Life is Emerging: Review of Siddhartha Mukherjee’s Song of the Cell
The DNA double helix is often the image spiraling at the center of 21st century advances in biomedicine and the growing bioeconomy. And yet, DNA is molecularly inert. DNA, the code for genes, is not alive and is not strictly necessary for life. Ought life be at the center of our communication of living systems? Is not the Cell a superior symbol of life and our manipulation of living systems?
A code for life isn’t a code without the life that instantiates it. A code for life must be translated. The cell is the basic unit of that translation. The cell is the minimal viable package of life as we know it. Therefore, cell biology is at the center of biomedicine’s greatest transformations, suggests Pulitzer-winning physician-scientist Siddhartha Mukherjee in his latest book, The Song of the Cell: The Exploration of Medicine and the New Human.
The Song of the Cell begins with the discovery of cells and of germ theory, featuring characters such as Louis Pasteur and Robert Koch, who brought the cell “into intimate contact with pathology and medicine.” This intercourse would transform biomedicine, leading to the insight that we can treat disease by thinking at the cellular level. The slightest rearrangement of sick cells might be the path toward alleviating suffering for the organism: eroding the cell walls of a bacterium while sparing our human cells; inventing a medium that coaxes sperm and egg to dance into cellular union for in vitro fertilization (IVF); designing molecular missiles that home to the receptors decorating the exterior of cancer cells; teaching adult skin cells to remember their embryonic state for regenerative medicines.
Mukherjee uses the bulk of the book to elucidate key cell types in the human body, along with their “connective relationships” that enable key organs and organ systems to function. This includes the immune system, the heart, the brain, and so on. Mukherjee’s distinctive style features compelling anecdotes and human stories that animate the scientific (and unscientific) processes that have led to our current state of understanding. In his chapter on neurons and the brain, for example, he integrates Santiago Ramon y Cajal’s meticulous black ink sketches of neurons into Mukherjee’s own personal encounter with clinical depression. In one lucid section, he interviews Dr. Helen Mayberg, a pioneering neurologist who takes seriously the descriptive power of her patients’ metaphors, as they suffer from “caves,” “holes,” “voids,” and “force fields” that render their lives gray. Dr. Mayberg aims to stimulate patients’ neuronal cells in a manner that brings back the color.
Beyond exposing the insight and inventiveness that has arisen out of cell-based thinking, it seems that Mukherjee’s bigger project is an epistemological one. The early chapters of The Song of the Cell continually hint at the potential for redefining the basic unit of biology as the cell rather than the gene. The choice to center biomedicine around cells is, above all, a conspicuous choice not to center it around genes (the subject of Mukherjee’s previous book, The Gene), because genes dominate popular science communication.
This choice of cells over genes is most welcome. Cells are alive. Genes are not. Letters—such as the As, Cs, Gs, and Ts that represent the nucleotides of DNA, which make up our genes—must be synthesized into a word or poem or song that offers a glimpse into deeper truths. A key idea embedded in this thinking is that of emergence. Whether in ancient myth or modern art, creation tends to be an emergent process, not a linearly coded script. The cell is our current best guess for the basic unit of life’s emergence, turning a finite set of chemical building blocks—nucleic acids, proteins, sugars, fats—into a replicative, evolving system for fighting stasis and entropy. The cell’s song is one for our times, for it is the song of biology’s emergence out of chemistry and physics, into the “frenetically active process” of homeostasis.
Re-centering our view of biology has practical consequences, too, for how we think about diagnosing and treating disease, and for inventing new medicines. Centering cells presents a challenge: which type of cell to place at the center? Rather than default to the apparent simplicity of DNA as a symbol because it represents the one master code for life, the tension in defining the diversity of cells—a mapping process still far from complete in cutting-edge biology laboratories—can help to create a more thoughtful library of cellular metaphors to shape both the practice and communication of biology.
Further, effective problem solving is often about operating at the right level, or the right scale. The cell feels like appropriate level at which to interrogate many of the diseases that ail us, because the senses that guide our own perceptions of sickness and health—the smoldering pain of inflammation, the tunnel vision of a migraine, the dizziness of a fluttering heart—are emergent.
This, unfortunately, is sort of where Mukherjee leaves the reader, under-exploring the consequences of a biology of emergence. Many practical and profound questions have to do with the ways that each scale of life feeds back on the others. In a tome on Cells and “the future human” I wished that Mukherjee had created more space for seeking the ways that cells will shape and be shaped by the future, of humanity and otherwise.
We are entering a phase of real-world bioengineering that features the modularization of cellular parts within cells, of cells within organs, of organs within bodies, and of bodies within ecosystems. In this reality, we would be unwise to assume that any whole is the mere sum of its parts.
For example, when discussing the regenerative power of pluripotent stem cells, Mukherjee raises the philosophical thought experiment of the Delphic boat, also known as the Ship of Theseus. The boat is made of many pieces of wood, each of which is replaced for repairs over the years, with the boat’s structure unchanged. Eventually none of the boat’s original wood remains: Is it the same boat?
Mukherjee raises the Delphic boat in one paragraph at the end of the chapter on stem cells, as a metaphor related to the possibility of stem cell-enabled regeneration in perpetuity. He does not follow any of the threads of potential answers. Given the current state of cellular engineering, about which Mukherjee is a world expert from his work as a physician-scientist, this book could have used an entire section dedicated to probing this question and, importantly, the ways this thought experiment falls apart.
We are entering a phase of real-world bioengineering that features the modularization of cellular parts within cells, of cells within organs, of organs within bodies, and of bodies within ecosystems. In this reality, we would be unwise to assume that any whole is the mere sum of its parts. Wholeness at any one of these scales of life—organelle, cell, organ, body, ecosystem—is what is at stake if we allow biological reductionism to assume away the relation between those scales.
In other words, Mukherjee succeeds in providing a masterful and compelling narrative of the lives of many of the cells that emerge to enliven us. Like his previous books, it is a worthwhile read for anyone curious about the role of cells in disease and in health. And yet, he fails to offer the broader context of The Song of the Cell.
As leading agronomist and essayist Wes Jackson has written, “The sequence of amino acids that is at home in the human cell, when produced inside the bacterial cell, does not fold quite right. Something about the E. coli internal environment affects the tertiary structure of the protein and makes it inactive. The whole in this case, the E. coli cell, affects the part—the newly made protein. Where is the priority of part now?” [1]
Beyond the ways that different kingdoms of life translate the same genetic code, the practical situation for humanity today relates to the ways that the different disciplines of modern life use values and culture to influence our genes, cells, bodies, and environment. It may be that humans will soon become a bit like the Delphic boat, infused with the buzz of fresh cells to repopulate different niches within our bodies, for healthier, longer lives. But in biology, as in writing, a mixed metaphor can cause something of a cacophony. For we are not boats with parts to be replaced piecemeal. And nor are whales, nor alpine forests, nor topsoil. Life isn’t a sum of parts, and neither is a song that rings true.
[1] Wes Jackson, "Visions and Assumptions," in Nature as Measure (p. 52-53).
The Toxic Effects of Noise and What We’re Not Doing About It
Erica Walker had a studio in her Brookline, Mass. apartment where she worked as a bookbinder and furniture maker. That was until a family with two rowdy children moved in above her.
The kids ran amuck, disrupting her sleep and work. Ear plugs weren’t enough to blot out the commotion. Aside from anger and a sense of lost control, the noise increased her heart rate and made her stomach feel like it was dropping, she says.
That’s when Walker realized that noise is a public health problem, not merely an annoyance. She set up her own “mini study” on how the clamor was affecting her. She monitored sound levels in her apartment and sent saliva samples to a lab to measure her stress levels.
Walker ultimately sold her craft equipment and returned to school to study public health. Today she is assistant professor of epidemiology and director of the Community Noise Lab at the Brown University School of Public Health. “We treat noise like a first world problem—like a sacrifice we should have to make for modern conveniences. But it’s a serious environmental stressor,” she asserts.
Our daily soundscape is a cacophony of earsplitting jets, motorcycles, crying babies, construction sites or gunshots if you’re in the military. Noise exposure is the primary cause of preventable hearing loss. Researchers have identified links between excessive noise and a heightened risk of heart disease, metabolic disorders, anxiety, depression, sleep disorders, and impaired cognition. Even wildlife suffers. Blasting oil drills and loud shipping vessels impede the breeding, feeding and migration of whales and dolphins.
At one time, the federal government had our back… and our ears. Congress passed the Noise Control Act in 1972. The Environmental Protection Agency set up the Office of Noise Abatement and Control (ONAC) to launch research, explore solutions and establish noise emission standards. But ONAC was defunded in 1981 amidst a swirl of antiregulatory sentiment.
Impossibly Loud and Unhealthy
Daniel Fink. a physician, WHO consultant, and board chair of The Quiet Coalition, a program of the nonprofit Quiet Communities, likens the effect of noise to the invisible but cumulative harm of second-hand smoke. About 1 in 4 adults in the U.S. who report excellent to good hearing already have some hearing loss. The injury can happen after one loud concert or from years with a blaring TV. Some people are more genetically susceptible to noise-related hearing loss than others.
“People say noise isn’t a big deal but it bothers your body whether you realize it or not,” says Ted Rueter, director of Noise Free America: A Coalition to Promote Quiet. Noise can chip away at your ears or cardiovascular system even while you’re sleeping. Rueter became a “quiet advocate” while a professor at UCLA two decades ago. He was plagued by headaches, fatigue and sleep deprivation caused by the hubbub of Los Angeles, he says.
The louder a sound is, and the longer you are exposed to it, the more likely it will cause nerve damage and harmful fluid buildup in your inner ear. Normal speech is 50-60 decibels (dBs). The EPA recommends that 24-hour exposure to noise should be no higher than 70 weighted decibels over 24 hours (weighted to approximate how the human ear perceives the sound) to prevent hearing loss but a 55 dB limit is recommended to protect against other harms from noise, too.
The decibel scale is logarithmic. That means 80 dB is 10 times louder than 70 dB. Trucks and motorcycles run 90 dBs. A gas-powered leaf blower, jackhammer or snow blower will cost you 100 dBs. A rock concert is in the 110 dB range. Aircraft takeoffs or sirens? 120 dBs.
Walker, the Brown professor, says that sound measurements often use misleading metrics, though, because they don’t include low frequency sound that disturb the body. The high frequency of a screeching bus will register in decibels but the sound that makes your chest reverberate is not accounted for, she explains. ‘How loud?’ is a superficial take when it comes to noise, Walker says.
After realizing the impact of noise on her own health, Erica Walker was inspired to change careers and become director of the Community Noise Lab at the Brown University School of Public Health.
Erica Walker
Fink adds that the extent to which noise impairs hearing is underestimated. People assume hearing loss is due to age but it’s not inevitable, he says. He cites studies of older people living in quiet, isolated areas who maintain excellent hearing. Just like you can prevent wrinkles by using sunscreen, you can preserve hearing by using ear plugs when attending fireworks or hockey games.
You can enable push notifications on a Smart Watch to alert you at a bar exceeding healthy sound levels. Free apps like SoundPrint, iHEARu, or NoiseTube can do decibel checks, too, but you don’t need one, says Fink. “If you can’t carry a conversation at normal volume, it’s too loud and your auditory health is at risk,” he says.
About 40 million U.S. adults, ages 20-69, have noise-induced hearing loss. Fink is among them after experiencing tinnitus (ringing or buzzing in the ears) on leaving a raucous New Year’s Eve party in 2007. The condition is permanent and he wears earplugs now for protection.
Fewer are aware of the link between noise pollution and heart disease. Piercing noise is stressful, raising blood pressure and heart rate. If you live near a freeway or constantly barking dog, the chronic sound stress can trigger systemic inflammation and the vascular changes associated with heart attacks and stroke.
Researchers at Rutgers University’s Robert Wood Johnson Medical School, working with data from the state’s Bureau of Transportation, determined that 1 in 20 heart attacks in New Jersey during 2018 were due to noise from highways, trains and air traffic. That’s 800 heart attack hospitalizations in the state that year.
Another study showed that incidence of hypertension and hardening arteries decreased during the Covid-19 air lockdown among Poles in Krakow routinely exposed to aircraft noise. The authors, comparing their pre-pandemic 2015 results to 2020 data, concluded it was no coincidence.
Mental health takes a hit, too. Chronic noise can provoke anxiety, depression and violence. Cognitively, there is ample evidence that noise disturbance lowers student achievement and worker productivity, and hearing loss among older people can speed up cognitive decline.
Noise also contributes to health disparities. People in neighborhoods with low socioeconomic status and a higher percentage of minority residents bear the brunt of noise. Affluent people have the means to live far from airports, factories, and honking traffic.
Out, Out, Damn Noise
Europe is ahead of the U.S. in tackling noise pollution. The World Health Organization developed policy guidelines used by the European Environment Agency to establish noise regulations and standards, and progress reports are issued.
Americans are relying too much on personal protective equipment (PPE) instead of eliminating or controlling noise. The Centers of Disease Control and Prevention rank PPE as the least useful response. Earplugs and muffs are effective, says Walker, but these devices are “a band-aid on a waterfall.”
Editing out noise during product design is the goal. Engineers have an arsenal of techniques and know-how for that. The problem is that these solutions aren’t being applied.
A better way to lower the volume is by maintaining or substituting equipment intended for common use. Piercing building alarms can be replaced with visual signals that flash alerts. Clanking chain and gear drives can be swapped out with belt drives. Acoustical barriers can wall off highway noise. Hospitals can soften beeping monitors and limit loudspeaker blasts. Double paned windows preserve quiet.
Editing out noise during product design is the goal. Engineers have an arsenal of techniques and know-how for that. The problem is that these solutions aren’t being applied, says Jim Thompson, an engineer and editor of the Noise Control Engineering Journal, published by the Institute of Noise Control Engineering of the USA
Engineers have materials to insulate, absorb, reflect, block, seal or diffuse noise. Building walls can be padded. Metal gears and parts can be replaced with plastic. Clattering equipment wheels can be rubberized. In recent years, building certifications such as LEED have put more emphasis on designs that minimize harmful noise.
Walker faults urban planners, too. A city’s narrow streets and taller buildings create a canyon effect which intensifies noise. City planners could use bypasses, rerouting, and other infrastructure strategies to pump down traffic volume. Sound-absorbing asphalt pavement exists, too.
Some municipalities are taking innovative measures on their own. Noise cameras have been installed in Knoxville, Miami and New York City this year and six California cities will join suit next year. If your muffler or audio system registers 86 dB or higher, you may receive a warning, fine or citation, similar to how a red-light camera works. Rueter predicts these cameras will become commonplace.
Based on understanding how metabolic processes affect noise-induced hearing loss in animal models, scientists are exploring whether pharmacological interventions might work to inhibit cellular damage or improve cellular defenses against noise.
Washington, DC, and the University of Southern California have banned gas-powered leaf blowers in lieu of quieter battery-powered models to reduce both noise and air pollution. California will be the first state to ban the sale of gas-powered lawn equipment starting 2024.
New York state legislators enacted the SLEEP (Stop Loud and Excessive Exhaust Pollution) Act in 2021. This measure increases enforcement and fines against motorists and repair shops that illegally modify mufflers and exhaust systems for effect.
“A lot more basic science and application research is needed [to control noise],” says Thompson, noting that funding for this largely dried up after the 1970s. Based on understanding how metabolic processes affect noise-induced hearing loss in animal models, scientists are exploring whether pharmacological interventions might work to inhibit cellular damage or improve cellular defenses against noise.
Studying biochemical or known genetic markers for noise risk could lead to other methods for preventing hearing loss. This would offer an opportunity to identify people with significant risk so those more susceptible to hearing loss could start taking precautions to avoid noise or protect their ears in childhood.
These efforts could become more pressing in the near future, with the anticipated onslaught of drones, rising needs for air conditioners, and urban sprawl boding poorly for the soundscape. This, as deforestation destroys natural carbon absorption reservoirs and removes sound-buffering trees.
“Local and state governments don’t have a plan to deal with [noise] now or in the future,” says Walker. “We need to think about this with intentionality.”
A new way to help kids with ADHD: Treat adult ADHD
When a child is diagnosed with attention deficit hyperactivity disorder (ADHD), it can often be a surprise to the parents that one of them has ADHD as well. They may have experienced some of the symptoms but never had the condition diagnosed.
Physicians, however, are usually less surprised because they know that ADHD is a very heritable disorder. According to a 2015 study, if a parent has ADHD, the child has up to a 57 percent chance of having it, and the child’s risk is 32 percent if their sibling has it.
“There have been 20 to 30 twin studies that show that the heritability of ADHD is about 70 percent,” meaning that both twins have it, says Stephen Faraone, distinguished professor and vice chair for research at SUNY Upstate Medical University. “It is as heritable as schizophrenia, bipolar disorder, autism or other psychiatric disorders that people tend to think are more biological than ADHD for some reason.”
More attention needed for adult ADHD
Brad McAlister, CMSE, executive director of the American Professional Society of ADHD & Related Disorders, or APSARD, explains that the consequences of untreated ADHD in adults are very well documented. The prevalence of ADHD in U.S. adults is 4.4 percent or about 11 million people.
Many adults go undiagnosed for decades or are misdiagnosed by providers. McAlister says that 75 percent are not receiving treatment. “The U.S. economic burden of adult ADHD is $105 to $194 billion annually,” he says. “The negative consequences on peoples’ lives include higher risks of dropping out of school, losing jobs, financial debt, divorce, fractured relationships, substance use disorders, and co-occurring depression/anxiety.”
One of the negative impacts of undiagnosed ADHD in adults is the effect that it can have on their children who have ADHD.
Adult ADHD is currently treated by a broad range of health care providers with different educational backgrounds and in different practice settings. In August, APSARD published the first U.S. guidelines for adult ADHD. “The creation of guidelines for ADHD in adults will allow all practitioners to benefit from the best evidence about diagnosing and treating the disorder,” McAlister says.
Faraone explains that the guidelines are intended to help practitioners understand the best practices for adults with ADHD, including screening and other ways of evaluating whether someone has it. He recently completed a study of what he calls the Metrics of Quality Care for adults with ADHD.
“We looked at a sizable group of primary care practices in the U.S., and we learned that although quality care for adults with ADHD has been gradually improving over the past decade, there are many areas where it is still far behind where it needs to be,” he says. “That’s consistent with other studies that show that in primary care for adults, ADHD is not treated nearly as well as it is treated in specialty and psychiatry care.”
How kids with ADHD are affected
One of the negative impacts of undiagnosed ADHD in adults is the effect that it can have on their children who have ADHD because their ability to care for that child’s special needs may be impaired.
“The treatments that are most effective in treating children with ADHD are medication and behavioral interventions as their reward bait, and at home, it’s the parent that administers them,” says Mark A. Stein, director of the ADHD and Related Disorders Program at Seattle Children’s Hospital. “Adults with ADHD have difficulties with time management and organization skills, so they will have a hard time making sure their child is ready for school, has breakfast, has their medications, etcetera.”
Even more challenging than getting a prescription, Stein adds, is finding a psychologist or therapist who is skilled in evaluating and working with children with ADHD and their parents. If left undiagnosed and untreated, adult ADHD may also interfere with getting a good evaluation for the child.
“If you have ADHD and your mind is wandering and you don’t have all of the forms from the school for your provider, and you’re focused on the bad day you’re having rather than giving a history of your child, all of that is going to delay getting an effective treatment for your child,” Stein says. “So that’s why it’s important to identify ADHD in parents.”
Promising research and training
After delays due to the pandemic, Stein and his colleague Andrea Chronis-Tuscano, professor and director of the Maryland ADHD Program at the University of Maryland, are now about two years into what they anticipate will be a six-year study that involves treating parents who have children with untreated ADHD symptoms. The goal is to see whether treating the parent first with medication and training, or just the training, helps the child’s symptoms due to improved parenting. They are also studying whether they can postpone the need for medication until children are older, when it’s more effective.
“Pediatricians are more aware of ADHD in parents because of our study,” Stein says. “They’re also more aware of the shortcomings in our healthcare delivery system in terms of how hard it is to find providers who are comfortable treating adult ADHD.”
“Besides depression, ADHD is the other disorder that parents have that really impacts kids significantly," Stein says. “With treatment, many people with ADHD do very well."
That said, he’s seen a significant improvement in the past decade with increased recognition of ADHD in adults. “It started with pediatricians recognizing that post-partum depression impacted the mother’s ability to care for her children and making it routine to screen for depression in parents of kids,” he says. “Besides depression, ADHD is the other disorder that parents have that really impacts kids significantly, so it’s important for them to be aware of characteristics of [ADHD in] parents and have resources they can give parents to help them.”
Stein emphasizes that even if someone displays symptoms of ADHD, that does not mean that they have it. They should seek a physician’s evaluation to confirm a diagnosis, which would enable them to get the medication and behavioral treatment they need.
The medication can take effect in parents within an hour. Meanwhile, when parents participate in the behavioral parent training courses, their kids with ADHD start showing significant improvement within about four to five weeks, according to Stein.
“With treatment, many people with ADHD do very well,” he says. “Especially if they get through formal schooling, find the right fit with their job, and if they make the right choices with their relationships, those three things can go a long way to make their ADHD fade into the background.”