The Patient Had Bone Cancer. The Diagnosis Arrived 240 Million Years Too Late.

Certainly the patient never knew where the hip pain came from, or why its left leg stopped working. The diagnosis arrived only 240 million years later, when a femur turned up in an ancient lake bed in Germany, one side marred by a malignant bone tumor.

Cancer seldom appears in the fossil record, and its history among vertebrates is poorly understood. On Thursday, a team of researchers writing in JAMA Oncology have described the femur as the oldest known case of cancer in an amniote, the group that includes reptiles, birds and mammals.

Modern cancers are often diagnosed through soft-tissue examinations or biopsies, but that is a difficult prospect for cancer-hunters working with cold, hard fossils. Instead, it takes luck.

“When it comes to our understanding of cancer in the past, we’re really just at the beginning,” said Michaela Binder, a bioarchaeologist at the Austrian Archaeological Institute who’s researched cancer in ancient humans. “It’s not like people say, ‘Oh, I want to go study cancer in ancient turtles or in fossil mammoths,’ because we have so little evidence.”

The discovery of the femur was a stroke of luck. Originally collected by Rainer Schoch of the Stuttgart State Museum of Natural History, it belonged to a wide-bodied, long-tailed animal called Pappochelys, a shell-less relative of modern turtles.

The femur and its jagged growth caught the attention of Yara Haridy, a former medical student and paleontologist at the Natural History Museum, Berlin.

While many paleontologists look for the cleanest — or at least most representative — remains, Ms. Haridy said, the marks left by illness and injury also can shed light on the lives of ancient animals. The study of such fossils is called paleopathology, and it combines aspects of modern forensic and medical practices.

“I basically go through an elimination process, which is kind of how diagnostics in humans work,” Ms. Haridy said. “You go from the most general possibility to more specific and really strange diagnoses.”

Ms. Haridy and her colleagues brought the femur to Dr. Patrick Asbach, a radiologist at the Charité, a university hospital in Berlin. Examining micro-CT scans of the bone, the researchers began running through a checklist of possible causes.

“If you looked externally, you could easily think this was an incorrectly healed bone,” Ms. Haridy said. “I thought initially this animal had a broken femoral head or some sort of really bad shin splints.”

A drawing of the skeleton of Pappochelys and a scan of its cancerous leg bone.CreditRainer Schoch/Museum für Naturkunde Berlin

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A drawing of the skeleton of Pappochelys and a scan of its cancerous leg bone.CreditRainer Schoch/Museum für Naturkunde Berlin

Healed injuries are the most common type of fossil pathology, yet the micro-CT scans showed that underneath the growth, the bone was unbroken.

So Ms. Haridy considered other possibilities. A congenital abnormality would have been present on both sides of the femur, not just one. And while friction and excessive pressure can cause bone growth, the femur would have been protected by muscles.

That left the possibility of disease. But most diseases eat away at bone instead of building it up, or lead to infections that warp and wear away the underlying surface.

Benign tumors can sometimes grow on bones, but they tend to be formed from cartilage and look quite different: “They either make a bunch of cartilage or start to actually reabsorb bone,” Ms. Haridy said.

The team identified the swelling as an osteosarcoma, a type of bone cancer also found in humans. According to the National Organization for Rare Disorders, an estimated 750 to 1,000 cases are diagnosed in the United States every year.

The find is an important data point when it comes to learning more about cancer in the vertebrate family tree, Dr. Binder said.

The lack of evidence for prehistoric cancer has sometimes led researchers to speculate that the disease is a modern phenomenon related to unhealthy living, pollutant-filled environments or people getting much older than they used to in the past.

Other specialists have suggested the possible presence of a tumor-suppressor gene in vertebrates, the failure of which allows benign tumors to metastasize. In the absence of fossil evidence, however, there has been no proof.

Adding to the uncertainty, some animal lineages seem less susceptible to cancer than others: Crocodiles and a few other reptiles, along with sharks and naked mole rats, are rarely troubled by the disease, while tumors in invertebrates don’t much resemble those of vertebrates.

Still, there are other recent finds that suggest cancer’s antiquity. In 2001, a team of Russian paleontologists identified a possible cranial osteosarcoma in an Early Triassic amphibian, while a benign jaw tumor from a 255-million-year-old mammal forerunner was reported in 2016.

“What makes this really cool is that now we understand that cancer is basically a deeply rooted switch that can be turned on or off,” Ms. Haridy said. “It’s not something that happened recently in our evolution. It’s not something that happened early in human history, or even in mammal history.”

 

 

This article was originally published in The New York Times. Read the original article.

Studies Warn Against Minimally Invasive Surgery for Cervical Cancer

Two new studies revealed bad news about minimally invasive surgery for cervical cancer, a widely used procedure performed through small slits in the abdomen instead of a big incision.

Compared with the older, open abdominal operation, the minimally invasive approach was more likely to result in recurrence of the cancer and death, researchers found, in the first study that rigorously tested the two methods.

The results, published on Wednesday in The New England Journal of Medicine, had been circulating among cancer specialists in recent months and are already changing medical practices. Minimally invasive surgery for cervical cancer had been regarded as an advance that would help women: It lets patients recover faster, and since it had proved safe for other cancers, it was expected to be safe for cervical cancer, too.

“At M.D. Anderson, we have completely stopped performing minimally invasive surgery for cervical cancer,” said Dr. Pedro T. Ramirez, a leading expert in minimally invasive surgery for gynecologic cancers, and the lead author of one study. “Throughout the gynecologic oncology community, we’re seeing a transition back to the predominance of open surgery.”

But he also said that some surgeons, who had invested a lot of time, energy and money in learning the less invasive approach, did not want to give it up.

Dr. Ramirez and other researchers said the surprise findings show why it is essential to conduct clinical trials that test one treatment against another.

Surgery is not regulated the way drugs are. Although the Food and Drug Administration must approve new surgical devices, it does not control the way they are used. A tool approved for one purpose can be used for another. Surgeons can try new approaches, and innovations can catch on and spread, as long as hospitals allow it.

Some innovations have backfired. Morcellators, power tools that mince up tissue for extraction through small openings, were originally approved for orthopedic surgery and other procedures, but came into widespread use in operations to remove fibroids, a type of benign tumor, from the uterus.

But fibroids sometimes hide malignant tumors, and morcellation was found to spread cancer in some women, increasing their risk of death.

In that case, the F.D.A. did step in and recommend that the devices not be used “in the vast majority of women” undergoing fibroid surgery. Their use fell off sharply.

Morcellation is not used in surgery for cervical cancer. When minimally invasive surgery is performed, the uterus is removed intact through the vagina.

The study included 631 women and 33 hospitals in the United States, Colombia, Brazil, Peru, Italy, China, Australia and Mexico.

The results affect a relatively small number of women in the United States, where screening has reduced the incidence of cervical cancer to about 13,000 cases a year, with about 4,000 deaths. But worldwide, cervical cancer is the fourth most common malignancy and cause of cancer death in women, with 570,000 cases a year and 270,000 deaths.

The disease is caused in nearly all cases by the human papillomavirus, HPV, an extremely common, sexually transmitted virus. In most people, the immune system clears the virus and they never knew they were infected. But in some it persists, and can cause cervical cancer and other malignancies.

Dr. Ramirez said women with cervical cancer should discuss the types of surgery with their doctors, and should “question the approach of having minimally invasive surgery if that is what is suggested to them.”

Dr. Amanda N. Fader, director of the Kelly Gynecologic-Oncology Service at Johns Hopkins University, and the author of an editorial that accompanies the studies, said the results had “dealt a great blow” to the minimally invasive surgical method for cervical cancer. Johns Hopkins has also halted the procedure, reverting to open surgery “for the time being,” she said.

One question the findings raise is whether women who have already had minimally invasive surgery for cervical cancer have a higher risk of recurrence than previously thought. Dr. Ramirez said most recurrences happen within the first two years after surgery, so women who had the operation more than two years ago may have little to worry about.

For those who had the surgery more recently, doctors are still trying to determine whether extra follow-up is needed. In any case, doctors said, long-term survival rates after both types of surgery are still high.

Dr. Ginger Gardner, a gynecologic oncologist at Memorial Sloan Kettering Cancer Center in New York, said the studies were important, and her hospital was examining its own surgical results and discussing the findings with patients. She said decisions were being made on a case-by-case basis, and that the minimally invasive approach might still be appropriate for some women.

“This turns us on our heads a bit,” said Dr. Lee-may Chen, director of the gynecologic oncology division of the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco. “We thought laparoscopic surgery would be good for this patient population.”

She said that because of the findings, she now encourages most patients to have open surgery for cervical cancer. But she discusses the information with them, and would consider the minimally invasive approach for women who refuse open surgery, or for those who have a high risk of serious complications from open surgery.

Research had found that the minimally invasive approach, in use since around 2006, worked as well as open surgery to treat cancer of the uterus, which convinced many doctors that it would also be safe for cervical cancer.

But uterine cancer and cervical cancer are different diseases, and require different operations. Uterine cancer needs a simple hysterectomy, which means removing only the uterus.

Cervical cancer requires a radical hysterectomy, a more complex operation that takes out the uterus, part of the vagina and other surrounding tissues.

Dr. Ramirez and his team wanted to compare open and minimally invasive surgery, to find out if they were equally effective at eliminating cervical cancer. The research was paid for by M.D. Anderson and Medtronic, which makes instruments for minimally invasive surgery.

To ensure that all the surgeons were skilled in minimally invasive procedures, the team leaders required them to submit reports on at least 10 operations, and unedited videos of two.

Patients were recruited from June 2008 through June 2017, and were assigned at random to have either open or laparoscopic surgery, about half to each group. Their average age was 46, and all had early-stage cervical cancer (surgery is not used in advanced cases).

As the study progressed, it was monitored by an independent safety board that looked at the data to make sure patients were not being harmed. Partway through the project, the board saw too many deaths in the minimally invasive group. It recommended that the researchers temporarily stop adding new patients so the findings could be more closely examined.

A deeper analysis confirmed the higher death rate. The board said that no more patients should be enrolled, and that the hospitals should be told that minimally invasive surgery carried a higher risk of death. The original plan had been to include 740 patients, but the study stopped at 631.

After 4.5 years, 96.5 percent of the patients who had open surgery were free of cancer, as opposed to 86 percent in the minimally invasive group. At three years, 99 percent of the open-surgery patients were alive, compared with 93.8 percent of those who had minimally invasive operations.

With a median follow-up time of 2.5 years, 27 patients in the minimally invasive group had a cancer recurrence, compared with seven who had open surgery. There were 19 deaths in the minimally invasive group (14 from cancer), and three in the open group (two from cancer).

The researchers were stunned. Dr. Ramirez said they had expected to find that the two methods were equivalent.

Researchers do not know why there was a difference, but offer several theories. One is that an instrument passed through the cervix during some laparoscopic operations may inadvertently spread cancer cells. Another is that carbon dioxide, used to inflate the abdomen so that surgeons can see better during minimally invasive procedures, may help cancer cells invade tissue. Still another idea is that laparoscopic surgery may miss some cancerous tissue.

Dr. Fader said that if more research could explain the bad outcomes, it might become possible to identify patients for whom the minimally invasive approach would be safe.

A second study also found problems with minimally invasive surgery. It was not a clinical trial. Rather, it used information from databases to compare the results of the two surgical methods. It was paid for by the National Institutes of Health and charitable foundations.

In one analysis, 1,225 of 2,461 women had minimally invasive surgery, and the rest had open surgery. At four years, 9.1 percent in the minimally invasive group had died, compared with 5.3 percent who had open surgery.

Another analysis looked at the survival rate for cervical cancer surgery over time, and found that it began to decline when minimally invasive surgery was introduced, dropping by 0.8 percent a year after 2006.

“None of us expected this,” said, Dr. Jason D. Wright, an author of the study and the chief of gynecologic oncology at NewYork-Presbyterian/Columbia University Irving Medical Center. “We expected to find it was as safe.”

He said that because of the findings, most women at his hospital who need operations for cervical cancer are now having open surgery.

 

This article was originally published in The New York Times. Read the original article.

Immune-Based Treatment Helps Fight Aggressive Breast Cancer, Study Finds

Women with an aggressive type of breast cancer lived longer if they received immunotherapy plus chemotherapy, rather than chemo alone, a major study has found.

The results are expected to change the standard of care for women like those in the clinical trial, who had advanced cases of “triple-negative” breast cancer. That form of the disease often resists standard therapies, and survival rates are poor. It is twice as common in African-American women as in white women, and more likely to occur in younger women.

Researchers said the new study was a long-awaited breakthrough for immunotherapy in breast cancer. Until now, most progress had been in other cancers, including lung cancer and melanoma, an aggressive skin cancer.

These findings may lead to the first approval by the Food and Drug Administration for an immunotherapy drug to treat breast cancer. But the approval would likely be limited to a certain type of aggressive cancer.

Although triple-negative tumors occur in only about 15 percent of patients with invasive breast cancer in the United States (or nearly 40,000 each year), they account for a disproportionate share of deaths, as many as 30 percent to 40 percent.

“These women really needed a break,” Dr. Ingrid Mayer, a breast cancer specialist at Vanderbilt University, said in a telephone interview. “Nothing has worked well.”

Dr. Mayer, who was not part of the study, called the findings “very significant.” She said she had received consulting fees from seven drug companies, including Genentech, which is the maker of the immunotherapy drug in the study and paid for the research.

The term triple-negative refers to the tumors’ lack of sensitivity to the hormones estrogen and progesterone, and their lack of a protein called HER2, which is a target of treatment.

The immunotherapy in the study was atezolizumab (brand name Tecentriq), which belongs to a class of drugs called checkpoint inhibitors; the chemotherapy was nab-paclitaxel (Abraxane).

The findings were published on Saturday in The New England Journal of Medicine, and were to be presented at a meeting of the European Society for Medical Oncology, in Munich. The study included 902 patients treated at 246 medical centers in 41 countries. Genentech, which is part of Roche, has already submitted the data to the F.D.A. for approval.

Checkpoint inhibitors like atezolizumab work by helping T-cells — a type of white blood cell that is part of the immune system — recognize cancer and attack it. Research that led to these drugs won this year’s Nobel Prize in medicine.

The drugs generally work for fewer than half of patients but can bring lasting recoveries even to people who were severely ill. Side effects can be dangerous, even life-threatening, and treatment costs more than $100,000 a year.

In other cancers, researchers sometimes describe the tumors as “hot,” meaning they tend to have many mutations — genetic abnormalities that the immune system can recognize as foreign and attack.

But breast cancers tend to be relatively “cold,” with fewer mutations. The immune system is less likely to recognize them as invaders, which may help explain why previous studies of checkpoint inhibitors in breast cancer have been somewhat disappointing, researchers say.

In the new study, the key to success seems to have been giving chemotherapy along with immunotherapy.

“Chemo takes away the invisibility cloak the cancer has managed to put on,” Dr. Mayer said.

The chemo may help to ignite the immune system, in part by killing cancer cells that then spill substances the T-cells detect as foreign and begin to hunt.

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“This is truly a game changer,” said Dr. Sylvia Adams, an author of the study.CreditHilary Swift for The New York Times

The new study “is a big deal and has been the buzz of the breast cancer research world,” said Dr. Larry Norton of Memorial Sloan Kettering Cancer Center in an email. He was not involved in the study, although he said he had done paid consulting work for the past two years for the maker of Abraxane.

Beyond changing treatment practices, he said the research “opens the door to new approaches to harness the immune system to fight breast cancer, and there is every reason to expect major advances there.”

He cautioned that the combined treatment would have to be studied further, to assess side effects.

Dr. Kevin Kalinsky, a breast cancer specialist at NewYork-Presbyterian/Columbia University Irving Medical Center, suggested that patients like those in the study should talk to their doctors “about whether it is possible for them to get access to the medication while we’re waiting for F.D.A. approval.”

He did not take part in this study. He said he has received consulting fees from about 10 drug companies, including Genentech.

The women in the study had triple-negative breast cancer that had been newly diagnosed and had become metastatic, meaning it had begun to spread. Once that occurs, the outlook is grim, with many patients surviving 18 months or less.

Half received chemo alone, and half were given chemo plus immunotherapy.

Among those who received the combination, the median survival was 21.3 months, compared with 17.6 months for those who received chemo alone. The difference was not statistically significant.

But when the researchers looked at women who had a marker called PD-L1 on their cancer cells, the results were striking: The median survival was 25 months in the combination group, versus 15.5 months with just chemo. That finding has not been analyzed statistically, and the patients are still being followed.

Doctors say the survival difference is important.

“This is truly a game changer,” said Dr. Sylvia Adams, an author of the study from NYU Langone Health’s Perlmutter Cancer Center.

Cancer patients with the PD-L1 marker tend to respond better to checkpoint inhibitors than those without it. In this study, 41 percent of patients had the marker. Genentech is seeking approval for treatment in triple-negative patients with the marker.

Dr. Adams said some patients, after initial treatment with both types of drug, have been doing well for two or three years with immunotherapy alone.

The “million-dollar question,” she said, is whether they can safely stop the immunotherapy if they have no sign of cancer. For the time being, they are sticking with the treatment.

She noted that patients in the study had some of the expected side effects of immunotherapy, including lung and pancreas inflammation.

Dr. Adams said she accepted no money from drug companies, but her medical center did receive money from Genentech to pay for the research.

Maribel Ramos, 42, was being treated at another hospital, which recommended chemo for her advanced triple-negative breast cancer.

“I was very worried because I know with that type of cancer, chemo doesn’t work,” Ms. Ramos said. She has three daughters: a 23-year-old and 10-year-old twins.

Her sister, a nurse at New York University, told her about the study there, and she began treatment in February 2016. She didn’t know it at the time, but she had been picked at random to receive the combined treatment. Within a few months, her tumors began to shrink. Nine months ago, for the first time, a scan found no sign of cancer. She is staying on immunotherapy.

“I just feel so happy that you can live longer,” Ms. Ramos said. “I wish that all the ladies that are fighting cancer, especially triple-negative, could get this medicine. I would recommend that all women get a second opinion, and sometimes even a third opinion.” She added, “This can save your life.”

About 266,120 new cases of invasive breast cancer are expected in women in 2018 in the United States, and 40,920 deaths.

 

This article was originally published in The New York Times.  Read the original article.

Researchers Explore a Cancer Paradox

Cancer is a disease of mutations. Tumor cells are riddled with genetic mutations not found in healthy cells. Scientists estimate that it takes five to 10 key mutations for a healthy cell to become cancerous.

Some of these mutations can be caused by assaults from the environment, such as ultraviolet rays and cigarette smoke. Others arise from harmful molecules produced by the cells themselves. In recent years, researchers have begun taking a closer look at these mutations, to try to understand how they arise in healthy cells, and what causes these cells to later erupt into full-blown cancer.

The research has produced some major surprises. For instance, it turns out that a large portion of the cells in healthy people carry far more mutations than expected, including some mutations thought to be the prime drivers of cancer. These mutations make a cell grow faster than others, raising the question of why full-blown cancer isn’t far more common.

“This is quite a fundamental piece of biology that we were unaware of,” said Inigo Martincorena, a geneticist at the Wellcome Sanger Institute in Cambridge, England.

These lurking mutations went unnoticed for so long because the tools for examining DNA were too crude. If scientists wanted to sequence the entire genome of tumor cells, they had to gather millions of cells and analyze all of the DNA. A mutation, to be detectable, had to be very common.

But as DNA sequencing grew more sophisticated, Dr. Martincorena and other researchers developed methods for detecting very rare mutations, and they began to wonder if those mutations might be found in healthy cells, hidden below the radar.

Dr. Martincorena and his colleagues began their search in skin; its cells are battered daily by the sun’s ultraviolet rays, which trigger mutations. “We thought it was the lowest-hanging fruit,” Dr. Martincorena said.

In a study in 2015, he and his colleagues collected bits of skin left over from cosmetic surgeries to lift drooping eyelids. They examined 234 biopsies from four patients, each sample of skin about the size of a pinhead. They gently coaxed the top layers of cells, known as epithelial cells, from the underlying tissue.

Dr. Martincorena’s team then fished the DNA from the healthy epithelial cells, and carefully sequenced 74 genes that are known to play an important role in the development of cancer. Mutations that are common in cancer genes were remarkably common in these healthy skin cells, too, the researchers found. About one of every four epithelial cells carried a mutation on a cancer-linked gene, speeding up the cell’s growth.

It was possible, the scientists knew, that skin was peculiar. Maybe inside the body, away from the onslaught of ultraviolet rays, were healthy cells that didn’t carry these key mutations.

To find out, the researchers decided to study cells of the esophagus. The team gathered tissue samples from nine healthy organ donors who had died, then they sliced the tissue into dozens of tiny squares and examined the same 74 cancer-related genes.

Dr. Martincorena and his colleagues found that new mutations arose more slowly in the esophagus than in skin. But once those mutations emerged, they caused the esophageal cells to multiply faster than normal esophageal cells. Over time, these rogue cells spread out across the esophagus, forming colonies of mutant cells, known as clones. Although these clones aren’t cancer, they do exhibit one of cancer’s hallmarks: rapid growth.

“These mutant clones colonize more than half of your esophagus by middle age,” said Dr. Martincorena. “It was eye-opening for me.” Dr. Martincorena and his colleagues reported their findings on Thursday in the journal Science.

By examining the mutations, the researchers were able to rule out external causes for them, like tobacco smoke or alcohol. Instead, the mutations seem to have arisen through ordinary aging. As the cells divided over and over again, their DNA sometimes was damaged. In other words, the rise of these mutations may just be an intrinsic part of getting older.

“It seems that no matter how well one takes care of oneself by eating well, getting exercise and limiting certain vices, there’s likely only so much one can do against the need of the body to replace its cells,” said Scott Kennedy, a cancer biologist at the University of Washington who was not involved in the study.

The study also raised questions about efforts to detect cancer at its earliest stages, when cancer cells are still rare, Dr. Kennedy said: “Just because someone has mutations associated with cancer doesn’t mean actually they have a malignancy.”

Given the abundance of cancer mutations in healthy people, why isn’t cancer more common? Dr. Martincorena speculated that a healthy body may be like an ecosystem: Perhaps clones with different mutations arise in it, compete for available space and resources, and keep each other in check.

If so, fighting cancer might one day be a matter of helping harmless clones outcompete the ones that can lead to deadly tumors.

“There is no therapy being thought out in these terms now,” said Dr. Martincorena. “But I think it opens up new avenues. I think knowledge is always a weapon.”

 

 

This article was originally published in The New York Times.  Read the original article.

The ‘Zombie Gene’ That May Protect Elephants From Cancer

Elephants ought to get a lot of cancer. They’re huge animals, weighing as much as eight tons. It takes a lot of cells to make up that much elephant.

All of those cells arose from a single fertilized egg, and each time a cell divides, there’s a chance that it will gain a mutation — one that may lead to cancer.

Strangely, however, elephants aren’t more prone to cancer than smaller animals. Some research even suggests they get less cancer than humans do.

On Tuesday, a team of researchers reported what may be a partial solution to that mystery: Elephants protect themselves with a unique gene that aggressively kills off cells whose DNA has been damaged.

Somewhere in the course of evolution, the gene had become dormant. But somehow it was resurrected, a bit of zombie DNA that has proved particularly useful.

Vincent J. Lynch, an evolutionary biologist at the University of Chicago and a co-author of the paper, published in Cell Reports, said that understanding how elephants fight cancer may provide inspiration for developing new drugs.

“It might tell us something fundamental about cancer as a process. And if we’re lucky, it might tell us something about how to treat human disease,” Dr. Lynch said.

Scientists have puzzled over cancer, or the lack thereof, in big animals since the 1970s. In recent years, some researchers have started carrying out detailed studies of the genes and cells of these species, searching for unexpected strategies for fighting the disease.

Some of the first research focused on a well-studied anticancer gene called p53. It makes a protein that can sense when DNA gets damaged. In response, the protein switches on a number of other genes.

A cell may respond by repairing its broken genes, or it may commit suicide, so that its descendants will not have the chance to gain even more mutations.

In 2015, Dr. Lynch and his colleagues discovered that elephants have evolved unusual p53 genes. While we only have one copy of the gene, elephants have 20 copies. Researchers at the University of Utah independently made the same discovery.

Both teams observed that the elephant’s swarm of p53 genes responds aggressively to DNA damage. Their bodies don’t bother with repairing cells — they only orchestrate the damaged cell’s death.

Dr. Lynch and his colleagues continued their search for cancer-fighting genes, and they soon encountered another one, called LIF6, that only elephants seem to possess.

In response to DNA damage, p53 proteins in elephants switch on LIF6. The cell makes LIF6 proteins, which then wreak havoc.

Dr. Lynch’s experiments indicate that LIF6 proteins make their way to the cell’s tiny fuel-generating factories, called mitochondria.

The proteins pry open holes in the mitochondria, allowing molecules to pour out. The molecules from mitochondria are toxic, causing the cell to die.

“This adds an important piece to the puzzle,” said Dr. Joshua D. Schiffman, a pediatric oncologist at the Huntsman Cancer Institute at the University of Utah who has also studied cancer in elephants.

More experiments are needed to confirm that LIF6 works the way Dr. Lynch and his colleagues propose, Dr. Schiffman added. “As a start, I think this is fantastic,” he said.

LIF6 has a bizarre evolutionary history, as it turns out.

All mammals carry a similar gene, simply called LIF. In our own cells, it performs several different jobs, such as sending signals from one cell to another. But almost all mammals — ourselves included — have only one copy.

The only exceptions to that rule are elephants and their close relatives, such as manatees, Dr. Lynch and his colleagues found. These mammals have several copies of LIF; elephants have ten.

These copies arose thanks to sloppy mutations in the ancestors of manatees and elephants more than 80 million years ago.

These newer copies of the original LIF gene lack a stretch of DNA that acts as an on-off switch. As a result, the genes could not make their proteins. (Humans also carry thousands of copies of so-called pseudogenes.)

After the ancestors of elephants evolved ten LIF genes, however, something remarkable happened: One of these dead genes came back to life. That gene is LIF6.

Somewhere in the course of elephant evolution, a cellular mutation inserted a genetic switch next to LIF6, enabling the gene to be activated by p53. The resurrected gene now made a protein that could do something new: attack mitochondria and kill damaged cells.

To find out when the LIF6 gene first came back to life, the researchers took a close looks at DNA retrieved from fossils.

Mastodons and mammoths also carried LIF6. Scientists estimate that they shared a common ancestor with modern elephants that lived 26 million years ago.

Dr. Lynch speculated that LIF6 came back to life at the same time that the ancestors of living elephants evolved extra copies of p53. As they developed more powerful defenses against cancer, the animals could begin reaching their enormous sizes.

Elephants likely evolved other new genes that follow p53’s orders, Dr. Lynch predicted. He also suspects that elephants have also evolved ways to fight cancer that are separate from p53 altogether.

“I think it’s all of the above,” he said. “There are lots of stories like LIF6 in the elephant genome, and I want to know them all.”

 

This article was originally published in The New York Times.  Read the original article.

A targeted approach to treating glioma

Glioma, a type of brain cancer, is normally treated by removing as much of the tumor as possible, followed by radiation or chemotherapy. With this treatment, patients survive an average of about 10 years, but the tumors inevitably grow back.

A team of researchers from MIT, Brigham and Women’s Hospital, and Massachusetts General Hospital hopes to extend patients’ lifespan by delivering directly to the brain a drug that targets a mutation found in 20 to 25 percent of all gliomas. (This mutation is usually seen in gliomas that strike adults under the age of 45.) The researchers have devised a way to rapidly check for the mutation during brain surgery, and if the mutation is present, they can implant microparticles that gradually release the drug over several days or weeks.

“To provide really effective therapy, we need to diagnose very quickly, and ideally have a mutation diagnosis that can help guide genotype-specific treatment,” says Giovanni Traverso, an assistant professor at Brigham and Women’s Hospital, Harvard Medical School, a research affiliate at MIT’s Koch Institute for Integrative Cancer Research, and one of the senior authors of the paper.

The researchers are also working ways to identify and target other mutations found in gliomas and other types of brain tumors.

“This paradigm allows us to modify our current intraoperative resection strategy by applying molecular therapeutics that target residual tumor cells based on their specific vulnerabilities,” says Ganesh Shankar, who is currently completing a spine surgery fellowship at Cleveland Clinic prior to returning as a neurosurgeon at Massachusetts General Hospital, where he performed this study.

Shankar and Koch Institute postdoc Ameya Kirtane are the lead authors of the paper, which appears in the Proceedings of the National Academy of Sciences the week of Aug. 6. Daniel Cahill, a neurosurgeon at MGH and associate professor at Harvard Medical School, is a senior author of the paper, and Robert Langer, the David H. Koch Institute Professor at MIT, is also an author.

Targeting tumors

The tumors that the researchers targeted in this study, historically known as low-grade gliomas, usually occur in patients between the ages of 20 and 40. During surgery, doctors try to remove as much of the tumor as possible, but they can’t be too aggressive if tumors invade the areas of the brain responsible for key functions such as speech or movement. The research team wanted to find a way to locally treat those cancer cells with a targeted drug that could delay tumor regrowth.

To achieve that, the researchers decided to target a mutation called IDH1/2. Cancer cells with this mutation shut off a metabolic pathway that cells normally use to create a molecule called NAD, making them highly dependent on an alternative pathway that requires an enzyme called NAMPT. Researchers have been working to develop NAMPT inhibitors to treat cancer.

So far, these drugs have not been used for glioma, in part because of the difficulty in getting them across the blood-brain barrier, which separates the brain from circulating blood and prevents large molecules from entering the brain. NAMPT inhibitors can also produce serious side effects in the retina, bone marrow, liver, and blood platelets when they are given orally or intravenously.

To deliver the drugs locally, the researchers developed microparticles in which the NAMPT inhibitor is embedded in PLGA, a polymer that has been shown to be safe for use in humans. Another desirable feature of PLGA is that the rate at which the drug is released can be controlled by altering the ratio of the two polymers that make up PLGA — lactic acid and glycolic acid.

To determine which patients would benefit from treatment with the NAMPT inhibitor, the researchers devised a genetic test that can reveal the presence of the IDH mutation in approximately 30 minutes. This allows the procedure to be done on biopsied tissue during the surgery, which takes about four hours. If the test is positive, the microparticles can be placed in the brain, where they gradually release the drug, killing cells left behind during the surgery.

In tests in mice, the researchers found that treatment with the drug-carrying particles extended the survival of mice with IDH mutant-positive gliomas. As they expected, the treatment did not work against tumors without the IDH mutation. In mice treated with the particles, the team also found none of the harmful side effects seen when NAMPT inhibitors are given throughout the body.

“When you dose these drugs locally, none of those side effects are seen,” Traverso says. “So not only can you have a positive impact on the tumor, but you can also address the side effects which sometimes limit the use of a drug that is otherwise effective against tumors.”

The new approach builds on similar work from Langer’s lab that led to the first FDA-approved controlled drug-release system for brain cancer — a tiny wafer that can be implanted in the brain following surgery.

“I am very excited about this new paper, which complements very nicely the earlier work we did with Henry Brem of Johns Hopkins that led to Gliadel, which has now been approved in over 30 countries and has been used clinically for the past 22 years,” Langer says.

An array of options

The researchers are now developing tests for other common mutations found in brain tumors, with the goal of devising an array of potential treatments for surgeons to choose from based on the test results. This approach could also be used for tumors in other parts of the body, the researchers say.

“There’s no reason this has to be restricted to just gliomas,” Shankar says. “It should be able to be used anywhere where there’s a well-defined hotspot mutation.”

They also plan to do some tests of the IDH-targeted treatment in larger animals, to help determine the right dosages, before planning for clinical trials in patients.

“We feel its best use would be in the early stages, to improve local control and prevent regrowth at the site,” Cahill says. “Ideally it would be integrated early in the standard-of-care treatment for patients, and we would try to put off the recurrence of the disease for many years or decades. That’s what we’re hoping.”

 

 

 

This article was originally published in MIT News. Read the original article.

Sensor could help doctors select effective cancer therapy

MIT chemical engineers have developed a new sensor that lets them see inside cancer cells and determine whether the cells are responding to a particular type of chemotherapy drug.

The sensors, which detect hydrogen peroxide inside human cells, could help researchers identify new cancer drugs that boost levels of hydrogen peroxide, which induces programmed cell death. The sensors could also be adapted to screen individual patients’ tumors to predict whether such drugs would be effective against them.

“The same therapy isn’t going to work against all tumors,” says Hadley Sikes, an associate professor of chemical engineering at MIT. “Currently there’s a real dearth of quantitative, chemically specific tools to be able to measure the changes that occur in tumor cells versus normal cells in response to drug treatment.”

Sikes is the senior author of the study, which appears in the Aug. 7 issue of Nature Communications. The paper’s first author is graduate student Troy Langford; other authors are former graduate students Beijing Huang and Joseph Lim and graduate student Sun Jin Moon.

Tracking hydrogen peroxide

Cancer cells often have mutations that cause their metabolism to go awry and produce abnormally high fluxes of hydrogen peroxide. When too much of the molecule is produced, it can damage cells, so cancer cells become highly dependent on antioxidant systems that remove hydrogen peroxide from cells.

Drugs that target this vulnerability, which are known as “redox drugs,” can work by either disabling the antioxidant systems or further boosting production of hydrogen peroxide. Many such drugs have entered clinical trials, with mixed results.

“One of the problems is that the clinical trials usually find that they work for some patients and they don’t work for other patients,” Sikes says. “We really need tools to be able to do more well-designed trials where we figure out which patients are going to respond to this approach and which aren’t, so more of these drugs can be approved.”

To help move toward that goal, Sikes set out to design a sensor that could sensitively detect hydrogen peroxide inside human cells, allowing scientists to measure a cell’s response to such drugs.

Existing hydrogen peroxide sensors are based on proteins called transcription factors, taken from microbes and engineered to fluoresce when they react with hydrogen peroxide. Sikes and her colleagues tried to use these in human cells but found that they were not sensitive in the range of hydrogen peroxide they were trying to detect, which led them to seek human proteins that could perform the task.

Through studies of the network of human proteins that become oxidized with increasing hydrogen peroxide, the researchers identified an enzyme called peroxiredoxin that dominates most human cells’ reactions with the molecule. One of this enzyme’s many functions is sensing changes in hydrogen peroxide levels.

Langford then modified the protein by adding two fluorescent molecules to it — a green fluorescent protein at one end and a red fluorescent protein at the other end. When the sensor reacts with hydrogen peroxide, its shape changes, bringing the two fluorescent proteins closer together. The researchers can detect whether this shift has occurred by shining green light onto the cells: If no hydrogen peroxide has been detected, the glow remains green; if hydrogen peroxide is present, the sensor glows red instead.

Predicting success

The researchers tested their new sensor in two types of human cancer cells: one set that they knew was susceptible to a redox drug called piperlongumine, and another that they knew was not susceptible. The sensor revealed that hydrogen peroxide levels were unchanged in the resistant cells but went up in the susceptible cells, as the researchers expected.

Sikes envisions two major uses for this sensor. One is to screen libraries of existing drugs, or compounds that could potentially be used as drugs, to determine if they have the desired effect of increasing hydrogen peroxide concentration in cancer cells. Another potential use is to screen patients before they receive such drugs, to see if the drugs will be successful against each patient’s tumor. Sikes is now pursuing both of these approaches.

“You have to know which cancer drugs work in this way, and then which tumors are going to respond,” she says. “Those are two separate but related problems that both need to be solved for this approach to have practical impact in the clinic.”

 

 

 

This article was originally published in MIT News. Read the original article.

Plan to replicate 50 high-impact cancer papers shrinks to just 18

An ambitious project that set out nearly 5 years ago to replicate experiments from 50 high-impact cancer biology papers, but gradually shrank that number, now expects to complete just 18 studies.

“I wish we could have done more,” says biologist Tim Errington, who runs the project from the Center for Open Science in Charlottesville, Virginia. But, he adds, “There is an element of not truly understanding how challenging it is until you do a project like this.”

The Reproducibility Project: Cancer Biology (RP:CP) began in October 2013 as an open effort to test replicability after two drug companies reported they had trouble reproducing many cancer studies. The work was a collaboration with Science Exchange, a company based in Palo Alto, California, that found contract labs to reproduce a few key experiments from each paper. Funding included a $1.3 million grant from the Laura and John Arnold Foundation, enough for about $25,000 per study. Experiments were expected to take 1 year.

The project quickly drew criticism from authors of the original studies and others who worried that the replication studies would inevitably fail because the contract labs lacked the expertise needed to replicate the work.

Costs rose and delays ensued as organizers realized they needed more information and materials from the original authors; a decision to have the proposed replications peer reviewed also added time. Organizers whittled the list of papers to 37 in late 2015, then to 29 by January 2017. In the past few months, they decided to discontinue 38% or 11 of the ongoing replications, Errington says. (Elizabeth Iorns, president of Science Exchange, says total costs for the 18 completed studies averaged about $60,000, including two high-priced “outliers.”)

One reason for cutting off some replications was that it was taking too long to troubleshoot or optimize experiments to get meaningful results, Errington says. For example, deciding what density of cells to plate for an experiment required testing a range of cell densities. Although “these things happen in a lab naturally,” Errington says, this work could have proceeded faster if methodological details had been included in the original papers. The project also spent a lot of time obtaining or remaking reagents such as cell lines and plasmids (DNA that is inserted into cells) that weren’t available from the original labs.

One of the effort’s lessons: Disclosing more protocol details and making materials freely available directly from the original lab or through services like Addgene would speed scientists’ ability to build on the work of others. “Communication and sharing are low-hanging fruit that we can work on to improve,” Errington says. Another problem, Iorns adds, is that academic labs rarely validate their assays, making it difficult to know whether a positive result is real or “just noise.”

The project has already published replication results for 10 of the 18 studies in the journal eLife. The bottom line is mixed: Five were mostly repeatable, three were inconclusive, and two studies were negative, but the original findings have been confirmed by other labs. In fact, many of the initial 50 papers have been confirmed by other groups, as some of the RP:CB’s critics have pointed out.

The RP:CB team is now writing up the remaining eight completed studies and a meta-analysis and summary of the project. The 11 incomplete studies, which will be published in brief form, will still “have a lot of value, but not as much” as the completed replications, Errington says.

 

 

http://www.sciencemag.org/news/2018/07/plan-replicate-50-high-impact-cancer-papers-shrinks-just-18?utm_campaign=news_daily_2018-07-31&et_rid=349200915&et_cid=2225518

Artificial intelligence will improve medical treatments

OUR years ago a woman in her early 30s was hit by a car in London. She needed emergency surgery to reduce the pressure on her brain. Her surgeon, Chris Mansi, remembers the operation going well. But she died, and Mr Mansi wanted to know why. He discovered that the problem had been a four-hour delay in getting her from the accident and emergency unit of the hospital where she was first brought, to the operating theatre in his own hospital. That, in turn, was the result of a delay in identifying, from medical scans of her head, that she had a large blood clot in her brain and was in need of immediate treatment. It is to try to avoid repetitions of this sort of delay that Mr Mansi has helped set up a firm called Viz.ai. The firm’s purpose is to use machine learning, a form of artificial intelligence (AI), to tell those patients who need urgent attention from those who may safely wait, by analysing scans of their brains made on admission.

That idea is one among myriad projects now under way with the aim of using machine learning to transform how doctors deal with patients. Though diverse in detail, these projects have a common aim. This is to get the right patient to the right doctor at the right time.

In Viz.ai’s case that is now happening. In February the firm received approval from regulators in the United States to sell its software for the detection, from brain scans, of strokes caused by a blockage in a large blood vessel. The technology is being introduced into hospitals in America’s “stroke belt”—the south-eastern part, in which strokes are unusually common. Erlanger Health System, in Tennessee, will turn on its Viz.ai system next week.

The potential benefits are great. As Tom Devlin, a stroke neurologist at Erlanger, observes, “We know we lose 2m brain cells every minute the clot is there.” Yet the two therapies that can transform outcomes—clot-busting drugs and an operation called a thrombectomy—are rarely used because, by the time a stroke is diagnosed and a surgical team assembled, too much of a patient’s brain has died. Viz.ai’s technology should improve outcomes by identifying urgent cases, alerting on-call specialists and sending them the scans directly.

The AIs have it

Another area ripe for AI’s assistance is oncology. In February 2017 Andre Esteva of Stanford University and his colleagues used a set of almost 130,000 images to train some artificial-intelligence software to classify skin lesions. So trained, and tested against the opinions of 21 qualified dermatologists, the software could identify both the most common type of skin cancer (keratinocyte carcinoma), and the deadliest type (malignant melanoma), as successfully as the professionals. That was impressive. But now, as described last month in a paper in the Annals of Oncology, there is an AI skin-cancer-detection system that can do better than most dermatologists. Holger Haenssle of the University of Heidelberg, in Germany, pitted an AI system against 58 dermatologists. The humans were able to identify 86.6% of skin cancers. The computer found 95%. It also misdiagnosed fewer benign moles as malignancies.

There has been progress in the detection of breast cancer, too. Last month Kheiron Medical Technologies, a firm in London, received news that a study it had commissioned had concluded that its software exceeded the officially required performance standard for radiologists screening for the disease. The firm says it will submit this study for publication when it has received European approval to use the AI—which it expects to happen soon.

This development looks important. Breast screening has saved many lives, but it leaves much to be desired. Overdiagnosis and overtreatment are common. Conversely, tumours are sometimes missed. In many countries such problems have led to scans being checked routinely by a second radiologist, which improves accuracy but adds to workloads. At a minimum Kheiron’s system looks useful for a second opinion. As it improves, it may be able to grade women according to their risks of breast cancer and decide the best time for their next mammogram.

Efforts to use AI to improve diagnosis are under way in other parts of medicine, too. In eye disease, DeepMind, a London-based subsidiary of Alphabet, Google’s parent company, has an AI that screens retinal scans for conditions such as glaucoma, diabetic retinopathy and age-related macular degeneration. The firm is also working on mammography.

Heart disease is yet another field of interest. Researchers at Oxford University have been developing AIs intended to interpret echocardiograms, which are ultrasonic scans of the heart. Cardiologists looking at these scans are searching for signs of heart disease, but can miss them 20% of the time. That means patients will be sent home and may then go on to have a heart attack. The AI, however, can detect changes invisible to the eye and improve the accuracy of diagnosis. Ultromics, a firm in Oxford, is trying to commercialise the technology and it could be rolled out later this year in Britain.

There are also efforts to detect cardiac arrhythmias, particularly atrial fibrillation, which increase the risk of heart failure and strokes. Researchers at Stanford University, led by Andrew Ng, have shown that AI software can identify arrhythmias from an electrocardiogram (ECG) better than an expert. The group has joined forces with a firm that makes portable ECG devices and is helping Apple with a study looking at whether arrhythmias can be detected in the heart-rate data picked up by its smart watches. Meanwhile, in Paris, a firm called Cardiologs is also trying to design an AI intended to read ECGs.

Seeing ahead

Eric Topol, a cardiologist and digital-medicine researcher at the Scripps Research Institute, in San Diego, says that doctors and algorithms are comparable in accuracy in some areas, but computers have the advantage of speed. This combination of traits, he reckons, will lead to higher accuracy and productivity in health care.

Artificial intelligence might also make medicine more specific, by being able to draw distinctions that elude human observers. It may be able to grade cancers or instances of cardiac disease according to their risks—thus, for example, distinguishing those prostate cancers that will kill quickly, and therefore need treatment, from those that will not, and can probably be left untreated.

What medical AI will not do—at least not for a long time—is make human experts redundant in the fields it invades. Machine-learning systems work on a narrow range of tasks and will need close supervision for years to come. They are “black boxes”, in that doctors do not know exactly how they reach their decisions. And they are inclined to become biased if insufficient care is paid to what they are learning from. They will, though, take much of the drudgery and error out of diagnosis. And they will also help make sure that patients, whether being screened for cancer or taken from the scene of a car accident, are treated in time to be saved.

 

 

This article was originally published in The Economist. Read the original article.

A Crispr Conundrum: How Cells Fend Off Gene Editing

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Human cells resist gene editing by turning on defenses against cancer, ceasing reproduction and sometimes dying, two teams of scientists have found.

The findings, reported in the journal Nature Medicine, at first appeared to cast doubt on the viability of the most widely used form of gene editing, known as Crispr-Cas9 or simply Crispr, sending the stocks of some biotech companies into decline on Monday.

Crispr Therapeutics fell by 13 percent shortly after the scientists’ announcement. Intellia Therapeutics dipped, too, as did Editas Medicine. All three are developing medical treatments based on Crispr.

But the scientists who published the research say that Crispr remains a promising technology, if a bit more difficult than had been known.

“The reactions have been exaggerated,” said Jussi Taipale, a biochemist at the University of Cambridge and an author of one of two papers published Monday. The findings underscore the need for more research into the safety of Crispr, he said, but they don’t spell its doom.

“This is not something that should stop research on Crispr therapies,” he said. “I think it’s almost the other way — we should put more effort into such things.”

Crispr has stirred strong feelings ever since it came to light as a gene-editing technology five years ago. Already, it’s a mainstay in the scientific tool kit.

The possibilities have led to speculations about altering the human race and bringing extinct species back to life. Crispr’s pioneers have already won a slew of prizes, and titanic battles over patent rights to the technology have begun.

To edit genes with Crispr, scientists craft molecules that enter the nucleus of a cell. They zero in on a particular stretch of DNA and slice it out.

The cell then repairs the two loose ends. If scientists add another piece of DNA, the cell may stitch it into the place where the excised gene once sat.

Recently, Dr. Taipale and his colleagues set out to study cancer. They used Crispr to cut out genes from cancer cells to see which were essential to cancer’s aggressive growth.

For comparison, they also tried to remove genes from ordinary cells — in this case, a line of cells that originally came from a human retina. But while it was easy to cut genes from the cancer cells, the scientists did not succeed with the retinal cells.

Such failure isn’t unusual in the world of gene editing. But Dr. Taipale and his colleagues decided to spend some time to figure out why exactly they were failing.

They soon discovered that one gene, p53, was largely responsible for preventing Crispr from working.

p53 normally protects against cancer by preventing mutations from accumulating in cellular DNA. Mutations may arise when a cell tries to fix a break in its DNA strand. The process isn’t perfect, and the repair may be faulty, resulting in a mutation.

When cells sense that the strand has broken, the p53 gene may swing into action. It can stop a cell from making a new copy of its genes. Then the cell may simply stop multiplying, or it may die. This helps protect the body against cancer.

If a cell gets a mutation in the p53 gene itself, however, the cell loses the ability to police itself for faulty DNA. It’s no coincidence that many cancer cells carry disabled p53 genes.

Dr. Taipale and his colleagues engineered retinal cells to stop using p53 genes. Just as they had predicted, Crispr now worked much more effectively in these cells.

A team of scientists at the Novartis Institutes for Biomedical Research in Cambridge, Mass., got similar results with a different kind of cells, detailed in a paper also published Monday.

They set out to develop new versions of Crispr to edit the DNA in stem cells. They planned to turn the stem cells into neurons, enabling them to study brain diseases in Petri dishes.

Someday, they hope, it may become possible to use Crispr to create cell lines that can be implanted in the body to treat diseases.

When the Novartis team turned Crispr on stem cells, however, most of them died. The scientists found signs that Crispr had caused p53 to switch on, so they shut down the p53 gene in the stem cells.

Now many of the stem cells survived having their DNA edited.

The authors of both studies say their results raise some concerns about using Crispr to treat human disease.

For one thing, the anticancer defenses in human cells could make Crispr less efficient than researchers may have hoped.

One way to overcome this hurdle might be to put a temporary brake on p53. But then extra mutations may sneak into our DNA, perhaps leading to cancer.

Another concern: Sometimes cells spontaneously acquire a mutation that disables the p53 gene. If scientists use Crispr on a mix of cells, the ones with disabled p53 cells are more likely to be successfully edited.

But without p53, these edited cells would also be more prone to gaining dangerous mutations.

One way to eliminate this risk might be to screen engineered cells for mutant p53 genes. But Steven A. McCarroll, a geneticist at Harvard University, warned that Crispr might select for other risky mutations.

“These are important papers, since they remind everyone that genome editing isn’t magic,” said Jacob E. Corn, scientific director of the Innovative Genomics Institute in Berkeley, Calif.

Crispr doesn’t simply rewrite DNA like a word processing program, Dr. Corn said. Instead, it breaks DNA and coaxes cells to put it back together. And some cells may not tolerate such changes.

While Dr. Corn said that rigorous tests for safety were essential, he doubted that the new studies pointed to a cancer risk from Crispr.

The particular kinds of cells that were studied in the two new papers may be unusually sensitive to gene editing. Dr. Corn said he and his colleagues have not found similar problems in their own research on bone marrow cells.

“We have all been looking for the possibility of cancer,” he said. “I don’t think that this is a warning for therapies.”

“We should definitely be cautious,” said George Church, a geneticist at Harvard and a founding scientific adviser at Editas.

He suspected that p53’s behavior would not translate into any real risk of cancer, but “it’s a valid concern.”

And those concerns may be moot in a few years. The problem with Crispr is that it breaks DNA strands. But Dr. Church and other researchers are now investigating ways of editing DNA without breaking it.

“We’re going to have a whole new generation of molecules that have nothing to do with Crispr,” he said. “The stock market isn’t a reflection of the future.”