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Thank you again for reading The Perfect Generation. I spent a lot of time with the story, mainly because there were so many issues I had to go back and fix, but also because I’m so fascinated by the science. Hopefully you have a scientific bent yourself.

The Perfect Generation asks a fair bit of the reader. One of my challenges was to present a scientifically feasible story without getting bogged down in the details. Hopefully there’s just enough detail for you to understand what happens, but not so much that you’re like, “Wait—what?” Even so, I thought a handful of readers might appreciate a deeper dive.

I’m not a scientist. I thought that’s what I wanted to be when I was in high school, but a C in organic chemistry (which was unprecedented for me) changed my mind. Did I lock myself in a university library for months before writing this book? No. Did I conduct exhaustive interviews with real scientists to verify the authenticity of the research I did do? Again, no. But I did pose a lot of good questions and combed through hundreds of journal articles to find the answers.

I can’t stress enough how reductive this article is. There are thousands of books and articles about these topics, and I’m glossing over an awful lot for the sake of brevity, but again, my goal is just to help you make sense of the book and maybe answer some lingering questions.

**SPOILERS FOLLOW**

Story origins

The idea for this story grew out of another one I started called Immunity. That was about a kid who was the only one in the world with natural immunity to a killer virus (which is still fertile ground for a novel). As I wrote it, the anti-vaxxer “movement” was starting to become a thing. They seemed to believe that these lifesaving treatments we receive in childhood somehow planted the seeds of disorders like autism that were just as bad as the diseases they were trying to prevent. That’s pure, uncut bullshit with no valid research to back it up, but it did make me wonder. What if a treatment as common as the polio or measles vaccine came back to bite us somehow? Since genetic modification seemed to be the next big frontier in medicine, maybe that’s just the kind of treatment that would behave in ways we can’t predict.

Getting up to speed on genetic research (the extremely short version)

Genetics is among the newest of the sciences. Gregor Mendel was among the first to notice how traits were passed along in organisms in the mid-late 1800s, but no one really picked the baton back up until the early 20th century.

Over time, we learned that living things transferred information to their progeny, and that there was a way to describe that process. We learned that there are things called chromosomes in cells, and that humans have 23 pairs of them. We learned that those chromosomes contain something we now call DNA and RNA and that all living things use these basic materials to pass along genetic information. That information is expressed as proteins that do stuff.

DNA is like a frame of sorts, and hung on that frame are things called nucleotide sequences—different arrangements of the same four bases: thymine, adenine, guanine, and cytosine. Different sequences produce different proteins or encourage different processes at a microcellular level.

Starting (officially) in 1990, we began mapping the human genome, or the exact sequence of those nucleotides on human DNA. Humans were the first vertebrates to be completely mapped. The project was completed in 2000 and published in 2001. Based on that, it appears that we have roughly 20,000 genes capable of coding proteins. That’s a lot, but not as many as we thought.

Human genome timeline

A timeline of the human genome project (Wikipedia Commons)

We’ve been trying to make gene editing/gene therapy work since the early 80s. As of today, it’s still considered experimental because it hasn’t worked very well in practical terms. The idea is to “fix” a problematic cell at the molecular level and do it trillions of times across cells that have differentiated. Turns out that’s really fucking hard.

The next step is to synthesize the human genome, which is what something called the HGP-Write project aims to do. The potential implications are absolutely staggering and range from growing replacement organs (and synthetic organisms), to engineering viral immunity or curing cancer.

The current state of genetic modification

Diagram of how CRISPR works

How CRISPR works (MRS Bulletin)

The idea of gene therapy or gene editing is pretty straightforward. We know a lot of the genes that cause problems, and we have many of the tools we’d need to snip them out and replace them, like CRISPR-Cas9 or viral vectors. On paper, it all pencils out very nicely. But here’s just a sampler platter of what we don’t know:

  1. How to replace genes in differentiated cells
  2. How to do it trillions of times
  3. How to keep the immune system from freaking out
  4. Whether it will be stable years after the fact
  5. All the ethical implications

So far, no one has successfully “fixed” a genetic disorder at the molecular level. The gene responsible for cystic fibrosis, for example, was identified in the early 80s yet people still get CF. But there are signs that gene therapy is starting to mature as a technique.

The science behind the story

Fixing multiple genes at once

So if we haven’t been very successful fixing one gene at a human-body scale, is it even conceivable that Dr. Brent Geller could do 34 of them at once? In a word, yes.

We’re getting very good now at developing gene editing “tools” or “libraries,” which are groups of tools. You may have encountered news about CRISPR-Cas9, which is a very exciting and relatively new tool, but it has its limits, such as the fact that you can’t fit the CRISPR “package” into the virus usually used as a vector for gene therapy. That package is basically a strand of RNA that directs Cas9, a huge enzyme, to “cut” DNA in a specific place.

While we’re not there yet, this is a very exciting time of rapid innovations in gene editing and it’s a growing field. It’s not crazy talk to think that we’ll soon be able to replace or edit multiple genes at once, either through a single vector, several vectors, or some technique we haven’t discovered yet.

Delivering a treatment in-vitro

The Cure is delivered in-vitro. This makes good sense for a few reasons: One, there aren’t that many cells to treat compared to an adult, so you eliminate some of the challenges of editing at scale. Two, the cells haven’t really started to differentiate. They’re mostly stem cells, so if you eliminate a defect (or potential defect) at that point, it won’t be present ANYWHERE in the body as it matures, and therefore can’t be passed on. The “germline modification” section of this 2016 journal abstract gives further insights into this notion.

Developing a treatment “on the side” with resources from a large grant

My wife and I have both worked at major research universities. As you might expect, grant awardees must account for how federal funds are spent. That includes receipts for everything from travel and meals to purchases of expensive lab equipment. They must also account for the time of people in their employ, like grad assistants. So they care about more than just the results.

However …

The principal investigator (PI) on a grant has very broad discretion over how the money is spent and accounted for. It’s relatively easy to fudge numbers and shuffle things around when no one is really looking over your shoulder. It happens all the time, and not in an unethical way. For example, a piece of equipment needed for one aspect of a large grant may have broader applications for another, smaller grant. It gets purchased with the larger grant even though the smaller grant benefits more.

If a PI had given a great deal of control to, say, a postdoc or doc student on their project, it’s pretty feasible that they could funnel money into a side project that only used existing equipment and otherwise mostly needed time—in this case, Geller’s and Baz’s time and the time of their grad assistants. Could they do it completely under the radar and would Biermann never be the wiser? Probably not, but I don’t think it’s pure fantasy. That said, if something as huge as the Cure came out of research done at a university, like Geller and the University of Wisconsin, both the university and the grantor would want to take as much credit as possible. That would lead to questions about how it was developed and who owns the intellectual property, and that was a whole can of worms that wasn’t worth opening.

A quick note on researchers, though. I’ve known a lot of them, and I can tell you that the only currency that has any value in their world is reputation. Full stop. Is every researcher ethical? No. But if they want to be respected by their peers and awarded money, they have to be. I don’t know anyone who would do what Geller does just to further their own ambitions because they would almost certainly be called to account. The other thing about researchers is that they have dedicated their professional life to the study of not a field, but a tiny little aspect of that field. Most only seek the validation and respect of their peers and have little or no interest in the spotlight. Geller is neither very ethical nor reticent to toot his own horn, so he’s definitely not representative of the research community.

“Labeling” PGs with isotopes

Brain scan

Brain scan of Alzheimer’s patient using a radioactive diagnostic drug

Isotopic labeling is very much a thing. Usually it’s used to follow chemical reactions. Isotopes are just atoms with a unique variation (like an extra neutron or three) that can be swapped out with a molecule of the same element so that it is traceable. For example, carbon, the cornerstone of organic molecules, normally has 6 protons, 6 electrons, and 6 neutrons. But an isotope of carbon, like carbon-13, has an extra neutron that certain equipment can detect.

Genes switching places

Genes on a chromosome can, and occasionally do switch places. The type of switch that happens in The Perfect Generation is called inversion, and it’s a form of mutation. If that occurs, it could cause the genes to produce materials that damage cells or cause other problems. It’s very feasible that a gene edit could cause this to happen in ways (and at times) that we can’t predict.

What I’m not sure about is whether physical maturity—the age at which our cells stop dividing—would have the potential to trigger an inversion. But that is an “event” of sorts that typically happens in our early-mid twenties, so it made sense to hang the problem on that event.

How PGs die

In the book, that gene switch triggers spontaneous cell death on a massive scale. Programmed cell death is called apoptosis, and it occurs when enzymes called capsases break down the physical structure of a cell, causing its contents to be “spilled” and absorbed by the body. Other enzymes regulate the pace of this death.

If two genes inverted in all our cells and started producing an enzyme that breaks down the cytoskeleton (cell structure), and there wasn’t another enzyme to counter that action, our cells would effectively start to melt. If there was enough of that enzyme, it would spread very quickly (in theory) and cause unimaginable damage that we’d be powerless to stop. If that happened, no tissues would be safe.

Final thoughts

This is a work of fiction, so obviously liberties were taken with the science. I’m attracted to stories that take the current state of science and technology and look at the implications of going a little bit too far, too fast. A lot of Michael Crichton’s work does this, and he’s pretty much my literary hero. The science is important to me, so I want to get it right—right enough, at least, so it doesn’t leave the realm of possibility.

Hopefully you found Geller to be a compelling, if not very likable character. The Cure is definitely a moonshot kind of innovation and doesn’t reflect the reality of scientific inquiry, which in reality moves at a much slower pace. He acts mostly alone save for Baz and grad assistants who help run boring tests, and that’s also not very realistic. Quantum leaps in science are rare, but usually are the product of rich collaborations and the sharing of information, not a lone wolf who hoards information and data.

One of my other favorite characters in the novel is Marius Beecher, the legendary frontman for the all-PG band Clockwatchers. I wanted to delve further into the life of an actual PG, from early childhood, to finding out they were going to die young, to deciding what to do with the time they had. There wasn’t really room to do that here other than to touch on it with Lars and Jessa, and to make it clear what Marius meant to the Perfect Generation. I was intrigued enough about that idea to tell Marius’ story in my novella, Clockwatchers, which you can download for free from Bookfunnel if you haven’t already. It’s a little too dark to be considered YA even though the main character never gets older than age 15, so I guess you might call it a coming-of-age story for grown ups, set in the world of The Perfect Generation. It’s a short read and explores a different aspect of the Perfect Generation. It’s not science-y at all.

There are lots of questions about Geller and the story in the Perfect Generation Discussion Questions, which you’re welcome to download and print for your book club, writing group, or whatever. I hope it was a thought-provoking tale for you.

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