Monday, June 10, 2024

BrainBridge

https://www.youtube.com/watch?v=szXbuUlUhQ4

The internet has been set ablaze with a mind-bending video depicting a futuristic "head transplant machine" called BrainBridge. The footage, which has amassed hundreds of thousands of views, shows robotic arms swiftly removing a person's head and attaching it to a healthy body. 

The idea is to give people with severe disabilities a new lease on life by using artificial intelligence algorithms to direct robotic arms to remove a head and attach it to a new torso.

While the concept may seem straight out of a B-grade horror flick, it has ignited a fiery debate about the ethics and feasibility of such a procedure. Is BrainBridge a genuine biomedical endeavor or an elaborate hoax designed to provoke discussion?

The mastermind behind the viral sensation

As it turns out, BrainBridge is not a real company. The video is the brainchild of Hashem Al-Ghaili, a Yemeni science communicator and film director known for blurring the lines between reality and science fiction. Al-Ghaili's previous viral hit, "EctoLife," depicted artificial wombs and left journalists scrambling to separate fact from fiction.

While the BrainBridge video may be a work of fiction, it serves as a provocative billboard for a controversial scheme gaining traction among some life-extension proponents and entrepreneurs — head transplantation, or as some prefer to call it, "body transplantation."

The pursuit of radical life extension

For those dedicated to achieving radical life extension, the idea of head transplantation holds an alluring promise — the ability to bypass aging by transferring one's head onto a younger, healthier body. Proponents argue that while anti-aging medicine has yet to achieve significant breakthroughs, a head transplant could offer a comparatively straightforward solution, at least as long as the brain remains functional.

However, the concept raises a host of ethical and practical concerns. Where would the donor bodies come from? Would it be ethical to use a body to benefit only one person when its organs could save multiple lives? These are just a few of the thorny questions that have emerged in the wake of the BrainBridge video.

Kurt's key takeaways

While the public reaction to the BrainBridge video has been largely negative, with many decrying the idea as "disgusting" and "immoral," Al-Ghaili remains undeterred. He claims to have received inquiries from potential investors and individuals seeking relief from personal health challenges.

As the debate rages on, one thing is clear. The BrainBridge video has challenged our perceptions of what is possible and forced us to confront the ethical implications of pushing the boundaries of science and technology in the pursuit of longevity.

https://www.foxnews.com/tech/real-story-behind-creepy-head-swapping-operations-robotic-surgeons




Thursday, June 6, 2024

EBF3 neurodevelopmental disorder

Inspired by a patient

Ignatius E, Puosi R, Palomäki M, Forsbom N, Pohjanpelto M, Alitalo T, Anttonen AK, Avela K, Haataja L, Carroll CJ, Lönnqvist T, Isohanni P. Duplication/triplication mosaicism of EBF3 and expansion of the EBF3 neurodevelopmental disorder phenotype. Eur J Paediatr Neurol. 2022 Mar;37:1-7. doi: 10.1016/j.ejpn.2021.12.012. Epub 2021 Dec 26. PMID: 34999443.

Abstract

Deleterious variants in the transcription factor early B-cell factor 3 (EBF3) are known to cause a neurodevelopmental disorder (EBF3-NDD). We report eleven individuals with EBF3 variants, including an individual with a duplication/triplication mosaicism of a region encompassing EBF3 and a phenotype consistent with EBF3-NDD, which may reflect the importance of EBF3 gene-dosage for neurodevelopment. The phenotype of individuals in this cohort was quite mild compared to the core phenotype of previously described individuals. Although ataxia tended to wane with age, we show that cognitive difficulties may increase, and we recommend that individuals with EBF3-NDD have systematic neuropsychological follow-up.

Deisseroth CA, Lerma VC, Magyar CL, Pfliger JM, Nayak A, Bliss ND, LeMaire AW, Narayanan V, Balak C, Zanni G, Valente EM, Bertini E, Benke PJ, Wangler MF, Chao HT. An Integrated Phenotypic and Genotypic Approach Reveals a High-Risk Subtype Association for EBF3 Missense Variants Affecting the Zinc Finger Domain. Ann Neurol. 2022 Jul;92(1):138-153. doi: 10.1002/ana.26359. Epub 2022 Apr 16. PMID: 35340043.

Abstract

Objective: Collier/Olf/EBF (COE) transcription factors have distinct expression patterns in the developing and mature nervous system. To date, a neurological disease association has been conclusively established for only the Early B-cell Factor-3 (EBF3) COE family member through the identification of heterozygous loss-of-function variants in individuals with autism spectrum/neurodevelopmental disorders (NDD). Here, we identify a symptom severity risk association with missense variants primarily disrupting the zinc finger domain (ZNF) in EBF3-related NDD.

Methods: A phenotypic assessment of 41 individuals was combined with a literature meta-analysis for a total of 83 individuals diagnosed with EBF3-related NDD. Quantitative diagnostic phenotypic and symptom severity scales were developed to compare EBF3 variant type and location to identify genotype-phenotype correlations. To stratify the effects of EBF3 variants disrupting either the DNA-binding domain (DBD) or the ZNF, we used in vivo fruit fly UAS-GAL4 expression and in vitro luciferase assays.

Results: We show that patient symptom severity correlates with EBF3 missense variants perturbing the ZNF, which is a key protein domain required for stabilizing the interaction between EBF3 and the target DNA sequence. We found that ZNF-associated variants failed to restore viability in the fruit fly and impaired transcriptional activation. However, the recurrent variant EBF3 p.Arg209Trp in the DBD is capable of partially rescuing viability in the fly and preserved transcriptional activation.

Interpretation: We describe a symptom severity risk association with ZNF perturbations and EBF3 loss-of-function in the largest reported cohort to date of EBF3-related NDD patients. This analysis should have potential predictive clinical value for newly identified patients with EBF3 gene variants. ANN NEUROL 2022;92:138-153.

Zhu J, Li W, Yu S, Lu W, Xu Q, Wang S, Qian Y, Guo Q, Xu S, Wang Y, Zhang P, Zhao X, Ni Q, Liu R, Li X, Wu B, Zhou S, Wang H. Further delineation of EBF3-related syndromic neurodevelopmental disorder in twelve Chinese patients. Front Pediatr. 2023 Mar 3;11:1091532. doi: 10.3389/fped.2023.1091532. PMID: 36937983; PMCID: PMC10020332.

Abstract

Neurodevelopmental disorders (NDDs) have heterogeneity in both clinical characteristics and genetic factors. EBF3 is a recently discovered gene associated with a syndromic form of NDDs characterized by hypotonia, ataxia and facial features. In this study, we report twelve unrelated individuals with EBF3 variants using next-generation sequencing. Five missense variants (four novel variants and one known variant) and seven copy number variations (CNVs) of EBF3 gene were identified. All of these patients exhibited developmental delay/intellectual disability. Ataxia was observed in 33% (6/9) of the patients, and abnormal muscle tone was observed in 55% (6/11) of the patients. Aberrant MRI reports were noted in 64% (7/11) of the patients. Four novel missense variants were all located in the DNA-binding domain. The pathogenicity of these variants was validated by in vitro experiments. We found that the subcellular protein localization of the R152C and F211L mutants was changed, and the distribution pattern of the R163G mutant was changed from even to granular. Luciferase assay results showed that the four EBF3 mutants' transcriptional activities were all significantly decreased (p < 0.01). Our study further expanded the gene mutation spectrum of EBF3-related NDD.

Wednesday, June 5, 2024

Bilateral gene therapy in children with autosomal recessive deafness 9

Five children who were born completely deaf have had some reversal of hearing loss after receiving a "groundbreaking" gene therapy.

The clinical trial, which was co-led by Mass Eye and Ear in Boston and the Eye & ENT Hospital of Fudan University in Shanghai, was the first in the world to apply gene therapy to children in both ears, according to the researchers.

The research has just been published in Nature Medicine on June 5.

In addition to regaining their hearing, the children participating in the trial — who ranged in age from 1 to 11 years old — were also able to identify the origins and locations of sounds, even in noisy environments, researchers said.

This was a follow-up to an earlier trial that began in Dec. 2022, in which the research team successfully performed the gene therapy in just one ear. This new study showed that treating both ears led to even greater benefits.

All the children in the study had a hereditary form of deafness called DFNB9, which is caused by mutations in the OTOF gene.

The condition occurs when the OTOF gene is unable to produce a protein called otoferlin, which is essential for transmitting sound signals from the ear to the brain.

As a result, the children could not hear or speak.

"The children were chosen because they would benefit most from early intervention of gene therapy, especially in speech acquisition," study author Zheng-Yi Chen, DPhil, an associate scientist in the Eaton-Peabody Laboratories at Mass Eye and Ear in Boston, told Fox News Digital in an interview.

"From a safety standpoint, however, it is more risky for children."

How the procedure works

During the "minimally invasive" surgical procedure, the doctors administered an injection of the human OTOF gene into the children’s inner ears.

The children remained in the hospital for around seven to 10 days for observation.

"After four weeks, the kids showed hearing perception in tests, and then gradually they gained the ability to speak," Chen said.

Within the families, response to sound was noticed within two to three weeks.

"All five patients have restoration of hearing, speech perception improvements, and sound source perception in noisy environments," Chen said.

The participants experienced only low-grade adverse effects, such as fever and vomiting.

"This is the first time in history that hearing loss is being reversed by gene therapy."

"There were no serious adverse effects," he said. "They all recovered without any intervention."

The gene therapy is intended to be a one-time treatment and will not need to be repeated, the researchers said, although the children will likely require speech therapy.

Until now, there has not been any single treatment for hearing loss, other than cochlear implants, according to researcher Yilai Shu M.D., PhD, director of the Diagnosis and Treatment Center of Genetic Hearing Loss at Fudan Hospital in Shanghai.

"This is the first time in history that hearing loss is being reversed by gene therapy," Shu told Fox News Digital. "And, of course, we believe this will have a profound impact on children's lives."

Chang Yiyi, a mother in Shanghai whose 3-year-old son, Zhu Yangyang, participated in the trial, spoke to Fox News Digital about the experience.

"When Zhu couldn’t speak at 2 years old and didn’t have a response to sound, we realized there was a problem," she said.

After hearing tests, it was determined that Yiyi’s son had total deafness.

"It was unbelievable — the best feeling. It was like a miracle."

"He would get very frustrated because he couldn’t understand, couldn’t speak, couldn’t hear," she said.

Twenty-three days after receiving the gene therapy, the boy first responded to someone calling out to him.

"It was unbelievable — the best feeling," Yiyi told Fox News Digital. "It was like a miracle."

"Now he can say ‘Mommy’ and ‘I want’ and some simple sentences."

Approximately 430 million people worldwide have disabling hearing loss, including 34 million children, according to the World Health Organization.

Gene therapy is promising but limitations exist, expert says

Dr. Amy Sarow, the Michigan-based lead audiologist at Soundly, a hearing health care marketplace, noted that gene therapy has had some success in the treatment of cancer and eye disease, along with other emerging areas.

"It is exciting to think about how gene therapy could impact millions of individuals with hearing loss worldwide," Sarow, who was not involved in the experimental gene therapy, told Fox News Digital.

"However, it is essential to emphasize that there are many causes of hearing loss, and one type of gene therapy will not be right for every type."

Even among genetic causes of deafness, different genes may cause abnormalities or dysfunction that affect different auditory pathways, according to Sarow.

"Thus, development of specific treatment interventions is dependent on causality and will still take time to develop."

Additionally, Sarow noted, a "reversal" of hearing loss does not mean that an individual will have normal hearing ability fully restored.

"The first three years of life are very important to language acquisition, and although these children would be behind their normal-hearing peers (having spent the first few years of life profoundly deaf), they would still have the possibility to ‘catch up’ to some degree," she said.

"Research tells us that the younger the intervention, the better for potential language development."

As with any intervention, there can be risks with gene therapy. "One potential risk is that treatment may not be successful in every case," Sarow said.

"Another potential risk is that the targeted gene therapy may not work in the targeted region."

What’s next?

The next step is to follow the trial patients for a longer time period to ensure that the positive results are stable, Shu said.

Based on the results of the first study, the researchers expect that the patients’ hearing abilities will continue to improve over time.

"Then we want to expand to older patients, and gauge how the treatment works for aging adults," he said.

"Ultimately, we want the patient to have a choice about which treatment option they want to go with."

The researchers also plan to start the process of seeking FDA approval to bring the gene therapy to the U.S.

"We are working to bring this to people outside China, including the U.S., as quickly as possible," Shu Fox News Digital.

The researchers also hope to extend this type of gene therapy to treat other types of deafness in the future.

https://www.foxnews.com/health/children-total-deafness-regain-hearing-groundbreaking-gene-therapy-miracle

Wang, H., Chen, Y., Lv, J. et al. Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results. Nat Med (2024). https://doi.org/10.1038/s41591-024-03023-5

Abstract

Gene therapy is a promising approach for hereditary deafness. We recently showed that unilateral AAV1-hOTOF gene therapy with dual adeno-associated virus (AAV) serotype 1 carrying human OTOF transgene is safe and associated with functional improvements in patients with autosomal recessive deafness 9 (DFNB9). The protocol was subsequently amended and approved to allow bilateral gene therapy administration. Here we report an interim analysis of the single-arm trial investigating the safety and efficacy of binaural therapy in five pediatric patients with DFNB9. The primary endpoint was dose-limiting toxicity at 6 weeks, and the secondary endpoint included safety (adverse events) and efficacy (auditory function and speech perception). No dose-limiting toxicity or serious adverse event occurred. A total of 36 adverse events occurred. The most common adverse events were increased lymphocyte counts (6 out of 36) and increased cholesterol levels (6 out of 36). All patients had bilateral hearing restoration. The average auditory brainstem response threshold in the right (left) ear was >95 dB (>95 dB) in all patients at baseline, and the average auditory brainstem response threshold in the right (left) ear was restored to 58 dB (58 dB) in patient 1, 75 dB (85 dB) in patient 2, 55 dB (50 dB) in patient 3 at 26 weeks, and 75 dB (78 dB) in patient 4 and 63 dB (63 dB) in patient 5 at 13 weeks. The speech perception and the capability of sound source localization were restored in all five patients. These results provide preliminary insights on the safety and efficacy of binaural AAV gene therapy for hereditary deafness. The trial is ongoing with longer follow-up to confirm the safety and efficacy findings. Chinese Clinical Trial Registry registration: ChiCTR2200063181.

Tuesday, June 4, 2024

It's not the size that matters

A small, unassuming fern-like plant has something massive lurking within: the largest genome ever discovered, outstripping the human genome by more than 50 times.

The plant (Tmesipteris oblanceolata) contains a whopping 160 billion base pairs, the units that make up a strand of DNA. That’s 11 billion more than the previous record holder, the flowering plant Paris japonica, and 30 billion more than the marbled lungfish (Protopterus aethiopicus), which has the largest animal genome. The findings were published today in iScience.


Study co-author Jaume Pellicer, an evolutionary biologist at the Botanical Institute of Barcelona in Spain, who also co-discovered P. japonica’s gargantuan genome, had thought that the earlier discovery was close to the genome size limit. “But the evidence has once again surpassed our expectations,” he says.

Genomic giants

The world’s genomic champion, which is native to New Caledonia and neighbouring archipelagos in the South Pacific, is a species of plant called a fork fern. Its colossal number of base pairs raises questions as to how the plant manages its genetic material. Only a small proportion of DNA is made of protein-coding genes, leading study co-author Ilia Leitch, an evolutionary biologist at London’s Royal Botanic Gardens, Kew, to wonder how the plant’s cellular machinery accesses those bits of the genome “amongst this huge morass of DNA. It’s like trying to find a few books with the instructions for how to survive in a library of millions of books — it’s just ridiculous.”

There’s also the question of how and why an organism evolved to have so many base pairs. Generally, having more base pairs leads to higher demand for the minerals that comprise DNA and for energy to duplicate the genome with every cell division, Leitch says. But if the organism lives in a relatively stable environment with little competition, a gargantuan genome might not come with a high cost, she adds.

That could help to provide an explanation — although a rather boring one — for the fork fern’s large genome: it might be neither detrimental nor particularly helpful for the plant’s ability to survive and reproduce, so the fork fern has gone on accumulating base pairs over time, says Julie Blommaert, a genomicist at the New Zealand Institute for Plant and Food Research in Nelson.

For now, researchers can only speculate on answers to these questions. The largest genome to be sequenced and assembled belongs to the European mistletoe (Viscum album), with about 90 billion base pairs. Modern techniques might not be sufficient to do the same for the fork fern’s genome: even if it’s sequenced, there’s still the computational challenge of taking the data and “sticking them together in a way that biologically reflects what’s going on”, Leitch says.

Finding ways to analyse enormous genomes could yield crucial insights into how genome size influences where organisms can grow, how they are able to flourish in their environments and their resilience to climate change, independent of their specific DNA sequence, she adds. Pellicer says it’s remarkable that a tiny, non-flowering plant that most people “wouldn’t bother to stop and look at” could offer such important lessons. “The beauty of the plant is inside.”

https://www.nature.com/articles/d41586-024-01567-7

Kozlov M. Biggest genome ever found belongs to this odd little plant. Nature. 2024 May 31. doi: 10.1038/d41586-024-01567-7. Epub ahead of print. PMID: 38822106.



Researchers identify a genetic cause of intellectual disability affecting tens of thousands

Researchers at the Icahn School of Medicine at Mount Sinai and others have identified a neurodevelopmental disorder, caused by mutations in a single gene, that affects tens of thousands of people worldwide. The work, published in the May 31 online issue of Nature Medicine, was done in collaboration with colleagues at the University of Bristol, UK; KU Leuven, Belgium; and the NIHR BioResource, currently based at the University of Cambridge, UK.

The findings will improve clinical diagnostic services for patients with neurodevelopmental disorders.

Through rigorous genetic analysis, the researchers discovered that mutations in a small non-coding gene called RNU4-2 cause a collection of developmental symptoms that had not previously been tied to a distinct genetic disorder. Non-coding genes are parts of DNA that do not produce proteins. The investigators used whole-genome sequencing data in the United Kingdom's National Genomic Research Library to compare the burden of rare genetic variants in 41,132 non-coding genes between 5,529 unrelated cases with intellectual disability and 46,401 unrelated controls.

The discovery is significant, as it represents one of the most common single-gene genetic causes of such disorders, ranking second only to Rett syndrome among patients sequenced by the United Kingdom's Genomic Medicine Service. Notably, these mutations are typically spontaneous and not inherited, providing important insights into the nature of the condition.

"We performed a large genetic association analysis to identify rare variants in non-coding genes that might be responsible for neurodevelopmental disorders," says the study's first author Daniel Greene, PhD, Assistant Professor of Genetics and Genomics Sciences at Icahn Mount Sinai and a Visitor at the University of Cambridge. "Nowadays, finding a single gene that harbors genetic variants responsible for tens of thousands of patients with a rare disease is exceptionally unusual. Our discovery eluded researchers for years due to various sequencing and analytical challenges."

More than 99 percent of genes known to harbor mutations that cause neurodevelopmental disorders encode proteins. The researchers hypothesized that non-coding genes, which don't produce proteins, could also host mutations leading to intellectual disability. Neurodevelopmental disorders, which often appear before grade school, involve developmental deficits affecting personal, social, academic, or occupational functioning. Intellectual disability specifically includes significant limitations in intellectual functioning (e.g., learning, reasoning, problem-solving) and adaptive behavior (e.g., social and practical skills).

"The genetic changes we found affect a very short gene, only 141 units long, but this gene plays a crucial role in a basic biological function of cells, called gene splicing, which is present in all animals, plants and fungi," says senior study author Ernest Turro, PhD, Associate Professor of Genetics and Genomic Sciences at Icahn Mount Sinai and a Visitor at the University of Cambridge. "Most people with a neurodevelopmental disorder do not receive a molecular diagnosis following genetic testing. Thanks to this study, tens of thousands of families will now be able to obtain a molecular diagnosis for their affected family members, bringing many diagnostic odysseys to a close."

Next, the researchers plan to explore the molecular mechanisms underlying this syndrome experimentally. This deeper understanding aims to provide biological insights that could one day lead to targeted interventions.

"What I found remarkable is how such a common cause of a neurodevelopmental disorder has been missed in the field because we've been focusing on coding genes," says Heather Mefford, MD, PhD, of the Center for Pediatric Neurological Disease Research at St. Jude Children's Research Hospital who was not involved with the research. "This study's discovery of mutations in non-coding genes, especially RNU4-2, highlights a significant and previously overlooked cause. It underscores the need to look beyond coding regions, which could reveal many other genetic causes, opening new diagnostic possibilities and research opportunities."

The paper is titled "Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders."

The remaining authors of the paper are Chantal Thys (KU Leuven, Belgium); Ian R. Berry, MD (University of Bristol, UK); Joanna Jarvis, MD (Birmingham Womens' Hospital, UK); Els Ortibus, MD, PhD (KU Leuven, Belgium); Andrew D. Mumford, MD (University of Bristol, UK); and Kathleen Freson, PhD (KU Leuven, Belgium).

https://www.sciencedaily.com/releases/2024/05/240531122557.htm

Greene D, Thys C, Berry IR, Jarvis J, Ortibus E, Mumford AD, Freson K, Turro E. Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders. Nat Med. 2024 May 31. doi: 10.1038/s41591-024-03085-5. Epub ahead of print. PMID: 38821540.

Abstract

Most people with intellectual disability (ID) do not receive a molecular diagnosis following genetic testing. To identify new etiologies of ID, we performed a genetic association analysis comparing the burden of rare variants in 41,132 non-coding genes between 5,529 unrelated cases and 46,401 unrelated controls. RNU4-2, which encodes U4 snRNA, a critical component of the spliceosome, was the most strongly associated gene. We implicated de novo variants among 47 cases in two regions of RNU4-2 in the etiology of a syndrome characterized by ID, microcephaly, short stature, hypotonia, seizures and motor delay. We replicated this finding in three collections, bringing the number of cases to 73. Analysis of national genomic diagnostic data showed RNU4-2 to be a more common etiological gene for neurodevelopmental abnormality than any previously reported autosomal gene. Our findings add to growing evidence of spliceosome dysfunction in the etiologies of neurological disorders.

Wednesday, May 29, 2024

Relentless desire to help Rett syndrome patients

2022 Kavli prize in neuroscience

As told by Huda Zoghbi

I was born and raised in the beautiful city of Beirut, Lebanon. My father owned a business making olive oil and olive oil soap, and my mother was a homemaker, but they valued knowledge. The house I grew up in had an enormous library stacked floor to ceiling with books. My father loved reading history and sharing what he learned, while my mother insisted that her children take their studies seriously. She often kicked me out of the kitchen because she felt that was a distraction from studying. They clearly set a good example: my oldest brother became an electrical engineer and businessman, the second brother became a chemical engineer and researcher, and the third a professor of history. My older sister became a philosopher and professor, then a lawyer, and I entered academic medicine.

As a child I was drawn to my biology and math classes, but in high school I grew to love literature – both Arabic and English. I decided to major in literature at the American University of Beirut (AUB). My mother, however, had a practical bent and insisted that I study medicine. She said medicine would allow me to be independent and able to take care of myself. She also said, “It’s a much simpler career” and writing could be my hobby. I resisted initially, but eventually yielded and majored in biology.

Civil war in Lebanon

I continued on to medical school at AUB. This changed the course of my life in every way. I met the love of my life, William Zoghbi, who has been my great joy for the past 46 years. Then, halfway through the first year of medical school, civil war broke out in Lebanon. Students could no longer commute to campus because of the bombing and sniper attacks. The students and faculty debated whether to finish the year or cancel the term and go home. We thought the war couldn't last long and made the decision to keep going. Our lives became centered on avoiding bombs. We went to classes during the day and stayed together at night. Those of us who had been commuting and didn't have dorm rooms had to find safe places to stay below ground on campus. I found a nook inside the ladies’ room, put a sleeping bag on the floor, and made it my home until the end of the semester.

That spring, my younger brother, who was 16 years old at the time, was hit by shrapnel. This brought home the danger. My parents could not leave but they planned for my younger brothers and me to go abroad and visit relatives for a month or two in the summer, expecting that the war would end and we could return to normal by the time school started again in October. The airport was closed, so we drove to Syria, and from there flew to Europe where we stayed with my uncle for a few days, then flew on to the U.S. to stay with my sister, who was in Austin, Texas at the time. I arrived in Austin July 4, 1976, during the U.S. bicentennial celebration. I recall when I heard the fireworks, I thought bombs were going off and I burst into tears.

Meharry Medical College

The civil war in Lebanon only grew worse. When we tried to return home, the borders were closed. It was already October, so I started looking for a medical school to attend in the U.S. All my applications were rejected – only then did I learn that medical school starts in August in the States. A friend of the family in Nashville invited me to visit, and together we went to Vanderbilt to see if they would allow me transfer. They said they did not accept transfer students, but recommended another nearby medical school, Meharry Medical College, an historically African-American institution. I told the Dean and the head of admissions my story and gave them my transcript that my family had sent by telex. They agreed to take me on the spot, despite the fact that the semester had started two months earlier. I will forever be grateful to Meharry.

Although I was excited about being accepted into an American medical school, I was terribly homesick, constantly worrying about my family, but the students were kind-hearted and looked out for me. I coped that year by studying all the time, still hoping I could go back to Lebanon. I managed to return to Lebanon the following summer, but my professors at AUB, particularly Drs. Adel Afifi and Ronald Bergman, who inspired my love of neuroscience, said the war would continue for a long time, and I should not return to AUB. I was sad to leave home again but grateful when William transferred to Meharry the year after I.

Fell in love with pediatric cardiology

During the fourth year of medical school, I took electives at Stanford, Emory, and Baylor College of Medicine. During my rotation at Baylor College of Medicine, I fell in love with pediatric cardiology. I placed Baylor College of Medicine at the top of my list, and on Match Day learned that I would be in Houston for my residency training. The highlight of my pediatric training was being mentored by Dr. Ralph Feigin, the chair of pediatrics. He was the quintessential clinical scholar and a most compassionate physician. “Feigin Rounds” were an exercise in using every clinical detail to solve a medical mystery, and a great reminder of the importance of mastering the literature. He taught with passion, ultimately influencing the lives of thousands of patients through his many sterling trainees.

Tug-of-war

As a pediatric resident, I rotated in many sub-specialties. I wanted to study pediatric cardiology, but when I rotated in pediatric neurology, I met Dr. Marvin Fishman, the chief of that section. Marv is a fantastic clinician and teacher, and he was the next big influence on the course of my life. On rounds, we often saw children who were in the hospital for heart defect, but who also had neurological problems. For the entire month of my rotation, there was a tug-of-war between heart and head: I would go on about how fascinating the heart was, and Marv would tease me about how the brain was so much more interesting. The rotation ended and I thought that was the end of neurology for me. But Marv had gotten to me. I missed the challenge of neurology, the detective work of taking a history and solving the puzzle of a patient through a detailed history, physical exam, and rigorous logic, so I decided to become a child neurologist.

Emotional pain

What I did not realize at the time was the emotional pain I would feel in that specialty. Even in the early 80’s, Texas Children’s Hospital was a major referral center. It always drew the most difficult cases. Every day I sat with parents and had to tell them that their child had a disorder whose cause was probably genetic but we could not be certain. What was certain was that their child would suffer and perhaps die prematurely, and there was nothing we could do to help. Many nights, I went home and cried over the bad news I had to deliver.

My career path was further defined by one of my patients. Ashley had appeared healthy at birth but lost her language and motor skills around the age of two, and she could only wring her hands incessantly. Ashley was referred by her pediatrician, Dr. Merlene McAlevy, who suspected Rett syndrome based on a paper describing the syndrome for the first time in English, just published by Bengt Hagberg (October 1983). (Rett syndrome is a rare neurological and developmental disorder that affects the way the brain functions after birth, causing a progressive loss of motor skills and speech). I saw Ashley with Drs. Alan Percy and Vincent Riccardi, the attending neurologist and geneticist. I was intrigued by Ashley’s diagnosis, but a serendipitous meeting a week later sealed my relationship with Rett syndrome. As residents, we could look over patient charts and choose which patients to evaluate, and I chose to see a 12-year-old girl with cerebral palsy. When she walked into the exam room wringing her hands, I immediately realized it wasn’t cerebral palsy, rather Rett syndrome. (For many years, Rett girls were commonly misdiagnosed as having cerebral palsy.) Having seen two girls in one week – despite no one having reported the disorder in the U.S. – I concluded there must be more patients who were simply being missed. I reached out to the volunteers in our pediatric neurology outpatient clinic, the Blue Bird Circle Clinic, to help me. These volunteers, whom we affectionately called “Blue Birds,” had dedicated their time and resources to help patients with neurological disorders and assist the physicians in the clinic. I gave them a list of key features and asked them to pull the records (these were paper records at the time) with such features. Within a few weeks, I identified and examined six girls with Rett syndrome. After seeing these girls, I could not continue as just a clinician; I had to figure out what was happening to these patients and do something to help.

Grant from the Blue Birds

I approached Dr. Art Beaudet, a renowned human and molecular geneticist at Baylor College of Medicine, to ask if he would allow me to undertake a postdoctoral research fellowship in his lab to learn molecular genetics. I wanted to work on Rett, and was convinced it was genetic because it almost exclusively occurred in girls, leading me to believe it resulted from a mutation on the X chromosome. With a $50,000 grant from the Blue Birds, I collected DNA samples from many families, but they all had just one child with the disorder. With the technology available in 1985, it was impossible to identify the causal mutation without other affected family members to help narrow down which genomic regions could harbor the gene. Art urged me to find another disease to study so that I could start my own independent career with a more tractable problem. While disappointed, I listened to him and told him I was also interested in dominantly-inherited neurodegenerative disorders because I was intrigued by their late onset and the lack of protection from the normal allele (the variant form of a gene). He introduced me to a family in Montgomery, Texas, with a dominantly-inherited spinocerebellar ataxia – a degenerative disease that causes progressive problems with movement and balance. I wrote my first National Institutes of Health (NIH) grant, known as a K08, while still finishing my pediatric neurology fellowship. The only preliminary data I had was a drawing of a large familial pedigree. I was a candidate with no research experience, but I possessed passion and promise, along with an incredible mentor. The NIH grant was awarded the first day I started in the lab. I share this story because finding support for physicians with little or no research experience is practically impossible today. If I had been held to today’s standard, my career in science never would have happened.
 
With funding secured for five years, I moved from the clinic and took basic science graduate courses at Baylor College of Medicine, immersing myself in cloning and linkage mapping. I traveled to Montgomery, Texas, for a few months to examine the extended family and collect blood for DNA. I then commenced my work on finding the genetic basis of their disease. Dr. William O’Brien, a collaborator of Dr. Beaudet’s on urea cycle studies, was a co-mentor. (The main purpose of the urea cycle is to eliminate toxic ammonia from the body.) The three of us became good friends and had coffee every Friday morning for years to discuss science and how best to solve the diseases I was interested in. Several computational geneticists helped me along the way. First, Steve Daiger at the University of Texas (Houston Health Science Center) collaborated to help me with data analysis, then Jürg Ott and his postdoctoral fellow, Lodewijk Sandkuyl, at Rockefeller University taught me how to perform linkage analysis. Art was very supportive despite the fact that his lab worked on a completely different set of disorders. He taught me how to perform rigorous research with well-controlled experiments and how to prepare the best possible slides when giving a talk – two traits he learned as a postdoc in Marshall Nirneberg’s lab. Art’s advice on choosing a clearly Mendelian disorder also proved sound. Studying ataxias led me to one of the highlights of my scientific career and ensured that I could be productive while I was still struggling to understand Rett.

Reaching out to Harry Orr

I read a paper by a scientist named Harry Orr about a family in Minnesota with ataxia that had its gene localized to chromosome 6 – the same chromosome my research pointed to. I wanted to reach out to him to see if we could collaborate, but I was petrified because he was a tenured, Associate Professor – an established scientist! – and I was just learning my way around the lab. Art met Harry at a conference and when he returned, he encouraged me to reach out to Harry. I gathered up my courage and called Harry on the phone, explaining that since we were each working with large families we could make faster progress if we joined forces. I found Harry easy to talk to and very kind. Curiously, because of where the genes mapped in our respective families, we were looking at two different parts of chromosome 6 despite being fairly certain we were studying the same disease. At that time, there weren’t many DNA markers, but a wonderful geneticist, David Cox, had developed an approach called radiation hybrid mapping to generate fragments of chromosomes that would help us pinpoint the disease-causing region of DNA. I read the protocol paper but wasn’t completely clear on it, so I called David. He was kind enough to walk me through the entire experiment. I developed radiation hybrid markers for chromosome 6 and was excited that the hybrids gave me something to offer Harry for a solid two-way collaboration, even if we were working on two differently-mapped ataxias.

Setting up a lab

By then it was 1988 and I had secured my first NIH grant (an R01) following the K08, so Art felt I was ready to start my own lab. I was concerned, however, about the location of my new lab. After all, my primary appointment was in pediatrics and neurology and the expectation was that I would be with more clinically-oriented researchers near the hospital. But I still had so much to learn and wanted to be with the basic scientists. I approached the Chair of Genetics, Dr. C. Thomas Caskey, for space. His vision for the department was that it would place researchers from diverse fields near each other to stimulate those ever-important serendipitous encounters in hallways and water-coolers that so often inspire new ideas, so I used his vision in my plea for space. He graciously gave me lab space, and although there would be no office, just open desks and lab benches, I was thrilled. In retrospect, not having an office was a gift because it meant that I was in the lab working at the bench alongside my trainees, having fun, encouraging them, and not being distracted by emails and other things.

OK, let’s do it

Harry and I worked on our different regions of chromosome 6, but it bothered me that the same clinical entity could map to two different regions of the same chromosome (this would not seem strange today, given our knowledge of genetic heterogeneity). I did a lot of detective work and figured out that in a small branch of my family, the disease did not come from the main bloodline but from a spouse who was likely to have the same mutation but died before developing symptoms. The odds of a disease with a prevalence of 1/100,000 running in the same family through two unrelated bloodlines were unfathomable, but I suspected exactly that and it turned out to be the case. I realized that by including this individual as the one passing on the disease to his three daughters, my gene mapped on top of the gene in Harry’s ataxia family. I was excited and telephoned Harry to tell him. His first reaction was, “Do you want your radiation hybrids back?” I said, “No, now we can collaborate more intensely because we’re working on the same gene!” He was silent for about 15 seconds, processing this new information, then said, “Okay, let’s do it.”

Between 1988 and 1993 we continued marching through genes. Then Dr. Caskey gave a noon conference describing the discovery of the myotonic dystrophy gene, which was the third gene to be identified with a triplet repeat expansion (after the androgen receptor and fragile X). He described how the repeat was bigger in the children than their mother, which explained the phenomenon of anticipation, wherein the disease strikes each subsequent generation at an earlier age with more severe symptoms. I realized this was exactly what I was seeing in my spinocerebellar ataxia (SCA) family. The last generation had a four-year-old who was affected, whereas the father didn’t show symptoms until his 30s. This raised the possibility that the ataxia was a triplet repeat disease, so I called Harry. We agreed this was very likely and designed an experiment to test the hypothesis. The region we were looking at was one million base pairs. We split the region in half and each of us started working from the outside in, searching for triplet repeats as we worked toward the middle. We would both screen a 70Kb region of overlap in the middle so we do not miss anything. Finally, on April 8, 1993, we both discovered the disease-causing gene on the same day, right in the middle of the candidate region. Harry was sending me a fax of the expansion he detected in his family, while I was sending him ours – both Southern blots made it into the paper. We had the pleasure of sharing the discovery and our data at an international ataxia meeting in Capri, Italy, that summer. After the gene discovery, we had to plan the next steps: do we continue to collaborate or do we go our different ways? We chose to continue our collaboration.

Friendship

Beyond that, Harry and I forged a decades-long friendship that we and our families cherish. When our daughter went to camp in Minnesota while in middle school, Harry was “the responsible adult” should she need help. Harry visited Lebanon as well, where he met my family and William’s family, visited my alma mater, enjoyed Lebanese food, and experienced driving on narrow mountain roads.

This collaboration inspired another, with the superb Drosophila geneticist Juan Botas (Baylor College of Medicine). Juan and his lab created fly models of SCA1 and identified many modifiers that helped us gain insight into Ataxin-1 biology. Collectively, our studies are continuing to help us understand the mechanisms driving disease and how the glutamine expansion stabilizes Ataxin-1 leading to its accumulation and toxicity. Our preclinical proof of concept studies revealed that lowering Ataxin-1 levels in SCA1 knockin-mice rescued disease features, providing promise for future interventional studies in people with SCA1. Moving forward, we are using our SCA1 knock-in mice that recapitulate SCA1 features and pathology to understand how a mutation in a broadly expressed protein can cause selective neuronal degeneration.

Not forgotten Rett

While SCA1 research was advancing, I had not forgotten Rett. I continued to collect Rett data and had DNA samples from over 200 families. The work, however, was one disappointment after another. One patient had a translocation on the X chromosome, but when my graduate student cloned the region spanning the translocation, there was no gene at the breakpoint site. Another family had two second cousins with Rett, but they shared no regions of the X chromosome. Yet another patient had a null allele in a gene involved in carnitine biosynthesis, but it turned out the father had the same null allele so we knew it could not be causing the disease. Despite the disappointments, I could not let go. The Rett symptoms were so distinctive and consistent that only an underlying genetic defect could cause such features. The children are born looking perfectly normal. They achieve developmental milestones and everything seems to be fine, but then they regress around the age of two. They lose the abilities they had gained in language and motor control and start moving their hands in stereotypic ways (wringing, flapping, etc.). Not only was this an unmistakable and puzzling constellation of symptoms, but the mechanism of disease was a mystery, too. At the time we thought there were two types of neurological disease: congenital and degenerative. But the girls were not like that: they were born normal, and the few neuropathology studies that had been done showed there was no degeneration of the brain even though there was loss of function.

Studying two families with two affected half-sisters helped eliminate two-thirds of the X chromosome based on discordance between the affected half-sisters. Carolyn Schannen and Uta Francke at Stanford studied another family with an aunt and a niece with Rett, so we combined our data and helped eliminate a few more megabases. After a decade of negative results, graduate students and fellows refused to work on Rett as they viewed it as a dead-end project with too much negative data. I could not obtain a grant to study Rett because it was hard for reviewers to imagine that a gene could underlie a sporadic disorder. Thankfully, a couple of fortuitous things happened: First, Ruthie Amir, a physician with no research experience, wanted to join my lab as a staff scientist. I was concerned this would not be a good title for her career, so I offered her a postdoctoral fellowship on the condition she work on Rett. She accepted. Second, Ruthie received a fellowship from the International Rett Syndrome Association and I was fortunate to obtain funding from the Howard Hughes Medical Institute (HHMI) that allowed us to keep going. (I confess I did not tell HHMI about Rett in my research proposal, fearing rejection.) At long last, in 1999 Ruthie found the genetic mutation that causes Rett. I had just opened the door of my house – returning from a trip to Lebanon – when the phone rang. I picked it up, and it was Ruthie. I asked her to bring her notebooks to my house, and she was there within the hour. She showed me patient after patient with a null mutation in MECP2 that was not in the parents. I knew this was it. People often ask me what kept me going despite years of negative data. Beyond my intuition that Rett was genetic and my feelings for the Rett girls, the support of family, friends, and colleagues was essential. Ralph Feigin encouraged me and always believed I would find the gene, even when many were doubtful.

Humbled by the complexity

Since then, understanding how loss of this protein causes Rett syndrome has been a major focus of my lab. Adrian Bird showed that MeCP2 binds methylated DNA, and it's clear that it is important for neurons and that it somehow orchestrates gene expression. The Bird lab also showed that restoring normal MeCP2 levels rescues the disease phenotype in mice. Our animal model studies led us to patients with MECP2 duplication syndrome, which can also be ‘corrected’ in mice when MeCP2 protein levels are returned to normal. These results tell us that the brain architecture is still intact enough to regain function, when a treatment is found. Preclinical work using antisense oligonucleotides to reduce the concentrations of MeCP2 has provided proof of concept and led to the currently ongoing clinical trial readiness studies. After 23 years of research following the discovery of the gene, I am humbled by the complexity of this disorder, but believe we are beginning to understand it well enough to develop therapies that work through neuromodulation or manipulation of MeCP2 levels.

I am indebted to all the patients and families I have encountured for inspiring me and for persevering while we pursued gene discovery and the critical studies of mechanisms driving their diseases. We hope that the proof of concept preclinical studies will soon lead to clinical trials to help alleviate their symptoms.

HHMI support also allowed me to discover Atoh1, which took me into many interesting areas of biology. I asked my fellow HHMI and Baylor College of Medicine colleague, Hugo Bellen, about fruit fly genes important for balance. He told me about atonal, discovered by Yuh Nung Jan at UCSF to be critical for the formation of chordotonal organs and proprioreception in flies. I set out to identify the mammalian homolog with the help of my long-time technician Alanna McCall (this year marks our 35th anniversary working together). We succeeded and named it Mouse atonal homolog 1 (Math1), which is now known as Atoh1. We created mouse models that lack this gene, traced its lineage, and learned about its critical role for genesis of cerebellar granule neurons, inner ear hair cells, a variety of brain stem neurons critical for hearing, proprioception, interoception, and respiration, and cells in other parts of the body such as secretory cells in the intestines and Merkel cells in the skin.

The joy from the advances I have experienced collaborating with Harry, Juan, Hugo and others guided me in founding the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children’s Hospital and Baylor College of Medicine. The NRI is dedicated to basic neurological disease research and incorporates all the ingredients that I have found most helpful in my career: collaboration, access to expertise outside our field, a culture of sharing, cross-species studies, and commitment to mentorship. It is rewarding to watch young faculty build their careers and work together to solve the unsolvable. The NRI has enabled my lab to broaden our studies to other neurodegenerative disorders and embark on collaborations within the Alzheimer’s disease JPB consortium to study regulators of tau levels in hope of revealing druggable targets that can reduce pathogenic tau accumulation in Alzheimer's disease and other tauopathies.

Navigating busy lives

The collaborative environments at Baylor College of Medicine and Texas Children’s Hospital have been incredible for my growth as a geneticist and neuroscientist. My profoundest gratitude goes to my husband, William, who has been my partner every step of the way even while reaching great heights in his own career as a cardiologist. His unconditional love and support while we raised our two wonderful children, Roula and Anthony, allowed me to go to the lab on nights and weekends and kept me positive when experiments did not succeed. I am grateful to our children for their support, enduring dinner conversations about rejected papers and negative results, providing comforting words, and doing their part as we navigated busy lives with two parents in academia. Now my children are grown, and they have made me more proud than I could ever have imagined. Our family now includes their wonderful spouses, Tyler and Zena, whom we love dearly, and their wonderful children Camila, Tate, and Sienna. Being a “Tata” (the modified nickname for grandma in Lebanese) is one of my favorite and most enjoyable jobs. I love traveling with William, going on long nature walks together, and enjoying the opera. Besides reading, I love to cook. When the children were young, Sunday night was my “innovative cooking” night. Now that the family has grown, weekly Sunday dinners are a tradition and the grandkids have developed a sophisticated palate given the variety of foods I prepare. My favorite meals are those made with fish William has caught in the Pacific Northwest or with vegetables he grows in our garden.

“The Zoghbians”

My other extended family of trainees, technicians, and staff, “the Zoghbians” as they like to refer to themselves, made my science career a most rewarding one. I am grateful for their dedication, patience, trust, and friendship. They taught me so much and made me look forward to coming to work everyday. Their hard work, commitment and passion give me faith that neurobiological disease research will be in capable hands for decades to come.

https://www.kavliprize.org/huda-zoghbi-autobiography

A new atlas of the human body

NPR's Ayesha Rascoe talks with Kalyanam Shivkumar, a cardiologist at UCLA, about his push to create a new anatomical atlas after discovering the one used by doctors for decades was made by the Nazis.

AYESHA RASCOE, HOST:

The images of "The Pernkopf Topographic Anatomy Of Man" are delicately complex, clearly diagrammed and full of detail. It's an illustrated atlas of the human body, showing layers of tissues, organs, and bones, and as helpful as the multivolume anatomical atlas has been for generations of doctors, it's no longer in print because it's problematic to say the very least. Eduard Pernkopf, the Austrian doctor who oversaw its creation, was a loyal supporter of Adolf Hitler. The bodies he used as models belong to prisoners who died in Nazi prisons. Many of them were dissidents, gay men, lesbians, and Jews. The LA Times reported last week about a project that's underway to create a new atlas of the human body, one without this horrific history. We're joined by Dr. Kalyanam Shivkumar, who is a cardiologist at UCLA behind that project. Welcome to the program.

KALYANAM SHIVKUMAR: Thank you so much.

RASCOE: How did you first learn about the Pernkopf atlas?

SHIVKUMAR: So the atlas came to my attention around the year 2012. This entire collection was gifted to me by a colleague. We were at that time searching for the very best resources on anatomy of the heart in our case, but obviously also to understand nerves in the human body. And when this entire collection arrived, I was almost, you know, taken aback by the quality of the work. But my colleague who gifted the book had already sort of indicated to me that it actually had a very disturbing link in historical background, and that's how my sort of introduction to the Pernkopf atlases came about.

RASCOE: And I understand that you, as well as many other doctors, have been incredibly conflicted about using this atlas. Why not just use a different one? Like, why is this one still in use?

SHIVKUMAR: So the answer is twofold. One is, the time and effort that was put into creating the original atlases shows in the quality of the work they had produced. It actually has fine details which you simply don't find in other books. And many bootleg copies were floating around after its sort of very depressing history came into being, and it went out of print. Of course, older copies were still acquired and so forth.

RASCOE: So tell us about your project, starting with the name.

SHIVKUMAR: Yes, so in medical school, one of our founding, you know, principles is to make sure that there are no ethical violations. We teach our students, you know, some of the huge violations that have happened. And of course, when you see this type of work, where you see that, you know, there were prisoners, and these were people who were murdered, and people just went on to say, OK, let's just acknowledge it and move on, but still continue to use it. That didn't sit well with me. And at that time, to answer you, the first part of your question, we coined the term "Amara Yad." And that is sort of a combination of two words. Amara in Sanskrit means eternal. Yad in the Hebrew language means hand. So we coined the term "Immortal Hand" for this project to say that we're going to surpass this and create completely new atlases that will be far more detailed, way more artistic, and something that will really inform what medicine needs today.

RASCOE: Well, how are you getting cadavers for this project?

SHIVKUMAR: This comes from a UCLA program, which is called the willed body program, where many people leave their body for medical research. And it's one of the most noble contributions people make.

RASCOE: Well, you talked about how detailed the Pernkopf atlas was. How does this one - and you want this one to surpass it. How do you feel like it's better?

SHIVKUMAR: We spent a lot of time, in fact, a few years, contemplating how we would go about doing it. We'd take various parts of the body, but especially the heart, since we started with it, and we use very powerful laser microscopes to get very fine structural details. I would say that this is almost like the space program, but it's the inner space. We're looking at the human body in a completely new light. And that is how we surpass Pernkopf, by completely leapfrogging it. It's ethically sourced, and it's also highly contemporary. And we are working with our collaborators around the world who have this type of expertise. So that is how Pernkopf can and will be beaten.

RASCOE: You know, think about the Hippocratic Oath, that - do no harm. In a way, is your project an attempt to undo a harm?

SHIVKUMAR: I think what Pernkopf and those types of people have done is they've harmed what should be very pure, which is medical education. What one rabbi very poignantly said, it's a fruit of a poisonous tree. So in that sense, it's a moral corrective. We are undoing a harm. And in doing so, we are also providing a vastly superior source of information for the world to use.

RASCOE: That's Dr. Kalyanam Shivkumar, talking about his ongoing project to create a better anatomical atlas. Thank you so much for talking with us.

SHIVKUMAR: Thank you so much for the interview, and we appreciate the opportunity to share our work with all your listeners.

https://www.npr.org/2024/05/26/nx-s1-4974797/the-anatomical-atlas-used-by-doctors-has-a-dark-history-one-man-is-pushing-for-change