Society Needs Regulations to Prevent Research Abuses
A tension exists between scientists/doctors and government regulators.
[Editor's Note: Our Big Moral Question this month is, "Do government regulations help or hurt the goal of responsible and timely scientific innovation?"]
Government regulations help more than hurt the goal of responsible and timely scientific innovation. Opponents might argue that without regulations, researchers would be free to do whatever they want. But without ethics and regulations, scientists have performed horrific experiments. In Nazi concentration camps, for instance, doctors forced prisoners to stay in the snow to see how long it took for these inmates to freeze to death. These researchers also removed prisoner's limbs in order to try to develop innovations to reconnect these body parts, but all the experiments failed.
Researchers in not only industry, but also academia have violated research participants' rights.
Due to these atrocities, after the war, the Nuremberg Tribunal established the first ethical guidelines for research, mandating that all study participants provide informed consent. Yet many researchers, including those in leading U.S. academic institutions and government agencies, failed to follow these dictates. The U.S. government, for instance, secretly infected Guatemalan men with syphilis in order to study the disease and experimented on soldiers, exposing them without consent to biological and chemical warfare agents. In the 1960s, researchers at New York's Willowbrook State School purposefully fed intellectually disabled children infected stool extracts with hepatitis to study the disease. In 1966, in the New England Journal of Medicine, Henry Beecher, a Harvard anesthesiologist, described 22 cases of unethical research published in the nation's leading medical journals, but were mostly conducted without informed consent, and at times harmed participants without offering them any benefit.
Despite heightened awareness and enhanced guidelines, abuses continued. Until a 1974 journalistic exposé, the U.S. government continued to fund the now-notorious Tuskegee syphilis study of infected poor African-American men in rural Alabama, refusing to offer these men penicillin when it became available as effective treatment for the disease.
In response, in 1974 Congress passed the National Research Act, establishing research ethics committees or Institutional Review Boards (IRBs), to guide scientists, allowing them to innovate while protecting study participants' rights. Routinely, IRBs now detect and prevent unethical studies from starting.
Still, even with these regulations, researchers have at times conducted unethical investigations. In 1999 at the Los Angeles Veterans Affairs Hospital, for example, a patient twice refused to participate in a study that would prolong his surgery. The researcher nonetheless proceeded to experiment on him anyway, using an electrical probe in the patient's heart to collect data.
Part of the problem and consequent need for regulations is that researchers have conflicts of interest and often do not recognize ethical challenges their research may pose.
Pharmaceutical company scandals, involving Avandia, and Neurontin and other drugs, raise added concerns. In marketing Vioxx, OxyContin, and tobacco, corporations have hidden findings that might undercut sales.
Regulations become increasingly critical as drug companies and the NIH conduct increasing amounts of research in the developing world. In 1996, Pfizer conducted a study of bacterial meningitis in Nigeria in which 11 children died. The families thus sued. Pfizer produced a Nigerian IRB approval letter, but the letter turned out to have been forged. No Nigerian IRB had ever approved the study. Fourteen years later, Wikileaks revealed that Pfizer had hired detectives to find evidence of corruption against the Nigerian Attorney General, to compel him to drop the lawsuit.
Researchers in not only industry, but also academia have violated research participants' rights. Arizona State University scientists wanted to investigate the genes of a Native American group, the Havasupai, who were concerned about their high rates of diabetes. The investigators also wanted to study the group's rates of schizophrenia, but feared that the tribe would oppose the study, given the stigma. Hence, these researchers decided to mislead the tribe, stating that the study was only about diabetes. The university's research ethics committee knew the scientists' plan to study schizophrenia, but approved the study, including the consent form, which did not mention any psychiatric diagnoses. The Havasupai gave blood samples, but later learned that the researchers published articles about the tribe's schizophrenia and alcoholism, and genetic origins in Asia (while the Havasupai believed they originated in the Grand Canyon, where they now lived, and which they thus argued they owned). A 2010 legal settlement required that the university return the blood samples to the tribe, which then destroyed them. Had the researchers instead worked with the tribe more respectfully, they could have advanced science in many ways.
Part of the problem and consequent need for regulations is that researchers have conflicts of interest and often do not recognize ethical challenges their research may pose.
Such violations threaten to lower public trust in science, particularly among vulnerable groups that have historically been systemically mistreated, diminishing public and government support for research and for the National Institutes of Health, National Science Foundation and Centers for Disease Control, all of which conduct large numbers of studies.
Research that has failed to follow ethics has in fact impeded innovation.
In popular culture, myths of immoral science and technology--from Frankenstein to Big Brother and Dr. Strangelove--loom.
Admittedly, regulations involve inherent tradeoffs. Following certain rules can take time and effort. Certain regulations may in fact limit research that might potentially advance knowledge, but be grossly unethical. For instance, if our society's sole goal was to have scientists innovate as much as possible, we might let them stick needles into healthy people's brains to remove cells in return for cash that many vulnerable poor people might find desirable. But these studies would clearly pose major ethical problems.
Research that has failed to follow ethics has in fact impeded innovation. In 1999, the death of a young man, Jesse Gelsinger, in a gene therapy experiment in which the investigator was subsequently found to have major conflicts of interest, delayed innovations in the field of gene therapy research for years.
Without regulations, companies might market products that prove dangerous, leading to massive lawsuits that could also ultimately stifle further innovation within an industry.
The key question is not whether regulations help or hurt science alone, but whether they help or hurt science that is both "responsible and innovative."
We don't want "over-regulation." Rather, the right amount of regulations is needed – neither too much nor too little. Hence, policy makers in this area have developed regulations in fair and transparent ways and have also been working to reduce the burden on researchers – for instance, by allowing single IRBs to review multi-site studies, rather than having multiple IRBs do so, which can create obstacles.
In sum, society requires a proper balance of regulations to ensure ethical research, avoid abuses, and ultimately aid us all by promoting responsible innovation.
[Ed. Note: Check out the opposite viewpoint here, and follow LeapsMag on social media to share your perspective.]
Researchers Are Discovering How to Predict – and Maybe Treat — Pregnancy Complications Early On.
Katie Love cradles her newborn daughter, born after a bout with preeclampsia.
Katie Love wishes there was some way she could have been prepared. But there was no way to know, early in 2020, that her pregnancy would lead to terrifyingly high blood pressure and multiple hospital visits, ending in induced labor and a 56-hour-long, “nightmare” delivery at 37 weeks. Love, a social media strategist in Pittsburgh, had preeclampsia, a poorly understood and potentially deadly pregnancy complication that affects 1 in 25 pregnant women in the United States. But there was no blood test, no easy diagnostic marker to warn Love that this might happen. Even on her first visit to the emergency room, with sky-high blood pressure, doctors could not be certain preeclampsia was the cause.
In fact, the primary but imperfect indicators for preeclampsia — high blood pressure and protein in the urine — haven’t changed in decades. The Preeclampsia Foundation calls a simple, rapid test to predict or diagnose the condition “a key component needed in the fight.”
Another common pregnancy complication is preterm birth, which affects 1 in 10 U.S. pregnancies, but there are few options to predict that might happen, either.
“The best tool that obstetricians have at the moment is still a tape measure and a blood pressure cuff to diagnose whatever’s happening in your pregnancy,” says Fiona Kaper, a vice president at the DNA-sequencing company Illumina in San Diego.
The hunt for such specific biomarkers is now taking off, at Illumina and elsewhere, as scientists probe maternal blood for signs that could herald pregnancy problems. These same molecules offer clues that might lead to more specific treatments. So far, it’s clear that many complications start with the placenta, the temporary organ that transfers nutrients, oxygen and waste between mother and fetus, and that these problems often start well before symptoms arise. Researchers are using the latest stem-cell technology to better understand the causes of complications and test treatments.
Pressing Need
Obstetricians aren’t flying completely blind; medical history can point to high or low risk for pregnancy complications. But ultimately, “everybody who’s pregnant is at risk for preeclampsia,” says Sarosh Rana, chief of maternal-fetal medicine at University of Chicago Medicine and an advisor to the Preeclampsia Foundation. And the symptoms of the condition include problems like headache and swollen feet that overlap with those of pregnancy in general, complicating diagnoses.
The “holy grail" would be early, first-trimester biomarkers. If obstetricians and expecting parents could know, in the first few months of pregnancy, that preeclampsia is a risk, a pregnant woman could monitor her blood pressure at home and take-low dose aspirin that might stave it off.
There are a couple more direct tests physicians can turn to, but these are imperfect. For preterm labor, fetal fibronectin makes up a sort of glue that keeps the amniotic sac, which cushions the unborn baby, attached to the uterus. If it’s not present near a woman’s cervix, that’s a good indicator that she’s not in labor, and can be safely sent home, says Lauren Demosthenes, an obstetrician and senior medical director of the digital health company Babyscripts in Washington, D.C. But if fibronectin appears, it might or might not indicate preterm labor.
“What we want is a test that gives us a positive predictive [signal],” says Demosthenes. “I want to know, if I get it, is it really going to predict preterm birth, or is it just going to make us worry more and order more tests?” In fact, the fetal fibronectin test hasn’t been shown to improve pregnancy outcomes, and Demosthenes says it’s fallen out of favor in many clinics.
Similarly, there’s a blood test, based on the ratio of the amounts of two different proteins, that can rule out preeclampsia but not confirm it’s happening. It’s approved in many countries, though not the U.S.; studies are still ongoing. A positive test, which means “maybe preeclampsia,” still leaves doctors and parents-to-be facing excruciating decisions: If the mother’s life is in danger, delivering the baby can save her, but even a few more days in the uterus can promote the baby’s health. In Ireland, where the test is available, it’s not getting much use, says Patricia Maguire, director of the University College Dublin Institute for Discovery.
Maguire has identified proteins released by platelets that indicate pregnancy — the “most expensive pregnancy test in the world,” she jokes. She is now testing those markers in women with suspected preeclampsia.
The “holy grail,” says Maguire, would be early, first-trimester biomarkers. If obstetricians and expecting parents could know, in the first few months of pregnancy, that preeclampsia is a risk, a pregnant woman could monitor her blood pressure at home and take-low dose aspirin that might stave it off. Similarly, if a quick blood test indicated that preterm labor could happen, doctors could take further steps such as measuring the cervix and prescribing progesterone if it’s on the short side.
Biomarkers in Blood
It was fatherhood that drew Stephen Quake, a biophysicist at Stanford University in California, to the study of pregnancy biomarkers. His wife, pregnant with their first child in 2001, had a test called amniocentesis. That involves extracting a sample from within the uterus, using a 3–8-inch-long needle, for genetic testing. The test can identify genetic differences, such as Down syndrome, but also carries risks including miscarriage or infection. In this case, mom and baby were fine (Quake’s daughter is now a college student), but he found the diagnostic danger unacceptable.
Seeking a less invasive test, Quake in 2008 reported that there’s enough fetal DNA in the maternal bloodstream to diagnose Down syndrome and other genetic conditions. “Use of amniocentesis has plunged,” he says.
Then, recalling that his daughter was born three and a half weeks before her due date — and that Quake’s own mom claims he was a month late, which makes him think the due date must have been off — he started researching markers that could accurately assess a fetus’ age and predict the timing of labor. In this case, Quake was interested in RNA, not DNA, because it’s a signal of which genes the fetus’, placenta’s, and mother’s tissues are using to create proteins. Specifically, these are RNAs that have exited the cells that made them. Tissues can use such free RNAs as messages, wrapping them in membranous envelopes to travel the bloodstream to other body parts. Dying cells also release fragments containing RNAs. “A lot of information is in there,” says Kaper.
In a small study of 31 healthy pregnant women, published in 2018, Quake and collaborators discovered nine RNAs that could predict gestational age, which indicates due date, just as well as ultrasound. With another set of 38 women, including 13 who delivered early, the researchers discovered seven RNAs that predicted preterm labor up to two months in advance.
Quake notes that an RNA-based blood test is cheaper and more portable than ultrasound, so it might be useful in the developing world. A company he cofounded, Mirvie, Inc., is now analyzing RNA’s predictive value further, in thousands of diverse women. CEO and cofounder Maneesh Jain says that since preterm labor is so poorly understood, they’re sequencing RNAs that represent about 20,000 genes — essentially all the genes humans have — to find the very best biomarkers. “We don’t know enough about this field to guess what it might be,” he says. “We feel we’ve got to cast the net wide.”
Quake, and Mirvie, are now working on biomarkers for preeclampsia. In a recent preprint study, not yet reviewed by other experts, Quake’s Stanford team reported 18 RNAs that, measured before 16 weeks, correctly predicted preeclampsia 56–100% of the time.
Other researchers are taking a similar tack. Kaper’s team at Illumina was able to classify preeclampsia from bloodstream RNAs with 85 to 89% accuracy, though they didn’t attempt to predict it. And Louise Laurent, a maternal-fetal medicine specialist and researcher at the University of California, San Diego (UCSD), has defined several pairs of microRNAs — pint-sized RNAs that regulate other ones — in second-trimester blood samples that predict preeclampsia later on.
Placentas in a Dish
The RNAs that show up in these studies often come from genes used by the placenta. But they’re only signals that something’s wrong, not necessarily the root cause. “There still is not much known about what really causes major complications of pregnancy,” says Laurent.
The challenge is that placental problems likely occur early on, as the organ forms in the first trimester. For example, if the placenta did a poor job of building blood vessels through the uterine lining, it might cause preeclampsia later as the growing fetus tries to access more and more blood through insufficient vessels, leading to high blood pressure in the mother. “Everyone has kind of suspected that that is probably what goes wrong,” says Mana Parast, a pathologist and researcher at UCSD.
To see how a placenta first faltered, “you want to go back in time,” says Parast. It’s only recently become possible to do something akin to that: She and Laurent take cells from the umbilical cord (which is a genetic match for the placenta) at the end of pregnancy, and turn them into stem cells, which can become any kind of cell. They then nudge those stem cells to make new placenta cells in lab dishes. But when the researchers start with cells from an umbilical cord after preeclampsia, they find the stem cells struggle to even form proper placenta cells, or they develop abnormally. So yes, something seems to go wrong right at the beginning. Now, the team plans to use these cell cultures to study the microRNAs that indicate preeclampsia risk, and to look for medications that might reverse the problems, Parast says.
Biomarkers could lead to treatments. For example, one of the proteins that commercial preeclampsia diagnostic kits test for is called soluble Flt-1. It’s a sort of anti-growth factor, explains Rana, that can cause problems with blood vessels and thus high blood pressure. Getting rid of the extra Flt-1, then, might alleviate symptoms and keep the mother safe, giving the baby more time to develop. Indeed, a small trial that filtered this protein from the blood did lower blood pressure, allowing participants to keep their babies inside for a couple of weeks longer, researchers reported in 2011.
For pregnant women like Love, even advance warning would have been beneficial. Laurent and others envision a first-trimester blood test that would use different kinds of biomolecules — RNAs, proteins, whatever works best — to indicate whether a pregnancy is at low, medium, or high risk for common complications.
“I prefer to be prepared,” says Love, now the mother of a healthy little girl. “I just wouldn’t have been so thrown off by the whole thing.”
Dec. 17th Event: The Latest on Omicron, Boosters, and Immunity
The Omicron variant poses new uncertainty for the vaccines, which four leading experts will address during our virtual event on December 17th, 2021.
This virtual event will convene leading scientific and medical experts to discuss the most pressing questions around the new Omicron variant, including what we know so far about its ability to evade COVID-19 vaccines, the role of boosters in eliciting heightened immunity, and the science behind variants and vaccines. A public Q&A will follow the expert discussion.
EVENT INFORMATION:
Date: Friday Dec 17, 2021
2:00pm - 3:30pm EST
Dr. Céline Gounder, MD, ScM, is the CEO/President/Founder of Just Human Productions, a non-profit multimedia organization. She is also the host and producer of American Diagnosis, a podcast on health and social justice, and Epidemic, a podcast about infectious disease epidemics and pandemics. She served on the Biden-Harris Transition COVID-19 Advisory Board.
Dr. Theodora Hatziioannou, Ph.D., is a Research Associate Professor in the Laboratory of Retrovirology at The Rockefeller University. Her research includes identifying plasma samples from recovered COVID-19 patients that contain antibodies capable of neutralizing the SARS-CoV-2 coronavirus.
Dr. Onyema Ogbuagu, MBBCh, is an Associate Professor at Yale School of Medicine and an infectious disease specialist who treats COVID-19 patients and leads Yale’s clinical studies around COVID-19. He ran Yale’s trial of the Pfizer/BioNTech vaccine.
Dr. Eric Topol, M.D., is a cardiologist, scientist, professor of molecular medicine, and the director and founder of Scripps Research Translational Institute. He has led clinical trials in over 40 countries with over 200,000 patients and pioneered the development of many routinely used medications.
This event is the fourth of a four-part series co-hosted by Leaps.org, the Aspen Institute Science & Society Program, and the Sabin–Aspen Vaccine Science & Policy Group, with generous support from the Gordon and Betty Moore Foundation and the Howard Hughes Medical Institute.
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.