Hello HereandThere, welcome to the Monastery. Hmm, did you try this code that you posted?

$_="FourThreeTwoOne, Three, Four, One, Two";
$1="Three";
$second="&&&&";
s/$2/$second/g;
print;
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I am pretty sure it cannot work. For a start, $1 is a read-only value that can be set only by a regex.

$1="Three";
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I do not think that the perl compiler accepts that, but even if it did, it should not be done. In my view, $1 is a special variable that should be kept for just one single purpose: the first capture in a regex.

s/$2/$second/g;
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This makes even less sense, since $2 has not been set anywhere, it is undefined, there is just no way this is gonna work. In addition, I would suggest that if you set $_ to something, you first localize it within some lexical block:

{
    local $_="FourThreeTwoOne, Three, Four, One, Two";
    # ...
}
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Furthermore, you should probably have these pragmas at the top of your script:

use strict;
use warnings;
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and they would force you to rewrite the third line of your code as:

my $second="&&&&";
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Finally, I don't even understand what your code is supposed to demonstrate to the OP. Well, to tell the truth, if you were not so new on this forum, I would probably down vote your post (although I almost never down vote posts for other reasons than spamming, insults, completely off-topic posts or other clear netiquette violations). I'll refrain from doing it here in consideration of the fact that you are new here.