Jo Cameron (born 1948; age years), also known as Patient PFS, is a

Scottish Scottish usually refers to something of, from, or related to Scotland, including: *Scottish Gaelic, a Celtic Goidelic language of the Indo-European language family native to Scotland *Scottish English *Scottish national identity, the Scottish ide ...

woman who feels no pain and experiences little to no

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

or other aspects of

negative affect In psychology, negative affectivity (NA), or negative affect, is a personality variable that involves the experience of negative emotions and poor self-concept. Negative affectivity subsumes a variety of negative emotions, including anger, contem ...

. She has two

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

s, one in the

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

encoding

fatty acid amide hydrolase Fatty-acid amide hydrolase 1 (FAAH) is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide (AEA), an ''N''-acylethanolamine (NAE) in 1993. In humans, it is encoded by the gene ''FAAH''.; Function ...

(FAAH) and one in the

pseudogene Pseudogenes are nonfunctional segments of DNA that resemble functional genes. Pseudogenes can be formed from both protein-coding genes and non-coding genes. In the case of protein-coding genes, most pseudogenes arise as superfluous copies of fun ...

'' FAAH-OUT'' modulating FAAH expression, which are theorized to be responsible for her condition. FAAH is an

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

involved in the

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

endocannabinoid Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...

s like

anandamide Anandamide (ANA), also referred to as ''N''-arachidonoylethanolamine (AEA) is a fatty acid neurotransmitter belonging to the fatty acid derivative group known as N-acylethanolamine (NAE). Anandamide takes its name from the Sanskrit word ''ananda ...

. Cameron has high levels of anandamide and other endocannabinoids. She was first presented as a

published Publishing is the activities of making information, literature, music, software, and other content, physical or digital, available to the public for sale or free of charge. Traditionally, the term publishing refers to the creation and distribu ...

case report In medicine, a case report is a detailed report of the symptoms, signs, diagnosis, treatment, and follow-up of an individual patient. Case reports may contain a demographic profile of the patient, but usually describe an unusual or novel occurrenc ...

in 2019 and was subsequently featured widely in the

mainstream media In journalism, mainstream media (MSM) is a term and abbreviation used to refer collectively to the various large Mass media, mass news media that influence many people and both reflect and shape prevailing currents of thought.Noam Chomsky, Choms ...

. Development of

pharmaceutical drug Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the ...

s (specifically FAAH inhibitors) for treatment of pain and psychiatric disorders has been encouraged by her case.

Clinical presentation

Cameron was identified at the age of 66years when she underwent trapeziectomy surgery for severe

hand A hand is a prehensile, multi-fingered appendage located at the end of the forearm or forelimb of primates such as humans, chimpanzees, monkeys, and lemurs. A few other vertebrates such as the Koala#Characteristics, koala (which has two thumb#O ...

osteoarthritis Osteoarthritis is a type of degenerative joint disease that results from breakdown of articular cartilage, joint cartilage and underlying bone. A form of arthritis, it is believed to be the fourth leading cause of disability in the world, affect ...

. This condition had led to deformity of her thumbs such that she could not hold a pen properly, although Cameron reported experiencing no pain from it. She had also developed severe

hip In vertebrate anatomy, the hip, or coxaLatin ''coxa'' was used by Celsus in the sense "hip", but by Pliny the Elder in the sense "hip bone" (Diab, p 77) (: ''coxae'') in medical terminology, refers to either an anatomical region or a joint on t ...

osteoarthritis, resulting in lopsided walking abnormality noticed by others, but also reported no pain from this. She had undergone

hip replacement Hip replacement is a surgery, surgical procedure in which the hip joint is replaced by a prosthetic implant (medicine), implant, that is, a hip prosthesis. Hip replacement surgery can be performed as a total replacement or a hemi/semi(half) repl ...

surgery the year before at the age of 65. Recovery from trapeziectomy surgery is normally very painful or "excrutiating". Cameron had assured her

anesthesiologist Anesthesiology, anaesthesiology or anaesthesia is the medical specialty concerned with the total perioperative medicine, perioperative care of patients before, during and after surgery. It encompasses anesthesia, intensive care medicine, critica ...

, Dr. Devjit Srivastava, that she would not need

painkiller An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

s for this surgery, to which Srivastava was skeptical. Extraordinarily, Cameron indeed experienced no pain during recovery and required no

analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

s. Her pain ratings were 0/10 and only

paracetamol Paracetamol, or acetaminophen, is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain. It is a widely available over-the-counter drug sold under various brand names, including Tylenol and Panadol. Parac ...

(acetaminophen; Tylenol) was administered, but this medication was routinely given to all patients by the nurses. Her surprising lack of pain led to further investigations by Srivastava. Review of her

medical chart Medicine is the science and practice of caring for patients, managing the diagnosis, prognosis, prevention, treatment, palliation of their injury or disease, and promoting their health. Medicine encompasses a variety of health care pract ...

showed that she had also reported little to no pain with hip replacement, for which her pain scores were 0/10 or 1/10 once on the postoperative evening. Srivastava remained slightly skeptical until Cameron allowed him to perform a normally very painful maneuver used by

s on patients who are having difficulty regaining

consciousness Consciousness, at its simplest, is awareness of a state or object, either internal to oneself or in one's external environment. However, its nature has led to millennia of analyses, explanations, and debate among philosophers, scientists, an ...

following

sedation Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...

. This maneuver involves pressing hard on the inner edges of the eye sockets, which results in strong pain that shocks people awake. Cameron felt no pain from the maneuver, instead experiencing only pressure. At that point, Srivastava developed a research protocol involving a team of highly regarded scientists from around the world in an attempt to figure out what was responsible for her lack of pain. Cameron subjectively reported a lifetime lack of pain, including with

childbirth Childbirth, also known as labour, parturition and delivery, is the completion of pregnancy, where one or more Fetus, fetuses exits the Womb, internal environment of the mother via vaginal delivery or caesarean section and becomes a newborn to ...

broken bone A bone fracture (abbreviated FRX or Fx, Fx, or #) is a medical condition in which there is a partial or complete break in the continuity of any bone in the body. In more severe cases, the bone may be broken into several fragments, known as a ''c ...

s, and numerous

burn A burn is an injury to skin, or other tissues, caused by heat, electricity, chemicals, friction, or ionizing radiation (such as sunburn, caused by ultraviolet radiation). Most burns are due to heat from hot fluids (called scalding), soli ...

s and cuts. She had often not noticed burns and other injuries until she smelled burning flesh or saw blood on herself. Her burns and cuts also seemed to heal quickly with less or no

scarring A scar (or scar tissue) is an area of fibrous tissue that replaces normal skin after an injury. Scars result from the biological process of wound repair in the skin, as well as in other organs, and tissues of the body. Thus, scarring is a nat ...

. Eating Scotch bonnet chili peppers left only a "pleasant glow". Attempts by researchers to induce pain, including burning her, sticking her with pins, and pinching her with tweezers until she bled, resulted in no pain. Aside from her lack of pain, Cameron was additionally described as characteristically happy, friendly, talkative, optimistic, and compassionate, as well as exceedingly affectionate and loving towards family members. Moreover, she was lacking in

, depression,

worry Worrying is the mental distress or agitation resulting from anxiety, usually coming from a place of anticipatory fear (terror) or fear coming from a present threat (horror). With more understanding of the situation, worry becomes concern, the ...

fear Fear is an unpleasant emotion that arises in response to perception, perceived dangers or threats. Fear causes physiological and psychological changes. It may produce behavioral reactions such as mounting an aggressive response or fleeing the ...

panic Panic is a sudden sensation of fear, which is so strong as to dominate or prevent reason and logical thinking, replacing it with overwhelming feelings of anxiety, uncertainty and frantic agitation consistent with a fight-or-flight reaction. ...

grief Grief is the response to the loss of something deemed important, particularly to the death of a person to whom or animal to which a Human bonding, bond or affection was formed. Although conventionally focused on the emotional response to loss, ...

, dread, and

generally. She reported a long history of mild memory lapses and forgetfulness as well. Cameron also experienced characteristic severe

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

and

vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...

caused by the

opioid Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...

morphine Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...

that had been given to her postoperatively after hip replacement surgery.

Genetic evaluation

Genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...

revealed that she was

heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...

for a common hypomorphic

single nucleotide polymorphism In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...

(SNP) in her ''FAAH''

(rs324420; C385A; C

allele An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule. Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...

frequency 74%, A allele frequency 26%) that has been associated with reduced activity of the

and increased

levels as well as with decreased pain sensitivity, fear, and anxiety. As this polymorphism is common in the population however, it could not explain her presentation alone. In addition to the

in ''FAAH'', Cameron showed a heterozygous

microdeletion In genetics, a deletion (also called gene deletion, deficiency, or Deletion anomaly, deletion mutation) (sign: delta (letter), Δ) is a mutation (a genetic aberration) in which a part of a chromosome or a sequence of DNA is left out during DNA rep ...

s downstream of FAAH overlapping a

. This novel pseudogene was named ''FAAH-OUT'' and was considered likely to encode a

long non-coding RNA Long non-coding RNAs (long ncRNAs, lncRNA) are a type of RNA, generally defined as transcripts more than 200 nucleotides that are not translated into protein. This arbitrary limit distinguishes long ncRNAs from small non-coding RNAs, such as mic ...

(lncRNA). It was found to be expressed widely in tissues, including in the

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

and the

dorsal root ganglia A dorsal root ganglion (or spinal ganglion; also known as a posterior root ganglion) is a cluster of neurons (a ganglion) in a dorsal root of a spinal nerve. The cell bodies of sensory neurons known as first-order neurons are located in the dors ...

of the

spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...

. The researchers hypothesized that the microdeletion negated the normal function of FAAH by reducing its expression. Measurement of circulating endocannabinoid levels revealed that anandamide (''N''-arachidonoylethanolamine; AEA) levels were increased by 1.7-fold while

oleoylethanolamide Oleoylethanolamide (OEA) is an endogenous peroxisome proliferator-activated receptor alpha ( PPAR-α) agonist. It is a naturally occurring ethanolamide lipid that regulates feeding and body weight in vertebrates ranging from mice to pythons. OEA ...

(OEA) and

palmitoylethanolamide Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, and lipid modulator. A main target of PEA is proposed to be the peroxisome proliferator-activated receptor alpha (PPAR-α). PEA also has affinity to cannabinoid-like G-coupled recept ...

(PEA) levels were elevated by approximately 3-fold relative to several controls. Conversely, levels of 2-arachidonylglycerol (2-AG), another endocannabinoid mainly metabolized by a different enzyme called

monoacylglycerol lipase Monoacylglycerol lipase (EC 3.1.1.23; systematic name glycerol-ester acylhydrolase, also known as MAG lipase, acylglycerol lipase, MAGL, MGL or MGLL) is an enzyme that, in humans, is encoded by the ''MGLL'' gene. MAGL is a 33-kDa, membrane-associ ...

(MAGL) rather than by FAAH, were largely unchanged relative to controls. Studies of ''FAAH''

knockout mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...

have found that brain levels of anandamide and other endocannabinoids are increased by 10- to 15-fold in several regions and this correlated well with

and

anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...

s in these animals. Endocannabinoids like anandamide are

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

s of the

cannabinoid receptor Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system of vertebrates a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cann ...

s, such as the CB₁ and CB₂ receptors, among others. These receptors are the same molecular targets of the

phytocannabinoid Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoac ...

s, like Δ⁹-tetrahydrocannabinol (THC), that are present in

cannabis ''Cannabis'' () is a genus of flowering plants in the family Cannabaceae that is widely accepted as being indigenous to and originating from the continent of Asia. However, the number of species is disputed, with as many as three species be ...

. Cameron's son was also heterozygous for the ''FAAH-OUT'' microdeletion, but did not also have the hypomorphic ''FAAH'' polymorphism, and had a lesser and only partial reduction in pain sensitivity. His psychological and affective characteristics were not described. In spite of the preceding genetic and biochemical findings, it is not fully clear the extent to which Cameron's mutations in ''FAAH'' and ''FAAH-OUT'' are involved in her presentation. Hence, it has been stated that decreased FAAH expression remains only a possible causative factor. A subsequent study by the team characterized the molecular basis of Cameron's ''FAAH-OUT''-associated pain insensitivity, including changes in

gene expression Gene expression is the process (including its Regulation of gene expression, regulation) by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, proteins or non-coding RNA, ...

. They confirmed that her ''FAAH-OUT'' microdeletion reduced expression of FAAH. In addition, they found alterations that might help to explain her positive mood and low anxiety levels, for instance a dramatic increase in

brain-derived neurotrophic factor Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the can ...

(BDNF) expression in

fibroblast A fibroblast is a type of cell (biology), biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and ...

s derived from Cameron. Systemic FAAH inhibition has been found to increase BDNF levels in the

hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...

by approximately 25% in mice. BDNF, signaling through its receptor

tropomyosin receptor kinase B Tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the ''NTRK2'' gene. TrkB is a recept ...

(TrkB), has been highly implicated in protecting against depression and in

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

action.

Pharmaceutical development

Cameron's case has helped encourage interest in pharmaceutical development and

repurposing Repurposing is the process by which an object with one use value is transformed or redeployed as an object with an alternative use value. Description Repurposing is as old as human civilization, with many contemporary scholars investigating ho ...

of FAAH inhibitors for the treatment of

pain Pain is a distressing feeling often caused by intense or damaging Stimulus (physiology), stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sense, sensory and emotional experience associated with, or res ...

and

psychiatric disorder A mental disorder, also referred to as a mental illness, a mental health condition, or a psychiatric disability, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. A mental disorder is ...

s like depression and

. FAAH inhibitors are under development for various medical uses and several have reached

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s, but none have reached the market as of 2023. The most advanced drug candidate is JNJ-42165279, which has reached

phase 2 Michael Lawrence Marrow (August 2, 1955 – December 12, 2019), known as PHASE 2 and Lonny Wood, was an American aerosol paint artist based in New York City. Mostly active in the 1970s, Phase 2 is generally credited with originating the "bubble ...

clinical trials for the treatment of

anxiety disorder Anxiety disorders are a group of mental disorders characterized by significant and uncontrollable feelings of anxiety and fear such that a person's social, occupational, and personal functions are significantly impaired. Anxiety may cause phys ...

s and pervasive child development disorders (e.g.,

autism spectrum disorder Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing di ...

s) and has also been studied in the treatment of anxious depression. However, clinical trials of FAAH inhibitors in the treatment of pain, anxiety, and depression have so far been unsuccessful or disappointing. Results in these studies have been less than would be suggested by Cameron's case or those observed in

animal model An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...

s, in which the drugs are highly effective. Potential reasons for these discrepancies include species differences between animals and humans, lack of

predictive validity In psychometrics, predictive validity is the extent to which a score on a scale or test predicts scores on some criterion measure. For example, the validity of a cognitive test for job performance is the correlation between test scores and, for ...

s, differences between

preclinical studies In drug development, preclinical development (also termed preclinical studies or nonclinical studies) is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and dr ...

and clinical trial designs, and various others.

References

External links

Profile: The Far Out Initiative - Astral Codex Ten (Scott Alexander)
{{DEFAULTSORT:Cameron, Jo 1948 births 20th-century Scottish women 21st-century Scottish women Anxiety Congenital disorders of nervous system Endocannabinoids Famous patients Feeling Living people Pain Rare diseases

Clinical presentation

Genetic evaluation

Pharmaceutical development

See also

References

External links