gov/reports/2002/NBIC
  • 3. Scale Canary Island palm Mosquito Nano-needle penetration micropenetration nanopenetration Offshore oil rig macropenetration 0.1 m 0.001 m 0.01 m 10 m
  • 4.
  • 5.
  • 6.
  • 7. First, the Promises… 'Nano-needle' operates on cell BBC News, December 15, 2004 - Japanese scientists have performed a delicate surgical operation on a single living cell, using a needle that is just a few billionths of a metre wide. (200-300 nanometers) The needles used much less force to penetrate the cell than a conventional Atomic Force Microscope probe, causing less damage and deformation to the cell. In one experiment, on a human embryonic kidney cell, the scientists managed to insert the needle accurately into the cell's nucleus, which contains its genetic material.
  • 8. The humble mosquito http://www.nomorebites.com Malaria Viral encephalitis Dengue fever
  • 9. Malaria Malaria kills 2 million people each year. Worldwide prevalence of falciparum malaria is half a billion people. The Current Global Picture Malaria is a public health problem today in more than 90 countries, inhabited by a total of some 2,400 million people - 40% of the world's population. How might nanomedicine help to fight diseases like malaria?
  • 10. Red blood cells Image taken from "The Microscopic Diagnosis of Tropical Diseases", Published by BAYER in 1955 (Public Domain). Each erythrocyte contains 270 million hemoglobin molecules 10,000 nm Plasmodium falciparum
  • 11. The Future: Nanorobots? Nanomachines are largely in the research-and-development phase, but some primitive devices have been tested. The first useful applications of nanomachines will likely be in medical technology, where they could be used to identify pathogens and toxins from samples of body fluid and destroy them. (Wikipedia)
  • 12.                                                                                                                                                                                                                  Optical tweezers stretch a healthy red blood cell (top row of images; left to right, increasing force in the picoNewton range) and a cell in a late stage of infection with the P. falciparum malaria parasite (bottom row; same force levels as above). Note the parasite visible in the bottom three images, and how the cell cannot be easily stretched by the tweezers. Photo courtesy / Suresh et al. http://www.voyle.net/Nano%20Medicine/Medicine%202004-0068.htm MIT professor Subra Suresh, left, and research scientist Ming Dao Here Now: Optical Tweezers Silica spheres or beads are attached to opposite sides of a red blood cell, and a laser beam is aimed at one bead. Under the right conditions, the laser "traps" the bead, so that the trapped bead can be pulled, stretching or deforming the cell.
  • 13. Genomics DNA molecule Complete 24 mb genome sequence of Plasmodium falciparum published in Nature [2002 Oct 3; 419(6906): 498-511 Information at the nanoscale 1 nm
  • 14. Plasmodium falciparum genome CTAAACCTAA ACCTAAACCC TGAACCCTAA ACCCTAAACC CTGAACCCTA AACCCTGAAC CCTGAACCCT AAACCCTGAA CCCTAAACCC TGAACCCTGA ACCCTAAACC CTAAACCCTA AACCCTAAAC CCTAAACCCT AAACCCTGAA CCCTAAACCC TGAACCCTAA ACCCTAAACC CTAAACCCTA AACCCTAAAC CCTGAACCCT AAACCCTGAA CCCTGAACCC TAAAACCTAA ACCCTAAACC CTAAACCCTG AACCCTAAAC CCTGAACCCT AAACCCTAAA CCCTGAACCC TAAACCCTAA ACCCTGAACC CTAAACCCTG AAACCTAAAC CCTGAACCCT AAACCCTGAA CCCTGAACCC TAACCCTAAA CCCTAAACCT AAAACCCTGA ACCCTAAACC CTGAACCCTG AACCCTAAAC CCTGAACCCT AAACCCTAAA CCCTGAACCC TAAACCCTGA ACCCTAAACC CTAAACCCTG AACCCTGAAC CCTAAAACCT AAACCCTAAA CCCTAAACCC TAAACCCTGA ACCTAAACCT AAAACCTAAA ACCTAAAACC CTGAACCCTT ACTTTTCATT TCTTCTTCTT ATCTTCTTAC TTTTCATTCT TTACTCTTAC TTACTTAGTC TTACTTACTT ACTCTTACTT ACTTACTCTT ATCTTCTTAC TTTTCATTTC TTAGTCTTAC TTACTTACTC TTACTTACTT ACTCTTATCT TCTTACTTTT CATTCCTTAC TCTTACTTAC TTACTGTTAT CTTCTTACTT TTCATTCCTT ACTCTTACTT ACTTACTCTT ACTTACTTAC TCTTACTTAC TTACTCTTAT CTTCTTACTT TTCATTCCTT ACTCTTACTT ACTTACTCTT ACTTACTTAC TCTTATCTTC TTACTTTTCA TTCCTTACTT TTCATTTCTT AGTCTTACTT ACTTACTCTT ACTTACTTAC TCTTACTTAC TTACTCTTAC TTTCTTCTTC TTATCTTCTT ACTGTTATCT TCTTACTTTT CATTCCTTAC TCTTACTTAC TTACTCTTAT CTTCTTACTT TTCATTCCTT ACTCTTACTT ACTTACTCTT ATCTTCTTAC TTTTCATTCC TTACTCTTAC TTACTTACTC TTATCTTCTT ACTTTTCATT CCTTACTCTT ACTTACTTAC TCTTACTTAC TTACTCTTAC TTACTTACTG TTATCTTCTT ACTTTTCATT CCTTACTCTT ACTTACTTAC TCTTACTTAC TTACTCTTAC TTACTTACTC TTATCTTCTT ACTTTTCATT TGTTAGTCTT ACTTTCTTCT TCTTAGGTCC TTACTTTTCA TTTCTTAATC ATATATTCTT ACTCATATAG TTCTTGACTT AACTTCTTAT TCTTACTTAC TTACTCTTAT ATTCTTTTTA TCATGTTCAA GGTCTTACTT CTTAAATATT AGGTCCTTAA TCTCATAATT CTACTCTTAC TTTCTTACTT CTAGAACCTT ATTCTTACTT TCTTCATCTT ACATCCTCAG TCTCAAGTCT TTAATCTTAT CTTCTTACTC TTACTTACTT ACTCTTATCT TCTTACTTCT CATTTCTTAC TCTTACATAC CTTCTCTTCA TTCTTCAATC ATCAATTCTC ACTCTTCATT CCTTGGTCTT ACTTCTTTCT TCTTAATGTC ATACTTTTAT CCCCTATTAT CATCTACTTA GTCTTCATTT ACTCTTCTAA CTTCTTCATC TATCACTTTT CATCATCATT CATGCTTACT TAACTTACTT TCATATACTT ACTTCTACTA CATCTTCACC AAATCCGGAC TTAGCTTAAC TTTTCTCTCT TTATTCTTAC CTTACTTAGC TCTTACATAC TTAGGATCTA CTTCTTACTT ACTACTACCT TACTTACCTC TTATTTCACT TACATCTAGG TACTTATCCT ACTTTACTTC TCTTATCTTA CTTCTTTATT CTCAGATTCC GGACTTAGCT TAACTTTTTT GTGTTTGTTC TTATCTTACT TAGCTCTTAC ATACTTAGGA TCTACTTCTT TACTTACTTT CTTCTTACTT ATGTGGTAAT AAGCTACTCG GTTGGGCACT AAGGTTAGGT TTAGCTGTTC TTTAGTTCTT AAAGGGTAAG AATTTAAGGT TTGTATTGAA TTATTATTAC TATTTCATTA CTATTGTTGC TATTAAGGAC TTATAATGTT ATGTTTTCTA TCCATTTTGT TCTTTTATGT TACTAAATTC ATTGTAGATT CCGGATTTAG CTCATTAACT ATGCTTCTTA CTTCTTCTTT TACTCTTTTT AGGTCTTATG TTGTATTTAG AGTAGTAATG TTACTTAATT AGTACTTAGG ATTCATCTCA TGTAGGTTAT ATGTTCTTAT AAGGTGCACC TACATGCATA ATATCATCCA ATATATCTCA TTTAGTACTA CTATGATGAC TTATATTATC ATTATCTTAC etc. etc. nucleoside diphosphate kinase B
  • 15. Proteomics and drug targeting Pfal007254AAA Plasmodium falciparum/ Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key glycolytic enzyme. This target has been an exploratory target for drug design by the MMV (Medicines for Malaria Venture: http://www.mmv.org ).
  • 16.
  • 17. Nanopore immuno-isolation devices Nanoporous membrane with 24.5-nm pores. S.L. Tao and T.A. Desai, Microfabricated drug delivery systems: from particles to pores, Adv Drug Delivery Rev 55 (2003), pp. 315–328
  • 18. Nanoshells Metal “nanoshells” are 100 nm diameter spheres of gold-coated silica. Molecular conjugates can be designed to recognize and bind to tumor cells. Nanoshells have size-dependent tunable optical properties. When they come into contact with cancer-specific membrane biomarkers, their absorption peak shifts to the near-infrared spectrum. Light passing harmlessly through normal tissue causes cancer cells to heat up and be destroyed. Drezek and West, Rice University
  • 19. Nanofiber scaffolds Stupp, Kessler, et al., Northwestern University Self-assembling nanofiber scaffold Mouse neurons growing within scaffold
  • 20. Self-aggregating structure Beta-amyloid plaque of Alzheimer’s disease Beta-amyloid fibril aggregates have been used as templates for growing metal nanowires.
  • 21. Nanoencapsulation Lambda cyhalothrin capsules attach to the mosquito’s hairs when it comes into contact with a treated net. This insecticide is highly effective at low doses against many insects that vector human diseases. Syngenta has developed a water-based, capsule suspension formulation for the treatment of bednetting and is exploring nanoencapsulation methods.
  • 22.
  • 23.
  • 24. Chances are, you have recently been monitored by this optical surveillance structure: 1 mm
  • 25.
  • 26. Ecological effects need further study Water concentration of 500 ppb led to a 17-fold increase in lipid peroxidation in largemouth bass brain tissue. Eva Oberdorster of Southern Methodist University Buckyballs cause brain damage in fish New Scientist, 29 March 2004
  • 27. Protecting Our Borders: The Blood-Brain Barrier Experiments by University of Rochester toxicologist Gunter Oberdoerster showed that nanoparticles can make their way from a rat's throat into its brain, apparently via the nasal cavities and olfactory bulb. “ Who knows how they interact with cells there?” Oberdoerster asked. “Maybe they do something bad and lead to brain diseases.” For Science, Nanotech Poses Big Unknowns Rick Weiss, Washington Post Sunday, February 1, 2004; Page A01
  • 28. Nanotech ‘borg’ dystopia? “ The twenty-first century could end in world peace, universal prosperity, and evolution to a higher level of compassion and accomplishment. . . . It may be that humanity would become like a single, distributed and interconnected ‘brain’ based in new core pathways of society.” (NBIC, p. 6)
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