Physicians say fish is good for you, but new research is showing that fish could be even better for human health than doctors ever dreamed: in medical therapies to kill cancer cells and pathogens that are growing ever more drug-resistant and dangerous.
Scientists at the College of William Mary say striped bass peptides, bound with copper, could be amazingly effective not only at boosting the human immune system, but in directly attacking tumors and infectious agents.
“We hear a lot about superbugs,” said Myriam Cotten, an associate professor in the Department of Applied Sciences. “The main application here is to find an alternative to those traditional antibiotics that lead to bacterial resistance.
“How can we find new ways to fight bacteria — because they fight back.”
The big advantage of fighting bacteria by boosting the host’s immune system is that, because the bacteria isn’t being attacked directly, it also isn’t being triggered to evolve to resist the drug.
Meanwhile, initial results using copper-charged peptides to attack cancer cells show remarkable potential.
Cotten collaborated with a colleague at the University of Michigan, Hao Hong, who conducted “in vivo” tests — or tests on living organisms. In this case, peptides bound to copper were applied to a cancer tumor on a mouse.
“They can actually destroy cancer cells,” said Cotten. “It’s a very exciting aspect.”
Cotten and her team applied for state funding last year to study how effective the compounds could be against brain cancer cells, but were denied because they didn’t have a commercial partner to bring it to market.
Today their research continues on a fundamental level to unlock the possibilities.
First, it’s important to note that there are two types of immune systems: innate and adaptive.
Innate systems are genetically hardwired right from the start, while adaptive systems respond to fight specific pathogens when they attack.
Striped bass and other fish and amphibians have rather fierce innate immune systems — even more robust than humans and other mammals.
This is because the creatures evolved to survive in what’s basically a watery environment teeming with all sorts of nasty stuff.
So when bacteria try to enter through the fish’s skin, gills or mucus membrane, the innate immune cells secrete peptides, or chains of two or more amino acids, which hustle to fight them off fast.
“When you think about taking antibiotics for two weeks,” said Cotten, “the fish can actually eradicate a bacterial infection within minutes.”
According to The Antimicrobial Peptide Database, of the more than 3,000 known antimicrobial peptides, nearly half are from marine species or amphibians and only 282 from mammals.
A fish’s adaptive immune system, however, is rather lame. An adaptive system produces antibodies to fight off pathogens, making it easier to fight them in future.
Humans have well-developed adaptive immunity, but our innate immunity pales in comparison to fish and amphibians.
A couple of years ago, Cotten began wondering if peptides produced by the striped bass’s innate system might work together to attack bacterial cells more effectively.
She also wondered if copper — a strong antimicrobial on its own — might bind with peptides and work synergistically in the battle against bacteria.
“And it turns out that’s exactly true,” Cotten said.
“We found that this particular family of peptides in the hybrid striped bass bind physically to copper. And when they’re bound to each other, they can attack bacteria much more efficiently.”
This is tricky, though — copper is actually too strong on its own and, left unchecked, can kill not only bad bacteria, but good cells, too.
But when copper binds to a peptide, the peptide carries it to a bacterial target “with specificity,” said Cotten, sparing the good cells.
These findings were published recently in The Journal of Biological Chemistry, and is fueling a broader range of study.
“We’ve become very, very interested in metals like copper acting with proteins or peptides to be synergistic and fight bacteria,” Cotten said.
“This is a little bit of a niche we have found here at William and Mary — to study on a fundamental level how molecules from the innate immune system bind to metals and their antimocrobial effects.”
The atomic view
Their research requires studying interactions at the atomic level.
And this requires a nuclear magnetic resonance machine — a two-story superconducting magnet that Cotten refers to with a sense of awe as “the beast.”
The NMR is part of a $1.5 million lab that was secured for the college in 2005 by Robert L. Vold, now a professor of science emeritus, and physics professor Gina Hoatson, whose office overlooks the NMR lab at Small Hall.
The facility was funded by the National Science Foundation, the U.S. Navy and the college and is “very unique in the whole world,” Cotten said.
Vold and Hoatson use the 17.6-tesla, 750 megahertz machine to study nonbiological samples, while Cotten uses it to get an atomic view of biological membranes and the proteins that bind to them.
With it, she can zoom in to study how peptides attack the membranes of bacteria, killing them.
She places her biological samples on glass plates inside static probes, or smooth cylinders about three feet high. The probes are then inserted into the bottom of the machine.
One of her collaborators, Peter Gor’kov at the National High Magnetic Field Lab at Florida State, custom-built the probes for her.
The NMR zaps the sample with a magnetic field, causing the atomic nuclei in the samples to resonate at their own unique frequencies. Those signals from the nuclei are decoded and essentially report on shape — the molecular structure of the sample.
“It takes quite a bit of work,” said Cotten. “You have to collect the data, then you have to interpret it. It’s not instant.”
With that data, they can create 3D models of the peptide molecules.
To demonstrate, research scientist and NMR specialist Alex Greenwood pulled up a 3D image of a peptide molecule on a computer screen.
He colored the different elements of the structure and swiveled the image around to examine the many chains branching off from the backbone. Bound to the structure was the gold-colored, oval shape of a copper atom.
The NMR creates a magnetic field using miles of coil encased in a non-magnetic metal container. Keeping that coil supercold — at about 2.5 kelvin, or minus-455 degrees F — makes it superconducting.
The supercold state is achieved using more than a hundred gallons of liquid helium and liquid nitrogen that must be topped off regularly. The machine must be monitored constantly.
Greenwood said the machine is one of the first 750s ever built.
“At the time of installation, this was one of the highest field instruments in the country,” Greenwood said.
Today there are higher-frequency instruments, but at the time anything higher was considered too unstable.