Early in Vincenzo Natali's Splice, rogue scientist couple Clive and Elsa (Adrien Brody and Sarah Polley) watch as their latest massively transgressive experiment is set in motion. They are fertilizing an egg to create a human-creature hybrid, messing with the fundamental building blocks of biology. No one can so much as guess who or what will emerge: Will it be dangerous? Beautiful? Deformed? In horrible pain? They are standing on the breach of the unknown. For a long moment, the camera considers Clive and Elsa's faces as they stare, wide-eyed and beside themselves with excitement, at their handiwork. We're excited too. This is big, existential stuff, and for once the movie seems to know it.

The great English horror writer Ramsey Campbell has written about the value of wonder in the genre: "Many horror stories communicate awe as well as (sometimes instead of) shock, and it is surely inadequate to lump these stories with fiction that seeks only to disgust." In the introduction to one of his venerable short story collections, he wrote that he hopes his work offers "a little of the quality that has always appealed to me in the best horror fiction, a sense of something larger than is shown." A number of authors besides Campbell have intuitively understood this: H.P. Lovecraft and Arthur Machen, with their tales of unfathomable terrors lurking behind a thin veneer of reality; Ray Bradbury's terrifying early short stories (think "The Night," "The Crowd" and "The Veldt"); Philip K. Dick's high-tech paranoia; more recently Stephen King (at his least ponderous) and Clive Barker (at his least gross).

Finding genre filmmakers who concern themselves with evoking a sense of awe is more difficult. James Cameron seemed to approach what I have in mind with The Abyss, as did Spielberg with Close Encounters of the Third Kind. Richard Kelly's The Box was an ambitious and woefully underappreciated piece of neo-Lovecraftian cosmic horror. The Mist, based on a Stephen King novella, culminated in an apocalyptic collision of two worlds that left me slack-jawed. Signs, which withheld crucial information to peerless effect, also headed in this direction before turning goofy in the last act. But I can think of only one working director who seems to consistently take awe as his organizing principle, his raison d'etre as a filmmaker. That would be Natali, the Canadian former storyboard artist who burst into the scene with the 1997 cult classic Cube, and seems to have finally entered the mainstream with Splice.

One of the keys to Natali's work is the way he is able to blend the concrete and the abstract in mesmerizing, often bone-chilling ways. Cube, still his best film, epitomizes this. The adventure at its center – seven strangers wake up in a booby-trapped maze of cubical rooms and must cooperate to find a way out – works on its own terms; the movie is tense and scary, it doesn't cheat, and you want very badly to learn what happens next. It's the context that turns suspense into terror. Who built this hellish thing and why? We learn that the cube is 24 x 24, for an impossible total of nearly 14,000 rooms. The rooms move and appear to behave according to a fiendishly complex system of prime numbers and coordinate maps. We get a glimpse outside it, and see only infinite darkness – is it in space? On another planet? Is it being surveilled? Is it an experiment? One character, who may or may not have reason to know, suggests that the cube is a farce, a giant bureaucratic sinkhole – shades of Kafka. We never learn the truth (except, to some degree, in the unacceptablesequels, which were produced without Natali's involvement), but we see enough eerie details that our imagination can start filling in the blanks in the terrifying big picture.

Cube ends with a man passing through a doorway into the blinding light on the other side – a metaphor for what Natali invites us to do, or at least for what he teases us with. We see the same image early on in Cypher, Natali's terrific, somewhat more conventional second feature. Cypher, a paranoid techno-thriller very much indebted to Philip K. Dick, gives us brainwashing, corporate espionage, and a none-too-subtle meditation on the nature of identity; sort of a blend of Total Recall, The Matrix, and Duplicity. What's interesting is the way Natali and screenwriter Brian King repeatedly strip away layers of reality to reveal something more expansive and sinister underneath. Each time you think the conspiracy at the core of the film can't get any bigger or more macabre, it does. The ending seems upbeat and pat, but that subtly disquieting final shot seems to suggest that there are still more layers left to peel back.

Natali followed Cypher with Nothing, a conceptual comedy starring Cube's David Hewlett and Andrew Miller as two dysfunctional pals who literally wish the world away, finding themselves alone in the middle of an infinite white expanse. Nothing eventually grows a bit wearisome and shrill – it's certainly Natali's weakest movie – but it says something about a director when his "lighthearted departure" involves fundamental changes to the fabric of reality. He's a filmmaker determined to ask the biggest "what if" questions he can get his hands on.

Which brings us back to Splice, seven years later. Like Cube, it combines engaging genre film details with the grandest imaginable context. There's an undeniable creature feature appeal to the movie, but it's the existential mystery of Dren – her disquieting beauty and fundamental alienness, both beautifully conveyed by Natali's effects team and French actress Delphine Chaneac – that sent chills down my spine. She is not a zombie, or a vampire, or a giant squid, or anything else comfortingly familiar. Instead she's the unknown result of a sinister experiment: a complete and hugely important mystery. The movie and its characters are fascinated with her – distressingly rare in science-fiction, where anything new and interesting usually ends up being used as a weapon instead of the subject of genuine curiosity – and so are we.

The fact that Natali is able to bring that fascination to the screen – on a big budget, in a mainstream film – is the reason that he is one of the most talented and promising filmmakers currently working.