“…I would have to learn to live in a different way, seeing death as an imposing itinerant visitor but knowing that even if I’m dying, until I actually die, I am still living.”
–When Breath Becomes Air, Paul Kalanithi
Paul Kalanithi was working as a neurosurgery resident, when at the peak of his career, he received a devastating diagnosis. After years of reading CT scan images (which provide detailed images of the body), it was his own CT scans that were being analyzed, to the conclusion that he had stage IV metastatic lung cancer.
Although this autobiography centers on Kalanithi’s own battle against cancer and his personal experiences that accompany it, When Breath Becomes Air is remarkable in that every sentence has been written with intention, and Kalanithi’s style of writing and tone conveys a charisma that enraptures readers and makes each page profound. Although Kalanithi’s journey is deeply personal and specific to his own life, the experiences he has, as well as the book’s themes and morals, can resonate with people from all walks of life.
Doctors can learn from his insight about life and death, and about respect for lives beyond merely centering on disease and symptoms. College students can relate to his journey in trying to find a life trajectory and calling. And with respect to the HD community, anyone suffering from a terminal illness that rips at your fundamental being and robs you of the life you’d dreamed of can relate to Kalanithi’s experiences, as he grapples with the experience of watching himself die, attempts to restructure his goals and life plans, and decisions about having children and building a family.
The book begins with a poem called “Caelica 83,” which describes souls as eternal and says life changes form after death, like breath when it turns into air. The poem not only explains the title’s origins, but gives readers insight on some of the book’s themes: time, life and its various forms, and death.
After a foreword comes the prologue, which describes the beginning of Kalanithi’s symptoms, when he didn’t yet know what was going on and dealt with all sorts of questions and doubts. He also tells readers about the worry that gnawed at him and his wife, and how their lack of communication put a strain on their relationship. This part of the prologue can apply to HD: different but parallel to pre-diagnosis uncertainty and the struggle to reconcile the personal experience of coping with marital sharing. Later he also describes a dissonance between feeling and knowing that your body is dying, but at the same time being surrounded by vibrant life, which is relatable for anyone with a terminal illness.
The rest of Kalanithi’s story is divided into parts, with the first one describing his complex love-hate relationship with medicine, his journey from high school to medical school, and the plethora of moral and ethical concerns he experienced through medical school and the beginning of his residency. Part II becomes more relevant to the HD community, as he switches perspective back to the present, post-diagnosis. In this section, he navigates concerns about what to do with his life, his family, and his career. He decides to continue working as a neurosurgeon and to have a child with his wife, so he and his wife “would carry on living, instead of dying.”
With that, Kalanithi chronicles the ways in which he carries on living through the birth of his child, until his treatments stop working and his cancer forces him to carry on dying. His words conclude with a message to his daughter, and his life abruptly ends before he can finish telling his story, conveying the sudden nature of death itself.
Kalanithi’s story, although not specifically written about or for the HD community, offers perspective on hardships many individuals and families with HD must also face. His attitude towards living without knowing how long he has left, him and his wife’s thought process before having their child, and his final moments watching himself decline are all pertinent to those who have HD. Reading When Breath Becomes Air will not only take readers through Kalanithi’s personal journey, but will leave readers with insights that make them consider their own journeys through life. More
HD is commonly categorized as a late-onset neurodegenerative disease, as its defining symptoms typically appear late in life. However, HD is caused by mutated huntingtin protein (mHTT), which is present in cells long before the onset of symptoms, and is necessary for fetal development, as shown in a study with mice embryos. This led researchers Barnat et. al. to investigate the effects HD can have on cells and brain development in both human and mouse fetuses.
Existing Mice Research
There is some pre-existing research on wild-type, or unmutated, huntingtin protein (HTT) and mHTT’s effects on fetal and early brain development. Reiner et. al. used a mouse model in which the wild-type huntingtin gene was completely deleted in mice embryos to determine the function of HTT in early development. Deletion of HTT resulted in the death of mice embryos after 8 to 10 days, because it plays a critical role in embryo development, at least with mice.
Further mice models of HD reveal that mHTT hinders various processes that are necessary for neuron development. These processes include brain cell differentiation, the migration of neurons to their proper locations in the brain, and maturity of neuronal cells. These studies—that show the effects of mHTT and HTT on early brain development in life—suggest that HD could be involved in human brain development as well.
HD in the Pre-symptomatic Brain
Beyond the mice models, there are also studies that show the effects of the mHTT present in HD on the human brain before symptom onset. One study by Nopoulos et. al. compared the intracranial volume, which is essentially brain size, of children with the HD gene expansion to children without the gene expansion. They found significantly smaller intracranial volumes in gene-expanded children, which means that mHTT may impede brain development long before symptom onset.
Additional studies show that mHTT more specifically causes defects in the corticostriatal pathway, which is a brain pathway involved with physical movement and learning, and even alters gene expression in stem cells. When HD changes gene expression in fetal stem cells, growing fetuses will receive different instructions for brain and body development, and may develop abnormally.
Huntingtin Location in the Fetal Brain
To investigate the impacts of mHTT on human fetal development, Barnat et. al. analyzed brain tissues from four fetuses with the HD mutation and four healthy fetuses. These tissues were collected at gestational week 13, which means 13 weeks from the parent’s last menstrual cycle, not from conception. At this point of fetal development, cortical neurons, which are brain cells located in the outer layer of the brain, begin to form. In fetal development, these cortical neurons come from the ventricular zone, which is a layer of tissue made of stem cells that will eventually become neurons.
The researchers wanted to examine where HTT and mHTT are present in the ventricular zone of fetuses. To do so, they used an antibody, which is a natural part of the human immune system that recognizes proteins on disease-causing viruses or bacteria. Instead of identifying those types of proteins, however, the antibody used in this study recognizes both HTT and mHTT. This antibody acts as a stain, as it binds to the proteins and makes them visible to researchers.
After this staining process, researchers could see a difference between wild-type fetuses and fetuses with the HD mutation. In wild-type tissues, HTT was present in the apical surface, or the innermost end, of the ventricular zone, and was also spread throughout the basal region, which is the area opposite to the apical end. However, the protein patterns in brain tissue with the HD mutation are different: HTT and mHTT are mainly located at the apical surface, and are less present in the basal region than the wild-type. Because the location of proteins is different in the ventricular zone for HD fetuses, this could mean that HD causes brain cells to develop differently before birth.
Because brain tissue for fetuses with HD mutations is rare, the researchers also repeated the same process with a mice model. The mice model gave similar results, that mHTT is present in the apical surface and decreased in the basal region as compared to the wild-type.
Huntingtin Interactions with Protein Pathways
Proteins play a very important role in fetal development, partly because they are a way for cells to communicate with each other and can influence a cell’s identity. For instance, a certain mixture and amount of proteins can tell a cell to divide and eventually become a different kind of cell. Because of the importance of proteins to fetal development, Barnat et. al. also looked at HTT and mHTT’s relationship to cell processes that create and move proteins.
To do so, researchers also used staining to see if HTT and mHTT are present at the same locations as other proteins associated with protein assembly, modification, or transport processes. In the wild-type samples, HTT colocalized partially with these proteins, which means that HTT was present in the same place but not in very high amounts. In the human and mouse HD samples, HTT and mHTT strongly colocalized with some of the proteins, which means they were present in much higher amounts compared to unmutated tissue. Researchers interpreted this to suggest that mHTT changes the way cells transport and secrete proteins very early in human development
Huntingtin Interactions with Junction Proteins
Further, the researchers examined HTT’s interactions with junction proteins in the apical ventricular zone. These junction proteins connect the cells in this region, stabilize the tissue, regulate what goes in and out of cells, and also play a role in cell growth and division. So, if junction proteins are not present in the correct places or in the right amounts, these processes will be affected. To analyze these important junction proteins, the researchers looked at fetuses at gestational week 16, because at this age the junction structures would be more developed. In the images of mutant tissues, there was a bright line of HTT along the apical surface of cells that was not present in the wild-type.
Researchers also looked at junction proteins Z01, NCAD, β-catenin, and PAR3 in the mouse model. In wild-type fetuses, Z01, NCAD, and β-catenin are found towards the sides of cells they join together, while PAR3 is found closer toward the center. In mice with the HD mutation, Z01, NCAD, and β-catenin are not concentrated on the sides but spread throughout, and PAR3 was less visible. These differences in junction proteins between wild-type and HD mice may have implications for brain tissue stability and cell division.
mHTT and the Cell Cycle
The cell cycle describes a process in which cells grow, prepare to divide, and then divide into two cells, called daughter cells. In the region that researchers mainly focused on, the apical ventricular zone, the junction proteins influence the cell cycle and are improperly arranged. Because of this, phases of the cell cycle last different amounts of time in the HD mutant mice, compared to the wild-type. The G1 and G2 phases, during which cells normally grow and prepare for division, take longer in HD mutated cells. The transition from G1 to S phase, S phase being the portion in which genetic material is replicated, takes less time. Researchers also looked for a substance called PH3, which is present when cells divide in two to create more cells. The mutant mice had about half the amount of PH3 compared to wild-type mice, which means that there are less dividing cells in the brain tissue.
The study conducted by Barnat et. al. shows that HD has impacts on brain development in fetuses with the HD mutation. Their findings point out differences between the ventricular zones of wild-type and mutant tissues, which set the stage for further brain development later on in life. While the specific differences that researchers found between wild-type and mutants have not been tied to differences in brain function throughout the life of a pre-symptomatic HD patient, the study sets the stage for further research on HD and development. It also invites future studies about HD treatments delivered early in life, because treatments in adulthood might be too late to reverse the impact mHTT has already had on brain circuitry.
The Wahls Protocol is a diet program designed to mediate symptoms of Multiple Sclerosis (MS), an autoimmune disease that acts by removing the protective coverings that surround neurons. Terry Wahls introduced this diet around 2011, with the claim that it helped her go from using a wheelchair to walking and biking. Since its release, the diet protocol has gained popularity within the MS community, with Wahls publishing books, doing a Ted Talk, and selling lifestyle products on her website. Although the diet is targeted toward the MS community, it could be of interest to the HD community because both diseases target the brain.
What is the Wahls Protocol?
The Wahls Protocol is a modified Paleolithic (Paleo) diet, in which people can only eat types of food that hunter-gatherers used to eat in the Paleolithic era over 12,000 years ago. Wahls altered this diet to better suit MS, placing special importance in foods with anti-inflammatory properties and vitamin K. These modifications were chosen to combat brain inflammation, increased autoimmune activity, and digestive issues that are characteristic of MS.
Main components and claimed benefits:
High consumption of sulfur rich and leafy green vegetables.
- Dark green leafy vegetables, such as arugula and kale, contain carotenoids and vitamin K. Wahls et. al. claim that these nutrients support immune function, neuron health, and calcium absorption.
- Vegetables like cabbage and mushrooms are rich in sulfur, which is said to prevent brain inflammation and brain degeneration, and help with immune function.
Meat and fish recommended.
- Meat and fish are typical components of a Paleo Diet, and are recommended due to protein content, but not for any MS-specific nutritional benefits.
Organ meats encouraged.
- Organ meats, such as liver and kidneys, are a rich source of vitamins A, B, and D, phosphorus, zinc, selenium, copper and manganese, which provide nutrition that are absent in other parts of the diet. Typically, individuals do not consume sufficient daily amounts of these vitamins.
- Liver is a source of retinol, which helps with bone growth and immune function.
Avoid grains and dairy.
- Grains are excluded due to their lectin content, which can cause digestive problems and increase autoimmune activity. This has been shown to break down brain cells in MS.
- Dairy can also trigger intestinal issues or inflammation, and may be associated with higher MS prevalence.
- Seaweed is a source of carotenoids (benefits listed in 1.a.) and antioxidants, which reduce inflammation and have general health benefits due to rich mineral composition.
Nutritional yeast encouraged.
- Nutritional yeast is a source of Vitamin B and can be a cheese substitute.
Fermented foods encouraged.
- This includes teas and pickled vegetables, which have favorable impacts on the gut microbiome and may help with digestion.
Potential Impacts on HD
One aspect of the Paleo Diet and the Wahls Protocol that may impact HD involves elimination of grains. Grains are a major source of gluten, which has been linked to the protein aggregates that characterize HD, although evidence is limited. This potential connection between HD and gluten may be one of the reasons individuals with HD have considered the Wahls Protocol. For more information about gluten and HD, click here.
Additionally, a recent study by Wasser et. al. has linked HD to gut dysbiosis, an imbalance of healthy bacteria in the gut. In this study, HD patients had less diversity of their gut bacteria and had different gut enzymes, which are needed to digest food. These microorganisms are important, not only because they affect the quality of digestion and nutrient absorption, but because a connection exists between gut bacteria and brain function. However, more research is needed to connect gut dysbiosis to HD specifically. This relates to the Wahls Protocol because many foods that impair digestion–such as wheat and dairy–are eliminated, and foods that promote digestion–such as fermented foods–are encouraged. These aspects of the diet could potentially help mediate the digestive issues that HD patients face, and a better-functioning gut may also improve brain function.
While some components of the Wahls Protocol focus on supporting the digestive system, other elements, such as sulfur rich vegetables and seaweed, are catered toward reducing brain inflammation. With respect to HD, there is limited evidence of a relationship between brain inflammation and HD symptoms. In 2016, Rocha et al. reviewed existing evidence about HD and brain inflammation, and suggested that there is an association. However, it remains unclear whether brain inflammation contributes to HD symptoms, or if inflammation is a result of HD symptoms. Because there is a lack of substantiated information, it is unclear whether the anti-inflammatory foods recommended in the Wahls Protocol would help with HD.
Wahls Protocol Validity
Although the Wahls Protocol is widely known among the MS community, there is limited evidence that proves its validity. While the story about founder Terry Wahls becoming a long distance biker after being wheelchair-ridden for years is quite remarkable, most of the evidence that supports the diet’s claims is in the form of success stories. There are a few published articles that examine the scientific nutritional mechanisms behind the Wahls Protocol, but none of them prove real, observed improvements for MS patients who adhere to the protocol. Additionally, all of these articles have been co-written by Terry Wahls, which may present a conflict of interest because she developed the protocol and sells diet products on her website. As for clinical studies, Wahls began a trial that began in 2016 and was supposed to end in January 2020, but results have yet to be published. All in all, there is a lack of evidence that proves a cause-and-effect relationship between specific foods and their claimed physical effects on the body.
Aside from the story about founder Terry Wahls, another piece of anecdotal evidence comes from Dawn Hovey. Hovey participated in a pilot study for the protocol, and apparently experienced results early on. After a month of adhering to the protocol, doing physical activity, and receiving electrical stimulation, Hovey went from using her wheelchair to walking without a cane. She also decreased the medication she took for MS-related fatigue.While this sounds promising, it is unclear whether the improvements came from the diet or the other lifestyle changes she made, and this isn’t sufficient evidence to prove that the regime will work for others.
Concerns for any Diet Protocol
Before trying any restrictive diet regime, it is important to discuss the topic with a physician and/or nutritionist. While following individual elements of the protocol might not hurt (unless you’re allergic to them) and may even be beneficial, this diet in particular restricts all sources of wheat, dairy, and some fruits, among other things. These food groups normally are a source of energy, protein, and essential nutrients, so strictly adhering to the Wahls Protocol may not only be difficult in a practical sense, but might also cause some harmful nutritional deficiencies. Because of the restrictive nature of the Wahls Protocol and lack of studies connecting it to physical benefits, it is not yet clear whether it could be useful to the MS community it was made for, let alone the HD community.