Q&A with Erica Jonlin PhD, Author of Perspective on Informed Consent Published in Stem Cell Reports


In November 2018, Dr. He Jiankui used a series of YouTube videos to announce the birth of the world’s first genetically-modified babies, twin girls who soon became known as the CRISPR babies. In a stunning, unapologetic presentation to the international scientific research community, Dr. He reported that he had edited a specific gene in the hopes of conferring resistance to HIV. The Chinese authorities charged and imprisoned Dr. He for forgery, for practicing medicine without a license, and for ethical breaches, including violating Chinese regulations for scientific research. Scientists around the world called for a moratorium on human embryo gene editing. The fate of the babies remains unknown.

Erica Jonlin PhD is the Regulatory Manager for the Institute for Stem Cell and Regenerative Medicine

About the Author

Erica Jonlin, PhD, is the Regulatory Manager for the Institute for Stem Cell and Regenerative Medicine. Her specialty at the ISCRM is ensuring that research projects with human subjects and human specimens adhere to strict ethical and procedural standards and regulations. Jonlin has administered informed consent to participants and has reviewed and written consent forms, IRB applications, and clinical protocols for hundreds of clinical research studies. As the news of the Dr. He affair broke, Jonlin took a particular interest in the issues of oversight and informed consent of participants in Dr. He’s study. Her cautionary perspective has now been published in the journal Stem Cell Reports.

 What motivated you to write this article?

The main motivation was to discuss Dr. He’s ethical breaches, with respect to his treatment of human subjects, in China. My goal is not to endorse human genome editing for reproductive purposes. This article is not about the pros and cons of genome editing or what conditions it could be used for. The article assumes that it could happen, not whether it should, so let’s be ready, and consider how we would protect the participants in such a study.

 What troubled you most about the situation?

There was no oversight whatsoever. There was no ethics review. Dr. He’s consent form had clearly not been reviewed by anyone with ethics training.

 Explain what you mean by consent in this context

I think you have to use the modifier informed consent. Consent itself just means to say yes. Informed consent means the individual had the information to weigh the pros and cons of participating in a clinical research trial, to say yes or no in an intelligent manner.

 And explain exactly what you mean by a clinical research trial

A clinical research trial is a research trial involving human beings. When people think of a clinical trial, they think of there being an intervention. Something is being given to a portion, if not all, the people enrolled.  The word trial implies testing something in humans, like genome editing, or a drug. You’re administering something to somebody and measuring the effects. The word research is important. It’s not care. It’s investigational. You would do studies in the lab in cell systems first, in culture. If you see that it works, then you test it in animal models and look at, what are side effects? When you have something you think will be safe, meaning not toxic, and has the effect you want, then you seek FDA permission to test it in humans.

 Talk about the differences between consent in a clinical research context and other examples of consent in our daily lives

We are so used to having to agree to things or we won’t get the services of whatever it is that we want. So consent is often neither informed nor given of our free will. In a research context, participation in research is voluntary. You join that research study of your own free will. And you can only do that if signing up for it is not coercive. Part of not being coercive is knowing that you’re not forced to join, that you have a choice.  You know what you’re getting in to. It’s being informed and being able to make an intelligent and informed and intentional decision about whether to participate or not.

On the other hand, if you’re an investigator who is running a research project, you can’t just give the consent form to the potential participants and expect a signature. You have to have a discussion before the participant signs the form, so you can explain what you’re doing and the participant can ask questions. That’s a huge distinction between consent in a research context and other situations. You can’t ask AT&T questions or cross out parts of the contract you don’t like. You just have to accept the whole thing whether or not you understand it.

Erica Jonlin’s artice, Informed Consent for Human Embryo Genome Editing, appears this week in the journal Stem Cell Reports

 It’s also not one-size fits all, correct?

That’s right. Informed consent is different for different people, because everyone has their own value system. For example, if somebody is asked to participate in genome-editing, and they realize in the process that a number of embryos might be destroyed, and that isn’t in keeping with their values, then they won’t sign up. It’s a weighing of benefits vs. risks within your own personal context.

 Let’s go back to the Dr. He scandal. Can you first explain what human embryo genome editing is?

We’re talking about changing both copies of a gene in the very earliest embryo, optimally when it’s a single cell, immediately after fertilization in a dish. By changing the gene at that stage, as the cell divides and multiplies, the changed gene will appear in every cell, so that is a change to the genetic makeup of the individual who would result from the embryo. The changed gene will also appear in the reproductive cells of that genetically-modified individual (oocytes or eggs, if the individual is female, or sperm, if they are male), meaning the changes could be inherited by their offspring.

 Why would someone do human embryo genome editing?

First off, there is scientific consensus that we don’t want to do this for enhancement, if at all. If genome-editing is used, and that’s not certain, it’ll be used first in the case of a rare inherited life-threatening disease, like cystic fibrosis, which is caused by a single gene defect. Another example is if someone has the gene for Huntington’s disease. Even if his or her spouse doesn’t have the gene, half of their children will inherit the gene, and those children will get Huntington’s. Such a couple may choose to have embryo editing. The alternative is to go to an IVF clinic and have preimplantation genetic testing of their embryos, choosing to implant only unaffected embryos. Genome editing could be a way for a couple to have healthy, viable embryos.

 How does it relate to IVF?

Human genomic embryo editing has to be done in a laboratory dish. In IVF, an egg is fertilized with sperm in a dish and you get an embryo. It’s at that point that you would do the embryo editing. You have to do IVF to do embryo editing.

Informed consent for human genome editing should be its own consent form separate from a consent form for IVF, which is a clinical procedure. We wouldn’t want people to equate genome editing with clinical care. Human genome editing is an experiment. We are gathering information. For preventing disease it is an unproven technology.  While the parents participating in a genome editing study would undoubtedly hope to benefit, and the investigator also hopes they benefit,every research study is for the benefit of society first.

 What risks did Dr. He fail to explain to the participants?

There’s a lot of risk in genome editing. You risk that the gene is not edited in the correct way, and that you introduce a new alteration in the gene that could be deleterious. Or you risk that the edit can go into the wrong place in the genome and cause other unforeseen problems. Optimally you edit an embryo when it’s a single cell, but if you do it when there are 2, 4, 8, or 16 cells, you might not edit the gene in every cell. We don’t know what the results of that would be, either. We know the resulting child would likely not be protected from the disease you were trying to prevent in the first place. It’s also important to note that we’re talking about changing the genetic make-up of a person who may have children themselves, who will also carry those changes. The effects of that are unknown. We just don’t know what we’re creating long term. Technologically, this is a big leap.

 What about implications for the field of genetic research?

By going ahead and doing this before there was a full scientific and ethical review, what Dr. He did was a blow to the field. What any individual does, if they don’t follow the rules, hurts their peers badly. It happened in gene therapy, where was a death and it harmed the field for 20 years. That’s a real risk of doing this the wrong way.

 Do you see this as a learning experience?

This is a good reminder of the things that we’ve been overlooking. I think it’s important to expand the discussion from what Dr. He did wrong to how this should be done correctly. By that I mean, how should we administer informed consent for high risk research like this? There are many, many articles that have come out about Dr. He and what he did wrong, but none about the right way to administer informed consent, should human embryo editing be attempted again for reproductive purposes.

Do we need to change the way we do informed consent, or just be better at it?

In many ways, we are not in new territory in terms of informed consent because consenting for participation in research studies for high risk populations is already happening. One new aspect about this is the fact that the individual whose genome will be changed could pass on that genetic change to their own offspring. That’s the biggest technology change.

In general, informed consent is being administered appropriately and it’s also being administered inappropriately. There needs to be enhanced appreciation of what it takes. Informed consent is always challenging and always takes training and consideration. Inexperienced research teams may not realize that. There need to be constant reminders. For example, anyone contemplating administering informed consent should practice on non-participants before they approach a real participant.  That’s true of any research study. It’s a whole dance that needs to be practiced. And informed consent includes who are you consenting. What kind of population? What are their personal vulnerabilities? And that’s something I tried to point out in the article.

 What about standards that already exist?

The important thing is recognizing that informed consent should not be taken lightly. The rules are there for a reason. Dr. He claimed to have administered informed consent in accordance with regulations. That’s completely untrue. He obviously did not review regulations at any great depth and obviously does not know how to administer informed consent. That’s why people have to focus on the words informed consent. Informed directly implies the person receiving the information is getting the information they need to make an informed decision – to say yes or no. Not just yes.

 What are the qualities of good informed consent?

Good informed consent starts with a researcher who is sensitive to the people he or she is talking to about participation. It’s really about withholding judgment and not being coercive. Being truthful – they have to be truthful. They have to be sensitive to the way the individual is reacting. A sensitive researcher will be able to see when someone is not ready to sign up, or if someone doesn’t want to sign up at all or has more questions. Part of good informed consent is just taking the time and maybe even having multiple conversations with the individual. To let them really cogitate and ask the questions they have. To reassure them they have time to discuss it with their family. That’s especially for a study like genome-editing, where the ramifications are so large.

It’s also important who is administering the consent. Sometimes the doctor in the white coat is too formidable and it needs to be someone else who is getting the final consent. There are a lot of soft social skills involved in good informed consent. In some cases, a closing assessment of understanding is important too.

Sometimes it’s good to have a disinterested third party around. That’s something that an ethics committee or an IRB can require – that there be someone there to witness the consent process or even to help the potential participant go through the consent form and talk among themselves and with others to figure out if they really want to participate.

A lot of this is common sense.  Be sensitive. Don’t rush anyone into it. If someone decides to sign up, say thank you. It’s a partnership. We want to consider them partners, for teaming with us to move this research forward.

 You mention some other best practices for informed consent in your article.

The form should be written in plain language, at a 6th-8th grade level. The researchers should think about participants’ vulnerabilities (such as desperation to have a baby)  and consider enrolling parents who have other options for having a baby. Responsibility for complex medical decisions, such as whether to implant an embryo with incorrect editing, should not be transferred to the participants. There should never be penalties for withdrawing.

 What about the bad actor factor?

It’s true that Dr. He was a bad actor. His consent form gives us a perfect opportunity to see what a consent form should say, and what his said instead. We’re learning from example. How to do it right is illustrated by how Dr. He did it wrong, or not at all. Some of Dr. He’s missteps are actually very common. For example, Dr. He used a lot of technical jargon in his consent form.

 So you could also look at his case and say that things he did willfully are also mistakes people are making even with better intentions.

Right. It’s a reminder.

 Would stricter protocols stop bad actors?

Ethical people will do ethical things. Unethical people will find their way around it. Most people are just trying their best.  Unfortunately, Dr. He flagrantly disobeyed the rules to the point where he forged an ethics committee approval. His whole research team didn’t report on him either. It could be  intimidation, fear of losing their job. Often there is a whistleblower, and there’s oversight, and whistleblowers have a place to report to. There wasn’t in this case. Most people want to follow the rules – they just need to know what they are.  Education and enforcement have to be strong.

 Is there an example in history of a pariah or maverick who ended up being right?

There are examples where people have said that no one was unreasonably harmed and the data was valuable, so the means justifies the end. But, it’s very important to understand that a research study has to be ethical going in. It can’t become ethical post hoc.