One of the things I really enjoyed in the stories was when Sherlock went under disguise. Maybe he could go undercover? Or what about someone reenacting Jack the Ripper's crimes? Or some other less famous serial killer. Or someone is killing homeless people, but the Yard isn't that concerned about it to call Sherlock in because TPTB don't care, but Sherlock does because they are 'his network'. Maybe someone kidnaps Mycroft for some reason and his assistant comes to Sherlock to get help to find out where they are hiding him. You could have someone kidnap Sherlock and John has to come to his rescue...or vice versa. If you want angst in it, it could be something that is beyond Sherlock's abilities to fix and John's in danger. Sherlock could be going crazy knowing he can't help. Depending on what you want, you could have Sherlock collapse on a case because he hasn't eaten (I really think this would have happened sometime) and John putting his foot down as a doctor and making him eat.