In the wake of news last month that researchers had created a version of the deadly bird flu that was easily transmissible by air, a heated debate has arisen in the scientific community about whether or not the research should be published. But some experts are taking the discussion a step further back, and wondering why the research was conducted at all.

“Why should our tax dollars be used to create new pandemic pathogens?” said Richard Ebright, a chemical biologist at Rutgers University.

The bird flu breakthrough came from two separate groups, one at Erasmus University in the Netherlands and another at the University of Wisconsin, Madison, who successfully converted H5N1 into a form that can be transmitted between ferrets in droplets through the air. Soon after, the National Science Advisory Board for Biosecurity, an advisory group to the US government, took the unusual step of asking Science magazine to censor specific details of the methodology.

But many scientists and security experts are questioning the value of such research and wonder whether stepping in at the publication stage is simply too late.

In the era of Wikileaks and the ease of posting things on the Internet, it’s unlikely that simply excluding the data from Science or Nature will keep the details under wraps for long, said Randall Larsen, who was the executive director of the Congressional Commission on the Prevention of Weapons of Mass Destruction Proliferation and Terrorism.

By the time the research gets to publication, “the genie’s already out of the bottle,” he said.

The risks

The argument that such research should be conducted but not published stems from the chance, however remote, that groups with malicious intent could deduce how to make a deadly biological weapon. Many countries have biological weapons programs, for example, which are developing deadly pathogens, Larsen said. When the Soviet Union collapsed, Sergei Popov, one of the heads of the country’s genetic weapons program defected. While debriefing Popov, Larsen learned that the Soviet Union had active programs to weaponize Legionnaire’s disease, Ebola, smallpox, and HIV.

And now, with biotechnology continuing to advance, even a small, but determined terrorist group or an apocalyptic cult could conceivably generate a weaponized pathogen that was capable of doing great damage, he added.

Ebola virionsWikimedia Commons, PLoS

But some scientists say the biggest problem isn’t the risk of a terrorist group using an engineered pathogen as a weapon, but simply the existence of such pathogens. A likelier scenario, said Ebright, is that a disgruntled or unhinged employee may voluntarily release small pox or Ebola, as the FBI says occurred in the 2001 anthrax scares.

Another fear is the possibility of accidental release. Not every country that could acquire these pathogens will follow robust safety protocols and rigorous oversight, said D. A. Henderson, an epidemiologist and physician who headed the effort to eradicate smallpox. And while the World Health Organization issues guidelines for pathogen security, each country must decide for themselves how to regulate such research, said WHO spokesperson Gregory Hartl.

Henderson suspects influenza has escaped the lab at least once before. In 1977, a flu epidemic in Russia was largely identical to the 1950 strain, and likely originated in a research lab in China or Russia, he said. “The details of it are still mysterious, but all of a sudden we had a virus which we hadn’t seen for quite a number of years, which began causing real major epidemics. So far as we can make out it’s identical to one that had been in the laboratory.”

Misguided benefits?

If the real problem is mere existence of engineered pathogens in the first place, why is the research being conducted at all, and why are organizations like the National Institutes of Health funding it? The NIH funded the bird flu research and the US government funds much of the world’s bio-defense research.

The rationale behind such funding is, of course, the exploration of virulence for the purpose of developing countermeasures to these pathogens, such as vaccine and treatments. “The argument is that knowing what can be done provides help in planning,” Ebright said. But research to make flu, Ebola, or smallpox deadlier or more infectious will likely not help in combating the spread of such diseases, he added.

Viruses can evolve different mutations than those created in the lab, agreed Henderson, and the real bottleneck in preventing casualties is a slow and outdated system of developing vaccines. For instance, the United States uses the same method to develop flu vaccines as it did 50 years ago, which takes 2 weeks to produce a vaccine even when the potential mutations a pathogen harbors are known, Henderson said. And even if our vaccine manufacturing capabilities increase, there aren’t surveillance systems in place that could catch early signs of a pandemic before it had spread, he added.

Not all scientists think that research on pathogen virulence should be tabled, however. It depends on the pathogen being studied and the research being conducted, said microbiologist and infectious disease specialist David Relman, who was part of the working group which recommended censoring the bird flu data.

But one thing that most scientists can agree on is the need for a more thorough and standardized oversight process to ensure that the risks of pathogen research don’t outweigh the benefits. Some types of research may merit increased oversight, but which projects should qualify remains a point of contention, Relman said. “We need to come to a mutually agreed upon process for deciding what work even deserves this type of more careful scrutiny.”

Clarification: This story has been updated to clarify that the University of Wisconsin researchers who made H5N1 transmissible among ferrets never made an official announcement of the results.

Earlier this month, celebrity chef Paula Deen announced that she has adult-onset or type 2 diabetes, then accepted a multimillion dollar deal to promote Novo Nordisk’s type 2 diabetes drug, Victoza. Before there was Paula Deen, there was figure skater Dorothy Hamill and actor Wilford Brimley. Indeed, there has been a long line of celebrity spokespeople for pharmaceutical companies, and their track record thus far has been quite poor in terms of honesty, openness, and promoting the public’s health.

Middle-aged arthritis sufferers flocked to their doctors demanding Vioxx for pain relief after watching Hamill figure skate in TV ads touting the drug shortly into the new millennium. We now have evidence that Vioxx caused as many as 140,000 extra cases of serious heart disease in the United States during the years that its maker concealed evidence of its risks, and it was withdrawn from the US market in 2004.

All right, you say, Hamill was paid to shill for a dangerous drug. But what could be wrong with Brimley telling diabetics to check their blood sugar?

There is one group of patients with type 2 diabetes, the most common form of the disease, who need to check their sugar levels frequently and who really need those cute little machines. Those are also those (apparently including Brimley) who take insulin shots. But the majority of type 2 diabetes folks take only oral medicines or use diet and exercise to regulate their blood sugar. From those ubiquitous TV ads in the late 1990s and early 2000s, however, you’d guess that scientific studies show great health advantages to religiously using home glucose monitors.

Funny thing, though. The available research shows overwhelmingly that there’s no known health benefit to home glucose monitoring for people not on insulin. A number of large studies on improving outcomes and death rates in diabetes show consistently that tight blood sugar control is not where the action is. Rather, type 2 diabetes tends to strike through severe complications like heart attacks, strokes, kidney failure, and other diseases that basically are caused by diabetes’ effects on both large and small blood vessels. Doing things to protect yourself from those diseases—diet, exercise, stopping smoking, controlling blood pressure, and so on—improves and lengthens life in diabetics. Lowering blood sugar by itself hardly helps at all.

Don’t hold your breath waiting for highly-paid celebrity spokespersons to tell you these important medical facts on TV. And the reason they won’t is part of why the whole system of celebrities touting drugs and medical devices is unfortunate for public health. These ads don’t just sell us products. They sell us ways to think about disease. And the industry wants to be sure that the way we think about a disease is whatever way is best for pushing their sales and profits.

Physician and historian Jeremy Greene wrote about this a few years ago. He showed how the pharmaceutical industry jumped onto the preventive medicine bandwagon to convince both doctors and the rest of us to “prescribe by the numbers”—not to ask what drugs actually lengthened life or improved quality, but simply to be happy when a lab test result, such as blood sugar or cholesterol, was high and a drug made it go lower. It turns out that it’s much easier to discover and market a drug that makes your lab values look prettier than it is to find drugs that really save lives and prevent heart attacks. But most of us simply assume that lower lab numbers mean less risk and a healthier future—a connection that medical research informs us is often missing. (A great book on this frequent lack of connection is Overdiagnosed  by W. Gilbert Welch.)

Now, at this point I have to add the usual disclaimer, and then a disclaimer on the disclaimer. The disclaimer is that you should treat your medical condition based on your doctor’s advice and not what you read on a blog or news outlet. If you have diabetes, for instance, find a physician that you trust and follow that physician’s advice, though you should also ask questions and feel free to do your own research.

But here’s disclaimer squared: when a drug or device company markets products to you with a celebrity spokesperson, you can be sure that the same marketing, probably on steroids, is going on behind the scenes in doctors’ offices and hospital corridors. When at least 84 percent of American doctors regularly rely on industry salespeople for critical information about drugs, the “prescribe by the numbers” message is just as ingrained in their thinking as it is in the general public’s. (The celebrities that drug companies use to brainwash doctors are not the Wilford Brimleys of the world, but rather distinguished medical school faculty physicians who happily take company money to serve on their speakers’ bureaus and to push the company marketing message.)

So, bottom line: is there something especially bad about any single celebrity deciding to shill for a particular drug or medical device, like Paula Deen telling us to eat cheeseburgers and also take good care of our diabetes? Maybe yes, maybe no. Is there a problem with how these products are marketed in the United States today? Absolutely.

Howard Brody is a family physician and medical ethicist and directs the Institute for the Medical Humanities at the University of Texas Medical Branch in Galveston. He maintains a blog on the ethics of the relationship between the medical profession and the pharmaceutical industry.

After the pioneering stem cell company Geron, which launched the first-ever clinical trial for a human embryonic stem cell (hESC) therapy in 2010, shuttered its stem cell program last November for financial reasons, a shadow fell over the field of stem cell medicine. But yesterday, optimism rose as the stem cell research company Advanced Cell Technology (ACT) published in The Lancet preliminary data from two human patients, each with a different degenerative eye disorder, showing safety and perhaps even some efficacy of an hESC treatment.

“This is a milestone that will offer tremendous encouragement to the field, and promises hope for many families,” said George Daley, director of the stem cell transplantation program at Children’s Hospital Boston who was not involved in the research, in an email to The Scientist. “But these are still very early days of an uncontrolled and unblinded trial, and we have much more to learn about the safety and effectiveness of this new treatment before we can claim success.”

ACT currently has two clinical trials in the US to study hESC therapies underway, and both are treating degenerative eye disorders. Dry age-related macular degeneration and Stargardt’s macular dystrophy, the former affecting older adults and the latter a genetic disorder affecting children, both lead to blindness and originate from the breakdown of a one-cell-thick protective layer under the retina called the retinal pigment epithelium (RPE).

Replacing this RPE with a fresh layer of stem cells to halt disease progression was the goal of ACT’s Chief Scientific Officer Robert Lanza and his colleagues from the Jules Stein Eye Institute at the University of California, Los Angeles. They induced hESCs into early-stage bone and nervous tissue cells, which then differentiated into retinal epithelial cells with more than 99 percent purity. Around 50,000 of these dissociated cells were injected under the retina of two patients, the first from each trial: a woman in her 70s with dry age-related macular degeneration, and a middle-aged woman with Stargardt’s, both of whom were legally blind.

After 4 months, the researchers observed that the RPE had been replaced physically, and asked the women to perform some basic tests such as reading an eye chart to measure their vision. “There was structural evidence to confirm that cells were able to survive and persist throughout the study, and measureable improvement in their vision,” Lanza said. Regarding the visual improvement, he noted that “there could be some placebo component, but clearly there’s a biological component as well.”

Lanza will begin treating more patients in the coming weeks, for a total of 12 per early-stage trial, and treated the first patient in a similar European trial last week.

A strategic eye

Teratomas with three differentiated layers from stem cells visible. Wikimedia Commons

Though the results are promising so far, there are still many challenges ahead for the stem cell community because the eye, in many ways, is an alluring testing ground for stem cell therapy. Most obviously, the eye is easily accessible and visible, and thus “can be operated on very easily” compared to internal organs in case anything goes wrong, said Sheng Ding, a stem cell biologist at the Gladstone Institutes who was not involved in the study. The eye is also an immune-privileged site in the body, along with parts of the brain and central nervous system. Few pathogens troll the brain, said Ding, so the immune system has little presence in the area and doesn’t cross the blood-brain barrier from the body to the eyes and brain. This makes immune system rejection, the Achilles’ heel of most hESC therapies and organ transplants, a non-issue, and the first two patients in the ACT trials were taken off of preemptive immunosuppressant drugs after just 6 weeks.

Working with the eye also evades another major risk of stem cell therapy: tumor formation. Tumors can form if undifferentiated stem cells are accidentally injected into a patient along with the derived cells of interest, and then differentiate within the body to form a small tumor resembling malformed tissue called a teratoma. Most stem cell therapies require tens or hundreds of millions of cells to be injected into the body, said Ding, increasing the chances that a few undifferentiated cells could sneak through quality control and turn cancerous. But because replacing the retinal epithelium only requires 50,000 cells, the risk of teratoma formation decreases significantly. Just to be sure, however, ACT does employ an assay that can detect one undifferentiated cell in a million, said Lanza.

But these two patients still need continued surveillance for teratoma formation, argued Ding. If just a few undifferentiated stem cells are injected, “you may not see [an effect] at all, or you may be able to see it over a much longer period of time,” he said. The 4-month follow-up received by the trial patients thus far is “very short in this regard, and I think the patients need a much, much longer-term follow up to make sure there’s no tumor cells.”

But Lanza is hopeful that the news, however preliminary, will provide the stem cell field the boost it needs after losing the Geron trial. The trials in the eye “definitely pave the way for other pluripotent stem cell therapies,” he said. “The fact that these pluripotent stem cells can be differentiated, go into the eye, and behave well—knock on wood—has significance for the entire field.”

The current breast implant scandal in Europe has nothing to do with celebrity news. On December 23, the French Agency for the Safety of Health Products recommended that more than 30,000 French women with silicone-filled breast implants made by the medical device company Poly Implant Prothese have them removed because more than 10 percent ruptured within a year of surgery, releasing the implants’ contents into the body.

To make matters worse, these particular implants are filled with industrial-grade silicone, instead of medical-grade, which could contain unregulated and dangerous chemicals.

“They used industrial grade silicone; I cannot believe this,” said polymer chemist Judit Puskas from the University of Akron, who is developing new implant materials. “You have all kinds of additives in there that are carcinogenic.”

Breast implants are composed of a silicone sac that contains silicone or saline gel, and the silicone sacs of the PIP implants are weaker than normal, leading to rupture. In this case, the implants were filled with silicone that has not passed regulatory approval and was intended to waterproof bricks: not exactly a material doctors want circulating in women’s bodies.

After an implant ruptures, the silicone filling slowly seeps into the body’s tissues, bloodstream, and lymphatic system. The French health agency has confirmed that the leaked silicone from PIP implants causes generalized pain and irritation, and that the material can be identified in lymph nodes with an ultrasound. Fortunately, preliminary animal studies showed no evidence of higher DNA mutation rates as a result of rupture.

But all breast implants come with risks: within 10 years, up to 30 percent of patients have their implants removed or replaced, according to the US Food and Drug Administration’s (FDA) 2011 silicone breast implant report. Part of the reason is just standard wear and tear, said Malcolm Roth, American Society of Plastic Surgeons president and chief of plastic surgery at Albany Medical Center.  “Patients shouldn’t think of these as lifelong devices.”

Silicone gel-filled implants. FDA, WIkimedia Commons

Most of the time, rupture simply results in the slow leakage of harmless silicone or saline. “If it’s medical grade silicone that’s been scrutinized by the FDA, and the company is doing what it’s supposed to do, it does not appear to be a health risk,” said Roth. “It sounds horrible, but you might never even know that there’s a leak.” Occasionally, however, women can experience pain and irritation following rupture, and require surgical removal of the implants. Others, if they are aware of the rupture, simply opt for surgery to rid their body of the deflated silicone sac.

Another concern is capsular contracture, which occurs when the body recognizes the implant as a foreign body and constructs a collagen shell around it. Sometimes these collagen shells remain pliable and go unnoticed, but in up to 20 percent of women with implants, they can harden and squeeze the implant, causing discomfort, disfiguration, and rupture.

“It’s essentially like a thickened sort of scar that forms around the implant that subsequently causes pain, distortion of the shape of the breast, to the point where the implant actually moves,” said Anand Deva, head of plastic surgery at Liverpool Hospital in Australia. “What was before a soft and palpable implant becomes like a hard rock.”

Additionally, the FDA released a report last year suggesting that breast implants cause a small increased risk of a rare cancer called anaplastic large cell lymphoma (ALCL), although researchers don’t know why. “The risk of contracting lymphoma in the breast in the normal population is one in a million, and that risk goes up minutely with an implant—but still goes up,” said Deva. Indeed, there have been eight cases of the disease reported in women with the PIP implants, but there’s no indication that rate is higher than seen in other types of implants. “It’s a rare cancer that occurs perhaps slightly more frequently with certain types of implants,” Deva said, “but it’s a bit sensationalist.”

Researchers not happy with the current 30 percent failure rate of implants are working to find something better. Puskas has developed a non-silicone-based polymer that she hopes will result in fewer adverse reactions and fewer reoperations. “I don’t know any other medical devices that are approved with this high of a failure rate,” she said.

And the San Diego, California-based biotech company Cytori is seeding women’s breasts with fat and stem cells to try and regrow breasts after a mastectomy. To do this, they harvest a patient’s abdominal fat using liposuction, and inject the fat cells and stem cells found in fat into the breast. The stem cells don’t turn into breast tissue; rather, the fat cells fill up the space leftover from a mastectomy and the stem cells generate blood vessels to sustain the new tissue. The company released safety data from a 71-person trial of former breast cancer patients last March, but they have no other active trials registered with the US National Institutes of Health.

1. Abel N Kho1,
2. M Geoffrey Hayes1,
3. Laura Rasmussen-Torvik1,
4. Jennifer A Pacheco1,
5. William K Thompson1,
6. Loren L Armstrong1,
7. Joshua C Denny2,
8. Peggy L Peissig3,
9. Aaron W Miller3,
10. Wei-Qi Wei4,
11. Suzette J Bielinski4,
12. Christopher G Chute4,
13. Cynthia L Leibson4,
14. Gail P Jarvik5,
15. David R Crosslin5,
16. Christopher S Carlson6,
17. Katherine M Newton7,
18. Wendy A Wolf8,
19. Rex L Chisholm1,
20. William L Lowe1

+ Author Affiliations

1. 
   
   ¹Northwestern University, Chicago, Illinois, USA
2. 
   
   ²Vanderbilt University, Nashville, Tennessee, USA
3. 
   
   ³Marshield Clinic, Marshfield, Wisconsin, USA
4. 
   
   ⁴Mayo Clinic, Rochester, Minnesota, USA
5. 
   
   ⁵University of Washington Seattle, Seattle, Washington, USA
6. 
   
   ⁶Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
7. 
   
   ⁷Group Health Cooperative, Seattle, Washington, USA
8. 
   
   ⁸Division of Genetics, Children’s Hospital Boston, Boston, Massachusetts, USA

1. Correspondence to Abel N Kho, Northwestern University, Division of General Internal Medicine, 750 N. Lake Shore Drive, 10th Floor, Chicago, IL 60611, USA; abel.kho@nmff.org

1. Contributors ANK developed the algorithm, collected and analyzed data, performed chart reviews, and wrote the manuscript. MGH conducted genetic analyses, and wrote the manuscript. LRT conducted genetic analyses, and reviewed and edited the manuscript. JAP collected and analyzed data, and wrote the manuscript. WKT created the standardized data and workflow within KNIME. LLA conducted genetic analyses. JCD collected data, performed chart reviews and reviewed and edited the manuscript. PLP collected and analyzed data and reviewed and edited the manuscript. AWM collected and analyzed data. WQW collected and analyzed data and reviewed and edited the manuscript. SJB collected and analyzed data. CGC reviewed and edited the manuscript. CLL collected and analyzed data. GPJ collected and analyzed data. DRC performed genetic analyses. CSC collected and analyzed data. KMN reviewed and edited the manuscript. WAW reviewed and edited the manuscript, RLC reviewed and edited the manuscript. WLL developed the algorithm and wrote the manuscript.

• Received 22 June 2011
• Accepted 27 October 2011
• Published Online First 19 November 2011

Abstract