By New Times
By Connor Radnovich
By Robrt L. Pela and Amy Silverman
By Ray Stern
By Keegan Hamilton
By Matthew Hendley
By Monica Alonzo
By Monica Alonzo
Outside the BNI building, marching protesters accuse them of torture. Sporadic death threats pop into their e-mail inboxes or get funneled through the hospital switchboard. There are incoming questions from concerned public officials, reporters and grant-funding agencies -- questions they are tired of answering.
So they stay in the bunker, under siege from all sides and seeming rather resentful about it. They're trying to save lives, after all.
In his federally funded research project, Berens operates on pregnant beagles. Around day 36 of each dog's pregnancy, Berens makes an incision into its swollen abdomen and, using ultrasound to guide his hand, injects cancer cells into the hind legs of the fetal puppies. If a puppy develops a tumor after birth, Berens surgically removes the lump and places it into the pup's brain through a drilled hole. The idea is to develop a tumor model on which researchers can test potential treatments for human brain tumors. But after 10 years of study and a couple hundred euthanized and aborted dogs, only three pups have successfully developed cancer. So in 1999, the Arizona State University animal research oversight committee told Berens to remove his dogs from their kennels and house them someplace else.
As a target for an animal rights crusade, the beagle project could hardly be more ideal. Here is a study with a documented failure rate, criticism from an otherwise research-friendly university and subjects that are a particularly adorable species of man's best friend. It's like blood in the water. The founder of the Bay Area group In Defense of Animals calls the beagle study the "Achilles' heel" of animal research. People for the Ethical Treatment of Animals has issued an "Action Alert" against Berens, dubbing him the "Beagle Butcher." Animal rights Web sites urge protesters to call the sheriff's office (charge Berens with animal cruelty!), Berens' grant provider (take away his money!) and his employers at BNI (make him stop!).
"If I was running gerbils down a maze, and it wasn't working after 10 years, I would change it," says Dr. Patricia Haight, a psychologist who is leading the protests. "All of the killing of these puppies is never going to give him the information he is looking for."
Through it all, Berens and his colleagues have remained defiant, yet they confess they are privately alarmed.
The vice president of research at BNI, Dr. Joan Shapiro, received an e-mail with a description of her car, her license plate number and a message remarking that she drives home late at night, alone. Undescribed "things" have been left at Berens' home, and threats have been made against his family.
"I'm in the crossfire," says Berens. "Their mind is already made up: 'Don't confuse me with the facts.' There are people who are steeped in the effort to move forward with challenging diseases, and there are people who say, 'Yeah, we should have better opportunities for treatment, but nobody should get hurt in the process.' Well, that's not going to happen."
Shapiro, thinking about how she tenses up every time a driver pulls alongside her car, speaks a bit more aggressively.
"People could be very seriously injured by me because I will do something first and ask questions later," she says.
But beyond all the noise and exclamations and claims and threats from both sides, there has been little real examination of Berens and his study. Berens' critics see him as the Captain Ahab of animal research -- an unstoppable menace plunging on regardless of the cost, obsessed with an impossible outcome. To fellow cancer warriors, however, his passion is understandable, even admirable. Sometimes it takes an Ahab determination to fight the most clinically frustrating and lethal disease on the planet.
"To give up is not acceptable," declares Berens. "[The research is] not going nowhere; it's having labored success. If you want to see a real lack of success, come on over here to our brain tumor clinic."
Half of American men and a third of American women will get cancer in their lifetimes. It's the plague of all centuries with a different variety named after every organ it attacks. Cancer of the brain has one of the most dire outcomes. A tumor, either a spontaneous development (primary) or a growth inspired by cancer cells spread from another organ (metastatic), takes up residence in your gray tissue. The cancer cells quickly infect and mutate neighboring cells. It's what researchers call "walking," as in, "His tumor has already started walking." The multiplication is exponential as cell after cell is conquered, each transformed into something that's deathly dysfunctional yet maddeningly unique, like diseased snowflakes. A photo of cancer DNA even looks villainous -- schizophrenic clumps of broken chromosomes. Since the brain has no pain receptors, a tumor can grow for years without symptoms. After a while, there are little things: headaches, dizziness, blurred vision. If diagnosed with a primary brain tumor, as 16,500 Americans are each year, the patient most likely faces toxin treatments such as chemotherapy and radiation therapy. Both have been significantly refined over the years, but they are still physiological sledgehammers. Speech, motor control and mental faculties deteriorate. You lose your ability to recognize loved ones. It's a horrific way to die.
"It's difficult for many people to grasp just how dreadful this type of cancer is. It is cancer in the organ that makes us human," says John Henson, executive director of the Brain Tumor Center at Massachusetts General Hospital. "[Gliobastoma] tumors take the lives of patients in one year, on average. And despite very aggressive research efforts over 25 years . . . the improvement in median survival is about a couple months."
Michael E. Berens grew up in Phoenix, the son of a BNI surgeon. Berens says his father would take him along on house calls to visit recently discharged patients.
"I'd pick grapefruit in the trees and he'd pick out stitches," Berens says. "That was how I grew up."
After receiving degrees from Arizona State University and the University of Arizona, Berens completed his postdoctoral training in oncology at the University of Zurich. In 1990, he was working as a research biologist at the University of California-San Francisco when he was recruited by Barrow Neurological Institute, a division of St. Joseph's Hospital.
"I was sure that I was going to find some things that would make a difference," he says.
Not just any difference, a major difference. Most cancer studies prove our limitations, but Berens wanted to "swing for the fence," and he thought he knew how to do it.
Cancer researchers needed a large-animal model for studying the most deadly form of brain tumor, a gliobastoma. Berens had performed tumor studies in mice, but mouse brains are about a fifth the size of a thimble. Beagle brains are about the size of a small child's, and beagles have a high incidence of naturally occurring brain tumors. But how can you make an animal sprout a gliobastoma tumor on command?
The answer hit Berens while driving down a freeway: He could teach the animal's immune system to accept a tumor, then transplant it into its brain.
The way he figured it, a fetal animal's immune system is the same as its mother's. It accepts her system as its own. Berens thought if he injected cancer cells into a beagle early enough, the developing immune system would not fight the cancer and would allow it to grow -- thus becoming a perfect model for testing new therapies.
It was a clever idea, and Berens was optimistic. He arranged some private funding and, later, was awarded a grant from the National Institutes of Health. He ordered some pregnant beagles (at $2,000 each) from Marshal Farms in New York, a breeder of "purpose-bred animals." He also had a talk with his wife.
"I said, 'Patty, I have this idea, and it involves some animal research, and I'm sure that people will have a hard time with it.' And so she asked, 'Why us? Why can't somebody else do it?'"
There was a real cause for concern. Berens' grant manager at the National Institutes of Health, Dr. Tom Jacobs, says many researchers are reluctant to develop large-animal models. They worry about protesters and the increased level of peer-review scrutiny. One reason the NIH agreed to fund Berens in 1998, despite his history of trouble with this project, was the study's inherent technical and political difficulty -- and inherent promise.
"He's considered a pioneer by his peers and by us," says Jacobs. "He has taken on a formidable challenge of developing an animal model that, until this time, has been extremely difficult and has hampered our understanding of brain tumors."
From the start, there was another issue as well: Berens' protocol is undeniably grim. ASU says the study is at least three on the standardized one-to-four pain scale for animal research.
Though the pregnant dogs can be adopted out, their puppies are another matter.
The puppies that don't get cancer are euthanized.
The puppies that do get cancer are given large doses of chemotherapy and radiation -- then euthanized.
It is not fair to an adopting family, researchers say, if their pet later develops a brain tumor because of the fetal surgery. Also, once an animal is adopted, Berens is not allowed to examine it again. It is now a pet, and researchers, perhaps out of psychological necessity, draw a fine distinction between research animals and pets. To Berens, he is not killing Snoopy.
"Snoopy is a pet," Berens says. "It should be cuddled and loved and played with on the floor with rolled-up socks and those kinds of things. It's a very sensitive thing. Nobody in the United States for the past 15 years does research on pets. The decision was made decades ago that there is such a thing as a pet population and there's such a thing called a 'purpose-bred animal population.' Every animal that we've worked on has been a purpose-bred research animal. They were never bred for purposes of being Snoopy. Is that different? That's hugely different. We're not dealing with the emotionally charged issue of pets."
Less emotionally charged for Berens, perhaps, but certainly not for animal lovers. A dog is a dog. And a dog does not know why it was bred.
Yes, Berens himself has pets. A Shetland sheepdog, but no beagles.
"I can't think of doing an experimental surgical procedure on my pets," he says.
Then what does he think about when injecting cancer into the pups?
"I get one or two phone calls a month from friends of friends whose wife/sister/cousin/uncle has been diagnosed with a brain tumor. So before every procedure, I look my research assistant in the eye and say, 'Last Tuesday I got a call from a 38-year-old mom with two kids who's just been diagnosed. And by all statistics, she won't be here next year. Let's do this as well as we can.'"
And when the experiment does not yield the desirable results, Berens reassembles his staff to try another batch.
"I ask my staff, 'Are you willing to help me try again?' What a horrible question to ask. Everybody wants it to go well, everybody has tremendous tension, everybody has pets."
Berens has received support from BNI, a longtime proponent of animal research studies. In one notable breakthrough, a BNI researcher used baboons to develop a dramatic brain surgery technique called Cardiac Standstill. In that procedure, a patient is chilled and his heart is stopped. The patient lies clinically dead on the operating table for more than 20 minutes, allowing an unprecedented degree of surgical intrusion. Then the patient is resuscitated.
"Yes, 11 baboons died," says Shapiro. "But 89 people have walked out of here totally cured. No one else would touch these people."
Cardiac Standstill was introduced in the early 1990s. About the same time, Berens seemed to be on the verge of a similar success. One of his beagles had produced a tumor. The tumor was transplanted to its brain. And it grew.
Berens was ecstatic. He had proven his model could work.
Then, over the years, the elation turned to frustration. And his short-lived success turned into an animal rights controversy.
Dr. Patricia Haight is at Orbit Restaurant to talk about the beagles. The meeting is for lunch, but she does not eat. Haight is very intent, very determined. Her tremulous voice rises and falls as she practically vibrates with outrage. She quit teaching at Paradise Valley Community College last semester to concentrate full-time on protesting Berens' project, yet objects to being called a "protester," or her efforts being called a "campaign."
"I don't consider this a campaign," she says. "I consider myself a psychologist with some concerns."
Haight has performed animal research studies herself, and says she even worked at BNI as a research assistant some 25 years ago. She does not object to all animal research, she says, just the beagle project. When Haight first heard about Berens' research from a student in her Abnormal Psychology class, she filed a Freedom of Information Act request for more information.
By any standard, the documents she received raise serious concerns.
Only three successful tumors out of 138 puppies in 10 years. Unknown numbers of aborted dogs and birth defects because of trauma suffered during the fetal implant procedure. Admissions by Berens that, because of the difficulty of successfully injecting cancer cells at such an early stage of development, oftentimes it was impossible for him to tell which pups were injected and which were not. And in 1998, BNI's animal labs were cited for a number of noncompliance issues; a Department of Health and Human Services director harshly summarized, "It was the opinion of the site visitors that [Barrow] has placed itself and the research community as a whole at risk by operating in the manner in which it is presently proceeding."
BNI brought itself into compliance with most of the complaints six months later, Haight says, but still . . .
"I'm tired of this," she says. "They should have planned well ahead of time for the possibility that these puppies wouldn't develop tumors. They should have had a control group that was never injected. They never did that. They never thought it through. They should have thought it through!"
And then, there was the criticism from ASU's animal research oversight committee.
ASU received a portion of Berens' $200,000 annual grant to house the beagles. The committee repeatedly urged Berens to change his protocol, and Berens refused. The school veterinarian said the pups were confined in pens for "much longer than is necessary or justified."
One crucial difference between the institutions, say observers on both sides, is that BNI staffers have daily exposure to cancer patients.
"If our dogs were at the University of Arizona, you and I wouldn't be having this conversation," says Shapiro. "Because they have a cancer institute, their thought patterns are different. While ASU has very good animal facilities, and does good animal research work, their questions are different."
ASU's animal oversight chairman, Edward Castañeda, says BNI is willing to "go further" than the university in its use of animals, and he does not think ASU is being too squeamish or setting the bar too high.
"The use of the animals and the basic research, I think, is totally valid," he says. "Now the problem starts when you're not collecting any valid data, then it becomes difficult to justify using the animals. If he had come to us with a proposal to change his approach -- and by that I don't mean so much to improve the success rate as to try to improve the success rate -- we would have been delighted."
To Haight, such infighting simply underscores her belief that there are some serious divisions in the scientific community over the validity of the beagle project. To further illustrate her point, she whips out photos of painful-looking surgical restraints and an autopsied dog.
"You want the bottom line on this? Every night I go to bed and I know that those 22 puppies are at risk. I know that they're going to be killed. We know that there's very little chance that they're going to give them any more information than they got from the rest of the puppies."
The release of the remaining beagles, currently housed in an undisclosed Tucson kennel, is one of the main goals of the anti-Berens contingent. On an animal rights Internet discussion board, Haight described a tour of the beagles' ASU kennels as "like visiting Treblinka or Dachau."
Wanting to see the BNI research labs, and speak with Berens about Haight's concerns, New Times arranged to take a tour of Barrow.
Shapiro says she is a firm believer in freedom of the press, notes that the beagle study is funded by taxpayers and says BNI has "nothing to hide." She gladly arranges a tour of BNI's labs, a tour that plays out like an elementary school filmstrip.
There are spotless labs full of beakers and computers. There are introductory "What Is a Cell?" diagrams on poster board and cancer DNA models. There are researchers in white coats and peeks through microscopes. There's even some scripted patter. ("In this room, you might say we're all working in the dark -- it's a dark room!")
Which is all fine and interesting, but . . . where are the animals? Animal research is the reason we are here, yet the animal kennels and veterinary surgical suite are not part of the tour. The vivarium is downstairs, and, apparently, off limits. Yet Shapiro repeatedly asks if we would like to meet cancer patients, the visceral counterpart to Haight's research-roadkill dog photo.
Later we are told media are not allowed in the vivarium out of concern for "the safety of the animals." This is not quite as bogus as it sounds, but it's close. The potential for animal infection is a genuine concern for researchers, and so are fears of security details being leaked to animal rights activists. Media are allowed on tours at other animal research labs, however. ASU, for instance, allows tours in all but its primate labs.
Even more problematic than being denied access to the one area that's under protest is some of the conflicting information from BNI.
Shapiro insists Berens has patented only his discovery of when beagles become immune tolerant, but records at the U.S. Patent Office show he has actually patented his entire fetal implant procedure. There is nothing illicit about patenting your work, but protesters insist one reason Berens continues his project is to make it commercially viable to sell to pharmaceutical research companies. Berens wholeheartedly denies this, and a BNI media relations representative says Shapiro simply misspoke.
And though Shapiro also comes clean about the study's failure rate -- "Do we have all the answers? Are we perfect? Has this thing been a great success? We're perfectly willing to say no, no and no" -- she stresses that Berens' beagle research can be used for learning about early genetic detection for brain tumors.
Berens himself dismisses this possibility. "Early detection is not where the project is going," he says.
Then where is this project going?
Michael Berens is tall, with white hair and compact glasses. He wears a lab coat to our interview and talks with kindly passion. He's not only a doctor, he could play one on TV. But his warm composure cracks when he talks about animal activists.
"Ascribing the term 'torture' to me is inappropriate," he says. "It's very inaccurate. If you read [protester] literature, everything is the most derogatory, aggressive kind of adjectives, and that's not what I'm like. I'm not a torturer. I'm not cruel. That's wrong, wrong, wrong. I'm compassionate from the get-go."
Berens is initially hesitant to permit an interview, and outright refuses to sit for a photo. Each news story about his research has sparked more death threats, and he has developed a Pavlovian dread of the press.
It should come as no surprise, then, that Berens is not very First Amendment-friendly. He declares that activists should have to go through a peer-review panel before they're allowed to protest, just as he does for his research grants, and at one point says that by interviewing him, New Times has "set back cancer research by several hours."
He retracts that last statement when challenged, but the sentiment feels genuine. Berens is frustrated at having to defend his work. Berens is frustrated with his project. Most of all, Berens is frustrated with being afraid of unseen threats, threats that may or may not be real.
"When you have a reaction in the press about this research, you feel exposed to the last 10 to 15 years of press that talks about [activist violence]," he says. "When I think about my kid walking to school, it scares the hell out of me. Now, how much of [the threat] is real? Well, when you have those feelings, it's real. And how do you get that out of your head?"
Berens' wife is equally concerned, saying her family makes sacrifices to accommodate her husband's quest. "He's trying so hard to find some help for all the suffering," says Patty Berens. "That's why we, as a family, put up with the long hours and missed weekends and canceled vacations."
To gain some industry perspective on Berens' research, we contacted a neurologist, a tumor researcher and representatives of brain tumor associations (Naomi Burkowitz of the American Brain Tumor Association; Robert Tufel of the National Brain Tumor Foundation; Mitchell Berger, chief of neurosurgery at UCSF; and John Henson, executive director of the Brain Tumor Center at Massachusetts General Hospital).
All have heard of Berens and the beagle study. All made a point to mention that Berens has an excellent reputation in the field of tumor research -- save one, who also noted that tumor research on beagles sounded "somewhat unusual." Two knew the specifics of Berens' protocol and affirmed that the research is valid. But both declined to say whether Berens should continue despite his failure rate.
Berens' 10 years of frustration, some pointed out, is not necessarily a long time for a research study. A researcher must take a cool, collected dive at death, inflicting pain to potentially prevent it. Listening to Berens talk about his research, it seems animal rights activists are correct about his past failure driving his current determination to succeed, except they got it backward -- Berens doesn't press on despite the beagles' suffering, he presses on to validate the suffering that he has already caused.
"This is not fun. There is no thrill in this procedure," Berens says. "I wish I could have stopped nine and a half years ago. And I lose sleep over it -- 'Why did that litter abort?' -- and rack my brains and call other people. When things go well, we are excited and grateful. And when things go poorly, we are devastated."
Then why proceed with the same technique that has yielded so few results and so much criticism?
"I feel the next procedure is going to work," he says. "It would be real easy for me if we had been completely unsuccessful, because then I'd say, 'This doesn't work.'"
In a significant new development, Berens' grant manager, Dr. Tom Jacobs, says it's time for Berens to rethink the beagle project. Jacobs notes that funding will cease in April as planned, and predicts that Berens -- who has several ongoing grants and research projects aside from the beagle work -- will quit.
"Once he evaluates all the data, he'll be in a better position to decide what to do," Jacobs says. "He has not applied for additional funding, so the project, as I see it now, will end this spring."
Berens, however, is hopeful that his final batch of data will reinvigorate the project. Laying out a best-case scenario for the future of his work, Berens runs down his hopes:
"Year 2001, we develop a large-animal model for brain tumors. I have some wild, therapeutic ideas that are different than how we traditionally approach cancer therapy. I would like to test them in a large-animal model system for ways to change the behavior of tumor cells to make them much more responsive to therapy -- and I would do that in 2002. And in 2003, we take this to clinical trials. And the audience I need to sell this to is the oncologists . . . [who] will be interested because they know the outcome for these patients.
"That's the scope, and I could be wrong," he says. "Or, I could be something else. And that something else is pretty exciting."
That something else keeps him going, keeps him injecting and euthanizing, focusing on potential outcome rather than past failures. He's getting better, he says. The fetal injection procedure once took 14 hours; now it takes four. He's fine-tuning the lab animals, ordering beagles bred with certain genetic variables that increase his probability for success. Besides, about 40,000 animals are euthanized in Maricopa County every year. They die for no reason. At least his beagles have a chance -- however small -- of contributing to a cure for a lethal disease.
He's on the verge. He's sure of it. Except . . .
"I always feel like this one is going to be the one that's going to have a perfect outcome," he says. "And, of course, that hasn't been the reality."
And when fighting brain cancer, the disease that always seems to win, Berens will not allow that reality to burden him.
"I don't feel the weight of failure," Berens says. "Which amazes me."