The award-winning New York Times science writer Carl Zimmer.
(Courtesy of Zimmer)
Carl Zimmer, the award-winning New York Times science writer, recently published a stellar book about human heredity called "She Has Her Mother's Laugh." Truly a magnum opus, the book delves into the cultural and scientific evolution of genetics, the field's outsize impact on society, and the new ways we might fundamentally alter our species and our planet.
"I was only prepared to write about how someday we would cross this line, and actually, we've already crossed it."
Zimmer spoke last week with editor-in-chief Kira Peikoff about the international race to edit the genes of human embryos, the biggest danger he sees for society (hint: it's not super geniuses created by CRISPR), and some outlandish possibilities for how we might reproduce in the future. This interview has been edited and condensed for clarity.
I was struck by the number of surprises you uncovered while researching human heredity, like how fetal cells can endure for a lifetime in a mother's body and brain. What was one of the biggest surprises for you?
Something that really jumped out for me was for the section on genetically modifying people. It does seem incredibly hypothetical. But then I started looking into mitochondrial replacement therapy, so-called "three parent babies." I was really surprised to discover that almost by accident, a number of genetically modified people were created this way [in the late 90s and early 2000s]. They walk among us, and they're actually fine as far as anyone can tell. I was only prepared to write about how someday we would cross this line, and actually, we've already crossed it.
And now we have the current arms race between the U.S. and China to edit diseases out of human embryos, with China being much more willing and the U.S. more reluctant. Do you think it's more important to get ahead or to proceed as ethically as possible?
I would prefer a middle road. I think that rushing into tinkering with the features of human heredity could be a disastrous mistake for a lot of reasons. On the other hand, if we completely retreat from it out of some vague fear, I think that we won't take advantage of the actual benefits that this technology might have that are totally ethically sound.
I think the United Kingdom is actually showing how you can go the middle route with mitochondrial replacement therapy. The United States has just said nope, you can't do it at all, and you have Congressmen talking about how it's just playing God or Frankenstein. And then there are countries like Mexico or the Ukraine where people are doing mitochondrial replacement therapy because there are no regulations at all. It's a wild west situation, and that's not a good idea either.
But in the UK, they said alright, well let's talk about this, let's have a debate in Parliament, and they did, and then the government came up with a well thought-through policy. They decided that they were going to allow for this, but only in places that applied for a license, and would be monitored, and would keep track of the procedure and the health of these children and actually have real data going forward. I would imagine that they're going to very soon have their first patients.
As you mentioned, one researcher recently traveled to Mexico from New York to carry out the so-called "three-parent baby" procedure in order to escape the FDA's rules. What's your take on scientists having to leave their own jurisdictions to advance their research programs under less scrutiny?
I think it's a problem when people who have a real medical need have to leave their own country to get truly effective treatment for it. On the other hand, we're seeing lots of people going abroad to countries that don't monitor all the claims that clinics are making about their treatments. So you have stem cell clinics in all sorts of places that are making all sorts of ridiculous promises. They're not delivering those results, and in some cases, they're doing harm.
"Advances in stem cell biology and reproductive biology are a much bigger challenge to our conventional ideas about heredity than CRISPR is."
It's a tricky tension for sure. Speaking of gene editing humans, you mention in the book that one of the CRISPR pioneers, Jennifer Doudna, now has recurring nightmares about Hitler. Do you think that her fears about eugenics being revived with gene editing are justified?
The word "eugenics" has a long history and it's meant different things to different people. So we have to do a better job of talking about it in the future if we really want to talk about the risks and the promises of technology like CRISPR. Eugenics in its most toxic form was an ideology that let governments, including the United States, sterilize their own citizens by the tens of thousands. Then Nazi Germany also used eugenics as a justification to exterminate many more people.
Nobody's talking about that with CRISPR. Now, are people concerned that we are going to wipe out lots of human genetic diversity with it? That would be a bad thing, but I'm skeptical that would actually ever happen. You would have to have some sort of science fiction one-world government that required every new child to be born with IVF. It's not something that keeps me up at night. Honestly, I think we have much bigger problems to worry about.
What is the biggest danger relating to genetics that we should be aware of?
Part of what made eugenics such a toxic ideology was that it was used as a justification for indifference. In other words, if there are problems in society, like a large swath of people who are living in poverty, well, there's nothing you can do about it because it must be due to genetics.
If you look at genetics as being the sole place where you can solve humanity's problems, then you're going to say well, there's no point in trying to clean up the environment or trying to improve human welfare.
A major theme in your book is that we should not narrow our focus on genes as the only type of heredity. We also may inherit some epigenetic marks, some of our mother's microbiome and mitochondria, and importantly, our culture and our environment. Why does an expanded view of heredity matter?
We should think about the world that our children are going to inherit, and their children, and their children. They're going to inherit our genes, but they're also going to inherit this planet and we're doing things that are going to have an incredibly long-lasting impact on it. I think global warming is one of the biggest. When you put carbon dioxide into the air, it stays there for a very, very long time. If we stopped emitting carbon dioxide now, the Earth would stay warm for many centuries. We should think about tinkering with the future of genetic heredity, but I think we should also be doing that with our environmental heredity and our cultural heredity.
At the end of the book, you discuss some very bizarre possibilities for inheritance that could be made possible through induced pluripotent stem cell technology and IVF -- like four-parent babies, men producing eggs, and children with 8-celled embryos as their parents. If this is where reproductive medicine is headed, how can ethics keep up?
I'm not sure actually. I think that these advances in stem cell biology and reproductive biology are a much bigger challenge to our conventional ideas about heredity than CRISPR is. With CRISPR, you might be tweaking a gene here and there, but they're still genes in an embryo which then becomes a person, who would then have children -- the process our species has been familiar with for a long time.
"We have to recognize that we need a new language that fits with the science of heredity in the 21st century."
We all assume that there's no way to find a fundamentally different way of passing down genes, but it turns out that it's not really that hard to turn a skin cell from a cheek scraping into an egg or sperm. There are some challenges that still have to be worked out to make this something that could be carried out a lot in labs, but I don't see any huge barriers to it. Ethics doesn't even have the language to discuss the possibilities. Like for example, one person producing both male and female sex cells, which are then fertilized to produce embryos so that you have a child who only has one parent. How do we even talk about that? I don't know. But that's coming up fast.
We haven't developed our language as quickly as the technology itself. So how do we move forward?
We have to recognize that we need a new language that fits with the science of heredity in the 21st century. I think one of the biggest problems we have as a society is that most of our understanding about these issues largely comes from what we learned in grade school and high school in biology class. A high school biology class, even now, gets up to Mendel and then stops. Gregor Mendel is a great place to start, but it's a really bad place to stop talking about heredity.
[Ed. Note: Zimmer's book can be purchased through your retailer of choice here.]
In a recent research trial, patients with Parkinson's disease reported that their symptoms had improved after stem cells were implanted into their brains. Martin Taylor, far right, was diagnosed at age 32.
Martin Taylor
For years, there's been little improvement in the standard treatment. Patients are typically given the drug levodopa, a chemical that's absorbed by the brain’s nerve cells, or neurons, and converted into dopamine. This drug addresses the symptoms but has no impact on the course of the disease as patients continue to lose dopamine producing neurons. Eventually, the treatment stops working effectively.
BlueRock Therapeutics, a cell therapy company based in Massachusetts, is taking a different approach by focusing on the use of stem cells, which can divide into and generate new specialized cells. The company makes the dopamine-producing cells that patients have lost and inserts these cells into patients' brains. “We have a disease with a high unmet need,” says Ahmed Enayetallah, the senior vice president and head of development at BlueRock. “We know [which] cells…are lost to the disease, and we can make them. So it really came together to use stem cells in Parkinson's.”
In a phase 1 research trial announced late last month, patients reported that their symptoms had improved after a year of treatment. Brain scans also showed an increased number of neurons generating dopamine in patients’ brains.
Increases in dopamine signals
The recent phase 1 trial focused on deploying BlueRock’s cell therapy, called bemdaneprocel, to treat 12 patients suffering from Parkinson’s. The team developed the new nerve cells and implanted them into specific locations on each side of the patient's brain through two small holes in the skull made by a neurosurgeon. “We implant cells into the places in the brain where we think they have the potential to reform the neural networks that are lost to Parkinson's disease,” Enayetallah says. The goal is to restore motor function to patients over the long-term.
Five patients were given a relatively low dose of cells while seven got higher doses. Specialized brain scans showed evidence that the transplanted cells had survived, increasing the overall number of dopamine producing cells. The team compared the baseline number of these cells before surgery to the levels one year later. “The scans tell us there is evidence of increased dopamine signals in the part of the brain affected by Parkinson's,” Enayetallah says. “Normally you’d expect the signal to go down in untreated Parkinson’s patients.”
"I think it has a real chance to reverse motor symptoms, essentially replacing a missing part," says Tilo Kunath, a professor of regenerative neurobiology at the University of Edinburgh.
The team also asked patients to use a specific type of home diary to log the times when symptoms were well controlled and when they prevented normal activity. After a year of treatment, patients taking the higher dose reported symptoms were under control for an average of 2.16 hours per day above their baselines. At the smaller dose, these improvements were significantly lower, 0.72 hours per day. The higher-dose patients reported a corresponding decrease in the amount of time when symptoms were uncontrolled, by an average of 1.91 hours, compared to 0.75 hours for the lower dose. The trial was safe, and patients tolerated the year of immunosuppression needed to make sure their bodies could handle the foreign cells.
Claire Bale, the associate director of research at Parkinson's U.K., sees the promise of BlueRock's approach, while noting the need for more research on a possible placebo effect. The trial participants knew they were getting the active treatment, and placebo effects are known to be a potential factor in Parkinson’s research. Even so, “The results indicate that this therapy produces improvements in symptoms for Parkinson's, which is very encouraging,” Bale says.
Tilo Kunath, a professor of regenerative neurobiology at the University of Edinburgh, also finds the results intriguing. “I think it's excellent,” he says. “I think it has a real chance to reverse motor symptoms, essentially replacing a missing part.” However, it could take time for this therapy to become widely available, Kunath says, and patients in the late stages of the disease may not benefit as much. “Data from cell transplantation with fetal tissue in the 1980s and 90s show that cells did not survive well and release dopamine in these [late-stage] patients.”
Searching for the right approach
There's a long history of using cell therapy as a treatment for Parkinson's. About four decades ago, scientists at the University of Lund in Sweden developed a method in which they transferred parts of fetal brain tissue to patients with Parkinson's so that their nerve cells would produce dopamine. Many benefited, and some were able to stop their medication. However, the use of fetal tissue was highly controversial at that time, and the tissues were difficult to obtain. Later trials in the U.S. showed that people benefited only if a significant amount of the tissue was used, and several patients experienced side effects. Eventually, the work lost momentum.
“Like many in the community, I'm aware of the long history of cell therapy,” says Taylor, the patient living with Parkinson's. “They've long had that cure over the horizon.”
In 2000, Lorenz Studer led a team at the Memorial Sloan Kettering Centre, in New York, to find the chemical signals needed to get stem cells to differentiate into cells that release dopamine. Back then, the team managed to make cells that produced some dopamine, but they led to only limited improvements in animals. About a decade later, in 2011, Studer and his team found the specific signals needed to guide embryonic cells to become the right kind of dopamine producing cells. Their experiments in mice, rats and monkeys showed that their implanted cells had a significant impact, restoring lost movement.
Studer then co-founded BlueRock Therapeutics in 2016. Forming the most effective stem cells has been one of the biggest challenges, says Enayetallah, the BlueRock VP. “It's taken a lot of effort and investment to manufacture and make the cells at the right scale under the right conditions.” The team is now using cells that were first isolated in 1998 at the University of Wisconsin, a major advantage because they’re available in a virtually unlimited supply.
Other efforts underway
In the past several years, University of Lund researchers have begun to collaborate with the University of Cambridge on a project to use embryonic stem cells, similar to BlueRock’s approach. They began clinical trials this year.
A company in Japan called Sumitomo is using a different strategy; instead of stem cells from embryos, they’re reprogramming adults' blood or skin cells into induced pluripotent stem cells - meaning they can turn into any cell type - and then directing them into dopamine producing neurons. Although Sumitomo started clinical trials earlier than BlueRock, they haven’t yet revealed any results.
“It's a rapidly evolving field,” says Emma Lane, a pharmacologist at the University of Cardiff who researches clinical interventions for Parkinson’s. “But BlueRock’s trial is the first full phase 1 trial to report such positive findings with stem cell based therapies.” The company’s upcoming phase 2 research will be critical to show how effectively the therapy can improve disease symptoms, she added.
The cure over the horizon
BlueRock will continue to look at data from patients in the phase 1 trial to monitor the treatment’s effects over a two-year period. Meanwhile, the team is planning the phase 2 trial with more participants, including a placebo group.
For patients with Parkinson’s like Martin Taylor, the therapy offers some hope, though Taylor recognizes that more research is needed.
BlueRock Therapeutics
“Like many in the community, I'm aware of the long history of cell therapy,” he says. “They've long had that cure over the horizon.” His expectations are somewhat guarded, he says, but, “it's certainly positive to see…movement in the field again.”
"If we can demonstrate what we’re seeing today in a more robust study, that would be great,” Enayetallah says. “At the end of the day, we want to address that unmet need in a field that's been waiting for a long time.”
Editor's note: The company featured in this piece, BlueRock Therapeutics, is a portfolio company of Leaps by Bayer, which is a sponsor of Leaps.org. BlueRock was acquired by Bayer Pharmaceuticals in 2019. Leaps by Bayer and other sponsors have never exerted influence over Leaps.org content or contributors.