Saturday, September 18, 2021

Bidding farewell to my ‘mind coach,’ a major ally in in my fight to avoid Huntington’s disease


In December, my psychotherapist will retire, ending for me a professional relationship of 24 years that became the most personal of bonds and an emotional bulwark in my fight to delay – and prepare for – the inevitable onset of Huntington’s disease.


I had consulted therapists in my twenties and early thirties for non-HD-related matters. However, after my mother’s diagnosis with HD in 1995 and her inexorable physical and mental decline, I spiraled downward into clinical depression and anxiety. I needed more profound, long-term psychological support.


I contacted the local psychoanalytic society, which, after an intake interview, put me in touch with a psychoanalyst who best matched my needs and goals. I was fortunate that she proved to be a good fit. I recommend a proactive attitude about therapy, with a willingness to ask questions, and, if necessary, switching to another analyst or therapist.


For me, so began a journey of seeking greater personal and social enrichment. HD researchers and physicians have long encouraged a healthy lifestyle, although no one has found evidence to prove its effect. However, as discussed below, scientists are seeking ways to use HD-affected individuals’ sense of meaning and purpose as a possible path to alleviating symptoms.


My psychotherapist has certainly helped me build meaning and purpose not just in my fight against HD, but in life in general.


As the format of my therapy went from classic psychoanalysis (multiple sessions per week lying on a couch) to a face-to-face encounter on a weekly, bi-weekly, and then monthly basis, I have referred to my therapist in different ways.


“My therapist is like a personal trainer,” I wrote in 2009. “She’s my mind coach. She helps me keep my mind working at its best to meet the challenges of living at risk for HD, just as a personal trainer or coach helps a professional athlete keep his body in top shape.”


Gene Veritas, aka Kenneth P. Serbin (photo by Yi Sun, Ph.D.)


Psychoanalysis: unleashing personal growth


Founded by the Viennese doctor Sigmund Freud in the early 1900s, psychoanalysis became the basis for modern talk therapies, in which the patient shares inner thoughts with the analyst, or therapist.


Although in the United States in the latter 20th century psychoanalysis was reduced to a small branch of the burgeoning psychological profession, it remained important in parts of Latin America, including Brazil, my second home. I researched the history of the Roman Catholic Church in Brazil for my Ph.D. dissertation, published as Needs of the Heart in 2006.


From the 1960s to 1980s, the Brazilian Church became the world’s most progressive. In Needs of the Heart, I wrote that in this period Brazil helped give birth to the important and controversial

liberation theology, “but also to liberation psychology, whose implications for the Church were even more revolutionary than the new theology.”


“Liberation psychology had a dual significance,” I asserted, referring to psychology in the broad sense, including psychoanalysis and many other approaches. “It could free people not only from poverty of spirit and mind but also from the repressive structures of Catholicism.” Liberation psychology sought to release people from such beliefs as the need to repress sexuality and unquestioningly accept religious authority. This history resonated deeply with my Catholic upbringing.


Igor Caruso, a Viennese Russian Orthodox analyst and an inspiration for Brazil’s pioneers of liberation psychology, viewed psychoanalysis as ultimately an encounter of love “between two unique and equally valuable personalities.” As I wrote, he believed that without love, there was no cure.


One leading priest-analyst in Brazil described psychoanalysis as a “special grace received from God” because of the profound self-discovery and personal growth it unleashed in people.


Although psychoanalysis in the U.S. fell behind other areas of psychology and medicine in terms of scientific innovation, it has, with the rise of neuroscience and molecular biology, experienced a renaissance. Using brain imaging, researchers have been exploring how different types of psychotherapy, including psychoanalysis, affect brain structure. (For details, see Nobel Prize laureate and brain scientist Dr. Eric Kandel’s In Search of Memory.)


Also, as I experienced, psychoanalysis could be aided with psychiatric medications.


About a year after learning about my mother’s HD diagnosis, during a year-long research stay in Brazil, I did therapy with a local analyst for several months. She urged me to continue analysis in the U.S. after my return in mid-1997.


Sharing the trials and triumphs of the HD cause


I, too, became liberated by psychoanalysis. As is often the case, the process took years.


In December 1997, I met my analyst for the first time. After a few preliminary weekly conversations, I lay on my therapist’s couch four times weekly, for 45 minutes, over about five years.


I always paid out-of-pocket: my insurance did not cover psychoanalysis. Fortunately, the psychoanalytic society sought to help people of all income levels. In retrospect, paying privately gave me a greater sense of security about confidentiality, because (in one of those terrible ironies of the U.S. health system!) I was deliberately keeping my HD status from my health plan, for fear of discrimination and losing my health coverage, until fully going public in 2012 (click here to read more).


As we talked, my analyst took copious notes on my thoughts and asked questions. I spoke mainly about my fears, feelings, and past, especially with regard to my relationship to my family, in particular my mother, who was slowly dying of Huntington’s.


My therapist listened intently and compassionately to my many struggles with HD and, more than anyone else, came to know how my fear of the disease – along with other factors – hindered clear thinking and the ability to enjoy life. She also shared my pride and joy in the many fundraising and awareness-building triumphs I achieved with others for the local chapter of the Huntington’s Disease Society of America (HDSA).


My psychotherapist helped me cope with the impact of my positive test for the HD mutation in 1999, my daughter’s negative test in the womb in 2000, and my mother’s death from HD in 2006.


Descending into the bedrock


By early 2003, we had reached a point in the analysis where I needed – and wanted ­– to descend into what I called the “bedrock,” the deepest, most difficult feelings, fears, and memories, which are the hardest to access and confront. Rooted in childhood and adolescence, they long preceded my family’s struggles with HD. However, I seemed incapable of entering the bedrock. Part of my mind resisted both my therapist, and myself, preventing me from being completely honest with myself and gaining more self-understanding.


My therapist gently pushed me to consider psychiatric medication to overcome that resistance.


Holding a Ph.D., but not an M.D., my therapist could not prescribe medicines, leading me to work with psychiatrists at my health plan.


That process proved difficult and frustrating; rather than specify my true concerns to these doctors, who knew nothing of my HD status, I had to speak in generalities.


Finding a winning combination


In addition, finding the right medication and the right dosage required years of trial and error. My first attempt, with Zoloft (sertraline), nearly proved disastrous: while driving my wife and daughter, I blanked out and ran the car onto the curb. Luckily, no one was injured. I immediately quit the medication.


Next, Prozac (fluoxetine) left me disoriented and extremely drowsy, so I was switched to Zyprexa (olanzapine). My mother was also taking this drug for her HD symptoms as an alternative to Haldol. Haldol was one of the standard prescriptions for HD but, we heard from the HD community, not recommended in many cases.


With worsening clinical depression and especially anxiety after my mother’s death in 2006, and working with a highly sympathetic psychiatrist (but who still did not know my risk for HD), I found a winning combination of escitalopram and risperidone for the respective conditions.


Since the late 1990s, I had also taken trazodone for sleep but quit in 2016 because I had improved on that front considerably. I have also wanted to avoid overloading my system with medications.


In contrast with Zoloft and Prozac, escitalopram and risperidone apparently did not cause any unpleasant side effects, although, according to my doctors, I have taken these last two drugs at very low doses. A general caution I heard from doctors: certain antidepressants can negatively impact sexual function.


Taking these medications was a huge step, because growing up I learned that psychological counseling and especially anything psychiatric were taboo and seen as shameful by many in my extended family.


Fear of HD diminished dramatically


In my late 40s, this successful treatment of escitalopram and risperidone relieved me of depression and greatly reduced my anxiety. In tandem with my therapy, these drugs finally helped me psychologically to feel as well as I ever had in my adult life. I have now taken them at the same dosage for more than a decade, and will do so for the foreseeable future.


Entering the bedrock, I continued to gain new insights with my therapist. The fear of unconditionally trusting her disappeared. I was able to comprehend my psyche. I became more perceptive and more self-aware – and also more accepting of others and more loving towards my family.


My fear of HD diminished dramatically – even though I knew that each day brought me closer to the likely onset.


I have the normal ups and downs we all have, but the medications continue to help keep me stable.


The benefits of stability


In 2011, my therapist helped me prepare for, and then marveled at, a major achievement in my HD advocacy, the first major step outside the “terrible and lonely HD closet”: my keynote speech at the Sixth Annual HD Therapeutics Conference, sponsored by CHDI Foundation, Inc., the nonprofit virtual biotech firm that is the largest private funder of efforts to develop treatments.


My therapist provided support for another milestone, and the beginning of the fully public phase of my advocacy: the publication of my article “Racing Against the Genetic Clock” in The Chronicle of Higher Education in 2012.


Psychological stability enabled me to work ever more effectively as an advocate and to concentrate on activities such as exercise that have bolstered my health. By then, I had also come off the couch, and our meetings became less frequent.


My therapist also became a regular reader of this blog. In some sessions, we have discussed concerns I have expressed in articles. On other occasions, therapy has helped suggest blog topics.


My therapist has been a true friend and partner in the fight against HD!


A broad strategy for avoiding symptoms


In recent years, as I have proceeded into my sixties, I have reflected on how I have so far avoided HD symptoms. On September 17, during my annual neurological checkup, the doctor found no signs of HD. My mother became symptomatic in her late forties and died at age 68. (Click here to read more.)


Psychotherapy forms part of a broad range of interrelated strategies for keeping healthy, including physical and mental exercise, blogging on HD, and taking supplements, some of which were ultimately proved ineffective. I also eat a healthy diet, and I meditate and practice spirituality. I have the benefit of a stable, solid-paying job and a close relationship with my wife and daughter.


As psychotherapy has helped enrich my life, it has also given me a greater overall sense of meaning and purpose.


Researchers are carefully studying these factors as a way to alleviate symptoms.


Meaning and purpose are key


In July, a team of twelve researchers published “Meaning and purpose in Huntington’s disease: a longitudinal study of its impact on quality of life,” in Annals of Clinical and Translational Neurology, a journal of the American Neurological Association.


The researchers studied 322 HD-affected individuals: 50 just starting to experience symptoms, 171 with early-stage disease, and 101 with late-stage disease. The participants did both an in-person assessment and an online survey. Data were collected between 2012 and 2016.


The results of the study demonstrated that “higher” meaning and purpose were “positively associated” with “positive affect [mood] and well-being,” the researchers stated.


Meaning and purpose also were associated with “decreased depression, anxiety, anger, emotional/behavioral disruptions, and cognitive decline at 12 and 24 months across all disease stages,” they wrote.


More research needed


The article pointed out the study’s limitations: correlation does not necessarily mean causation.


Thus, the researchers recognized the need to verify their findings with “additional instrumentation” to measure the connection between meaning and purpose and the patient-reported data. The study also did not account for possible bias from people on “psychoactive medications.”


Nevertheless, the researchers described the study as a “compelling first step” toward understanding the primary mechanism behind meaning and purpose – and how they might improve quality of life in HD-affected individuals.


Finding ways to help patients


The researchers concluded that their findings “parallel” those seen in those affected by cancer and might help point the way to “palliative HD interventions,” approaches that might relieve symptoms without removing the root cause.


They also pointed to the value of psychotherapy. They cited articles from studies of cancer patients and other conditions focusing on psychotherapy and other palliative measures such as spirituality.


Critically, a sense of meaning and purpose “may serve as a resiliency factor for suicide in people with the HD gene in that it can impact factors associated with suicidal ideation (e.g., depression, anxiety) as well as suicidal behaviors (e.g., impulsivity and anger).”


As the article pointed out, and as is well-known in the HD community, “suicide is a leading cause of death.”


Nostalgia, and looking ahead


As I read the journal article, I recalled my own fantasies about suicide in the first few years after my mother’s diagnosis and as I worried whether I had inherited the mutation.


The birth of our daughter in 2000 gave me immense meaning and purpose. I stopped thinking about suicide as a way to escape HD. My fight against HD became not only advocacy for the cure, but a personal quest to maintain stable health so that I could see my daughter grow up.


My mind coach has been an invaluable companion in this journey.


As we have our final sessions, I will become deeply sad. It feels like a lifelong friend moving to another city, with little chance of a visit.


My therapist and I have discussed the pain of separation. As usual, she will be helping me to remain stable and find a good path forward.


With nostalgia, we have also discussed the tremendous progress I have made, including the highlights of my HD advocacy.


In July, I began meeting occasionally with another therapist, so that I have psychological support beyond my mind coach’s retirement.


I am looking forward to discovering another ally in the fight against Huntington’s.

Wednesday, July 14, 2021

CRISPR, curing Huntington’s disease, and humanity’s future in Isaacson’s ‘Code Breaker’

In a new book about the broad issue of editing human DNA, a prominent biographer of scientific innovators proposes that such cutting-edge, potentially curative gene editing research prioritize Huntington’s disease.


“Our newfound ability to make edits to our genes raises some fascinating questions,” writes historian Walter Isaacson – author of studies of Leonardo da Vinci, Steve Jobs, Albert Einstein, and Benjamin Franklin – at the outset of his recently published The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race.


Code Breaker presents a crucial account of the biggest breakthrough in genetics since the discovery of DNA’s structure in 1953 by Francis Crick and James Watson.


Editing our DNA, the molecule that makes up our genes and guides our biological lives, to make us less susceptible to microbes like the coronavirus would be a “wonderful boon,” Isaacson suggests in the introduction.


“Should we use gene editing to eliminate dreaded disorders, such as Huntington’s, sickle-cell anemia, and cystic fibrosis?” he asks. “That sounds good, too.”


Jennifer Doudna, Ph.D., the subject of Code Breaker, has also embraced the concept of gene editing for HD if it can become a safe and effective therapy. Dr. Doudna won the 2020 Nobel Prize in Chemistry for her work in identifying and understanding the natural gene editing process now widely known as CRISPR, and the insight that this tool could potentially be refined for use not only in the laboratory, but ultimately also in the clinic, to alter human DNA.


Above, author Walter Isaacson learns CRISPR editing, and, below, the cover of Code Breaker (images from Simon & Schuster website).


A historic breakthrough, major consequences


In Code Breaker, Isaacson traces the influence of the controversial Watson, now 93, on Dr. Doudna and others. He also interviewed Watson.


For both general readers and specialists, Code Breaker furnishes an excellent description of Dr. Doudna and others’ investigation of the structure and actions of CRISPR-Cas9, the specific type of gene editing feasible for use in humans.


CRISPR stands for “clustered regularly interspaced short palindromic repeats,” a strand of RNA, and Cas-9 for the enzyme associated with the RNA. Cas-9 acts as a type of scissors to cut DNA. The RNA guides the enzyme to the cutting target. There are other types of CRISPR.


Ultimately, Isaacson delves into the significance of CRISPR (and related themes such as biohacking and home genetic testing) for the future of humanity. CRISPR can perhaps end single-gene disorders like Huntington’s – but might ultimately also permit us to change such characteristics as IQ, muscle size and strength, and height. Russian President Vladimir Putin has extolled CRISPR as a potential way to produce “super-soldiers,” as Isaacson notes.


A powerful bioethical story


Isaacson has produced a powerful bioethical study of when and how gene editing should be done. He interviewed Dr. Doudna other scientists on their views. He also consulted bioethicists and their writings.


He also contrasts competing political theories regarding editing, pitting the idea of a free-market “genetic supermarket,” where the individual decides, against that of a society (and its government) that would permit editing only if it did not increase inequality.


Thus, Code Breaker is a major contribution to bioethics (the ethics of medical and biological research). Isaacson analyzes the potential social, moral, ethical, political, and ultimately biological consequences of gene editing and the conflicts it might produce. Editing the human race could produce many wonders, but also less biological diversity and greater and more permanent inequality, as the rich will almost inevitably gain privileged access to therapies and enhancements.


Isaacson illuminates this dilemma by recounting Dr. Doudna’s own “ethical journey” on gene editing.


“By limiting gene edits to those that are truly ‘medically necessary,’ she says, we can make it less likely that parents could seek to ‘enhance’ their children, which she feels is morally and socially wrong,” he writes. The lines between the different types of edits can be blurry.


“As long as we are correcting genetic mutations by restoring the ‘normal’ version of the gene – not inventing some wholly new enhancement not seen in the average human genome ­ – we’re likely to be on the safe side,” Dr. Doudna affirms.


Code Breaker also offers important evidence of the tension between so-called open science, where researchers (and some biohackers) freely share data, and the scientists, universities, and corporations that fight to establish patents and earn profits. (Click here for more on this development.)


Making the case for editing the HD mutation


Isaacson recounts how, in 2016, Dr. Doudna was especially moved by a visit at her workplace, the University of California, Berkeley, with a man from an HD family, who described to her how his father and grandfather had died of the disease, and that his three sisters, also diagnosed with the disorder, now “faced a slow, agonizing death.”


Putting Huntington’s first in a series of bioethical case studies, Isaacson underscores the crucial need for an HD CRISPR treatment, noting the disease’s devastating symptoms and rare, dominant genetic nature (inheriting the mutation from just one parent is sufficient for getting symptoms).


“If ever there was a case for editing a human gene, it would be for getting rid of the mutation that produces the cruel and painful killer known as Huntington’s disease,” Isaacson asserts.


Eliminating HD forever


For HD, Isaacson suggests a germline edit—removing the elongated piece of DNA in the huntingtin gene that causes HD in an embryo. A treatment done at this stage would restore the normal function of the HD gene in all the body cells, including that individual’s eggs or sperm. This genetic repair would then be inheritable, thus erasing HD forever from the future generations of the family.


Scientific protocol and governments have not yet approved such edits, though they have been done in animal subjects. As narrated in great detail in Code Breaker, a Chinese researcher did such an edit – to prevent AIDS – in twin babies in 2018, only to be punished by his country’s government and criticized as irresponsible by scientific colleagues. However, Dr. Doudna and other pioneers of CRISPR remain hopeful that safe, inheritable edits will become acceptable for at least some conditions.


Isaacson mentions two alternatives to germline editing that can eliminate HD from a family’s lineage. First, adoption. Second, preimplantation genetic diagnosis (PGD), which involves in vitro fertilization using embryos screened for the mutation. PGD has been used in the HD community for about 20 years. Before PGD arrived, some families, like mine, have had our offspring tested in the womb. However, neither of these strategies have been used widely in the HD community by at-risk couples.


If it can be harnessed safely, to target only the abnormal HD gene, and delivered effectively to human cells, CRISPR could provide the all-out cure for Huntington’s long sought by science and so deeply hoped for by HD families.


Isaacson concludes, “it seems (at least to me) that Huntington’s is a genetic malady that we should eliminate from the human race.”


For now, don’t ‘hold your breath’ for an HD CRISPR therapy


Isaacson states that “fixing Huntington’s is not a complex edit,” but he does not elaborate further.


However, while leading HD scientists are eagerly using CRISPR as a research tool, the technique is far from ready as a therapy.


CRISPR was a key topic at the “Ask the Scientist … Anything” panel of the virtual 36th Annual Convention of the Huntington’s Disease Society ofAmerica (HDSA), held June 10-13. Noting that many in the HD community have inquired about CRISPR, HDSA Chief Scientific Officer George Yohrling, Ph.D., asked the panel to comment on its potential as a therapy.


“CRISPR is really an exciting tool,” said researcher Jeff Carroll, Ph.D., co-founder of the HDBuzz website and, like me, an HD gene carrier who lost his mother to the disease. “CRISPR allows us really for the first time to edit DNA itself in a very precise way, to make very precise cuts in the DNA of a cell or even in an intact organism.” He added: “scientists are using it like crazy” in lab experiments.


In his own HD-focused lab at Western Washington University, Dr. Carroll and his team have developed a line of experimental mice with cells containing enzymes (proteins that act as chemical catalysts) necessary for doing CRISPR edits, Dr. Carroll explained. Such enzymes do not normally occur in human cells, he added.


Using CRISPR, “we can mess with these mice’s genome [DNA] in ways that were unimaginable just a few years ago,” Dr. Carroll continued.


Dr. Jeff Carroll commenting on HD science at the virtual 2021 HDSA national convention (screenshot by Gene Veritas, aka Kenneth P. Serbin)


For an HD family, “the idea of cutting out the DNA and fixing it is very, very appealing and something we can do in animal models and [animal and human] cell lines in the lab already, and it looks really promising.”


However, Dr. Carroll offered a blunt assessment of the current state of research on CRISPR as an HD treatment.


“As an actual HD therapy, I’m less excited about CRISPR,” he said. “I think it’s many years away. Something based on it may someday help us, but you have to realize that these enzymes that you need to enact CRISPR are themselves giant proteins that actually originate from bacteria, and we have to put them into the cell.


“So, if you want to use CRISPR as a therapy for Huntington’s and we want to modify all the DNA in the whole brain, we have to get into every one of your 84 billion neurons and put a CRISPR factor in there and modify the DNA.”


As a result, “Huntington’s will not be the first disease treated with CRISPR,” Dr. Carroll concluded. “I wouldn’t hold your breath for it as a therapy for HD in the medium or short term.”


Currently, a possible better candidate for a CRISPR treatment would be a disease involving immune cells that could be removed from the body, edited, and then reintroduced into the individual, Dr. Carroll observed.


Elaborating on Dr. Carroll’s comments, Ed Wild, M.D., Ph.D., another speaker at the HDSA science panel and also a co-founder of HDBuzz, cited the example of a blood cancer as a possible early target for CRISPR.


He agreed with Dr. Carroll that an HD CRISPR treatment remains difficult at this time and underscored why: unlike parts of the body like blood cells or bone marrow, brain cells cannot be removed, treated, and reinserted or given replacements.


Further cautions


An August 2020 HDBuzz article also urged caution in the use of CRISPR for HD and other genetic diseases in the wake of three experiments with human embryos that resulted in “unintended changes in the genome.” These so-called “off-target” effects suggest that “CRISPR is less precise than previously thought,” the article stated. Like desired edits, the unwanted ones make permanent changes to the DNA.


Such unintended edits are “bad because our DNA code is a very precise set of instructions, which can be thought of like a cooking recipe,” the article explained. “If you rearranged the steps in a recipe or got rid of some of the ingredients the outcome would not be good!”


When CRISPR is used in an embryo, the mistaken edits would not only affect that individual, but could also be passed on to the next generation.


Clarifying some key points


As an HD advocate and family member who has tracked the research for two decades, I felt that Code Breaker could have gone into greater depth about HD science. Given all the valuable detail about Dr. Doudna’s and other scientists’ efforts to discover the workings of CRISPR, it would have been helpful to present some scenarios about how it might work in HD.


Code Breaker also states that in HD the “wild sequence of excess DNA serves no good purpose.” This is a confusing term, as so-called “wild” type DNA in this context usually means “normal” DNA. Isaacson might better have done better to avoid the use of this term, but instead to emphasize that the normal huntingtin gene is essential for life and brain cell stability, as HD research has demonstrated. Normal huntingtin is present in all humans without the mutation and even in those who have inherited a mutation from one parent, because the non-HD parent has passed on a normal copy of the gene.


The book could have further benefited from additional references to both the scientific and social significance of the disease as presented in works such as Dr. Thomas Bird’s Can You Help Me? Inside the Turbulent World of Huntington Disease. There was also no reference to the pathbreaking research on modifier genes, which can hasten or delay the onset of HD.


Contemplating the ‘gift’ of life


Citing the philosopher Michael Sandel, Isaacson points out that finding “ways to rig the natural lottery” of genetics could lead humanity to humbly appreciate the “gifted character of human powers and achievements. […] Our talents and powers are not wholly our own doing.”


Still, I agree with Isaacson that “few of us would regard Alzheimer’s or Huntington’s to be a result of giftedness.”


Even so, it’s important to recall that HD researchers continue to investigate the role of the huntingtin gene not only in the disease, but, in the words of one study, in intelligence and the “evolution of a superior human brain.”


Faced with the daunting challenges of the disease, many HD mutation carriers and affected individuals have also grown in unexpected ways. I, for one, consider myself a lucky man because of the richer life I have lived as a result of my family’s fight against Huntington’s.


In this new reality, advocating once again for our families


HD families like mine have lived on the frontier of bioethics, facing challenges such as genetic testing, prenatal testing, genetic discrimination, decisions on family planning, and many others.


Perhaps, as Code Breaker speculates, gene editing may someday be considered morally acceptable in the way that in vitro fertilization and PGD have come to be.


However, as seen in the case of abortion, the HD community does not have a monolithic bioethical stance (click here and here to read more).


It remains an open question as to whether the HD community would wholeheartedly embrace CRISPR as a therapy. Some might celebrate it as a cure, but others might see it as going against nature or even as a return to the era of eugenics in the early- to mid-20th century, when medical professionals advocated sterilization for HD-affected individuals. Taking a cue from the United States, the Nazis were said to have forcibly sterilized as many as 3,500 people affected by Huntington’s.


No book can offer a definitive answer to these ethical quandaries. Code Breaker provides us with at least some basic guideposts.


It will ultimately fall to HD-affected individuals and their families (and those families affected by other diseases) to navigate what could very soon become the new reality of gene editing – and, when necessary, to act as powerful advocates. To assist us in this journey, we will need ethically informed health professionals and patient organizations.

Sunday, May 16, 2021

‘Inequality is unsustainable’: a view of the quest for Huntington’s disease treatments from the Global South

(I dedicate this article to the worldwide HD community as we mark Huntington’s Disease Awareness Month in many countries around the planet.)


Both the COVID-19 pandemic and the quest for treatments for rare and genetic diseases have laid bare deep social divisions across the world, and it behooves the scientific establishment to help resolve this ethical dilemma, says a leading Brazilian Huntington’s disease clinician.


“The world should not be divided between those who have money and those who don’t,” Mônica Santoro Haddad, M.D., a neurologist with 33 years’ practice at the Universidade de São Paulo (USP) School of Medicine, told me in an April 30 Zoom interview about the 16th Annual HD Therapeutics Conference. “The pandemic has already shown us that. This inequality is unsustainable.”


Dr. Haddad has assisted HD patients from 600 families at the USP neurology clinic and her private office. A participant in the 2013 Therapeutics Conference in Venice, Italy, and 2014 meeting in Palm Springs, CA, she watched all of this year’s three-day virtual event (April 27-29) online. The conferences are sponsored by CHDI Foundation, Inc.


“What we’re witnessing in Brazil [regarding the pandemic] is immoral – Brazil in relationship to the world and Brazil in general,” Dr. Haddad observed, speaking in her native Portuguese. “Two categories of people have been created: those with the vaccine, those without the vaccine.”


A South American giant struggles


Sadly, Brazil ranks second in the world behind the United States with more than 428,000 COVID-19 deaths.


As a history professor, I have dedicated much of my career to the study of Brazil, a country that I consider my second  home; my wife is Brazilian, and her extended family is there. Along the way, I have witnessed the development of the Associação Brasil Huntington and built ties to its leaders.


A major country of the Global South – the world’s developing countries – Brazil has an estimated 20,000-plus afflicted individuals and an active HD movement. An enthusiastic group of some 30 Brazilians took part in #HDdennomore, Pope Francis’ special audience with the HD in May 2017. Francis, a native of Argentina, is also the first pontiff from the Global South.


However, although Brazil’s medical system has gained international recognition for past vaccine campaigns and its model fight against AIDS, during the pandemic the country has lacked hospital beds, cemetery plots, and basic supplies. Like Donald Trump, Brazilian President Jair Bolsonaro denied the crisis, downplayed the dangers, and actively denounced such measures as mask-wearing.


In addition, Brazil has fallen victim to the international inequities in the rollout of vaccines. Both U.S. President Joe Biden and former Brazilian president Luiz Inácio Lula da Silva – a likely candidate in the 2022 presidential election – have backed waiving COVID-19 vaccine patents to assure global access.


Brazil’s deep internal disparities have led to inadequate vaccine distribution to the poor and marginalized.


Recognizing similar, longstanding neglect in other South American countries, the humanitarian organization Factor-H has continued to assist abandoned HD families during the crisis.


Providing everybody access to medicines


Echoing her concerns about COVID-19, Dr. Haddad affirmed the need for a “change in the paradigm” regarding rare and genetic diseases like Huntington’s.


As in the U.S. and elsewhere, fear and denial frequently underlie Brazilians’ decisions to avoid genetic testing and facing the terrible medical and social challenges posed by the disease. Many Brazilians have “prejudice against disease” in general, Dr. Haddad told me in a 2013 interview.


However, the trend against testing might be shifting for the younger generations, and could also change among older groups when the overall outlook for treatments has improved, Dr. Haddad wrote in a May 14 WhatsApp message. Clinical trials seeking presymptomatic HD gene carriers will require testing, she added.


Like medical professionals in many countries, Dr. Haddad believes genetic testing is a personal decision, with the procedure governed by established protocol and with professional medical and psychological support.


As of April 2021, the Brazilian government has required all private health plans and insurance to cover genetic testing. This represented a “small advance,” Dr. Haddad asserted in our Zoom interview, because health advocates want to see the country’s free public health service also provide that benefit.


For Dr. Haddad, for HD to be defeated, inequality must diminish.


“The question is: is it ethical to diagnose someone with one of those diseases and not have a treatment available?” Dr. Haddad said. “This is a question that I discuss with my patients and with my colleagues.”


She added: “It is certainly not ethical to have a treatment that not everybody has access to.”


The HD Therapeutics Conference left her with her “hope battery recharged” and confident that a treatment is possible, Dr. Haddad said.



Gene Veritas interviewing Dr. Mônica Haddad (screenshot by Gene Veritas, aka Kenneth P. Serbin)


Advocating for open science


At the close of the conference, Dr. Haddad was inspired by the presentation by featured speaker Aled Edwards, Ph.D., who in 2004 founded the Structural Genomix Consortium (SGC), which practices and advocates for open sharing of scientific information, particularly as it applies to protein science, chemical biology, and drug discovery.


Dr. Edwards, the SGC CEO and a scientist based at the University of Toronto, spoke on “HD drug discovery in the public domain – a model for CHDI.” A breath of “fresh air,” Dr. Edwards’ talk pointed the way to reducing inequality, Dr. Haddad told me.


“What we would also like to do is develop a drug discovery ecosystem that prioritizes affordability and global access, and, of course, to do this in collaboration with industry,” Dr. Edwards stated. “Now this might sound naïve, but I’d like to emphasize there’s quite a bit of drug discovery experience in the SGC and in our network.”


Dr. Edwards presented examples of researchers who have followed the open science model – including 16 “HD open science programs” that share science “as they go,” with some even blogging about their findings. He highlighted the work of Rachel Harding, Ph.D., an SGC researcher and postdoctoral fellow at the University of Toronto who achieved the “very challenging” task of purifying the huntingtin protein to a “resolution that is practically useful” to other scientists.


Dr. Harding has widely shared both the protein and reagents (compounds that facilitate chemical reactions) that enable the making of the protein, ultimately aiming to inform the discovery of potential HD drugs, in particular so-called small-molecule drugs, Dr. Edwards explained.


Discussed at the Therapeutics Conference, these drugs become distributed very evenly across the whole body, including the brain, whereas several drugs in other current or recently completed clinical trials need to be injected directly into the brain or via spinal tap.


“This is a really fantastic contribution to the public good that these folks have made,” Dr. Edwards said of Dr. Harding’s team.


Sharing science as they go: Huntington's disease "open science champs" as presented by Dr. Aled Edwards, at upper right (screenshot by Gene Veritas)


Seeking more efficient drug discovery


Dr. Edwards underscored a key point: despite spending $300 billion globally each year on research and development and producing many hugely successful drugs, the biomedical field is highly inefficient. “We need to do better as a society,” he asserted.


“For many diseases – Huntington’s, Parkinson’s, Alzheimer’s – we don’t even know the molecular mechanism of the disease, let alone how to design a therapeutic strategy,” Dr. Edwards said, adding that a system in which the “first past the post gets the money” in designing drugs has required “the pricing of medicines at levels that are unaffordable for most people on the planet.”


Dr. Edwards displayed data demonstrating how globally most research focuses on the familiar rather than explore new, potentially crucial areas of biology. Similarly, in industry, companies pursue drugs in parallel rather than collaborate, wasting valuable resources, he added.


SGC is working against the grain, trying to create the way for a new scientific culture. The SGC never files for patents “as a core principle,” Dr. Edwards explained. “All of the work we do goes into the public domain, including the reagents that we make.”


If labs and companies openly shared data before doing the final crucial test on a potential drug in a Phase 3 trial, the field could not only save money, but test multiple drugs at the same time, he said.


Rather than rely on patents, the system should take advantage of federal laws that give companies protection from competition for a fixed period, generally five to twelve years, Dr. Edwards affirmed. The law provides even longer periods for orphan and pediatric drugs.


Supporting the public good


“There is no law of physics that says industry has to invent a drug,” Dr. Edwards said. “That’s the social system that we’ve put in place. Let’s imagine a different system.”


To “walk the walk about open drug discovery,” SGC established the Agora Open Science Trust, a registered charity in Canada modeled on Newman’s Own Foundation, which funnels profits from food products with the picture of the late Academy-Award-Winning actor into philanthropy.


Dr. Edwards described its goal: “To support open science and the public good, and price new medicines to ensure global access. Whether you’re a rich American or live in Thailand, you’re going to get the medicine at a price you can afford.”


In its first project, Agora has focused on children’s cancers. As of yet the trust has not announced a plan for an HD drug program, although Dr. Edwards and the above-mentioned HD open science researchers have an abiding interest in finding treatments.


Indeed, regarding those treatments, Dr. Edwards concluded that “if we do it as a collective, we’ll get further faster.”



Dr. Aled Edwards explains the creation of for-profit drug companies to fund the Agora Open Science Trust, whose mission is to ensure global, affordable access to new medicines (screenshot by Gene Veritas).


Knowledge belongs to the world


If Dr. Edwards and SGC achieve their goals, they will have a place in history, Dr. Haddad observed. The emphasis on sharing data will “democratize” knowledge, she added.


“It’s obvious that a company does things to earn money,” Dr. Haddad continued. She noted, however, that Dr. Edwards is asking scientists and others to put their vanity aside to help the suffering.


Brazil has not yet hosted, and may not host in the future, any sites for the major HD clinical trials, Dr. Haddad pointed out. She noted that the local HD community attempted to bring to Brazil the historic Phase 3 gene silencing clinical trial by Roche, which reported the unfavorable results at the HD Therapeutics Conference. In South America, Roche ran the trial in Argentina and Chile.


“We did the paperwork to try to include a Brazilian research center, and because of questions raised by an ethics committee and political and legal issues, we were unsuccessful,” Dr. Haddad explained. “Brazil did not permit genetic material [from the clinical trial] to be sent out of the country.”


For now, Dr. Haddad said, Brazilians can at least look forward to the possibility of their government’s authorization of the drug Austedo, approved by the U.S. Food and Drug Administration in 2017 for chorea, the involuntary movements that occur in many HD-affected individuals.


At this time, Brazil’s lack of participation in clinical trials of drugs that aim to slow or stop the disease is “not important,” Dr. Haddad concluded. Echoing Dr. Edwards – and the hope of thousands of Brazilian HD families anxiously awaiting the arrival of effective treatments but fearful that the country might not be able to afford them – she added: “The knowledge obtained belongs to the world.”