Path: utzoo!utgpu!jarvis.csri.toronto.edu!rutgers!aramis.rutgers.edu!athos.rutgers.edu!nanotech From: mtgzz!davis@att.att.com Newsgroups: sci.nanotech Subject: Re: Why I think Nanotechnology is Bogus Message-ID: Date: 4 Jul 89 01:57:39 GMT Sender: nanotech@athos.rutgers.edu Lines: 122 Approved: nanotech@aramis.rutgers.edu [Pre-background: I received an earlier letter from Paul stating that he considered nanotechnology bogus because we do not understand protein folding. I challenged him to provide credentials to back up such a claim:] Background - BSc (first class honours/summa cum laude) Biomolecular Science, Portsmouth Polytechnic, UK Post-graduate fellowship at Weizmann Institute (Biopolymers) with Prof. E.N. Trifonov working on DNA sequence/structure relationships Pre-doctoral fellowship at European Molecular Biology Laboratory, in Biocomputing, examing the role of hydrophobic clusters in protein folding. Chris Sander, Patrick Argos and others in this group are all heavily involved in protein folding research. Further Comments [I pointed to work at DuPont which I claimed was the beginning of a general protein synthesis technology] I can't claim to have seen the work from DuPont, and in this sense my next comment is a little foolish - I don't believe it, at least not your description of it. Why not ? Consider the instance of the so-called TIM barrel, a colloquial term for the structure adopted by, amongst other things, the enzyme TIM (tri-isomerase-i-forget-the-rest). There are at least 5 instances of the TIM barrel, and even the best sequence homology algorithms cannot identify the commonality in the sequences of the proteins that adopt this fold. On the other hand, there are several proteins with highly homolgous sequences which fold into totally different conformations. We have a very vague notion of what sequences might be good at forming some elements of primary structure (helices, beta-sheets), but even that is subject to a cautionary clause invoking the environment (the solution, the rest of the molecule) as major agents in facilitating or preventing such structures from forming. We have basically no idea (unless you wish to include lunch time discussions as "ideas") how these primary elements get juxtaposed to form tertiary structure, let alone what the actual process of folding involves. To the best of my knowledge, which isn't saying much, all the work that has been done on modifying sequences to produce new proteins has essentially operated on primary structure and maybe a little secondary structure guesswork. We simply don't know the effects of changing particular amino acids in a protein to something else. I think that the optimism you are seeing in the scientific press is misplaced at this time. Work is being done, and progress is being made, but to imagine that what we know now can form the basis of a sophisticated range of molecular engineering techniques is a mistake, in my opinion. [I compared a natural genome to an operating system and said that right now we knew how to write a bubble-sort] As for the genome/OS comparison, I consider this a little fallacious too. What we know for sure about the genome so far is really only the genetic code itself. Some of my research work was concerned with trying to elucidate other "hidden" functions in DNA - based on the work of people like Trifonov, Claverie, and the Cambridge MRC group, who have begun to show that DNA sequences really do very much more than code for proteins, and are actively involved in defining the structure of the DNA itself. This in turn affects the binding of proteins to DNA which modulate its function, a highly complex procedure which we can only sketch right now as a general case (some specific instances, such as that of POLIII are better elucidated). If you want a computer-based analogy, I would suggest our current level of expertise with the genome as similar to knowing what sequence to punch onto a paper tape, but having almost no idea what shape the paper should be, how to build a reading system, or what the feeback implications of the whole setup might be. In short, we don't know very much. I have a feeling that genetic engineering and nanotechnology will forge ahead despite this ignorance, and may even help to dispell some of it. But it will not do so based on any real understanding of biomolecular systems, and as a result is likely to take many wrong turns, and possibly even be dangerous. And as a final question, I would ask this of all nanotechnologists, biomolecular and genetic engineers everywhere - WHO NEEDS THIS STUFF ? We have enough fascinating games to play already without molecular building blocks, and the problems of our world are political, social and psychological rather than technological. Nanotechnology, like the computers I use everyday,is just another toy for those of us who seem unable to accept what is, who can't the fact that there are simpler but more difficult decisions and choices in our world that will make us happier, healthier and more at ease with our world than fiddling with molecules, be they galium arsenide, proteins or DNA. If you can declare it as a toy, then great - but I don't want to play. Please don't tell me what a wonderful world it will bring - the world is already wonder-full enough for me. Paul [The Update gives a reference to DeGrado (ie the DuPont stuff) as Science 241:976-978 (19Aug88). I would have sworn I'd seen something later than that (also in Science) but I can't find it in the top few pitchforkfuls of my "files". I fear I wasn't specific enough in my description, however. The critical distinction is between science and engineering. Consider building a bridge. If you leave no margin for error, and the traffic gets heavier, it is impossible to predict on just which bounce of just which car the bridge will break, and just where every piece will fall. However, it is not impossible at all to design a bridge that won't break in the first place. Complicating the scientist's task in studying natural systems is the fact that these systems tend to operate near the edge of workability--that's the way evolution works. The engineer, including the molecular engineer, has the luxury of avoiding the structures he doesn't understand; the scientist doesn't. Of course the engineer needs to understand enough to have a "working vocabulary", but this can be a much smaller set than appears in a natural organism. The engineer's motto is "anything that works," but evolution's motto is "everything that works." As to the final paragraph, this seems a matter of personal perspective, and you are certainly entitled to your opinion. However, I really think that the statement "the problems of our world are political, social and psychological rather than technological" is unconsidered. There are not "social" vs "technological" *problems*, but rather social vs technological *solutions*. In my reading of history, social and political solutions *do not work*, but the problems technology has been applied to have been decimated. I further claim that the technological solution to the problems you are worrying about is to make human beings more intelligent; nanotechnology is a plausible approach. --JoSH]