It’s soft, malleable, conducts electricity and alloys with tin to make bronze. It’s the stuff of tools and weapons, architecture and sculpture, wiring and plumbing.
opper has been a part of human civilization for more than 9,000 years. But, as a micronutrient involved in a myriad of physiological functions, it is also essential to life. That’s made copper an endless source of fascination to biochemist Michael Petris, an MU professor who holds a joint appointment in the departments of biochemistry and nutrition and exercise physiology.
Petris’s research is adding new insights into copper’s role in genetic illnesses, in Alzheimer’s disease, the immune system and in cancer research.
His scientific interest in copper, which extends back to his undergraduate days in Australia at the University of Melbourne, has led him to explore the artistic side of copper as well. Hammering and engraving copper in his home basement studio, he creates remarkable works of art.
“There’s a lot of reasons to study the biochemical functions of copper,” Petris says. “We’re only really scraping the surface so far in understanding copper’s role.”
Copper is essential for the body’s absorption of iron and the creation of red blood cells. Copper is involved in the manufacture of enzymes and proteins that hold cells together, produce energy within cells and regulate nerve impulses. Destructive free radicals are removed by proteins that contain copper.
“You can’t harness the power of oxygen without copper in the cells. Copper is in some of the most ancient biochemistry we know, since oxygen was first released into the young earth atmosphere,” Petris says.
When the body can’t absorb enough copper to keep these processes going, the results can be devastating. That’s what happens in Menkes disease, a rare genetic illness that often is fatal within the first few years of life.
Infants born with Menkes have mutations of a gene that leaves them unable to adequately metabolize copper. The condition leads to developmental delays, seizures and strikingly unusual hair — sparse, kinky, and easily broken. “I’ve seen the children in wheelchairs. It’s a horrible, devastating disease,” he says.
Petris first heard about Menkes disease during a college lecture by David Danks, a pediatrician who was the first person to connect Menkes to copper deficiency.
Copper deficiency among grazing livestock had long been recognized in regions where soil compounds bind copper. Sheep, for example, develop a condition called swayback. Their wool also takes on a brittle texture.
Danks, who had worked on his family’s farm, made the connection between copper deficiency in farm animals and the symptoms of Menkes disease in children.
“He made this astute observation. I was intrigued by it,” Petris says. Two decades after this observation, scientists finally discovered that mutations of the gene called ATP7A were associated with Menkes. The gene is essential to transporting copper across cell membranes in the body.
Petris signed on as a graduate student at the University of Melbourne’s Murdoch Children’s Research Institute, where Danks was the director. “Since then, I guess I’ve seen the world through copper-tinted glasses, if you will.”
t his MU lab in the Bond Life Sciences Center, Petris has genetically engineered mice with an inactivated ATP7A gene to produce symptoms of human Menkes. Petris deletes, or “knocks out,” the genes selectively from tissues in order to study how ATP7A functions in particular tissues.
When Petris knocked out the gene from the intestinal tract of the mice — where copper from food is absorbed into the body — he was able to “rescue” the mice with copper injections and prevent Menkes symptoms.
Laurie Smith, a geneticist at Childrens Mercy Hospital in Kansas City, is excited by the possibilities Petris’s knockout mice have presented. Over a two-decade career, Smith has had only six patients with Menkes.
“Children with this disorder generally don’t do well,” Smith says. “You’ll see these poor children lying there who are very thin and having seizures. There’s really not a lot you can do for them. Basically, what you do is give comfort care.”
Smith called Petris’s knockout mice “a great first step.” To determine whether a treatment will be effective, she says, “you have to know where copper is most important and find ways to fool the body into accepting it. I think this is an ideal system for doing that.”
A key issue is finding a way to get across the blood-brain barrier, where it’s most difficult to replenish copper, Smith adds.
Petris agrees. “The challenge for Menkes disease is to use a form of copper that is bound to some kind of compound that can get across the blood-brain barrier and then give up its copper.”
Such compounds exist. They could be tested with mice whose ATP7A gene has been knocked out of the cells lining the brain’s blood vessels. “We really need to be able to trial some of them,” Petris says.
Further into the future is the possibility of gene therapy, using viruses to “infect” the body and deliver therapeutic ATP7A genes. Dr. Steve Kaler at the National Institutes of Health has been testing this approach in mice. “If successful, you can define that as a cure, that’s permanent,” Petris says. It also may be risky. But with an early death almost a certainty for children with Menkes, “you can make a fairly cogent argument that the benefits outweigh the risks,” Petris says.
Petris is also interested in using his knockout mice to address a “somewhat controversial” hypothesis that copper is involved in the development of Alzheimer’s disease.
Metal-induced Alzheimer’s can be traced to the 1970s and 1980s when there were several reports that aluminum might be an Alzheimer’s culprit. That theory was eventually debunked, but in the meantime it caused many people to fret about everyday sources of aluminum, such as pots and pans, antacids and antiperspirants.
More recently, copper, zinc and iron have been implicated in Alzheimer’s disease. The evidence for these metals is much stronger than for aluminum. High concentrations of the metals have been found in beta amyloid, protein fragments which collect as plaques where brain cells communicate with each other. They are considered the likeliest cause of Alzheimer’s.
Whether the copper causes these plaques to form or accumulates as a consequence of the plaques is still unknown. By knocking out the ATP7A gene in mice that have been bred to develop Alzheimer’s, Petris hopes to discover what role, if any, copper plays in the development of the disease. “I’ve always had an interest in addressing this question,” Petris says. “Now that we can remove ATP7A in specific cell types of the brain, we can.”
Petris also hopes to use his expertise with the ATP7A gene to find ways to make cancer treatment more effective. Copper transporters are known to be involved in the biochemistry of how cancer cells flush out certain platinum-based chemotherapy drugs. The cancer cells that are most successful at ridding themselves of the drugs survive and continue multiplying. That can make a second round of chemotherapy less effective.
Studies have shown that cancer cells that are resistant to platinum-based chemotherapy drugs have higher levels of the ATP7A protein than other cells, Petris says.
If that’s the case, it may be possible to improve the success of chemotherapy by giving cancer patients a drug ahead of time that temporarily inhibits the ATP7A protein, thus disarming the cancer cell’s ability to remove the chemotherapy agent. Right now, drugs to inhibit ATP7A don’t exist, but Petris’s lab is working to develop them. “We’re still very early in the scheme of things.”
But if they succeed, “there may be a double advantage” for controlling cancer, Petris says. Any rapidly dividing cells, such as cancer cells, have a voracious appetite for nutrients. “If you look at tumors, they take up and absorb a lot of copper.”
The ATP7A directs copper to enzymes involved in the growth and spread of cancer cells. So any drug that can suppress the activity of ATP7A offers the possibility not only of making chemotherapy more effective but also blocking the growth of tumors.
Petris is quick to pose and answer a theoretical question that might come to mind: Wouldn’t cancer patients whose ATP7A protein was suppressed also develop Menkes disease?
Not likely, Petris speculates. Menkes disease is largely a developmental disorder, so adult patients with a transient loss of ATP7A function would be unlikely to develop Menkes-like symptoms. However, he is quick to point out that one would not want to inhibit ATP7A for a prolonged period of time — only long enough for chemotherapy.
Petris has been at MU since 2000, when he was hired by MU’s Department of Nutritional Sciences (now the Department of Nutrition and Exercise Physiology) straight out of his post-doctoral studies at Deakin University in Australia. At the time, MU was building its program with experts on trace minerals who were applying molecular and biochemical techniques to problems of nutrition.
When he was offered the job, Petris was single and just 28 years old. “So I took a leap of faith that I could leave my home country and start a lab in a place I had never lived,” he says.
e would become one of the youngest tenure-track faculty at MU with his own lab. Some of his first graduate students and technicians were older than he was. “I was very green, looking back. I wasn’t even sure I was completely ready to run a lab, to be frank, especially in a foreign country. But I have never been short of ideas and I have always been lucky enough to have enthusiastic students willing to help test them.”
Petris was awarded tenure in 2005. And he met his wife, Carisa, now a physician, who was going through medical school and a residency in the University’s Department of Ophthalmology. Carisa’s continuing education is the reason why you won’t be seeing much of Michael Petris in Columbia for the next couple of years. She is currently doing advanced training in reconstructive and cosmetic plastic surgery of the eye at New York University’s Langone Medical Center.
The Petris’ and their two young daughters, Madeline, 4, and Abigail, 2, moved to an Upper East Side Manhattan apartment this past summer. They will be returning to MU in 2015.
Meanwhile, Michael Petris is continuing to run his MU laboratory in the Bond Life Sciences Center via Skype and frequent return visits to the campus.
Petris is staying busy in New York with still more research on copper, in this case the way it’s used by our immune system to fight infection.
Copper’s anti-microbial properties have been known for millennia. The ancient Greeks and Egyptians used copper salts on wounds. In the past few years, researchers have discovered that microbes switch on genes for copper resistance when they encounter a mammal’s immune system. It appears that macrophages, the white blood cells that circulate through the body engulfing and devouring bacteria, concentrate copper around these microbes.
Bacteria need copper tolerant genes in order to successfully colonize the host. “The evidence is emerging that copper is like a grenade that is being lobbed by the immune system at the bacterium,” Petris says.
Petris is using his knockout mice, with the ATP7A gene removed from their macrophages, to determine how important the gene is to the immune system. He has been using Salmonella bacteria in his MU lab, but in New York he’s collaborating with NYU microbiologist Heran Darwin on a much more dangerous organism, Mycobacterium tuberculosis.
Petris and Darwin have to conduct their research in a biosafety level 3 laboratory that’s engineered to contain such hazardous pathogens. They’ve been using the facilities at Rockefeller University because Darwin’s NYU lab was knocked out of commission by Hurricane Sandy in October 2012.
The laboratory at Rockefeller University is just a short walk from Petris’s apartment, a block from the East River. His family is taking full advantage of the city. “New York, what’s not to love?” he says.
One thing that he doesn’t have in the city is a basement for doing his artwork. That will have to wait until he returns to MU. “In reading about copper, I ventured more broadly than the science, so I tried my hand out of interest,” he says. “I’ve never taken a class. I just taught myself in my spare time. You get a sheet of metal and hammer it into shape.”
His works are striking: a burnished sculpture of a leaf, etchings of an elegant woman in a ball gown, of a slice of a mouse brain in shades of orange that appears to be an abstract image until you’re told what it is.
It has become a tradition that when people leave Petris’ lab he makes them a gift out of copper that will have a special meaning to them. One of his brain etchings, for example, went to a student who had been doing brain research.
“Good science, like art, is very creative. But to the lay person, scientists aren’t automatically associated with creativity,” Petris says. “I’ve always been tinkering with something.”