KJ Muldoon (infant) is the first person in the world who received in vivo gene-editing therapy making medical history in 2025. It was made at Children’s Hospital of Philadelphia/Penn Medicine.
KJ was born with a rare metabolic disorder known as severe carbamoyl phosphate synthetase 1 (CPS1) deficiency, a life-threatening metabolic disorder that impairs the body’s ability to clear ammonia.
Genetic Analysis:
Genetic analysis revealed that KJ inherited two distinct truncating (nonsense premature stop) variants in the CPS1 gene: Q335X (it means Glutamine into Stop codon at the site of CDS 335) and E714X (glutamic acid into stop codon at CDS 714). If you want to see the variant details about this mutation, click here:
Gene-Editing Treatment:
A team led by Drs. Rebecca Ahrens-Nicklas and Kiran Musunuru developed a therapy delivered via lipid nanoparticles to the liver that uses a base-editing CRISPR. The first dose was administered in February 2025 (at 6-7 months old) and followed by further escalating doses in March and April (7-8 months old).
Gene-Editing Design
The team chose to target one of the two mutants (rather than both), and selected the Q335X variant for the adenine base editing (A—>G conversion). Maybe this is a good strategy because of off-targets and bystand targets.
Outcome:
Doctors reported that the treatment was successful in correcting the genetic defect and reducing ammonia levels in KJ’s blood. He was able to go home from the hospital in June 2025 and is currently thriving.
We do not know editing efficiency, off-target and by-stand target rate, but saved a life.
I’ve always been fascinated by antibodies. My journey began in 2000, when I first took an undergraduate immunology class. During graduate school in Medical Biotechnology, I dove deeper—advanced immunology in 2001, psychoneuroimmunology in 2002—researching NKT cells and CD1d in autoimmune diseases. Back then, my curiosity was pure: I just wanted to understand how things worked. Papers, grants, and impact factors? I didn’t think about those. Honestly, even now, grant writing still feels like a mountain to climb!
Until 2018, during my third postdoc, I never actively pursued grants. I was fortunate to be in well-funded labs, free to follow my interests, attend meetings, and write papers when inspiration struck. That freedom was exhilarating. I often chose research topics my supervisors weren’t interested in—at least initially—giving me the joy of discovery.
But freedom has a cost. By the time I tried to apply for my own grant, it felt late. I wrote one in 2018, only to have my name removed by my PIs and replaced with a colleague’s. They told me it would increase our chances of funding. I also learned a hard lesson: in both academia and industry, even great data isn’t always shareable due to patents. At the end of the day, the only guaranteed rewards were a paycheck and the sheer pleasure of exploring science.
Sometimes I wonder if I should have pursued a Ph.D. in immunology instead of neurobiology. I missed a lot of immunology along the way. Still, I wouldn’t trade my journey—it shaped the scientist I am today.
Generating Antibodies: My Hands-On Experience
If you’ve worked in biology or medicine, you know antibodies are everywhere. They’re essential for research and diagnostics, from simple antibody staining to generating completely new reagents.
During my Ph.D., I generated antibodies both in-house and through companies. I provided expression constructs, sometimes purified proteins, and worked with animals like mice or ferrets. It took time, patience, and more than a few failed attempts—especially for antibodies against certain domains. For instance, when generating pan-antibodies against protocadherin 7, we eventually produced polyclonal antibodies, but monoclonal antibodies just didn’t cooperate.
Fast forward to 2020–2021: antibody engineering has advanced tremendously. I created numerous AAV constructs, including Fab and scFv, analyzing backbones, VH, VL, CDRs in detail. Companies sometimes tweaked CDRs sequences, either randomly or with AI. Even Fc regions required careful attention, as they could influence adverse effects in the case of Fc-fused proteins and full antibody drugs. To generate AAV constructs, all other parts, such as promoter regions, signal peptides, linkers, polyA, WPRE, etc., should be considered. The next steps are to check whether the antibody-based fragments are secreted and work properly by Western blots and ELISA. Of course, in the case of AAV constructs, we should check AAV property and yields and have AAV first.
Fc and Fab: The Power of Two
Antibodies have two main regions: Fab and Fc.
Fab or variable regions bind to antigens
Fc, often called the “effector arm or tail,” performs critical functions:
Cell-mediated and humoral immune activation: Fc binds Fc receptors on macrophages, neutrophils, NK cells, and dendritic cells and leads to ADCC (antibody-dependent cellular cytotoxicity) and ADCP (antibody-dependent cellular phagocytosis).
Complement system activation: Fc triggers pathogen lysis, opsonization, and inflammation.
Half-life regulation: Fc binds neonatal Fc receptor (FcRn) in endothelial cells, protecting antibodies from degradation.
Maternal-fetal transfer: IgG Fc interacts with FcRn in the placenta, passing immunity to the fetus.
When designing therapeutic antibodies, deciding whether to keep, engineer, or remove Fc is crucial. Fab fragments penetrate tissues better but have shorter half-lives. Fc is often necessary for cancer therapies, whereas autoimmune or blocking therapeutics benefit from Fc engineering to avoid harming self-tissues.
A Look at Therapeutic Antibodies
Here’s an overview of some major monoclonal antibody drugs and their Fc strategies:
Drug
Target
Indication
Fc Strategy
Engineering / Mutations
Rituximab
CD20
B-cell lymphoma, RA
Active Fc → ADCC + CDC
None
Trastuzumab
HER2
HER2+ breast & gastric cancer
Active Fc → ADCC
None
Adalimumab
TNF-α
RA, Crohn’s, psoriasis
Neutralizing
None
Cetuximab
EGFR
Colorectal & head/neck cancer
Active Fc → ADCC
None
Nivolumab
PD-1
Melanoma, NSCLC
Fc-silent → avoids killing T cells
IgG4 backbone + S228P
Pembrolizumab
PD-1
Similar
Fc-silent
IgG4 backbone + S228P
Omalizumab
IgE
Severe asthma, urticaria
Fc engineered to avoid mast cell activation
IgG1 backbone; avoids C1q binding
Bevacizumab
VEGF-A
Colorectal cancer, AMD
Neutralizing; Fc not critical
Wild-type IgG1
Key patterns:
Cancer drugs keep Fc active to kill tumor cells.
Checkpoint inhibitors silence Fc to avoid killing PD-1+ T cells.
Anti-cytokine drugs have no effector function, but increase half-life by FcRn recycling.
Anti-IgE drugs engineer Fc to prevent dangerous immune activation.
Fc-Free Antibodies: A Growing Field
Fc-free antibody fragments are also gaining attention. As of August 27, 2025:
Status
Count
%
FDA-approved
15
27%
Terminated / Withdrawn
10
18%
Under Clinical Development
26
47%
Regulatory review
4
7%
database for Therapeutic Antibodies (db.antibodysociety.org)
Even though Fc can trigger strong immune responses, careful control – through dosing or engineering – can make it highly beneficial. Fc-free fragments face challenges like short half-life or lack of effector function, explaining why some have been terminated.
Antibody research is a perfect blend of biology, engineering, and clinical innovation. It’s a field full of stories – both successes and failures – that teach us how to translate basic science into therapies.
I’ve recently started reading again a book on therapeutic antibody engineering (2012), and I plan to share insights and reflections here from time to time.
More than 100 people after using a drug – Elixir Sulfanilamide, died.
Sulfanilamide, a drug used to treat streptococcal infections with dramatic curative effects, and safely used in tablet and powder form. In June 1937, S.E. Massengill Co., in Bristol, Tenn., manufactured the drug in liquid form with diethylene glycol. No toxicity and pharmacological studies had been done on the new sulfanilamide preparation. Diethylene glycol (antifreeze) is a deadly poison.
On Oct 11, 1937, the American Medical Association (AMA) received incidental report from physician in Tulsa, Oklahoma, that an unfamiliar sulfanilamide compound was responsible for a number of deaths, and AMA laboratory isolated diethylene glycol as the toxic ingredient and immediately issued a warning through newspapers, and radio that Exlixir Sulfanilamide was toxic.
Next year 1938, FDA set out to make sure all of the drug was retrieved. 239 FDA inspectors and chemists was assigned to the task, and state and local health officials joined the search, and newspapers and radio stations continued to issue warnings.
Chaos
In some drug stores, the elixir had been sold without prescriptions to purchasers whose names the druggiest did not know. In other cases, doctors had incomplete records, or none at all- of the names and address of patients for whom they had prescribed. Even one East St. Louise woman told an inspector she had destroyed the drug. The inspector persisted in his questions how did she destroy. Her answer was that she had thrown the bottle out the window into an alley. The inspector found the bottle still unbroken, still containing enough elixir to kill any child.
A South Carolina doctor told an inspector that he had dispensed the medicine, but none had died, but the inspector found all his patients had died after taking the elixir.
Of 240 gallons manufactured and distributed, 234 gallons and 1 pint was retried.
Victims
Many of them were kids, treated for sore throats. All exhibited similar characteristic of failed kidney, stoppage of urine, abdominal pain, nausea, vomitting, stupor, convulsions.
However, the firm was not illegal, because in 1937, the law did not prohibit the sale of dangerous, untested, or poisonous dugs. Dr. Samual Evans Massengill, the firm’s owner said: My chemists and I deeply regret the fatal results, but there was no error in the manufacture of the product. We have been supplying a legitimate professional demand and not once could have foreseen the unlooked-for results. I do not feel that there was any responsibility on our part.” The Chief Chemist, Harold Watkins committed suicide after learning of the effects of his latest concoction.
1938 Federal Food, Drug and Cosmetic Act
FDA Commissioner Walter Campbell pressed for better federal regulation of drugs, and pointed out how the inadequacy of the law had contributed to the disaster.
The Elixir disaster hastened enactment of the 1938 Federal Food, Drug, and Cosmetic Act. New Drug section, added to prevent such tragedies, gave the US a new system of drug control which provided superior protection and 25 years later, this Act saved the Nation from an even greater global drug tragedy— a thalidomide disaster
In the 1938 Food, Drug, and Cosmetic Act, requires perform animal safety tests.
However, currently, that requirement, especially cosmetics is not mandatory, if the company provides an evidence of the safety
Reference: Carol Ballentine, FDA consumer magazine, June 1981 Issue
An embolus is any foreign materials that move with blood flow. The material of an embolus may be: air, fat, blood clot and any others.
A thrombus is a blood clot.
Both can block blood flow and increase the risk of a hear attack, pulmonary embolism and/or stroke
Think!! (Q1) Why do blood clots form inside the vessels, and why do blood clots increase with aging?
Think!! (A1) When we have scars outside, a blood clot forms to protect and stop bleeding. If blood vessels have internal wounds, blood clots form as well to protect inside organs and vessels . After the wounds have healed, the blood clots are detached like outside scars, and blood clots move away as thrombus, and could block the vessels.
Think (Q2) Could we resolve formed blood clot scrubs inside blood vessels safely and slowly or increase attachment (never dropping forever)? Instead of inhibiting formation process of the blood clots which could be dangerous, causing non-stop bleeding.
Long ago, in the 1980s, when we visited community pediatric centers, the first thing for a nurse to do was to put a thermometer under armpit (axillary). Also, sometimes, nurses measured my body temperature from under my tongue. I do not know exactly when we started using forehead scanners at home, but when my first daughter was born, I obtained a scanner type thermometer, and we are still using it. In Korea, we use the measure unit °C, instead of °F in the USA. The average normal body temperature is 36 °C. When the temporal forehead scanner indicates over 38 °C, I use acetaminophen (Tylenol) and ibuprofen (usually Motrin) at over 8-hour intervals. My family members respond well to Tylenol, but we use two different medicines alternately because the liver might need more time to recover. I also like watery handkerchiefs and cooling sheets (hydrogel patches, easy to get in Korea) for my kids.
Maybe you know that a high fever could damage our organs. Maybe you hear that someone becomes deaf after a high fever, or even death. One of my friends lost his voice with fever. I had been sick with high fevers (over 38 °C) when I was in the first grade of elementary school, maybe for a whole winter break. I recovered a week (or three days) before the second grade started from my deadly fever. What I remember now is that I was hospitalized for one month. I used a very big personal room with two beds. I used one bed and another bed, which mom usually occupied. I got a lot of presents from relatives and friends. I had IV injections all the time that they called Ringel. I do not know exactly what Ringel is. I thought that IV was Ringel, but maybe not really. I just guess now that Ringer IV was just helping with anti-dehydration and/or anti-inflammation agents. I also sometimes got nutrient IV because I could not eat normal foods and I could not have normal bowel movement. Fever made me eat and poop like a baby or less than an infant. I liked Cerelac (baby food power) more than any other Korean Juk (porridge). Nurses really wanted to check my poops all the time. Fever really made me hard to poop. I remember poop was like rabbit poops, maybe due to dehydration. However, my memory is not bad. Maybe I was too young to know about death. I was too busy to think of death and sickness. I enjoyed my hospitalization because I had a lot of new toys and I met a friend (a daughter from the hospital owner or related persons??, maybe a doctor’s daughter, I guess). I do not know her well except that she was a similar aged girl, because I never met her again after my release. I even missed her and the hospital because I hoped to see her again. She showed me here and there – the complexity of hospital, a long hallway, shortcuts – and even led me to the hospital rooftop (the top of four-story building). She once took some fancy bandages and syringes, and we played doctor and patient. I do not know which diseases I had. I heard doctors did not know what I had.
One day, my fever seemed to be going up, because I heard that a nurse who visited me in the morning, yelled, “Alcohol pad, high fever.” Suddenly, all the nurses and doctors came to me, and mom and dad were there together. At the moment, I could not speak out, but when an alcohol pad (a very big and orange rubber bag, if my memory is right) rubbed me, I bad-mouthed in my thought, “Who said that nurses are White Angels, They are not good”. The alcohol pad was really freezing and a pain in itself to me.
Suddenly, I felt my room whirling to me like water in a funnel, and all sounds in my room overwhelmed me, and I saw a bright light (maybe my brain works something ??); light is not a single object, just the room was full with Brightness. and I heard me shouting a Buddha’s name, “Gwansembosal”. I do not know why I shouted. Actually, shouting was a shame to me, and I was surprised with my shouting, and they (doctors and nurses) were also surprised of my shouting “Gwansembosal”. Google translator is saying that “Gwansembosal” in Korean is “Avalokitesvara Bodhisattva”. In Korea, Gwansembosal is the best of the Buddhas that I heard from my grandma. I was a kid who loved Buddha Kid story books published by Buddha temples. After my shouting or seeing Light, like a lie, my fever had gone, and 3 days later, I was released from a hospital (the hospital name was Chunchon Jail Hospital). I thought that I was unLuck because I should return to school without any absence, because I was recovered just on time. I remember when I had the first shower at home, it was a big deal to whole family members. They were all concerned and checked the bath temperature and the air temperature. When I recovered, I missed my baby food, so I teased mom and got a new baby food can, but when I got them, it was not yummy any more, even yucky. So I know that our body knows what we need sometimes automatically based on our conditions. I heard that I was lucky because my high fever did not damage any part of my body and even my mind. This might be my first Near-Death story when I was in the first grade of elementary school.
What I wanted to tell was not my fever story,…is the below!!
Measurement method
Normal temperature range
Temporal (forehead)
36.6°C to 37.8°C (97.9°F to 100.1°F );
Tympanic (ear)
35.8°C to 38°C (96.4°F to 100.4°F ); 35.7°C to 37.8°C (96.3°F to 100°F );
Oral
35.5°C to 37.5°C (95.9°F to 99.5°F )
Axillary (armpit)
34.7°C to 37.3°C (94.5°F to 99.1°F )
Rectal
36.6°C to 38°C (97.9°F to 100.4°F )
reference: Corpus ID: 3071933, Leduc et al., 2023, Medicine; baptis-health.com
Life and Biology stories with Sooyoung and Others 