When Drexler was writing Engines of Creation (published 1986), the atomic force microscope hadn't been invented yet. When his technical reference Nanosystems came out in 1992, carbon nanotubes hadn't been discovered yet.
The list of discoveries and capabilities since then is staggering: Schafmeister polymers, Rothemund staples, scanning probe chemistry, graphene, room-temperature atomic manipulation, de novo protein design, dip-pen nanolithography... the list goes on and on. All these, and more yet to be discovered, are giving us increasingly straightforward access to the nanoscale.
Several major theoretical advances have been made in molecular manufacturing architecture as well. From the initial picture of self-contained mobile cooperating manufacturing systems, Drexler had developed the nanofactory concept by 1992, and Merkle simplified it in the mid-1990's. The early 2000's saw my nanofactory paper, which explored the rapid bootstrapping of a nanofactory from a simple externally-controlled robot, and the concept of planar assembly as seen in the Burch/Drexler nanofactory animation.
Judging by the past two decades, we can expect continued development of new ideas that will make basic nanofactories even simpler to design and build. By their nature, we cannot predict these advances. All we can say is that, however difficult nanofactory development looks today, it will probably be easier than that.
Just a couple of days ago, Jim Moore posted a concept I hadn't seen before for building machine components out of stacked graphene. I don't know if this is actually going to be easier than the other pathways that are already being explored... but it might be, and it shows that the wellspring of ideas is still flowing strong.
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