Just how useful is human gene editing?

In the near-term, gene editing is not likely to be useful. Even in the long-term, it may not be very practical.

Just how useful is human gene editing?
Credit: ROBYN BECK via Getty Images
  • Once perfected, gene editing is likely to be useful only under limited conditions.
  • Multigenic diseases like schizophrenia and cardiovascular disease are probably too complicated to be fixed by gene editing.
  • Embryo screening is a far more effective way to achieve the same objective.

The following is an adapted excerpt from the new book CRISPR People, reprinted with permission of the author.

I see no inherent or unmanageable ethical barriers to human germline genome editing. On the other hand, I see very few good uses for it. That is mainly because other technologies can attain almost all the important hoped-for benefits of human germline genome editing, often with lower risk. Two such technologies are particularly noteworthy: embryo selection and somatic genome editing.

Gene editing vs. embryo selection

The most obvious potential benefit would be to edit embryos, or the eggs and sperm used to make embryos, to avoid the births of children whose genetic variations would give them a certainty or high risk of a specific genetic disease. And here it is time to explain the ways genetic diseases or other traits get inherited. If the disease or trait depends on just one gene, we call it a Mendelian condition or trait, named after Gregor Mendel, the Austrian monk who first discovered this kind of inheritance. If more than one gene is involved, we cleverly call them non-Mendelian conditions or traits. Most of the discussion below is about Mendelian conditions for the simple reason that there is more to say about them.

Mendelian conditions can largely be put into five main categories, depending on where the relevant DNA is found and how many copies of the disease-causing variant are needed to lead to the disease: autosomal dominant, autosomal recessive, X-linked, Y-linked, or mitochondrial. Autosomal dominant diseases require only one copy of the disease-causing genetic variation; autosomal recessive diseases require two copies, one from each parent. X-linked diseases typically require two copies in women (one from each parent) but only one in men (who have only one X chromosome, always inherited from the mother). Y-linked diseases, which are unusual, are found only in men and require only one copy — because only men have a Y chromosome and normally they have only one copy of it. Mitochondrial diseases are inherited only from the mother and any mother with the disease will necessarily pass it on to all her children.

Why take the new, riskier — and, to many people, disconcerting — path of gene editing rather than just selecting embryos?

So, if an embryo has 47 CAG repeats in the relevant region of its huntingtin gene, it is doomed (if born) to have autosomal dominant Huntington's disease. One might use germline editing to reduce those 47 repeats to a safe number, of under 37, and thus prevent the disease. Or if an embryo has two copies of the genetic variation for the autosomal recessive Tay-Sachs disease, it could be edited so that the embryo had one or no copies and would be safe. The same is true of X-linked, Y-linked, or mitochondrial diseases.

If this is safe and effective, it may make sense. But another technology that has been in clinical practice for about 30 years is known to be (relatively) safe and effective and can do the same thing — PGD [preimplantation genetic diagnosis]. PGD involves taking one or a few cells from an ex vivo embryo, testing the DNA in those cells, and using the results to determine whether or not to transfer that particular embryo to a woman's uterus for possible implantation, pregnancy, and birth. The first PGD baby was born in 1990. In 2016, the last year for which data are available, the U.S. Centers for Disease Control and Prevention (CDC) reported that about 22 percent of the roughly 260,000 IVF cycles performed that year in the United States involved PGD (or a version called preimplantation genetic screening, or PGS). That was up from about 5 percent the year before. Anecdotally, from conversations with people working in IVF clinics, it sounds as though PGD or PGS usage in 2019 may well be above 50 percent, at least in some areas of the United States.

If a couple wants to avoid having a child with a nasty Mendelian genetic disease or condition, they could, in a decade or more, use CRISPR or other gene-editing tools to change an embryo's variants into a safer form or, today, they could use PGD to find out which embryos carry, or do not carry, the dangerous variants. For an autosomal recessive condition, on average 25 percent of the embryos will be affected; for an autosomal dominant one, 50 percent will be. Even for dominant conditions, if one looks at 10 embryos, the chance that all 10 will have the "bad" version is one in 1,024. If you have 20 embryos to examine, it becomes one in 1,048,576.

So, why take the new, riskier — and, to many people, disconcerting — path of gene editing rather than just selecting embryos?

Credit: JAAFAR ASHTIYEH via Getty Images

Gene editing in somatic cells vs. germline cells

Somatic cell therapy does not change the germline, and it comprises a technology much closer to being shown safe and effective than human germline genome editing. Arguably, the fact that the change is only being made in one or a few of the many tissues of the body would improve its safety over a change that exists in every cell, including cells where a particular off-target change has harmful effects.

On the other hand, genome editing of an egg, a sperm, or a zygote needs to change only one cell. This might prove more effective than changing, say, 100 million blood-forming stem cells or several billion lung cells. Furthermore, somatic cell editing would not necessarily work for all conditions. For some, too many different cells or tissues may have to be targeted. For others, the damage may begin before birth, or even before the stage of fetal development where in utero somatic editing becomes plausible. For diseases with very early consequential effects, somatic cell therapy may be inferior to embryo editing or embryo selection.

Even when somatic editing is possible, human germline genome editing retains one advantage: the process would not have to be repeated in the next generation. If somatic editing is used, that person would still have eggs or sperm that could pass on the disease. If she or he wanted to avoid a sick child, PGD or somatic cell gene therapy might be necessary. If germline editing is used, that child's children will be free from the risk of inheriting the disease from their edited parents. But is this a bug or a feature? It adds a choice — not a choice for the embryo that is, or isn't, edited but for the parents of that embryo. Somatic cell editing continues the possibility of a disease in the next generation — but allows that generation's parents to make the decision. One might — or might not — see that as a benefit.

Gene editing in multigenic diseases

In non-Mendelian (sometimes called multigenic) diseases, no one variant plays a powerful role in causing the disease. Variations in two, or twenty, or two hundred genes may influence the condition. Collectively, those influences might be 100 percent, though the cases we know now add up to much lower certainties. We do not yet know of many good examples, though at least one paper claims to have found strong evidence of that variations of different genes, working together, increase the risk for some cases of autism. And, more generally, we know of many combinations of shared genomic regions that (slightly) increase or lower the risk for various diseases or traits in particular, studied populations. (These have led to the hot area of "polygenic risk scores," whose ultimate significance remains to be seen.)

The biggest problem with human germline genome editing for non-Mendelian conditions is that we do not know nearly enough about the conditions. We believe that many conditions are non-Mendelian, but how many genes are involved? Which genomic variations add or subtract risk? How do the effects of variations from different genes combine to create risks? In a simple world, they would be additive: if having a particular variation of one gene increases a person's risk of a disease by 10 percentage points and having a particular variation of a different gene increases that person's risk by 5 percentage points, then having both would increase the risk by 15 percent. But there is no inherent reason nature has to work that way; the combined effects may be greater or less than their sum. It is even conceivable that having two variations that each, individually, raise a person's risk might somehow lower the overall risk. We know almost nothing about the structure of these non-Mendelian, or multigenic, risks.

It is clear, though, that, in general, PGD would be much less useful for non-Mendelian diseases than for Mendelian ones. The chances of finding an embryo with "the right" set of genetic variations at five different spots along the genome will be much smaller than of finding an embryo with just one "right" variation. If the odds for any one variation are 50/50, the overall odds for any five variations in one embryo are one in 32. If gene editing could safely and effectively edit five places in an embryo's genome (or in two gametes' genomes), it could deliver the preferred outcome. On the other hand, if we can use genome editing to do that in an embryo or gamete, we may well be able to do the same in a fetus, a baby, a child, or an adult through somatic cell gene therapy — unless the condition begins to cause harm early in development, or broadly enough in the body that it needs to be delivered to all the body's cells.

Is gene editing practical?

Right now, there is no non-Mendelian condition for which we are confident we know the exact set of genes involved. Neither do we know the negative and positive effects of different combinations of genetic variants. Until these uncertainties are adequately resolved, human germline genome editing, though in theory better than PGD, will not be safe or effective enough for use. Once they are resolved, in many situations it will be no better than somatic cell genome editing, except for the possible absence of needing to hit targets in multiple tissues or cell types and the absence of a need to repeat the editing for the next generation.

Adapted from CRISPR PEOPLE: The Science and Ethics of Editing Humans by Henry Greely. Copyright 2021. Reprinted with Permission from The MIT PRESS.

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7 most notorious and excessive Roman Emperors

These Roman Emperors were infamous for their debauchery and cruelty.

Nero's Torches. A group of early Christian martyrs about to be burned alive during the reign of emperor Nero in 64 AD.

1876. Painted by Henryk Siemiradzki.
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  • Roman Emperors were known for their excesses and violent behavior.
  • From Caligula to Elagabalus, the emperors exercised total power in the service of their often-strange desires.
  • Most of these emperors met violent ends themselves.

We rightfully complain about many of our politicians and leaders today, but historically speaking, humanity has seen much worse. Arguably no set of rulers has been as debauched, ingenious in their cruelty, and prone to excess as the Roman Emperors.

While this list is certainly not exhaustive, here are seven Roman rulers who were perhaps the worst of the worst in what was one of the largest empires that ever existed, lasting for over a thousand years.

1. Caligula

Officially known as Gaius (Gaius Caesar Augustus Germanicus), Caligula was the third Roman Emperor, ruling from 37 to 41 AD. He acquired the nickname "Caligula" (meaning "little [soldier's] boot") from his father's soldiers during a campaign.

While recognized for some positive measures in the early days of his rule, he became famous throughout the ages as an absolutely insane emperor, who killed anyone when it pleased him, spent exorbitantly, was obsessed with perverse sex, and proclaimed himself to be a living god.

Caligula gives his horse Incitatus a drink during a banquet. Credit: An engraving by Persichini from a drawing by Pinelli, from "The History of the Roman Emperors" from Augustus to Constantine, by Jean Baptiste Louis Crevier. 1836.

Among his litany of misdeeds, according to the accounts of Caligula's contemporaries Philo of Alexandria and Seneca the Younger, he slept with whomever he wanted, brazenly taking other men's wives (even on their wedding nights) and publicly talking about it.

He also had an insatiable blood thirst, killing for mere amusement. Once, as reports historian Suetonius, when the bridge across the sea at Puteoli was being blessed, he had a number of spectators who were there to inspect it thrown off into the water. When some tried to cling to the ships' rudders, Caligula had them dislodged with hooks and oars so they would drown. On another occasion, he got so bored that he had his guards throw a whole section of the audience into the arena during the intermission so they would be eaten by wild beasts. He also allegedly executed two consuls who forgot his birthday.

Suetonius relayed further atrocities of the mad emperor's character, writing that Caligula "frequently had trials by torture held in his presence while he was eating or otherwise enjoying himself; and kept an expert headsman in readiness to decapitate the prisoners brought in from gaol." One particular form of torture associated with Caligula involved having people sawed in half.

He caused mass starvation and purposefully wasted money and resources, like making his troops stage fake battles just for theater. If that wasn't enough, he turned his palace into a brothel and was accused of incest with his sisters, Agrippina the Younger, Drusilla, and Livilla, whom he also prostituted to other men. Perhaps most famously, he was planning to appoint his favorite horse Incitatus a consul and went as far as making the horse into a priest.

In early 41 AD, Caligula was assassinated by a conspiracy of Praetorian Guard officers, senators, and other members of the court.

2. Nero

Fully named Nero Claudius Caesar, Nero ruled from 54 to 68 AD and was arguably an even worse madman than his uncle Caligula. He had his step-brother Britannicus killed, his wife Octavia executed, and his mother Agrippina stabbed and murdered. He personally kicked to death his lover Poppeaea while she was pregnant with his child — a horrific action the Roman historian Tacitus depicted as "a casual outburst of rage."

He spent exorbitantly and built a 100-foot-tall bronze statue of himself called the Colossus Neronis.

He is also remembered for being strangely obsessed with music. He sang and played the lyre, although it's not likely he really fiddled as Rome burned in what is a popular myth about this crazed tyrant. As misplaced retribution for the fire which burned down a sizable portion of Rome in the year 64, he executed scores of early Christians, some of them outfitted in animal skins and brutalized by dogs, with others burned at the stake.

He died by suicide.

Roman Emperor Nero in the burning ruins of Rome. July 64 AD.Credit: From an original painting by S.J. Ferris. (Photo by Kean Collection / Getty Images)

3. Commodus

Like some of his counterparts, Commodus (a.k.a. Lucius Aelius Aurelius Commodus) thought he was a god — in his case, a reincarnation of the Greek demigod Hercules. Ruling from 176 to 192 AD, he was also known for his debauched ways and strange stunts that seemed designed to affirm his divine status. Numerous statues around the empire showed him as Hercules, a warrior who fought both men and beasts. He fought hundreds of exotic animals in an arena like a gladiator, confusing and terrifying his subjects. Once, he killed 100 lions in a single day.

Emperor Commodus (Joaquin Phoenix) questions the loyalty of his sister Lucilla (Connie Nielsen) In Dreamworks Pictures' and Universal Pictures' Oscar-winning drama "Gladiator," directed by Ridley Scott.Credit: Photo By Getty Images

The burning desire to kill living creatures as a gladiator for the New Year's Day celebrations in 193 AD brought about his demise. After Commodus shot hundreds of animals with arrows and javelins every morning as part of the Plebeian Games leading up to New Year's, his fitness coach (aptly named Narcissus), choked the emperor to death in his bath.

4. Elagabalus

Officially named Marcus Aurelius Antoninus II, Elagabalus's nickname comes from his priesthood in the cult of the Syrian god Elagabal. Ruling as emperor from 218 to 222 AD, he was so devoted to the cult, which he tried to spread in Rome, that he had himself circumcised to prove his dedication. He further offended the religious sensitivities of his compatriots by essentially replacing the main Roman god Jupiter with Elagabal as the chief deity. In another nod to his convictions, he installed on Palatine Hill a cone-like fetish made of black stone as a symbol of the Syrian sun god Sol Invictus Elagabalus.

His sexual proclivities were also not well received at the time. He was likely transgender (wearing makeup and wigs), had five marriages, and was quite open about his male lovers. According to the Roman historian (and the emperor's contemporary) Cassius Dio, Elagabalus prostituted himself in brothels and taverns and was one of the first historical figures on record to be looking for sex reassignment surgery.

He was eventually murdered in 222 in an assassination plot engineered by his own grandmother Julia Maesa.

5. Vitellius

Emperor for just eight months, from April 19th to December 20th of the year 69 AD, Vitellius made some key administrative contributions to the empire but is ultimately remembered as a cruel glutton. He was described by Suetonius as overly fond of eating and drinking, to the point where he would eat at banquets four times a day while sending out the Roman navy to get him rare foods. He also had little social grace, inviting himself over to the houses of different noblemen to eat at their banquets, too.

Vitellius dragged through the streets of Rome.Credit: Georges Rochegrosse. 1883.

He was also quite vicious and reportedly either had his own mother starved to death or approved a poison with which she committed suicide.

Vitellius was ultimately murdered in brutal fashion by supporters of the rival emperor Vespasian, who dragged him through Rome's streets, then likely beheaded him and threw his body into the Tiber river. "Yet I was once your emperor," were supposedly his last words, wrote historian Cassius Dio.

6. Caracalla

Marcus Aurelius Antoninus I ruled Rome from 211 to 217 AD on his own (while previously co-ruling with his father Septimius Severus from 198). "Caracalla"' was his nickname, referencing a hooded coat from Gaul that he brought into Roman fashion.

He started off his rise to individual power by murdering his younger brother Geta, who was named co-heir by their father. Caracalla's bloodthirsty tyranny didn't stop there. He wiped out Geta's supporters and was known to execute any opponents to his or Roman rule. For instance, he slaughtered up to 20,000 citizens of Alexandria after a local theatrical satire dared to mock him.

Geta Dying in His Mother's Arms.Credit: Jacques Pajou (1766-1828)

One of the positive outcomes of his rule was the Edict of Caracalla, which gave Roman citizenship to all free men in the empire. He was also known for building gigantic baths.

Like others on this list, Caracalla met a brutal end, being assassinated by army officers, including the Praetorian prefect Opellius Macrinus, who installed himself as the next emperor.

7. Tiberius

As the second emperor, Tiberius (ruling from 42 BC to 16 AD) is known for a number of accomplishments, especially his military exploits. He was one of the Roman Empire's most successful generals, conquering Pannonia, Dalmatia, Raetia, and parts of Germania.

He was also remembered by his contemporaries as a rather sullen, perverse, and angry man. In the chapter on his life from The Lives of the Twelve Caesars by the historian Suetonius, Tiberius is said to have been disliked from an early age for his personality by even his family. Suetonius wrote that his mother Antonia often called him "an abortion of a man, that had been only begun, but never finished, by nature."

"Orgy of the Times of Tiberius on Capri".Painting by Henryk Siemiradzki. 1881.

Suetonius also paints a damning picture of Tiberius after he retreated from public life to the island of Capri. His years on the island would put Jeffrey Epstein to shame. A horrendous pedophile, Tiberius had a reputation for "depravities that one can hardly bear to tell or be told, let alone believe," Suetonius wrote, describing how "in Capri's woods and groves he arranged a number of nooks of venery where boys and girls got up as Pans and nymphs solicited outside bowers and grottoes: people openly called this 'the old goat's garden,' punning on the island's name."

There's much, much more — far too salacious and, frankly, disgusting to repeat here. For the intrepid or morbidly curious reader, here's a link for more information.

After he died, Tiberius was fittingly succeeded in emperorship by his grandnephew and adopted grandson Caligula.

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