Know This

by Mr. John Brockman

  Harmand et al. follow current convention in naming their artifacts “tools” rather than weapons. This more neutral terminology is, I think, a reflex of our continual and pervasive denial of Hobbes’s truth. Hobbes obviously did not have the information available to understand the time-depths or the bio-taxonomic and evolutionary issues involved, but had he known about Lomekwi 3 he would probably have called it differently, as Frere subsequently did at Hoxne.

  The prehuman emergence of weapons technology makes functional and evolutionary sense. We’re not talking about choosing appropriate twigs for the efficient extraction of termites, or the leaves best suited to carrying water, but about the painstaking modification of fine-grained igneous rocks into sharp-edged or bladed forms whose principal job was to part flesh from flesh and bone from bone.

  If the word “hunting” helps gloss over the reality of what such sharp stone artifacts were used for, then we can reflect on the type of hunting recently documented from the Aurora stratum at the site of Gran Dolina (Atapuerca), Spain. Here, Palmira Saladie Balleste and co-workers recently reported (Journal of Human Evolution, November 2012) on a group of Homo antecessor (or, arguably, erectus) who fed on individuals from, presumably, a rival group. The age profile of the victims was “similar to the age profiles seen in cannibalism associated with intergroup aggression in chimpanzees”—that is, those eaten were infants and immature individuals.

  That much of the data on early systematic endemic violence in our deeper (and shallower) prehistory comes as a surprise is due to the pervasive myth about the small-scale band societies of the archeological past having somehow been egalitarian. This idea has an odd genealogy that probably goes back to the utopian dreaming of Hobbes’s would-be intellectual nemesis, Jean-Jacques Rousseau, with his ideas of harmony and purity in nature and his belief that the savage state of humanity was noble rather than decadent.

  Rousseau, like Hobbes, lacked an evolutionary perspective and also dealt in more or less essentialist assertions. But once we have to bridge from wild primate groups to early human ancestors, the tricky question of the roots of egality arises. If the chimpanzees and gorillas we study in the wild have clear status hierarchies that are established, maintained, and altered by force, including orchestrated murder and cannibalism, then how could fair play magically become a base-line behavior?

  Somewhere along the way, we seem to have forgotten that the 19th-century founders of modern sociocultural anthropology, Lewis Henry Morgan, Edward Burnett Tylor, and Edvard Westermarck, recorded all kinds of unfairness in indigenous North American and Pacific societies. We may not want the Tlingit and Haida, Ojibwa and Shawnee to have had slaves, for instance, but avoiding mentioning it in modern textbooks does a great disservice to the original ethnographic accounts (and the slaves).

  Returning to the news from Lomekwi 3, we can now see that technology was not just a figurative but a literal arms race. Re-analyzing the increase in cranial capacity that began around 2 million years ago, we can see that blades and choppers needed to be already available to replace the missing biology—the massive ripping canines and heavy jaw muscles that previously hampered, in bio-mechanical terms, the expansion of the braincase. As Frere would immediately have understood, these artifacts included weapons, perhaps predominantly. Only by postulating high-level competition between groups can we understand the dramatic adaptive radiation of hominin types and the fact that, ultimately, only one hominin species survived.

  The paradox is that by sharpening the first knives to extend the range of possible forms of aggression, we opened up a much broader horizon, in which technology could be used for undreamed-of purposes. Yet Hobbes’s instinct that our nature was borne of war, and Frere’s conclusion that the world’s primal technology was offensive, should not be ignored. In the artificial lulls when atavism is forced into abeyance, we are happy to forget Hobbes’s admonition that it is only through the careful cultivation of institutions that stable peace is at least possible.

  The Immune System: A Grand Unifying Theory for Biomedical Research

  Buddhini Samarasinghe

  Molecular biologist; science communicator; co-creator of the Web site Know the Cosmos

  The germ theory of disease launched a revolution that transformed medicine. For the first time in history, disease was understood as an attack by microscopic organisms, organisms that were soon identified, characterized, and defeated. Yet we have not conquered disease. Cancer, heart disease, diabetes, stroke, and parasitic diseases are some of the top causes of death in the world today. Is there a unifying principle explaining them all? A common mechanism that could help us transform biomedical science once again? Perhaps there is: the immune system.

  We are just beginning to understand how deeply involved the immune system is in our lives. Its cellular sentries weave an intricate early warning network throughout the body; its signaling molecules—the cytokines—trigger and modulate our response to infection, including inflammation; it is involved even in as humble a process as the clotting of blood in a wound. At a fundamental level, the immune system provides us with a framework to better understand and treat a wide range of ailments.

  Cancer is often described as a “wound that never heals,” referring to the chronic inflammatory state that promotes tumor development. Cancer cells develop into a tumor by disabling and hijacking components of the immune system; immunosuppression and tumor-promoting inflammation are the two facets of cancer immunology. Both Type 1 and Type 2 diabetes are linked to the immune system; the former is an autoimmune condition in which the immune system attacks the insulin-producing cells in the pancreas; the latter is linked to insulin resistance through high levels of cytokines produced during inflammation. Pro-inflammatory cytokines are also linked to heart disease, which is the leading cause of death in the developed world. The malaria parasite is an expert at manipulating our immune system, cloaking itself in molecules that reassure our immune sentinels that nothing is amiss, while wreaking havoc in our blood cells.

  Most intriguing, we are now beginning to learn about the neuroimmune system, a dense network of biochemical signals synthesized in neurons, glial cells, and immune cells in our brains, and critical to the function of our central nervous system. These markers of the neuroimmune system are disrupted in disorders such as depression, anxiety, stroke, Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Cytokine levels have been shown to vastly increase during depressive episodes, and—in people with bipolar disorder—to drop off in periods of remission. Even the stress of social rejection or isolation causes inflammation, leading to the fascinating idea that depression could be viewed as a physiological allergic reaction rather than simply a psychological condition.

  With this knowledge comes power: Modulating the immune system to our advantage is a burgeoning field of research, particularly for cancer. Cancer immunotherapy marks a turning point in treatment, with astonishingly rapid remissions achieved in some patients undergoing early-stage clinical trials. New classes of drugs known as checkpoint inhibitors target specific immunological pathways, and we can reprogram “designer” immune cells to target cancer cells. Aspirin, a humble drug that reduces inflammation, may even be able to prevent some cancers—a tantalizing possibility currently being investigated in a large-scale clinical trial. Aspirin is already known to prevent heart attack and stroke in some people, through its anti-inflammatory and anti-clotting effects. Fascinating studies imply that supplementing antidepressants with anti-inflammatory drugs can improve their efficacy. Vaccines for such infectious diseases as malaria and HIV-AIDS are imminent. These advances couldn’t have come at a better time, since antibiotics have become increasingly ineffective due to widespread resistance (a problem classified by the World Health Organization as a “global threat”). Fields are converging in ways we haven’t seen previously; oncologists, parasitologists, neurobiologists, and infectious-disease specialists are all collaborating with immunologists.

  It is an exciting t
ime in biology and medicine. The new discoveries about the breadth and potential of our immune response merely hint at revelations to come. These research findings will always be newsworthy, because they promise to help us endure beyond disease and enjoy a longer life. Although we should beware the sham medicine of “miracle cures” and “immune boosting diets,” if we can drive research forward while communicating it effectively, we may be on the cusp of another revolution in biomedical science.

  Harnessing Our Natural Defenses Against Cancer

  Michael E. Hochberg

  Population biologist, Centre National de la Recherche Scientifique, University of Montpellier, France

  One out of every two people will have to deal with a diagnosis of cancer during their lifetime. The 10 percent of cancers that arise in genetically high-risk groups alone represents less than 1 percent of the total U.S. population but costs a staggering $15 billion to treat annually.

  Despite decades of research, the Holy Grail of a cure still eludes us, in part because of the fundamental unstable nature of cancer: It easily produces variant cells that resist chemotherapies, and this often results in relapse. Cancer is also difficult because cancer types differ considerably in their biology, meaning that a single drug is unlikely to be effective against more than one or a few types. Finally, even within a cancer type, patients can have differences in how their cancers react to a given drug. What all this means is that “one drug cures all” is not one drug and unfortunately for metastatic cancer, often not a cure.

  The problem can be stated thus, in brief: For late-stage cancers, which are the most difficult to treat, most new drugs are considered a success if they extend life for several weeks or months. The limited or disappointing results of many chemotherapies has led to concerted efforts to identify the Achilles’ heel, or rather heels, of cancers. To gauge where the most promising discoveries are being made, just read the titles any week of the world’s most prestigious scientific journals and parallel coverage in the popular press: It’s all about immunotherapies.

  The idea makes sense: Harness a patient’s own natural mechanisms for eliminating diseased cells, or give the patient man-made immune-system components to help specifically target malignancies. This is certainly better, all else being equal, than injections of toxic drugs. The basic challenge of traditional chemotherapies is that they affect both cancerous and, to some extent, healthy cells, meaning that for the drugs to work, doses must be carefully established to kill or arrest the growth of cancer cells, while keeping the patient alive. The more drug, the more the cancer regresses, but the higher the chance of side effects or even patient death. Many patients cannot withstand the doses of chemotherapies most likely to cure them, and even if they can, exposing rapidly dividing, mutation-prone cancer cells will strongly select for resistance to the therapy—which is why remission is often followed by relapse.

  Employing our own immune systems has intuitive appeal. Our bodies naturally use immuno-editing and immune surveillance to cull diseased cells. However, the tumor microenvironment is a complex adaptive structure that can also compromise natural and therapy-stimulated immune responses. This past year has seen important milestones. For example, based on promising clinical trials, the FDA recently approved a combination of two immunotherapies (Nivolumab and Ipilimumab) for metastatic melanoma. What one is not able to accomplish, the other is; this not only reduces tumor size but is expected to result in less evolved resistance to either drug. The same idea of using combinations can be applied to immunotherapies together with many of the more traditional radiotherapies, chemotherapies, and more recent advances in targeted therapies.

  Currently more than forty clinical trials are being conducted to examine effects of immunotherapies on breast cancer, with the hope that within a decade such therapies, if promising, can reduce or eliminate these cancers in the one in eight women who currently are affected during their lifetimes. This would be truly amazing headline news.

  Cancer Drugs for Brain Diseases

  Todd C. Sacktor

  Distinguished Professor of physiology, pharmacology, and neurology, SUNY Downstate Medical Center

  There has not been a new effective therapy for any neurodegenerative disease in decades. Recent trials of drugs for Alzheimer’s disease have been disappointments. Because of these expensive failures, many of the big pharmaceutical companies have moved away from targeting brain diseases to more profitable areas, like cancer. So is there any good news on the horizon for the millions who are suffering and will suffer from these devastating brain disorders?

  In 2015, there was news that a cancer drug showed remarkable benefits for patients with Parkinson’s disease. It was only one nonrandomized, nonblinded, non–placebo-controlled study that looked at only a few patients, so it’s too early to know whether it really works. But this is news to follow, and it’s big news for three reasons.

  First, unlike any other treatment, the drug appears to work close to the root cause of Parkinson’s. In Parkinson’s, the neurons that supply the brain with the neurotransmitter dopamine degenerate. The mainstay of treatment for the disease—Parkinson’s is one of the few neurodegenerative disorders for which there is any effective treatment—has been to replace that missing dopamine with a pill that provides a chemical that converts to dopamine in the brain. This therapy treats the symptoms of Parkinson’s—the tremors, the stiffness, and the slowness of movements—but not its root cause. So the death of the dopamine-containing neurons continues unabated and the pills work well only for around seven years.

  The new drug, called nilotinib, was developed for leukemia and has the same action as the better-known chemotherapeutic agent Gleevec. But unlike other similar drugs, nilotinib gets across the blood-brain barrier, which prevents most drugs from working well in the brain. Although the cause of the neuronal degeneration of Parkinson’s is still unknown, it is thought to involve the accumulation and misfolding of proteins inside the dying neurons, a process like the curdling of the proteins in milk. Nilotinib was predicted to suppress the accumulation of misfolded proteins inside neurons. After taking nilotinib, the patients not only did better clinically but the amount of the misfolding proteins released into their cerebral spinal fluid went down—a sign that it was working on the degenerative process itself.

  Second, the target that nilotinib inhibits is a new one for a brain disease. Like Gleevec, nilotinib inhibits an enzyme inside the cell called a protein kinase. There are around 500 different kinds of protein kinases in cells, and nilotinib targets one of them. Whereas there are many kinases in a cell, there are far more biochemical functions a cell has to do. So most kinases have multiple functions, some seemingly unrelated. Scientists focused on the kinase that nilotinib inhibits because if it becomes overactive, it can drive unchecked growth of white cells in the blood, causing leukemia. But they also found that it’s involved in the accumulation of neuronal proteins that can get misfolded. Nilotinib is big news because drugs that target kinases are relatively easy to develop, and nilotinib provides the first example showing that if they work for one disease, they might be used for a second seemingly unrelated disease. At the bedside, leukemia and Parkinson’s seem as far apart as you can get.

  Third, the timing with which the drug may work tells us something new and exciting about Parkinson’s itself, which might be relevant to other neurodegenerative diseases, such as Alzheimer’s. Protein misfolding in neurons is a general process in many neurodegenerative disorders. But no one knows whether suppressing protein misfolding will result in the slowing or stopping of a disease, or even in recovering function. The effect of nilotinib seems relatively fast—the trial lasted only a few months. If nilotinib’s beneficial action is really on inhibiting the accumulation and misfolding of neuronal proteins (and not secondarily, on increasing the release of dopamine), and if the patients improved, this could mean that the misfolding is one side of an active and dynamic battle in neurons between “good” folding and “bad” folding. In that case, we
would conclude that there are neuronal processes that are actively trying to repair the cell. This gives us hope for a cure and restoration of lost function in many neurological diseases.

  The Most Powerful Carcinogen May Be Entropy

  George Johnson

  Science writer; columnist, New York Times; author, The Cancer Chronicles

  Cancer is often described as a sped-up version of Darwinian evolution. Through a series of advantageous mutations, the tumor—this hopeful monster—becomes fitter and fitter within the ecosystem of your body. Some of the mutations are inherited, while others are environmental—the result of a confusion of outside influences. Much less talked about is a third category: the mutations that arise spontaneously from the random copying errors occurring every time a cell divides.

  In a recent paper in Science, Cristian Tomasetti and Bert Vogelstein calculated that two-thirds of the overall risk of cancer may come from these errors—entropic “bad luck.”* The paper set off a storm of outrage among environmentalists and public health officials, many of whom seem to have misunderstood the work or deliberately misrepresented it. And a rival model has since been published in Nature claiming to show that, to the contrary, as much as 90 percent of cancer is environmentally caused.* That to me is the least plausible of these dueling reports. As epidemiology marches on, the link between cancer and carcinogen grows ever fuzzier. The powerful and unambiguous link between smoking and lung cancer seems almost a fluke.