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  • What would you do? Neuroethics sheds light on our darkest dilemmas
    When machines and brains mix, who's in charge? This is the type of problem pondered by neuroethicists such as UAB's Josh May, Ph.D., who examine questions at the crossroads of neuroscience and ethics.

    Think about this: A 59-year-old Dutch man with advanced Parkinson’s disease is experiencing debilitating tremors. His doctors implant electrodes deep in his brain, which counteract the faulty signals but cause new troubles. The man starts behaving erratically, making grandiose claims, racking up sizable debts and generally making poor decisions. His doctors adjust the stimulation settings, and even prescribe mood stabilizing drugs, but they don’t help. Eventually, he has to make a choice: Stop the stimulation and be admitted to a nursing home, or keep it and be confined to a psychiatric ward.

    This real-life dilemma, pulled from the pages of a Dutch medical journal, illustrates the ethical quandaries that arise from new mind-altering technologies such as deep-brain stimulation, says Josh May, Ph.D., an assistant professor in the UAB College of Arts and Sciences Department of Philosophy.

    “The patient chose mental disorder over physical impairment,” said May. “But does a manic state limit one’s decisional capacity? Must we make sure his decision is made when he is suffering from the symptoms of Parkinson’s, free from an overactive mind prone to reckless behavior and delusions of grandiosity?”

    These are the kinds of questions you’ll find at the crossroads of neuroscience and ethics, in a new field known as neuroethics. “Neuroscience attempts to understand and manipulate the brain, which is still largely a mystery,” May said. “That makes the ethics of its research especially tricky and fascinating. And it makes the results directly relevant to ethics itself, especially perennial questions about what drives moral and immoral action, how we think about morality, and whether we’re really in control of our actions.”

    Brain scans are being used to advance longstanding arguments about ethical theories, for example. And researchers — May included — are taking advantage of the reach of the Internet to investigate ethical dilemmas in entirely new ways.

    What follows is an edited version of an email conversation with Dr. May.

    How are technologies like functional MRI being used to shape ethical debates?

    Josh MayOne famous example involves a philosopher-turned-neuroscientist at Harvard University, Josh Greene. He argues that neuroimaging can help prove utilitarianism — the ethical theory that we should always and only maximize happiness for the greatest number of people. This means that sometimes the ends justify the means, even if the means to the greater good are the most horrific acts you can imagine.

    Greene argues that our brains generate intuitions that conflict with utilitarianism, but these are the parts of our brains that involve automatic, emotionally driven processes that aren’t suited for today’s moral dilemmas, like euthanasia, global poverty, climate change, animal rights and health care reform.

    Greene wants us to trust the utilitarian intuitions we have, which he argues arise from areas of the brain developed later in evolution, that are more characteristic of our ability to think carefully and override emotional responses. For example, people tend to think it’s immoral to push a large man off of a bridge so that his body stops a train from hitting five other innocent people (assuming only his body could stop the train). Greene says, don’t trust that response! Act for the greater good and push that man! Trust the part of your brain that can override that automatic response and do the cold calculation.

    What do you think about this argument?

    This research is fascinating and certainly adding to our knowledge of how our moral brains work. But I do have several worries about the ethical conclusions Greene draws. For example, the brain’s automatic, emotional responses are not clearly untrustworthy, as evidence suggests they’re quite flexible and subconsciously shaped by rational thought. While Greene argues such responses aren’t equipped to resolve complex contemporary moral problems, they may provide a shared moral framework that is precisely suited to resolving moral disputes. After all, if these intuitions are so engrained in the brain, then they may provide a kind of common moral currency.

    In general, I think research on moral judgment is revealing that principles are more important to moral thinking than emotions, even for automatic responses. We certainly have biases, and emotions have their role, but morality involves complex social information and norms that we seem to tacitly navigate. Our automatic moral intuitions shouldn’t so easily be tossed aside, even if they conflict with utilitarianism, as they are guided by sophisticated information processing that is suited to rational social interaction.

    So how do you do your research, given that it crosses disciplinary boundaries?

    Philosophical research involves a lot of thinking for sure, as you have to consider arguments, objections, etc. Most of my research time is probably devoted to reading — hours upon hours of painstaking reading. Especially since my work straddles multiple disciplines, there’s always plenty to keep up on. Each article or chapter can take hours to read carefully, and I bet I read about 50 to 100 per year. While the reading is usually interesting, the writing is very poor and far from leisurely. The same goes for writing and revising my own papers. For me at least, a lot of my research ultimately involves thinking; but it’s often done while reading, writing or talking with other academics, although some of it does happen when I’m driving, cooking, watching a show, etc. I personally find it difficult to sit in silence for very long just thinking with my chin on my fist!

    I do sometimes conduct my own experiments, which requires design, ethics approval, etc. But a large part requires assessing the results, reading about other research, formulating arguments, assessing objections and writing it all up — a whole lot of thinking beyond just data gathering!

    And you’ve been doing some interesting experiments using Amazon’s Mechanical Turk service?

    I’ve been using MTurk for several years now. It allows me to quickly gather responses from a diverse group of people online, instead of doing paper-and-pencil surveys around campus. Often the studies I do involve variations on the famous trolley problem, which pits promoting the greater good against violating people’s bodily rights.

    For example, I’ll present participants with a version of a hypothetical scenario and ask them to provide their moral opinion about it — Did the person act wrongly? Then I compare the responses across scenarios that vary slightly in different respects, e.g., in whether the harm was brought about actively or passively, as a means to a goal or as an unintended side effect. Statistical analysis can tell us whether the differences are significant — providing evidence about whether the variable had a causal impact on responses. This technique — standard in so-called “experimental philosophy” — can help reveal the underlying distinctions and principles we make in moral judgment. I’ve followed a growing trend suggesting that our automatic intuitions are often in conflict with the prescriptions of utilitarianism, but I suggest that these intuitions aren’t necessarily due to factors that are morally irrelevant and so shouldn’t necessarily be rejected.

    How might these issues affect everyday moral problems?

    Here’s a medical example. Many people think a doctor shouldn’t help end a terminal patient’s life as a way to halt their immense suffering. That’s illegal in most states. But we don’t have such a problem with a doctor’s administering heavy doses of morphine to treat severe pain, even if she and the patient know it will hasten death. The patient’s death is then merely a foreseen and unintended side effect. Is this a quirk about euthanasia, or do we systematically treat harming as a mere side effect as more acceptable than harming as means?

    I’m currently working on a series of studies that involve presenting participants with hypothetical cases in different contexts to see if their judgments change just based on the difference in how the harm was brought about. I hope this will inform whether the distinction is a viable one.

    I understand you’ve been introducing UAB students to neuroethics with a course first offered this past spring?

    It was a seminar, offered at the 200 and 400 levels, serving as a capstone for the Philosophy major. It was a blast! I had some excellent students, some of whom had backgrounds in neuroscience. Mike Sloane, the director of the University Honors Program, sat in as well, and he added some great insights from his discipline (psychology).

    We covered a wide range of questions, including: Can the results of a brain scan constitute self-incrimination (thus violating the Fifth Amendment)? Does subconscious neural activity determine our behavior prior to conscious awareness? Is someone responsible for a criminal act if it was the result of a brain tumor? Do psychopaths have such an impaired understanding of morality that they can’t be liable for criminal acts? Which areas of the brain are responsible for moral thought and action? Is there something wrong with making oneself a better person by altering one’s brain directly (e.g., via pills or deep brain stimulation)? Can altering one’s brain yield a fundamentally different person? How does this affect consenting to brain interventions?

    I’m hoping to cover similar topics in a future seminar, but perhaps down the line this could become a more regular offering.

  • UAB Hospital ranked nation’s third-largest public hospital by Becker’s Hospital Review
    Becker’s Hospital Review lists UAB Hospital as third-largest in the nation.

    UAB Hospital is the third-largest public hospital in the nation, according to a survey by Becker’s Hospital Review. UAB’s 1,134 beds trails only Jackson Memorial Hospital in Miami and Memorial Hermann Southwest Hospital in Houston.

    According to the Becker’s website, the hospital bed counts reported include all medical/surgical and special care beds in children’s, critical access and acute care facilities under governmental control, as reported to the Center for Medicare Services by the hospitals in their most recent cost reports.

    Becker’s Hospital Review, the flagship publication of Becker’s Healthcare, a leading source of business and legal information for the health care industry, has also listed UAB Hospital as one of the “100 Great Hospitals in America” and named UAB Medicine as “One of the 150 Great Places to Work in Healthcare” for 2015, designations also received in 2014.

  • A novel toxin – and the first ever found – for a deadly pathogen, M. tuberculosis
    Until now, no toxin had been found in 132 years of study for the deadly pathogen Mycobacterium tuberculosis, which infects 9 million people a year and kills more than 1 million. The novel toxin induces necrotic cell death of macrophages to help the tuberculosis pathogen escape and spread to other cells.

    Despite 132 years of study, no toxin had ever been found for the deadly pathogen Mycobacterium tuberculosis, which infects 9 million people a year and kills more than 1 million.

    Now, Michael Niederweis, Ph.D., professor of microbiology at the University of Alabama at Birmingham, and colleagues have described the first known toxin of this pathogenic bacterium. This toxin — Tuberculosis Necrotizing Toxin, or TNT — is the founding member of a novel class of previously unrecognized toxins present in 246 bacterial and fungal species, as determined by protein sequence similarity. Before the Niederweis discovery, those toxins were identified only as the “Domain of Unknown Function 4237.”

    Bacteria with those newly recognized toxins include Yersinia pestis, the pathogen that caused the bubonic plague known as the Black Death in Medieval Europe, and Listeria monocytogenes, one of the most virulent and deadly food-borne infections and the cause of Blue Bell Creameries recalls this year.

    The lack of an identified toxin in M. tuberculosis had contrasted with nearly all other pathogenic bacteria whose toxins contribute to illness or death.

    M. tuberculosis is notable for its survival inside macrophages, the immune cells that ingest and destroy infectious bacteria. The newly identified TNT, Niederweis says, plays a key role to induce necrotic death of the infected macrophage. Thus, TNT enables the M. tuberculosis bacteria to escape from the macrophage and disseminate to other host cells in a person infected with tuberculosis, thus contributing to the survival of M. tuberculosis and spreading the disease.

    “The battle between M. tuberculosis and the human immune system to control the fate of infected macrophages is critical in determining the outcome of the infection,” Niederweis wrote in the TNT paper. “The control of host cell death is of utmost importance for the survival, escape and dissemination of M. tuberculosis.”

    The paper, “The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD,” was published online Aug. 3 in Nature Structural & Molecular Biology.

    How did this toxin evade discovery for more than a century? First, it is produced in very small quantities — the Niederweis lab could detect it only in a cell culture filtrate that was concentrated 1,000-fold, equivalent to concentrating a gallon of milk to about one-third of a teaspoon. Second, the toxin is deadly only when it is inside the host-cell cytosol; if the toxin is in the bloodstream or is added to the culture medium of in vitro host cells, it has no effect. Third, the toxin has no similarities to any other known toxin.

    Niederweis discovered TNT while searching for something completely different. He was hunting for outer-membrane proteins that can act as a door to let nutrients outside the bacteria pass through the extremely impermeable, outer-membrane barrier of M. tuberculosis. The Niederweis group thought they had found such a porin protein; but it had an unusual property — the end portion of the protein broke off after the pore formed in the outer membrane, and that end portion was extremely toxic, both in simple prokaryotic cells like bacteria and in the more complex eukaryotic cells of yeast, mammals and fish. In a paper published in Proceedings of the National Academy of Sciences in 2014, Niederweis said this discovery “challenges the paradigm that M. tuberculosis is one of few bacterial pathogens that does not produce toxins.”

    Credit: Mathew Schwartz (Advanced Institutes of Convergence Technology, SNU)The current paper fully establishes this new paradigm by identifying the mechanism of TNT-induced necrotic cell death at the functional and structural levels. Like an optical illusion where at first one sees a vase, and it then appears to be two faces peering at each other, Niederweis initially he believed he had found an outer-membrane porin that lets nutrients in and carried an artefact. Now he sees the pore part of that protein as a bacterial autotransporter (similar to those seen in other bacteria) that has the mission of exporting its TNT protein cargo to the outside of the outer membrane. After that export is done, the transporter pore remains in the outer membrane.

    The similarity of the TNT gene to DNA sequences in 246 other bacterial and fungal strains will enable research on how this novel class of toxins may function in other pathogens, especially in microorganisms that depend on induction of necrosis to survive or spread.

    Here are some details of TNT:

    1. In a laborious search for the molecular function of TNT, Jim Sun, Ph.D., a postdoc in the Niederweis lab, found that TNT hydrolyzes the essential co-enzyme nicotinamide adenine dinucleotide (NAD+). This explains why it kills every type of cell it is cloned into, because NAD+ is necessary for the cell’s normal metabolism. Researchers were able to clone the TNT gene only by placing it next to an inducible promoter that tightly represses transcription until induced. The TNT enzyme hydrolyzes NAD+ inside of cells and in vitro. It is blocked by antibodies against TNT, and specific TNT point mutations that eliminate all enzymatic activity.
    2. That noncatalytic TNT mutant is not able to kill macrophages, showing that the hydrolase activity is required for TNT-induced cell death.
    3. If TNT were produced inside M. tuberculosis, it would kill the cell. Niederweis and colleagues found that M. tuberculosis, similar to the bacterial pathogen Streptococcus pyogenes, produces an antitoxin to its toxin. The TNT antitoxin binds to the toxin and blocks its hydrolase activity, thus making it harmless inside the bacteria. The researchers have named the antitoxin immunity factor for TNT (IFT).
    4. Cloning the genes for both TNT and IFT into E. coli, where IFT protects the bacteria from death, allowed the researchers to produce milligram quantities of TNT and IFT. In a collaborative effort, Gino Cingolani, Ph.D., an associate professor from the Thomas Jefferson University, produced crystals of the purified protein complex and determined its molecular structure to an astonishing resolution of 1.1 Å in a matter of weeks. The TNT molecule is shaped like a grasping hand, with fingers on one side and an extended thumb on the other. The IFT fits into the TNT like a ball held in a hand.
    5. When pathogenic M. tuberculosis grows inside a macrophage phagosome, the TNT rapidly gains access to the cytosol of the infected macrophage and hydrolyzes NAD+, depleting that essential co-factor. This initiates necrotic cell death through downstream signals that are not yet characterized.

    Curiously, a literature search revealed that an uncharacterized, heat-stable NAD+-glycohydrolase activity in M. tuberculosis cell extracts had been described half a century ago, as well as an uncharacterized heat-labile inhibitor of that hydrolase activity. Several biochemical characteristics of TNT and IFT found by the Niederweis lab match those of the uncharacterized proteins described in the reports from the 1960s.

    However, the lack of the modern equipment and antibodies of today, and the very low levels of TNT present in M. tuberculosis, prevented those researchers from finding the toxin.

    Co-authors of the paper are Jim Sun, Ph.D., Axel Siroy, Ph.D., Alexander Speer, Ph.D., and Kathryn Doornbos, all in the Department of Microbiology, UAB School of Medicine; and Ravi Lokareddy, Ph.D., and Gino Cingolani, Ph.D., Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia. Siroy is now at the University of Maastricht, the Netherlands.

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