I reckon the show should have a three story structure, which is what Whedon does best.
Story One: "Monster of the Week" -- It's a syndication show, which works best with a "every episode is about something different" structure, designed so that you can turn on the TV and go, "oooh, Agents of SHIELD is on" and just watch an hour of TV without feeling like you missed something. I feel Joss does Monster of the Week better than anyone else and The Marvel Universe is made for this kind of storytelling.
"Oh no, it's Jackson Day, codename "The Corruptor" abilities: Psychoactive sweat that make everyone badass, even us, The Agents of Shield. Yet for some reason it didn't affect Agent Fitz, probably because he's in a wheelchair, there must be something wrong with his brain, ha, let's steal his wallet."
Story Two: "The Season Long Story" -- What most shows these days solely are, the events of the Season, episode one builds it up, episode 22 finishes the story, you even have your beginning, middle and end. This is your "You are the Vampire Slayer, The Vampire King has escaped the hellmouth and you are destined to die", and "A creepy girl and her brother are paying us to hide them from The alliance, we hate the alliance!" storylines. This is the kind of story that helped binge watching become a thing.
"Project PEGASUS (previously known to be destroyed in The Avengers, last mentioned in The Pilot Episode of Agents of SHIELD) is a SHIELD and NASA funded venture, formed to investigate phenomena beyond the range of conventional scientific understanding. A new branch, recently discovered to be helmed by a member of HYDRA, was tasked with discovering new forms of renewable energy. It turns out they were using those locked up in The Fridge as test subjects and have weaponized a renewable energy that could destroy the world if the wrong hands were to get their hands on it -- you know like HYDRA. We as the ONLY members of SHIELD must stop them using only our wits, our family dynamic and some cool James Bond-like fantasy gadgets from 1945. Also, Skye's mother, the season's Big Bad is hunting us down. Go team!"
Story Three: "The Series Long Story" -- The story that starts on episode 1 and if all goes to plan, ends X-number of years later. This is the story you watch the show for, while it could just be about how "being The Slayer is HAAAAAAARD and I wish I was dead, no seriously, I wish I was dead, as a slayer I get an automatic pass into Heaven, you selfish fuckers"; or your "This supernatural lawyer firm is MEEEEEEEAN and interfering with my supernatural detective agency, I don't know what they want and I'm stuck with carrying Cordelia and her emotional sensitivity" kind of story.
With all these supernatural fugitives running around hurting civilians that we need to re-imprison before it's too late, catching HYDRA will be a challenge. So long as our inter-family problems don't get in the way, there's nothing that can stop us. Oh look, beloved character died, we will literally never get over this."