Fifty years ago this week, on April 8, 1960, a little-known astronomer named Frank Drake sat at the controls of a radio telescope at an observatory in Green Bank, W.Va., and began to sweep the skies, looking for a signal from an alien civilization. It was the start of the most ambitious scientific experiment in history.

After five decades of patient listening, however, all the astronomers have to show for it is an eerie silence. Does that mean we are alone in the universe after all? Or might we be looking for the wrong thing in the wrong place at the wrong time?

If a civilization endures for long enough, it might seek to migrate beyond its planetary system and colonize, or at least explore, the galaxy. The Milky Way is huge—about 100,000 light years across—and contains 400 billion stars, but given enough time, a determined civilization could spread far and wide. Our solar system is about 4.5 billion years old, but the galaxy is much older; there were stars and planets around long before Earth even existed. There has been plenty of time for at least one of those expansionary civilizations to reach our galactic neighborhood—a prospect that once led the physicist Enrico Fermi to famously utter "Where is everybody?"

How do we know they haven't been here already?

It would be an incredible coincidence if Earth had been visited by aliens during the brief span of human history. On purely statistical grounds any visitation is likely to have been a very long time ago. To pluck a figure out of midair, imagine that an alien expedition passed our way 100 million years ago. Would any traces remain?

Not many. However, some remnants might still persist. Buried nuclear waste could be detectable even after billions of years. Large-scale mineral exploitation such as quarrying leaves distinctive scars that, in the case of Earth, would eventually become obscured by overlying strata but would still show up in geological surveys. Space probes parked in orbit round the sun might lie dormant yet intact for an immense period of time. Scientists could look for such hallmarks of alien technology on Earth and the moon, in near space, on Mars and among the asteroids.

Another physical object with enormous longevity is DNA. Our bodies contain some genes that have remained little changed in 100 million years. An alien expedition to Earth might have used biotechnology to assist with mineral processing, agriculture or environmental projects. If they modified the genomes of some terrestrial organisms for this purpose, or created their own micro-organisms from scratch, the legacy of this tampering might endure to this day, hidden in the biological record.

Which leads to an even more radical proposal. Life on Earth stores genetic information in DNA. A lot of DNA seems to be junk, however. If aliens, or their robotic surrogates, long ago wanted to leave us a message, they need not have used radio waves. They could have uploaded the data into the junk DNA of terrestrial organisms. It would be the modern equivalent of a message in a bottle, with the message being encoded digitally in nucleic acid and the bottle being a living, replicating cell.