Introduction

Victoria Gray, a Black American woman now in her mid-thirties, was just three months old when she suffered her first painful bout with sickle cell disease (SCD), a debilitating genetic blood disorder. SCD is caused by a mutation of the hemoglobin-beta (HBB) gene in chromosome 11 that alters the shape of normally flexible, round red blood cells into rigid, crescent shaped cells. When it does, the flow of red blood cells that usually deliver oxygen to bodily tissues is restricted resulting in limited oxygen delivery to tissues and associated severe pain. Until recently, treatment consisted primarily of strong pain relief medication and, also, frequent blood transfusions. SCD affects about 100,000 people in the United States, more than 90% of whom are African-American or non-Hispanic Black, and millions more worldwide.

In 2019, Ms. Gray became the first patient with any form of genetic disease to be treated by gene-editing technology known as CRISPR which modified blood cells taken from her bone marrow for subsequent infusion back into her body. Two years later, she was not only pain free, but doing well enough to no longer be part of the landmark study for which she volunteered, although she will continue to be followed for fifteen more years in order to check the long-term safety and efficacy of her treatment. 

The success of Ms. Gray’s treatment was remarkable in many ways. It began just seven years after a team led by bio-chemists Jennifer Doudna and Emmanuelle Charpentier developed a method of applying genetic scissors consisting of repeated sequences of genetic material, widely used by bacteria to fight viruses, to alter or edit human genes. CRISPR is an acronym for Clustered Regularly Interspaced Short Palindromic Repeats, a reference to those repeated sequences. For their success, the two women were awarded the Nobel Prize in Chemistry in 2020. 

In December, 2023, following the success of the clinical study in which Ms. Gray and others were enrolled, Casgevy, a CRISPR-based medicine, was approved by the U.S. Food and Drug Administration (FDA) for use in the treatment of sickle cell disease for patients twelve years of age and older. The same day that the FDA approved Casgevy, it also approved Lyfgenia which uses a different vehicle for genetic modification to treat SCD.

All this is truly great news for the patients who suffer from SCD and for science generally, but the story of genetic diseases and treatments for them is much more complex than may be apparent from this brief review of a recent success concerning a single disease caused by one misshaped gene.

Given the novel challenges involved in developing Casgevy, and the uncertainty of its success, the cost of the CRISPR-based therapy is, not surprisingly, quite high. Indeed, one review characterized the initial $2,200,000 treatment expense of Casgevy as “pricey.” For comparison, treatment with Lyfgenia was priced by its manufacturer at $3,100,000. And these costs are only the beginning. When the anticipated complications, hospital stays, transportation, and other expenses are included, both manufacturers estimated lifetime expenses to range between four and six million dollars per person.

Let’s split the difference and round the anticipated expense of treatment for one person, for this one genetic disease, to $5,000,000. Treating 100,000 patients in the United States would, then, cost $5,000,000,000,000, that is, five trillion dollars. And we still would not have precluded the possibility of future SCD patients in the United States, nor would we have dealt with any affected individuals in West and Central Africa, in European Mediterranean communities, or in India, where SCD is frequently found.

Whether you favor a system of medical expense coverage that includes government coverage, private insurance, direct patient payments, or some combination of those approaches, it’s hard to understand from where the money is going to come to pay for all these treatments. Now some may say that medical care is a right and, so, neither the scientists,  drug companies, hospitals, doctors, nor others involved along the treatment spectrum ought to be compensated to the extent that their collective activity results in multi-million-dollar therapies. Fine. Hold those concerns in mind for a bit.

Regardless of how one approaches the financial questions, they are not the only challenges presented by this new technology. Initially, Vertex, the manufacturer of Casgevy, indicated that there would be treatment centers in only nine states and the District of Columbia. This raises new questions. For instance, how many doctors and teams will be proficient enough to administer this therapy? And if they shift their practice to Casgevy, who will cover the work that they were doing previously? Again, hold these questions in mind.

While we are nothing but delighted that Ms. Gray, and now others, have received successful treatment for SCD, and have nothing but respect for the scientists, doctors, and others who helped bring substantial relief to the patients they served, you don’t have to be a rabbi, minister, or priest, or an atheist professor of philosophy for that matter, to begin to sense the considerable breadth and depth of ethical challenges which Casgevy raises. Not least among these are which diseases should be researched, which individuals should be treated, and who pays how much for the treatment. Add these questions to the list to be considered subsequently.

Before we can address those thorny concerns, though, we have to recognize one unalterable fact: Casgevy was developed to treat a pathogenic variant, that is, a disorder, in just one gene which when it deviates from the norm can cause severe adverse consequences. As we will see, there are many other diseases that are caused by mutations in other single genes and there are many more diseases that are caused by mutations in more than one gene and by factors other than genetic. To underscore and appreciate the true complexity and totality of the ethical challenges of bioengineering, we have to understand some basic biology. 

Fundamentals of Genetics

What makes us animals instead of plants, and humans instead of horses or whales or eagles, is information contained in our cells which instructs our cells as to how to behave. In humans, this information is housed in thread-like structurescalled chromosomes, located in the nucleus of each of our cells. Humans have 46 chromosomes, packaged into 23 pairs.

In 22 of these pairs, chromosomes are also called autosomes. Those in the twenty-third pair are the sex chromosomes. Typically, if, from that twenty-third pair, a baby is born with two X chromosomes, she will be female. If a baby has both an X and a Y chromosome, he will be male. 

Most cells in the human body are diploid, that is, normally they each contain two complete sets of chromosomes. The human sex cells, eggs and sperm (the gametes), are haploid. They have only a single set of chromosomes. 

Chromosomes are made up of protein and a molecule of deoxyribonucleic acid, which, for obvious reasons, we call DNA. DNA is structured with two strands that wind around each other to resemble a twisted ladder which forms a double helix pattern. Each strand of DNA

has a backbone made of alternating sugar (deoxyribose) and phosphate groups. Attached to each sugar is one of four different chemical bases — T (thymine), A (adenine), C (cytosine), and G (guanine) — that are organized in such a way as to form a code. Normally, each base on one strand of DNA is also linked to another base on the other strand, forming a set of genetic bases known as a base pair. Altogether, by one count, the human genome is comprised of about 3.2 billionbase pairs.

The DNA in a single cell is so tightly folded, coiled, looped, and compacted that if it were unraveled and extended from end to end it would be approximately two meters or about six feet long. As astonishing as that is, if you placed all of the strands of DNA in every one of a person’s cells end to end, that collection would run an astonishing 42 billion miles!

Genes are specific sections of DNA which are located in specific chromosomes. Some of these genes provide chemical instructions for making proteins which, in turn, act to make cells function normally and which, essentially, determine a person’s particular traits. Other genes serve to control yet other genes. Collectively, all of this information, all of these instructions, are an individual’s genome, the “operating manual” for an individual’s body.

Autosomes exist in different sizes and are numbered from the largest to the smallest. Different numbered autosomes contain different numbers of genes. Genes, in turn, contain varying numbers of base pairs, ranging from a few hundred to over two million. 

Despite the large number of nature’s building blocks in humans, about 99.9% of human genes are the same in everyone. Given the large number of base pairs in the human genome, though, that 0.1 percent difference includes about 3.2 million base pairs. So just a very small number of differences in the sequence of DNA bases accounts for many of our individual physical features. And they also influence an individual’s risk of developing diseases and that person’s responses to medications.

Moreover, because of those differences, an individual’s genome is unique to that person. No human alive today, nor any who lived previously, has, or ever had, the exactly same genome, even seemingly identical twins.

Identical, or monozygotic, twins are the consequence of an early embryo splitting either before or after implantation in the womb. While the twins share almost all of their DNA, they may develop differently from their earliest days and throughout their lives. For instance, depending on timing, the two developing bodies couldoccupy separate placentas and separate inner amniotic sacs, could share a placenta  with separate sacs, or could share both a placenta and inner sac. While in utero, their DNA might fold differently or be subject to different random mutations. After birth, one may encounter different environmental and lifestyle factors, from climate to diet and exercise, which could affect how their genes function.  

The Human Genome

Until quite recently, we had very little understanding about how many or what kinds of genes the human body contained. In 1990, The Human Genome Projectbegan an incredible scientific effort to gather that information by sequencing the human genome, that is the entire set of  human genetic material, as well as the genomes of a limited number of other organisms such as the fruit fly and mouse. 

Just over a decade later, in April, 2003, the International Human Genome Sequencing Consortium announced that it could account for 92% of the human genome. In March, 2022, the Telomere-to-Telomere Consortium reported that it had progressed to the point that it had generated the first “truly complete” human genome sequence. As a result, we now have a reasonably good grasp on the identity and location of protein producing human genes, but there is so much to learn about how they function or don’t. Based on studies that followed the Human Genome Project, a current estimate of protein producing genes is about 19,000, less than half of which have been well-studied.

Of course, we don’t need to know the identity of all genes, or the universe of all potential problems, to understand that it may only take a disorder with one gene to lead to serious consequences for an individual. That problem can arise when the DNA sequence within a single gene is changed, that is, when there is a variation or mutation, and cells do not receive the information that they should. 

Mutations can arise for various reasons. They can occur spontaneously or they can be inherited from one or both of a person’s parents or it. And a mutation can occur when just one of the chemical bases on a strand of DNA is changed or missing or supplemented. However the mutation arises, it can lead to abnormal protein production and health problems. 

Environmental and Developmental Causes

Some mutations may result from environmental factors, such as smoking tobacco, or exposure to chemicals, radiation, or even sunlight. A mutation may also arise early in life during the development of the egg or sperm or the new resulting individual. This essay will focus only on genetic disorders. 

Genetic Transmission

Whether an individual inherits a mutated gene and develops a genetic disease, depends in part on the fact, noted above, that human sperm and egg cells each have just one set of chromosomes. When a sperm cell meets and binds with an egg cell, it releases genetic material into that cell, meaning that the egg cell is fertilized. In that case, normally it will contain two sets of chromosomes, one from each parent. It is at this time that the fertilized cell, or zygote, first contains the diploid genome of a “new and unique individual.” 

Between 12 and 30 hours after fertilization, this single cell will begin the process of mitosis, or cell reproduction by division. After four divisions over a period of about three days, this new individual consists of a sixteen-cell package known as a morula. Cell division will continue and the cavity which holds them, called a blastocyst, ideally will attach itself to the female’s fallopian tube and develop into an embryo. Barring some problem, or intervention, the embryo will develop into a human fetus and emerge as a human baby. 

Sometimes, though, the genetic contributions of the new individual’s biological father or mother, or both, contain a particular variation which increases the chances that their child will develop a particular disease. Should that condition develop, the disease is called “hereditary or inherited.” In some cases, as with SCD, a single mutation from a single parent is sufficient to trigger a genetic disorder. In other cases, mutations from both parents are required before a problem occurs. 

Because, as we have seen, most genes are autosomal, so, too, are most inherited conditions, like SCD (see above) and Cystic Fibrosis (see below). Sometimes, though, as in the case of Duchenne Muscular Dystrophy, the disorder is linked to a sex chromosome. 

Estimates of prevalence of genetic disorders

Most of the time, mutations will not cause any genetic disorder. Still, the presence, absence, or change in just one letter of the genetic code can give rise to one more, one less, or one damaged protein with profound health consequences.  

Estimates of the varieties and extent of genetic diseases is challenging for a wide range of reasons ranging from diagnosis to reporting. They extend from 7,000different types of conditions to 10,000 depending on the population covered and limitations on the diseases considered. A report of the World Health Organization published in February, 2025 estimates that, though rare, genetic diseases affect more than 300 million people worldwide, the majority of whom are children. Regardless of the problems inherent in determining a precise rate of prevalence, what is clear is that for the individual directly affected, that person’s family, and that family’s community, the burden of dealing with the condition may by significant.

The Genetic Pre-History of American Jews

If genetic diseases are inherited, and by definition they are, then it follows that certain genetic disorders may, over time, become more prevalent in communities that are more closely knit than the general population. The circumstances that give rise to these situations may differ. It could be because of a population bottleneck. It could be because of consanguineous marriage, that is the marriage of second cousins or closer. It could be because of general endogamy, where a relatively small, homogenous, and traditional  community strongly encourages marriage within the group and discourages inter-marriage with those outside of the group. Regardless of the particular cause, the end result is a reduction of genetic diversity, an increased possibility that both parents will carry a gene mutation, and a greater chance that their child will receive that mutation and, then, display symptoms of a genetic disease.

The majority of all Jews alive today are Ashkenazim, a distinct ethno-cultural-religious group whose origins are not without controversy, but who seem to have first appeared in the Rhineland in the 10^th Century CE. Parenthetically, other Jews, like the Sephardim, can trace their ancestry to Spain and Portugal, while yet other Jews, the Mizrahim, look to the Middle East. Following expulsions in the 13^th and 15^th Centuries CE, the Ashkenazim likely migrated east to territory now controlled by Poland, Lithuania, and Russia. 

Recent studies of the medieval Ashkenazi community, by itself and in comparison to modern Ashkenazim, suggest that the population suffered a sharp reduction in size in the late Middle Ages and that modern Ashkenazim descend from a small set of founders. More specifically, about 40% of Ashkenazim can trace their genetic ancestry to just four women. This result suggests a Founder Effect, a recognized genetic phenomenon where a small group of individuals gives rise to a later larger population, but one with relatively limited genetic diversity. Add to this effect apparently limited genetic movement into the Ashkenazi gene pool over five to six centuries, and it is not surprising that the current Ashkenazi population is today “overall highly genetically homogeneous.” 

According to one study by the Pew Research Center, about two-thirds of American Jews identify as Ashkenazi Jews. Not surprisingly, then, American Jews are more susceptible than the general population to certain hereditary diseases. 

What follows Is a non-random, but also non-inclusive, collection of just half-a-dozen genetic disorders that demonstrates that certain mutations occurring in different genes located in different chromosomes can (1) affect different sexes, different age groups, and different bodily systems and (2) present disproportionate health risks to Jews, in particular Ashkenazi Jews. This selection, though small, is sufficient to illustrate both the wide variety of anomalies that might occur and how a traditionally discreet population might be impacted by a particular genetic mutation.

A Sample of Some Genetic Disorders

DISCLAIMER: The following material is not intended to be a complete review of any genetic disorder. Nor is it intended to serve as medical advice with respect to any disease. Rather, the information provided is derived from apparently credible sources solely to illustrate some important, but limited,  aspects of a mere handful out of thousands of genetic varitions in order serve as a background  for addressing ethical issues which may arise in connection with new gene-editing technology. Those who seek advice regarding the nature of, the evaluation for, the medical diagnosis of, or potential treatments for or regarding any real or possible condition should consult with a physician or other qualified health professional source rather than rely on any information contained here. 

          1.  Breast Cancer

After skin cancer, breast cancer is “the most common cancer diagnosed in women in the United States.” While the precise cause is not known presently, sometimes a change in cells in breast tissue causes too many cancerous cells to grow which may form a tumor that, in turn, can grow and spread to other parts of the body. 

The trigger for that change may involve one or more of many risk factors, but up to 10% of people with breast cancer have inherited genetic mutations, the most common being in BRCA1 and BRCA2 in chromosomes 17 and 13, respectively. Those are genes that when operating properly “produce proteins that help repair damaged DNA.” Mutations of either of these genes can lead to breast and other cancers. 

The incidence of breast cancer differs by ethnicity, as does the age at which any cancer may be diagnosed and the impact of any occurrence. For instance, Hispanic women have a lower incidence rate than women of other groups, but also tend to be diagnosed at later stages than white women. The end result is that breast cancer is the leading cause of cancer death among Hispanic women.

In the general population in the United States, about 1 in 400 women (0.25%) have the BRCA 1 or 2 mutation. It is, however, ten times more prevalent among Ashkenazi Jews meaning that about 2.5% of Ashkenazi Jews carry the mutation.  

While the prevalence of a BRCA mutation may seem low, statistically, any woman with BRCA1/2 has more than a 60% chance of developing breast cancer in her lifetime. That is more than four times greater than a woman who is not a carrier of BRCA 1/2. 

Overall, “1 in 8 women in the United States will develop breast cancer in her lifetime.” The National Breast Cancer Foundation has estimated that in 2025, 317,000 women and 2,800 men will be diagnosed with new cases of invasive breast cancer.

          2.  Canavan

Canavan disease is a “neurodegenerative condition” that progressively impairs the ability of brain to “send and receive messages.” It can develop when the ASPA gene in chromosome 17 mutates and allows levels of N-acetyl aspartic acid to build up which interferes with the ability of the brain’s protective myelin sheath to function properly. Affected infants develop symptoms related to motor control between 3 and 6 months of age. Most affected children do not survive beyond childhood. There is no known cure yet for Canavan disease. 

Canavan affects a variety of ethnic communities and occurs equally among genders. But it appears with greater frequency among Ashkenazi Jews for whom the carrier frequency has been estimated to be “as high as one in 40-82 people” and the “risk for an affected child of Ashkenazi parents is between 1 [in] 6,400 and 1 in 13,456.”

3.  Cystic Fibrosis

CFTR, in chromosome 7, is a gene that produces a protein that should regulate the flow of salt and fluids in and out of cells that makes secretions, like mucus, sweat, and digestive juices. While normal thin and slippery secretions protect various internal passages and ducts, a CFTR mutation can cause the secretions to become thick and sticky, potentially leading to blocked, damaged, or infected organs, especially the lungs and pancreas. The resulting condition is called Cystic Fibrosis      (CF).  Of the 2000  known variants of the CFTR gene, 700 can cause the disease. 

CF is a progressive and debilitating disorder for which a cure is not currently known, but for which treatments are increasingly available. The population affected by CF is about 40,000 people in the United States and 100,000 worldwide. Children born with CF in the United States have a life expectancy of 61 years. 

CF is one of the most common genetic disorders among people of Northern European descent in the United States. According to one relatively recent review, about 1 in very 25 such individuals are carriers of a CFTR mutation, and the prevalence in the Ashkenazi population is slightly worse, at 1/24. By contrast, the carrier frequency for Hispanic Americans, African American/Blacks, and Asian Americans is 1/58, 1/61, and 1/94, respectively. Importantly, within the Jewish population, there is also evidence of differences in CF mutations. For instance, among Ashkenazi Jews a CFTR variation called p.Trp1282Ter has been found in about 46% of CF cases, a rate thirty times greater than in persons of European descent. It is considered a founder mutation.

       4.   Gaucher Disease

By one measure, Gaucher disease (GD) is the most common  Ashkenazi  genetic disease. It is caused by a mutation of the GBA1 gene in chromosome 1, and a variant of that gene is carried by 1 of every 10 Ashkenazi Jews. 

GBA1 normally produces an enzyme, in this case     glucocerebrosidase, that breaks down fatty substances. Absent that enzyme, fatty substances can build to toxic levels in the cells in the spleen, liver, other organs, and tissues resulting in the condition known as GD. 

The symptoms of GD are manifold, e.g., enlarged organs, eye  disorders, bone pain, anemia, etc., so the disease is hard to diagnose.  There is no known cure.

Gaucher affects as many as 1 in 100,000 children born in the UnitedStates, but up to twenty times as many Jewish infants. While the carrier rate is high, the mutated gene must be carried and passed on by bothparents before a descendant can develop GD.

5. Parkinson’s Disease    

 Parkinson’s Disease (PD) is, after Alzheimer’s disease, the most common age-related degenerative brain disease in the United States, currently affecting about one million individuals, generally over 65 years of age, with an additional 90,000 being diagnosed every year. While Alzheimer’s causes memory and cognition problems, PD affects a person’s motor skills, and is marked by tremors, stiff and slow movements, and balance problems, among other symptoms.  

Many PD symptoms are related  to impairment of neurons located in the substantia nigra area of the brain, that is, the midsection of the brain right above the brainstem. These neurons are supposed to produce a chemical called dopamine. Absent sufficient dopamine, the brain’s signals to move are not transmitted normally and coordination with cells involved in movement is diminished. 

While a specific cause of PD is not currently known, both environmental and genetic factors appear to increase the risk of developing the condition. The environmental factors are diverse and include toxins, pesticides, and well water. 

Ten to fifteen percent of people with PD have one or more genetic ties to the condition. So far, at least seven genes have been associated with one form or another of PD.

In the last decade or so, studies have indicated that a repeat kinase 2 gene known as LRRK2 is the second most common PD-related gene. Located in chromosome 12, LRRK2 has been associated with late-onset PD. One study, conducted at Beth Israel Medical Center in New York City, found that a LRRK2 G2019S mutation was found in 18% of Ashkenazi Jewish patients with PD, and almost a third of patients with a family history of PD. These rates are reportedly “15 to 20 times as high” as rates previously determined for European subjects. This situation is possibly explained by two founding events, one about 2250 years ago and another more recently in the 13^th Century CE, both perhaps coinciding with Jewish diaspora migrations.

There is currently no known cure for PD, nor even a way to slow its progression, although medications, surgical options, and other supportive therapies are available and may reduce symptoms and improve life quality. 

6. Tay-Sachs

Tay-Sachs Disease (TSD), a rare, but fatal, genetic condition that affects a child’s nerve cells and is marked by movement and neurological problems. It is caused by a mutation in the HEXA gene in chromosome 15, which gene normally produces a vital enzyme, hexosaminidase, that helps to break down a fatty substance in the spinal cord and brain called GM2 ganglioside. When the enzyme fails to do its job, that substance can build to toxic levels. Symptoms of TSD vary with age, but signs of infant TDS in the form of hearing and vision loss or muscle weakness could be evident as early as three to six months of age. In the past, the life span of a child with an infantile form of TSD has been under four years. 

For TSD to be transmitted, both parents of a child must be carriers of a defective HEXA gene. While in the general population, the carrier rate is about 1 in 250, among Ashkenazi Jews it is more than nine times more frequent, as about one in every twenty-seven Ashkenazi Jews are carriers.

There are, mercifully, two bits of good news on this front. The first is that awareness of TSD in the Jewish community has led to genetic screening to the extent that the birth of a child with TSD has “come close” to elimination in that community. Second, researchers for UMass Chan Medical School and Auburn University developed a successful non-CRISPR gene therapy for two children with TSD. Caution: (1) the malevolent genetic variant has not been erased, (2) continued awareness must still be pursued on the educational front, and (3) the cost of the gene therapy for a limited group of patients is problematic.

Genetic Testing and Ongoing Research 

Given the risks and potentially devastating effects of developing what might be called a Jewish genetic disorder, testing to determine whether an individual is a carrier of one or more such disorders is often recommended for Ashkenazi Jews who are pregnant or who are planning to have biological children. Information about the nature, scope, and expense of such tests, as well as options available in the event a test indicates that the person tested is a carrier of one or more of the subject disorders, may be found from a variety of sources in the United States including, but not limited to, Boston Medical Center, Sarnoff Center for Jewish Genetics, Kaiser Permanente, UCSF Health, the Jewish Genetic Disease Consortium, and JScreen. Various foundations and other organizations that focus on a specific disorder may have additional information about current research, as well as clinical trials, designed to determine the safety and efficacy of various therapies. 

The Bioethics of Gene Editing

Gene editing is a new and rapidly developing technology for addressing genetic disorders. But, as suggested above, bioengineering gives rise to a host of challenges for us. These include disease selection, sufficiency of medical personnel and facilities, patient selection, affordability, economics, generational change, speculation and abuse, and species stewardship. Jewish perspectives on these challenges will be addressed in a subsequent paper.