England must launch their Grand Slam defence without three first-choice forwards - and face question marks over four more.
Joe Launchbury has joined Billy and Mako Vunipola on the sidelines after sustaining a calf injury that will rule him out of at least the RBS 6 Nations opener against France on February 4.
The Vunipola brothers are suffering from knee problems but while Billy will struggle to play any role in the tournament, it is hoped that Mako will figure at some point.
Doubts also exist over George Kruis, Chris Robshaw, Dylan Hartley and James Haskell, although it is thought the quartet will be ready for the visit of France to Twickenham.
The biggest concern is over Robshaw, who has aggravated a shoulder issue that will be assessed by Harlequins this week, with England head coach Eddie Jones raising the possibility of surgery.
Kruis has a fractured cheekbone, Haskell has yet to make his comeback from a foot operation for Wasps, while Hartley must prove his fitness if he is to lead England into the Six Nations having served a six-week ban.
"This is the way it is with injuries. As we said in November, it is chance to create some more depth," Jones said.
"For 2017 we are going to be missing potentially four of the starting pack, but we got through November without seven front-line players. So it's a great opportunity, exciting.
"People say 'relax and enjoy the job', but you never relax. You've got to get on with it. You wake up every day and hope someone else doesn't get injured."
Of England's established pack, only prop Dan Cole and lock Maro Itoje are inked in to begin the final stretch of the mission to surpass New Zealand's record of 18 successive Test victories.
The task facing Hartley is to demonstrate that his conditioning is sufficient to enable him to continue as captain despite being sent off for striking Leinster's Sean O'Brien on December 9 and incurring his latest ban.
"Dylan's got to come into our training camp in Portugal fit and ready to go," Jones said.
"He's doing all the right things at the moment and if he keeps on doing that, there's no reason why he won't be starting hooker and captain.
"He's got to train bloody hard, that's the thing. He's got to come into Portugal, he's got to be one of the fittest players there and if he's in the 23, he'll be captain.
"He is capable of coming back and playing, as long as he trains well. It's really important he trains well.
"Dylan made a mistake and that's the first mistake he has made for England. There are plenty of players in the squad who have made mistakes."
An update on Manu Tuilagi's knee injury is expected this week with the Leicester centre yet to discover the severity of the problem.