Quick summary:  the DTES is a really sketchy place, but it's not threatening once you understand its character.  Also, while you will be on its fringe, you most likely will not need to walk through it ever (unless you want to).

The only bad things that typically happen in the DTES are either (a) minor property crimes (B&Es, breaking into cars, vandalism), or (b) crimes committed against the people who live there by either other people who live there or those who are preying on them (the serial killer went after prostitutes and/or homeless women - the vulnerable and downtrodden). 

Random middle class programmer types are not their targets.  If you have a car parked on the street there, maybe it would be, but the parking garages are more-or-less secure.  I'd still recommend transit, though, it's just easier to deal with downtown.

One thing you will need to get used to is turning down people asking for change / food / whatever.  Usually they don't bother people in Gastown during the day, and on many nights of the week there are a fair number of clubgoers in Gastown as well.  Most of the addicts out there are fairly benign - I have had more issue with drunken/high idiots accosting me on the bus (far away from downtown) than I ever have while actually downtown.

When I was fairly new to Vancouver (back in my early university days), late one night I walked right through the middle of the DTES (through the notorious Pigeon Park) while I was looking for Gastown.  I felt somewhat uncomfortable, but back then I was but a wee Mennonite lad, new to the strange ways of the big city.

If you're working in Gastown, you have a good route back NW towards the Skytrain station, and up to Seymour/Howe where there are usually a fair number of night busses that run.  There's usually someone out there at night, and it shouldn't be more than a kilometer to a bus stop.

Without knowing exactly where this company is located in Gastown, it's hard to say what the immediate surroundings are like.  The entire area is becoming gentrified - the old empty buildings are being turned into new trendy lofts (and selling for ridiculous prices), and even the old Woodward's building (almost in the heart of the DTES) sold out in just over a day.  There's also a great restaurant called "The Alibi Room" at Main and Alexander - we held our wedding reception there, and that's only three blocks from Main and Hastings.  Alexander St. going west (along Water St., etc.) is just fine.

I can't guarantee that you will feel safe, but I wouldn't have a problem going to/from my company's offices at night, if they were in Gastown.  Actually I would be incredibly happy, because that would shave 40 minutes off my commute.  A lot of up-and-coming dot-com-style (or would it be "Web 2.0 style" now?) companies used to set up shop there, and probably still do.

The Granville mall strip, Robson St. and Gastown are very interesting areas of Vancouver that showcase how a large city can have a vibrant, dense downtown core that doesn't need to be locked down immediately after dark.  Yes, the DTES is a sketchy area, but it's really not that bad once you get used to it.  I can't say that I would spend any time there - it is rather unpleasant - but I don't feel threatened by it.

If you have any more specific questions about the area but don't want to post openly, you can always send me a private message (assuming that feature works) and I can answer you.

Hope this helps!