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Tue, Jun 23 11:15am · Controversial CRISPR case in China raises stakes for how genetic research is conducted

Mayo Clinic colleagues take a close look at what went wrong with the process in China and how it challenged the implicit “social contract” between science and society

In November 2018, a Chinese biophysicist used a gene-editing technique known by the acronym CRISPR to edit human embryos for reproductive purposes, and he announced the birth of the first-ever genetically modified children ­— twin girls named Lulu and Nana.

The reports rocked the biomedical research world. If true, the use of CRISPR to modify the DNA of human embryos defied global norms for research and ethics, and though no peer-reviewed data was published and many questions remain, the research community has been coming to grips with the news ever since.

“This announcement made waves among both scientific and bioethics scholars because the researcher cut corners — it was not done to the highest ethical standards,” says Karen Meagher, Ph.D., assistant professor of Biomedical Ethics at the Mayo Clinic College of Medicine and Science. “What’s more, these kinds of gene edits are heritable. They can be passed from one generation to the next. This raises questions about who makes such big decisions about what genetic changes are acceptable and why — decisions that could affect generations.”

Dr. Meagher and three Mayo Clinic colleagues have published a commentary in Mayo Clinic Proceedings that takes a close look at what went wrong with the process in China and how it challenged the implicit “social contract” between science and society. “Advances in genetics can inspire both hope and trepidation,” Dr. Meagher says. “We want to be sure that physicians feel equipped to help patients navigate this new science, and collectively shape the path forward.”

CRISPR has opened the door to amazing medical advances that will lead to life-changing cures and treatments. The array of DNA sequences was first described in a study more than 30 years ago, and the lessons learned for genetic editing have been used in farming, food production and other industries for years.

“Medical professionals should expect that patients may have questions about where we stand with gene editing and the ethical considerations that go along with it.” – Karen Meagher, Ph.D.

Over the past decade, CRISPR research has accelerated, and many scientists have recommended a moratorium on using it to manipulate the human germline until accepted research practices and ethical norms can catch up with the science. Calls for a moratorium were renewed with urgency after the experiment in China.

Karen Meagher, Ph.D., assistant professor of Biomedical Ethics at the Mayo Clinic College of Medicine and Science.

That case may have opened a Pandora’s box of negative consequences, including the potential for government getting involved in regulating how scientists and institutions do their research.

“Patient expectations of advances in genetics and the safety of research can be shaped by this type of event,” says Dr. Meagher, whose academic interests include the ethics of emerging genetic technologies and their health care implications. “Medical professionals should expect that patients may have questions about where we stand with gene editing and the ethical considerations that go along with it.”

‘Illegal medical practices’ lead to prison terms

The experiment in China didn’t end well for the researchers. The biophysicist, He Jiankui, went into hiding as an investigation was launched. In December 2019, he pleaded guilty to “illegal medical practices” and was sentenced to three years in prison. The court ruled that Jiankui and two associates violated Chinese regulations on biomedical research and ethics.

Among the lessons from the case: It is difficult—perhaps impossible—to establish shared norms of research and bioethics on a global scale, but it’s essential to work toward that goal. “Careful reflection and inclusive problem-solving are needed to ensure that high ethical standards, not scandal, lead the way forward,” Dr. Meagher says.

Among the concerns raised by the Jiankui case:

  • Results did not go through the standard peer review process, so details continue to emerge, causing confusion for researchers and the public.
  • The experiment defied the general consensus among researchers that scientific issues regarding the target gene were unresolved and not ready for human trial.
  • Researchers didn’t declare conflicts of interest.
  • Researchers failed to comply with regulations that govern research conduct, and as the Chinese court ruled, they violated Chinese law.

Those details weren’t known until months after the initial report, however. “In today’s world, news stories take shape so quickly that early reports often have important inaccuracies or omissions,” says Richard Sharp, Ph.D., co-author of the article and director of Mayo Clinic’s Biomedical Ethics Research Program. “These inaccuracies can linger and color public views of medical advances — or in this case, research scandals.”

Patients, physicians increasingly have a role to play

The experiment and the worldwide attention it attracted inevitably will raise questions for some patients. “A person may only see a headline or two, but it can raise questions about the future of gene editing,” Dr. Sharp says. “We wanted to make sure that providers have the information and tools to have those conversations.”

This is especially true as more stories about gene editing involving CRISPR and other tools are in the news. Just this month, U.S. researchers announced they had used the gene-editing technique to edit a gene to treat blindness while the DNA was still in the patient’s body.

To prepare for the questions patients may have and that research colleagues must address, Dr. Sharp and colleagues have these takeaways:

  • Physicians are uniquely positioned to correct misinformation: They can explain how gene-editing technology shows promise but needs more testing and commonly accepted guidelines.
  • Physicians and researchers must champion the values of self-governance, while acknowledging misconduct when it occurs: Regulatory oversight of reproductive gene editing is up for grabs, which would have a harmful impact on independent scientific research, delaying advances that could help millions of people. The research and health care communities must defend the importance of scientific self-governance, which includes addressing misconduct.
  • Patients expect to have a place at the table in developing policies on how research proceeds: Physicians can be vital links between patients and researchers as policies are formed.
  • As the research advances, physicians may advocate for patients confronting rare diseases: As patients are approached for participation in clinical trials, physicians can help move research forward ethically.

“Researchers, clinicians and patients all have a role to play in asking questions about genetic treatments or research studies available and whether they are a good option,” Dr. Meagher says. “At the local level, clinicians and patients can ask, how is this new study including the patient not as a subject of investigation but as a partner in research, and are researchers taking their values seriously?”

Those discussions are needed now more than ever, as breakthroughs occur daily, it seems, and long-established processes and norms are challenged.

“This scandal highlights the urgency of a coordinated response from the scientific community,” says Dr. Sharp. “Our task now is to pivot from this controversy to foster a broad, international conversation that aims to describe not only the types of gene-editing research that we believe is ethical but the types of research that are essential for advancing the goals of our patients.”

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Mon, Apr 27 6:00am · Noninvasive test may help some patients with melanoma avoid lymph node biopsy

Alexander Meves, M.D., center, with colleagues from SkylineDx: Mark Luna-Vargas, Ph.D. (left) and Jvalini Dwarkasing, M.D. (right)

A Mayo Clinic-led research team has developed a test for patients who have melanoma, the most serious form of skin cancer, that shows whether they’re at risk of the cancer spreading to other areas of the body.

The research, described in the journal JCO Precision Oncology, could allow some patients at low risk of metastasis to avoid having a sentinel lymph node biopsy, an invasive surgical procedure that turns out to be negative for 80% of patients.

“The test combines genetic information from a skin biopsy with certain patient characteristics,” says Alexander Meves, M.D. , a Mayo Clinic dermatologist and researcher whose laboratory works on cutting-edge methods to diagnose and treat melanoma. “The test tells patients whether their melanoma is so low-risk of spreading to other areas of the body that they do not need to undergo a sentinel lymph node biopsy.”

Melanoma develops in the cells that produce melanin, the pigment that gives skin its color. Skin cancer is the most common of all cancers, according to the American Cancer Society. Melanoma accounts for only about 2% of skin cancers but causes a majority of skin cancer deaths, and the rate of incidence has increased markedly in recent years.

The study involved Mayo Clinic researchers in Arizona, Florida and Minnesota, with assistance from a Dutch biotech company, SkylineDx. “We sought to identify molecular tools that indicate which cancer cells are likely to spread throughout the body and determine whether we could identify their presence with a test,” says Dr. Meves, the study’s senior author. First author is Domenico Bellomo, Ph.D., head of bioinformatics-melanoma at SkylineDx.

The study involved 754 patients who were diagnosed with melanoma at Mayo Clinic campuses in Arizona, Florida and Minnesota between 2004 and 2018. The patients had thin or intermediate thickness primary cutaneous melanoma tumors. The characteristics of the tumors, as well as the patient age at the time of diagnosis, were among the clinical factors taken into account along with gene expression from the tumor.

“This test, which incorporates key clinical and new genomic factors, outperforms all other diagnostics tools in identifying patients with a low risk of nodal metastasis and has the potential to reduce sentinel lymph node biopsy rates by up to 40% while keeping the false omission rate below 5%,” says Tina Hieken, M.D., a Mayo Clinic surgical oncologist whose specialty interests include melanoma.

The next step will be to validate the results in a larger prospective study, says Dr. Hieken, a study co-author. “We’re working on activating a registry trial to validate these results across key national and international sites,” she says.

Previous efforts to identify and validate molecular risk factors have been limited by the small number of patients and incomplete patient data. “We estimate that our test could eliminate as many as 70% of sentinel lymph node procedures for early stage melanoma and 40% of slightly more advanced melanoma, called T2 melanoma,” Dr. Meves says.

The study was funded by grants from the National Cancer Institute and the National Center for Advancing Translational Sciences, as well as the Mayo Clinic Center for Individualized Medicine, the Mayo Clinic Cancer Center and the Fifth District Eagles Cancer Telethon.

Dr. Meves reports a financial interest in the test being developed by SkylineDx. Mayo Clinic has reviewed this relationship and taken appropriate steps to protect the scientific integrity of the research.

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Dec 2, 2019 · Precision genomics may offer clues to unexplained low blood cell counts

Mrinal Patnaik, M.B.B.S.

Precision genomics has opened the door to identifying the drivers for cancer and other diseases. Its value as a diagnostic tool isn’t limited to the underlying disease biology, however. It also can help diagnose and determine targeted therapies for patients with unexplained illnesses.

Mrinal Patnaik, M.B.B.S., a Mayo Clinic hematologist, and colleagues conducted research with patients who had unexplained low blood cell counts, or cytopenias, and found that a precision genomics approach has the potential to change clinical treatments and enable personalized care. Dr. Patnaik is associate professor of medicine and assistant professor of oncology, Mayo Clinic College of Medicine and Science.

“Adult patients with unexplained cytopenias need appropriate testing before subjecting them to trial-and-error therapies,” says Dr. Patnaik, corresponding author of the study, published in Mayo Clinic Proceedings. “A significant proportion of these patients could have genetically defined inherited bone marrow failure syndromes, which need specialized treatment. Precision medicine testing has the potential to alter their clinical management.”

Researchers evaluated 68 patients with unexplained cytopenias. About one-third of patients were found to have inherited bone marrow failure syndromes, while 44% did not fit under a known clinical syndrome, diagnosed as clonal or idiopathic cytopenias of undetermined significance. The remaining patients didn’t fit either category.

“Adult patients with unexplained cytopenias need appropriate testing before subjecting them to trial-and-error therapies. A significant proportion of these patients could have genetically defined inherited bone marrow failure syndromes, which need specialized treatment. Precision medicine testing has the potential to alter their clinical management.”

Mrinal Patnaik, M.B.B.S.

Dr. Patnaik and colleagues then conducted a chart review to determine how the information was applied later in the clinical setting. In 25% of the cases, doctors and patients made changes in clinical management, including decisions regarding therapeutic interventions, donor choice and conditional regimens for stem cell transplantation.

Even when a definite diagnosis couldn’t be reached, patients received a tailored follow-up plan that was informed by the genomic work.

“Clearly the information was of value and led to changes in treatment,” says Dr. Patnaik, who has a special research interest in blood cancers called myelodysplastic and myeloproliferative neoplasms. “Our data suggests that it is possible to use this testing in routing clinical practice, and the results should encourage clinicians to consider these tests.”

The study was funded in part by the Center for Individualized Medicine’s Gerstner Family Career Development Award and a grant from the National Center for Advancing Translational Science, which is part of the National Institutes of Health.

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