Showing posts with label genomics. Show all posts
Showing posts with label genomics. Show all posts

Tuesday, September 12, 2023

New technologies and new controversies: using CRISPR to edit human genes

 New technologies are often accompanied by new repugnancies, i.e. by controversies about their moral appropriateness. The future of using CRISPR to edit human genes is still before us, and its history (even to date) has yet to be written. But I'm struck by how it both interacts with and recapitulates older controversies and repugnancies, including those involving HIV, and adoption and assisted reproduction.

The New Yorker has the story:

The Transformative, Alarming Power of Gene Editing. A rogue scientist showed that crispr gives humans the ability to transform ourselves. But should we?  By Dana Goodyear  September 2, 2023

"The Chinese researcher He Jiankui was jailed for creating customized babies. Some observers argue that the real problem wasn’t him—it was the lure of the technology.

...

"To start, he would focus on what he believed was an achievable task: eradicating a disease governed by a single gene. He selected aids, an illness regarded in China as both pernicious and shameful but one for which there might be an elegant fix. H.I.V. enters human cells by way of a receptor created by a gene called CCR5. JK planned to use the gene-editing tool crispr to disrupt CCR5 in human embryos, which would, in theory, render the babies impervious to infection.

"The experiment required volunteers, and, through a chat group associated with an H.I.V./aids charity, he began recruiting couples: H.I.V.-positive men married to uninfected women. Chinese law denies in-vitro fertilization and adoption to H.I.V.-positive people, and natural conception carries a risk of transmission. For couples with an infected partner, JK’s program was a chance at parenthood. It promised confidentiality, which was critical for a marginalized community; an H.I.V. diagnosis in China can cost a person his job. The treatments would take place discreetly, at facilities where only key employees were aware of the experiment.

...

"as scientists from around the world prepared for a gene-editing conference in Hong Kong, JK released a series of YouTube videos, announcing the birth of a set of twins, edited as embryos with crispr. A slim, nervous-seeming man in a pale-blue shirt, he looked earnestly into the camera and said, “Two beautiful little Chinese girls named Lulu and Nana came crying into the world, as healthy as any other babies.” He went on to explain how, when each was only a single cell, he had used crispr to delete CCR5. “I understand my work will be controversial,” he said. “But I believe families need this technology, and I’m willing to take the criticism for them.”

"China’s state-run media celebrated the news, but the scientific community reacted with dismay. A group of Chinese researchers condemned the study as madness. David Baltimore, a Nobel Prize-winning biologist who chaired the Hong Kong event, called it “irresponsible,” saying, “I think there has been a failure of self-regulation by the scientific community.

...

"There were three edited babies, he acknowledged: along with Lulu and Nana, another was on the way.

...

"The Chinese government swiftly withdrew its enthusiasm for JK’s research, and, soon after he returned to the mainland, his lab was locked and he was placed under house arrest. In 2019, he was sentenced to three years in prison for “illegal medical practices,” and fined nearly half a million dollars. Two of his collaborators were given lesser sentences and fined. Among scientists, there was a pervasive sense of embarrassment. JK had misused a powerful technology and gambled with the health of children—experimental subjects he himself had created—without, in the scientists’ view, a compelling medical reason to compensate for the risk. Urnov told me, “He has taken a jar of tar, poured it over the field of crispr, and left an indelible stain. We will never wash that stain off. I am prepared to say that he’s not a fellow-scientist. He’s persona non grata.”

"JK was released from prison in the spring of 2022, and quickly resumed his efforts at gene editing. 

...

"He said that his new lab would be a nonprofit providing affordable gene therapy for rare conditions, and that he would focus first on Duchenne muscular dystrophy, a fatal disease that causes irreversible muscle damage, primarily in boys. This time, his patients would be not embryos but young children desperate for a cure. I asked if it was an attempt to redeem himself in the scientific community. “I don’t know if I’d use the word ‘redeem,’ ” he said. “I want to do it to help people today.”

...

"As for the debacle that his experiment had caused, JK would admit to no greater error than bad timing. “I do acknowledge that I have done it too quickly,” he said. In one of his YouTube videos, he predicted that in twenty or thirty years gene-edited babies will no longer be controversial, or even remarkable. He likened himself to the pioneering founder of the field of I.V.F., Robert Edwards, whose career had followed a heroic arc. In 1978, when the first I.V.F. baby was born, Edwards was a figure of scandal and opprobrium. In 2010, he was awarded the Nobel Prize."

Friday, February 10, 2023

Human evolution in the last 12,000 years, in PNAS

My loose impression is that, not so long ago, scholars of human evolution discounted recent changes in the human genome, pointing out that maybe the frequency of lactose intolerance had been altered by the domestication of cattle, goats, and sheep, but suggesting that recent changes (i.e. since the invention of agriculture) were rare. This may have been an anti-racism perspective, or it may be that new data have changed this view, but indeed it seems to have changed.

Gene changes in recent milennia offer a window on how human patterns of interaction, regarding food acquisition and preparation, and communal living, may even cause changes in human biology.  

Here's a special feature on the subject, at the PNAS:

Special Feature: The Past 12,000 Years of Behavior, Adaptation, and Evolution Shaped Who We Are Today

"The authors of this Special Feature focus on challenges pertaining to dietary and nutritional quality and adequacy, resource inequality, interpersonal conflict and warfare, climate change, population trends, demographic transitions, migration, mobility, infectious disease and the rise of novel pathogens, and the transformative circumstances of human biology over the last 12,000 years.

Saturday, October 29, 2022

The end of anonymous sperm donation...

 In  Colorado, a new law ending anonymous sperm donation seeks to catch up with the technological developments involving genetic sequencing that have already made anonymity of sperm or egg donors fairly fragile. Here's an account in JAMA:

The End of Anonymous Sperm Donation in Colorado--A Step Forward to a New Fertility Future in the US?  by I. Glenn Cohen, JD1; Eli Y. Adashi, MD, MS2; Seema Mohapatra, JD, MPH3   JAMA. Published online October 24, 2022. doi:10.1001/jama.2022.19471

"On May 31, 2022, Colorado became the first state to effectively ban anonymous gamete donation.1 Starting in 2025, fertility clinics in Colorado must collect identity and medical information from sperm and egg donors and may not match donors that do not agree to such disclosure (the statute uses the word “donor” though in many instances compensation is provided). The new law also requires that the clinics make a request that donors update their contact information and medical history at least once every 3 years. The law provides that a donor-conceived person aged 18 years or older shall be provided donor information upon request. The statute purports to also prohibit fertility clinics outside Colorado from providing gametes to Colorado residents (or individuals located in Colorado) if they do not abide by these rules. The statute also instructs clinics not to match a donor once it is known or reasonably should be known that “25 families have been established using a single donor in or outside of Colorado.”1

...

"Two states, Utah and Washington, have enacted statutes requiring the collecting and sharing of identifying information about a donor with donor-conceived children who request it after reaching the age of 18 years.3 However, both states also permit a donor to opt out, thereby limiting the utility of the laws. By contrast, the UK, Germany, Sweden, France, and many other countries have created mandatory registries that donor-conceived individuals can access when they turn 18 years of age, having an effect similar to the new Colorado law.3,4

"The new Colorado law highlights the gap between the law and reality of gamete donor anonymity in the US outside Colorado. Banks have promised donors anonymity in other US states and prior leaks of donor information from banks’ files have been exceedingly rare, if they ever happened at all; the banks have litigated to protect the identifying information provided by the donor.3 But in a practical sense, the promise of anonymity is now much less thoroughgoing.4 Direct-to-consumer genetic testing has become very common, and it has been estimated that 100 million people worldwide have taken a direct-to-consumer genetic test by 2021.4 Studies estimate that a genetic database covering only 2% of the population could match nearly anyone in that population.4 The combination of direct-to-consumer genetic testing, publicly available information, and social media suggest that many donor-conceived individuals will in fact be able to reidentify their gamete donor."

Friday, December 10, 2021

The first children with germline-edited genomes are growing up: the CRISPR story so far

 Nature has the story:

The CRISPR children.  In China, the first children with germline-edited genomes are growing up.  by Vivien Marx

"Three years ago, the world was in uproar after a journalist broke the news about two babies born with genomes edited with CRISPR-Cas9. He Jiankui had been invited to speak in the session on human embryo editing at the Second International Summit on Human Gene Editing. Some of He’s advisors thought he should speak about the twins, while others advised him to wait until his manuscripts were published, and He was purportedly leaning toward focusing just on preclinical work. Then, when the news of the twins’ birth was revealed, he adjusted existing slides to address the news.

....

"The goal of these heritable gene edits was to generate HIV-resistant people, by introducing germline mutations into the C-C chemokine receptor type 5 (CCR5) gene, which encodes a co-receptor for HIV. This thinking was roundly criticized by researchers and ethicists because of a lack of a medical need given the availability of antiretroviral treatments.He’s rationale for germline editing was that the gene was well studied, that HIV remains a devastating disease and that HIV infection status leads to discrimination. The participants in this study were HIV-discordant couples: the wives are HIV negative and their husbands are HIV positive and being treated with antiretroviral drugs.

...

"As the chorus of criticism around the experiments mounted in the days after the announcement, He disappeared from public view. Some assumed he was given a kind of escort who accompanied him around campus and monitored him. In January he was fired from his university post, and apparently detained some time thereafter.The Chinese authorities initially touted He’s achievement, then backtracked, condemned the work and shuttered the lab. After a trial in Nanshan District People’s Court behind closed doors, He was sentenced to a fine and three years in jail for ‘illegal medical practice’, along with two members of his team.

...

"One key concern for the children is genetic mosaicism—a condition in which different cells from the same individual have different genomes. Such conditions can occur naturally during development, for example through post-zygotic mutations, when mitosis proceeds irregularly and mutated cells persist. It can also happen when, after an environmental insult, a DNA break is not properly repaired.

...

"Whitehead Institute researcher Rudi Jaenisch says that mosaicism is a major problem with current approaches to heritable embryo editing. When genome edits take place after a zygote has become a two-cell or multicellular blastocyst—as likely occurred in He’s experiments—the edited and unedited cells keep dividing.

...

"Adashi fears that, given how imperfect the gene-editing tools are, the type of genetic and genomic “mayhem” that can result might lead to the loss of entire chromosomes or pieces of them. “Basically they could have a scrambled genome,” he says about the girls. He points to several papers showing such damage when CRISPR-Cas9-based gene editing is performed in human embryos.

...

"Rather than edit embryos, both Jaenisch and Church think that if germline gene editing is ever considered, it would be more promising to, for example, edit spermatogonial stem cells that give rise to sperm. But for now neither heritable gene editing in embryos nor germ-cell editing are considered ready for application in people.

"What happened in He’s lab, says Musunuru, is a textbook ethics violation that should be extensively analyzed and discussed. To date, the manuscripts describing the work that led to the gene-edited children have not been published in a journal or placed on a preprint server (Box 2). But since the birth of Lulu, Nana and Amy, a host of reports about the safety and ethics of gene editing have been published.

...

"They may well grow up healthy, says Adashi. Considering the risks endured in their creation, that would be a wonderful outcome. But he worries that germline gene editing “has a significant potential to cause harm rather than good.”

“How and if it will manifest is unknown,” he says. It’s certainly no way “to start life.”

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Earlier:

Monday, December 14, 2015

Wednesday, November 11, 2020

Crispr gene editing is apparently not yet so well understood

 The NY Times has the story:

Crispr Gene Editing Can Cause Unwanted Changes in Human Embryos, Study Finds--Instead of addressing genetic mutations, the Crispr machinery prompted cells to lose entire chromosomes.  By Katherine J. Wu.

"A powerful gene-editing tool called Crispr-Cas9, which this month nabbed the Nobel Prize in Chemistry for two female scientists, can cause serious side effects in the cells of human embryos, prompting them to discard large chunks of their genetic material, a new study has found.

Administered to cells to repair a mutation that can cause hereditary blindness, the Crispr-Cas9 technology appeared to wreak genetic havoc in about half the specimens that the researchers examined, according to a study published in the journal Cell on Thursday.

"The consequences of these errors can be quite serious in some cases, said Dieter Egli, a geneticist at Columbia University and an author of the study. Some cells were so flummoxed by the alterations that they simply gave up on trying to fix them, jettisoning entire chromosomes, the units into which human DNA is packaged, Dr. Egli said."

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Previous post:

Monday, December 14, 2015


Monday, December 30, 2019

Some kinds of privacy may be gone forever

Lots of family secrets are revealed by DNA analysis, and it may no longer be possible to keep those secrets.  That is part of the argument made by Dr. Julia Creet, in an interview published at Bill of Health under the title "The End of Privacy?"


Dr. Julia Creet: I made the statement that any idea we had about privacy is over in response to a number of troubling trends in genetic genealogy. DTC genetic tests have revealed long-held family secrets, biological parents and siblings of adoptees, and the identities of sperm and egg donors. In each case, the question of the right of the searcher trumped the rights of those who wanted their privacy protected. In a few cases, sperm donors have sued for invasion of privacy. What these cases show is that even if we think we are protected by the privacy provisions of donor agreements or closed adoptions, genetic tests can leap over those privacy barriers. Many genealogists have declared that there will be no more family secrets in the future. So, family privacy is a thing of the past, which may or may not be a good thing. On a larger scale, law enforcement use of DTC genetic testing databases has demonstrated that data uploaded for one purpose can be used in the future for a completely unanticipated purpose. Without the ability to predict future uses of this information, we cannot put a privacy policy in place that will anticipate all the unforeseen future uses. I think the most telling cases in the last few weeks are the recent warrant that allowed law enforcement access to the GEDmatch database even though most users had opted out of having their results included in searches, and the rather frightening report for Peter Ney about the ease of malware intrusions on genetic genealogy databases.

Friday, December 6, 2019

Testing your own DNA is illegal in France

Statnews.com has the story:

In France, it’s illegal for consumers to order a DNA spit kit. Activists are fighting over lifting the ban  By ERIC BOODMAN

"The French ban on direct-to-consumer genetic testing is part of the country’s bioethics laws, which legislators are supposed to revise every seven years. When those discussions got underway earlier this year, some geneticists expected the National Assembly to relax the rules about commercial DNA analysis. It didn’t. Now, Jovanovic-Floricourt and the other genetics enthusiasts in her education and advocacy group, DNA Pass, are agitating more and more to get some of these tests legalized, contacting lawmakers, chatting up scientists, promising a more vociferous campaign than they’ve waged before.

"But as one of the most vocal pro-legalization advocates, Jovanovic-Floricourt may have found her match in geneticist Guillaume Vogt and his bioethicist postdoc Henri-Corto Stoeklé. Theirs is an unusual standoff, in that they’re all motivated by the same ideas. Both sides hope to protect French genomes from exploitation by foreign companies. Both sides believe that French institutions are the best guardians for the job. They just disagree about how, exactly, to realize that vision. As Vogt, a scientist at the National Center for Human Genomics Research, put it, “Don’t change the law!”

Thursday, April 4, 2019

A new repugnant use of DNA information--'clarifying' Who is a Jew

The Jerusalem Post has the story:
CHIEF RABBINATE ADMITS USING DNA TESTS TO HELP DETERMINE JEWISH STATUS
Orthodox organizations denounce the use of DNA testing as contrary to Jewish law

"Chief Rabbi David Lau has admitted for the first time that the Chief Rabbinate and the state Rabbinical Courts use DNA testing in certain circumstances to help determine whether a person is Jewish.

The admission is likely to generate outrage among mainstream religious-Zionist and Modern Orthodox groups, given that Jewish law does not recognize the validity of DNA testing to prove Jewishness."

Friday, January 13, 2017

Genetic testing for heritable diseases

JScreen is a genetic testing service associated with Emory University that allows individuals and couples to learn what heritable diseases they may carry.  It also offers advising on Preimplantation genetic diagnosis (PGD), Use of donor sperm or egg, Adoption, Prenatal Diagnosis, and Preparation and Early Treatment (when expecting a child who may have a congenital disease).

A well established service of this kind, with a focus on Tay Sachs disease, is Dor Yeshorim (which translates roughly as "straight generation") about which I blogged last year with particular attention to the privacy protecting part of their protocol:

A privacy-preserving market design intervention to avoid Tay Sachs disease


Sunday, January 1, 2017

Matchmaker Exchange: Matching genes and symptoms for patients with very rare diseases ("lonesome exomes")

There's a lot of genetic matchmaking going on in the world. In kidney transplantation we worry about HLA matching, which is even more important in bone marrow matching. Both of those matching processes mostly involve common gene sequences--if you have very rare HLA's, you will have less luck at finding a bone marrow match.

But as more patients with very rare disease have their exome sequenced, there are patients with particular phenotypes and symptoms and "lonesome exomes," which have a suspect gene that may be responsible for their disease, which will remain only a suspect until more patients with that disease and that gene variant can be identified. These data are mostly in separate databases at different clinical research institutions.

That's where Matchmaker exchange comes in--it's a protocol for looking for patients with the same gene variants and the same diseases, so that matches can be made and the genes responsible for rare diseases can be identified.

Here's the paper:
Philippakis AA, Azzariti DR, Beltran S, Brookes AJ, Brownstein CA, Brudno M, Brunner HG, Buske OJ, Carey K, Doll C, Dumitriu S, Dyke SOM, den Dunnen JT, Firth HV, Gibbs RA, Girdea M, Gonzalez M, Haendel MA, Hamosh A, Holm IA, Huang L, Hurles ME, Hutton B, Krier JB, Misyura A, Mungall CJ, Paschall J, Paten B, Robinson PN, Schiettecatte F, Sobreira NL, Swaminathan GJ, Taschner PE, Terry SF, Washington NL, Züchner S, Boycott KM, Rehm HL. 2015. The Matchmaker Exchange: A Platform for Rare Disease Gene DiscoveryHuman Mutation36: 915–921. doi:10.1002/humu.22858 


ABSTRACT: There are few better examples of the need for data sharing than in the rare disease community, where patients, physicians, and researchers must search for “the needle in a haystack” to uncover rare, novel causes of disease within the genome. Impeding the pace of discovery has been the existence of many small siloed datasets within individual research or clinical laboratory databases and/or disease-specific organizations, hoping for serendipitous occasions when two distant investigators happen to learn they have a rare phenotype in common and can “match” these cases to build evidence for causality. However, serendipity has never proven to be a reliable or scalable approach in science. As such, the Matchmaker Exchange (MME) was launched to provide a robust and systematic approach to rare disease gene discovery through the creation of a federated network connecting databases of genotypes and rare phenotypes using a common application programming interface (API). The core building blocks of the MME have been defined and assembled. Three MME services have now been connected through the API and are available for community use. Additional databases that support internal matching are anticipated to join the MME network as it continues to grow.


Here's a video presentation by Dr Kym Boycott, one of the authors.


Friday, December 16, 2016

Genos seeks to make a market for personal genetic (whole exome) information

Genos is a new company that seeks to make a market for personal genetic information--it wants to both sell sequencing services to individuals, and then serve as a broker between the individuals who will still own their own data, and research projects that wish to use those data.

Here's an article in WIRED:

Genos Will Sequence Your Genes—And Help You Sell Them to Science

"The latest contender is Genos, a genetic sequencing startup that is unveiling its whole exome-sequencing service today. The hot, shiny object of the industry, this type of next-generation sequencing offers a complete profile of all the expressed genes (the ones that code for proteins) in your genome. While a growing number of targeted genetic testing kits are currently on the market (Color, Myriad, and 23andMe, to name a few), whole exome sequencing produces 50 to 100 times more data.
...
"In a first for the personal genomics movement, the company is creating a research pipeline with academic and commercial partners, and paying customers to donate their data. The incentives range between $50 and $200 per project; the first four include a vaccine for breast cancer, a clinical trial for treating lymphoma, and research into prion diseases and common neurological disorders."
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A market for information will have some interesting design issues, and a market for genetic information will have to navigate issues of repugnance as well. I'm on their advisory board.

Here's a press release.

Monday, December 14, 2015

Technology watch: does Crispr create a new class of repugnant transactions?

The NY Times has the story:
Scientists Seek Moratorium on Edits to Human Genome That Could Be Inherited

"An international group of scientists meeting in Washington called on Thursday for what would, in effect, be a moratorium on making inheritable changes to the human genome.

"The group said it would be “irresponsible to proceed” until the risks could be better assessed and until there was “broad societal consensus about the appropriateness” of any proposed change. The group also held open the possibility for such work to proceed in the future by saying that as knowledge advances, the issue of making permanent changes to the human genome “should be revisited on a regular basis.”
...
“The overriding question is when, if ever, we will want to use gene editing to change human inheritance,” David Baltimore said in opening the conference this week.
...
"The meeting was prompted by a new genetic technique, invented three years ago, that enables DNA to be edited with unprecedented ease and precision. The technique, known as Crispr-Cas9 and now widely accessible, would allow physicians to alter the human germline, which includes the eggs and the sperm, to cure genetic disease or even enhance desirable physical or mental traits.
...
"“If we are going to view certain applications of human genome editing as permissible, can we draw a line and not throw out legitimate medical applications in order to stave off those that are less palatable to most of us?” Dr. Daley asked.

"Other scientists suggested that the possible risks of human genome editing would be rapidly reduced as the techniques were refined. “Many of these technologies are improving so fast it’s hard to measure,” said George Church, a professor of genetics at the Harvard Medical School. Erroneous cuts made by Crispr-Cas9 can now be reduced to less than one per three trillion base pairs of DNA; the human genome is three billion base pairs in length.

“The concept of a ban on gene editing does not make sense,” Dr. Church wrote in the current issue of the journal Nature. “Banning human germline editing could put a damper on the best medical research and instead drive the practice underground to black markets and uncontrolled medical tourism.”

Thursday, August 20, 2015

A privacy-preserving market design intervention to avoid Tay Sachs disease

Scott Kominers draws my attention to a 1987 news note in JAMA, with a privacy-sensitive market design for keeping people's sensitive genetic information private.

Tay Sachs disease is a lethal recessive-gene disease: when two carriers of the relatively rare gene have a child, they risk having a child who will be born with the disease. Genetic screening offers a chance to alert potential marriage partners if they both carry the gene. But in some of the Jewish communities in which the gene is relatively more common, there was a reluctance to be tested, for fear of being stigmatized as a carrier of the disease. An organization called Dor Yeshorim was formed to offer the following service:

 "All those taking the blood test would be assigned a number, and their test results filed at the screening center by number alone; names would not be recorded. Nor would those being tested be informed of the results, thus eliminating the anxiety of stigmatization. When a match was proposed, the matchmaker would call the screening center, revealing only the prospective couple's numbers. The matchmaker would then be informed whether the proposed match would involve two Tay-Sachs carriers.

"If the match were not to involve two carriers, marriage plans could proceed. If both parties were identified as carriers, the matchmaker would be told only that the two families should contact the center to verify the couple's numbers. The families would then be informed that both of the children were carriers and referred to counseling. Thus, carriers would learn their status only if they were to be matched with other carriers. Then both families could report that the match had failed to come about for other reasons and could look for new matches.

 by Beverly Merz, "Matchmaking Scheme Solves Tay-Sachs Problem," JAMA Nov 20, 1987, 2636-7 (Medical News and Perspectives)