Book summary #2 — The Gene: An Intimate History

Summarizing a book full of insights proves to be an impossible task. I flipped through 20 pages of notes I jotted down while reading the book and honestly couldn’t condense them any further. Instead of trying to summarize the whole book, I want to quickly walk through the five eras of genetics in the past 100+ year and share some personal thoughts on the moral complexity of genetics. If you are intrigued by any of those topics, go read the book! It’s one of the best I have read on this topic.

Five eras of genetics

A. Existence of heredity: From Darwin to Mendel

The essence of Darwin’s disruptive genius was his ability to think about nature not as a fact, but as a process. Following Darwin’s theory, Mendel discovered heredity as an abstract phenomenon, a determinant that is transmitted across generations in intact forms such as flower color and seed texture in peas. Mendel spent his entire life in a small garden in today’s Czech Republic working on English peas and his (now groundbreaking) paper on heredity was unnoticed by the science community for several decades. When he passed away, someone wrote his obituary: “ gentle, free-handed and kindly… flowers he loved” Little did people know then that Mendel’s pea experiment would become one of the most important foundations of modern biology

B. Cellular basis of heredity: The discovery of chromosome

Morgan observed the inseparability of certain features in the fruit fly (as if they are linked together) and hence raised hypothesis of the material base of genetics — a “string” along which certain genes were permanently strung. Muller observed during his experiments that X-ray significantly increased the frequency of mutants in the fruit fly (energy induced change); Griffin found in his experiment that viruses can inherit genetic traits from dead debris of other viruses — both evidence that the material base of genetics might be chemical. Avery advanced this understanding by identifying the chemical substance of gene — which we later call DNA (Nucleic acids).

C. Molecular basis of heredity: double-helix structure

Watson, Crick, Wilkins, and Franklin solved the double-helix molecular structure of DNA (what was seen as the Rosetta stone for unraveling the true secrets of life). The discovery of double-helix structure is certainly ground-breaking, but also hugely controversial. The controversy mostly centers around the appropriate use of data (Watson is rumored to obtain data from Franklin without consent) and the fair share of recognition to each individual scientists. Watson’s autobiographic account of the discovery of double-helix — The Double-Helix is an interesting read of that important period of history. But the controversy surrounding the publishing of that book (Harvard first decided to publish it and then dropped the arrangement due to protests from Crick and Wilkins; criticism around sexism towards Franklin) certainly reflects the not-so-glory side of the science world.

D. Information basis of heredity: understanding the mechanism of genes

One of the most important discoveries in biology is the central dogma of biology — a two-step process, transcription, and translation, by which the information in genes flows into proteins: DNA → RNA → protein. Francis Crick (the co-discoverer of DNA molecule structure) first used this term “central dogma” in 1958s, although many more scientists and discoveries contributed towards the forming of this theory.

Jumping a bit back in time, Fisher first discovered (in the early 1900s) the difference of genotype (an organism’s full genetic information) and phenotype (an organism’s observed properties). He later described the relationship between genotype and phenotype as: Genotype + environment = phenotype or more accurately: genotype + environment + triggers + chance = phenotype

How do environment, triggers, and chance impact the expression of genes? It turns out that, every gene has a regulatory sequence attached to it that controls the activation of that gene. And the regulatory switch can be impacted by the environment, triggers and chance — we call it the regulation of genes.

The genome is an active blueprint — capable of re-deploying selected parts of its code at different times and in different circumstances. The regulation of genes — the selective turning on and off of certain genes in certain cells, at certain times — must interpose a crucial layer of complexity on the unblinking nature of biological information

Scientists later discovered three cardinal principles that govern the regulation of genes:

1. When a gene is turned on and off, the DNA master copy is always kept intact in a cell (think of it as a hard-drive backup)
2. The production of RNA messages was coordinately regulated as a gene is turned on and off
3. Every gene has specific regulatory DNA sequences appended to it that acts like recognition tags( sometimes in the front, sometimes in the back) to regulate the “on” and “off” of a gene. The combination of regulatory sequence and the protein (that it encodes) defines a gene

In summary, if we add gene regulation into the theory of genetic information flow, the central dogma can be slightly expanded to write this way:

Gene(DNA) encodes RNAs → that builds Proteins → to form/regulate Organisms → that sense Environment → that influence Proteins/RNAs → that eventually regulate Genes

E. Genomics: read, understand and re-write our own instruction manual

The Human Genome Project (1990–2005) assessed the entire genomes humans. For the first time in history (that we know of), an intelligent being can begin to read, understand and re-write their own instruction manuals. Now the transcript of the entire manual is complete, scientists are actively working on deciphering and discovering tools to editing the transcript. Even though we are still very far away from being able to read, understand and re-write this manual end to end, we are probably still progressing on that path much faster than we are ready for.

The moral complexity of genetics

This new era of genomics leads us to all the messy topics on the moral complexity of genetics. I have a love and hate relationship with this topic. I love the intellectual pleasure of discussing such complex and abstract topics that span across biology, technology, ethics, morality; But I often feel uncomfortable with the moral ambiguity around this topic — there’s no clear black and white here, and every argument deeply challenges the consistency of my own moral beliefs.

Below is a summary of some of those discussions I had with friends or with myself (yes, I sometimes debate with myself in my head). I am well aware that reading a couple of books on biology does not give me much credibility in discussing those important topics. But these topics are too important for me to not think about it. My thoughts are still evolving as my knowledge grows in this area — I welcome and encourage any disagreement. Please challenge my thinking

Eugenics:

The word Eugenics has become almost a taboo due to recent history in the WWII. This term was originally coined by Galton (Darwin’s cousin), but the exact definition has been under debate since. Defined broadly, eugenics is a set of beliefs and practices that aims at improving the genetic quality of a human population. I believe that to some degree, certain level of “eugenics” is unavoidable, it comes from the ancient desire for wanting the best for yourself and your children. But it’s important to draw a line between “wanting the best” to “deliberately intervene genetics to achieve the best”. The latter is a huge slippery slope. In the last 100 years, Eugenics went from selective breeding to selective sterilization and then selective extermination. While such eugenics practices has been considered a crime against humanity since the Nazis, today’s gene editing technology, to some extent, is reviving the belief and practices of improving genetic quality in a different form. And again, we are potentially marching towards a huge slippery slope here

a. Whose genes are better? and where does our moral boundary lie?

From a genetic perspective, there’s no “good” or “bad”, there’s only “fitness” to a specific environment. Genetic traits are selected by the environment that individuals live in — dark skin for sun protection, rounder and a shorter body for heat preservation, etc, you name it. Most modern-day discrimination against certain populations are merely a social construct and has nothing to do with genetic superiority. In addition, even the usual boundaries we draw between populations (e.g., race, gender) is quite arbitrary in a genetic sense because those differences represent only a very small portion of genetic diversity. Recent estimates suggest that the vast proportion of genetic diversity (85–90%) occurs within so-called races (e.g. Asians) and only a minor proportion (7%) between racial groups. Racial assignment of individuals does not carry much implication about genetic differentiation after all.

But then if we extend this argument even further, the genetic boundary between species can also be quite blurry. We share a strikingly high percentage of genes with many mammals (over 95% with chimpanzees) and the way our biology works is not too different from other creatures — you can insert yeast genes into a human cell and for the most part, the human cell will take the yeast genes and make yeast. If we look at our evolutionary history, such boundary even more blurry. Species are distinctively different in the way they look, behave and think. But from a genetic and evolutionary perspective, we are all on a continuous spectrum of creatures. There’s no clear-cut line that makes us (human beings) more special than other species. If we are horrified today about how we treated the native Americans and African slaves back then, wouldn’t we be equally horrified in the future about how we treated animals today? I would hope the answer is yes, and that this thought of future will motivate us to stop our violence against animals. But I also know that I am a hypocrite on this manner. I have tried and failed to be a vegetarian; I still have one leather jacket and two pairs of leather boots that I love; I play with my neighbour’s dog who was castrated before he turned 1; I don’t think laboratories should stop testing new drugs on mice because those tests lead to better cure of cancer. I have thought about this dilemma for a long time but am still struggling to find a good middle ground that I feel morally comfortable with and can realistically adhere to.

b. What is the ethical limit of gene editing?

The discovery of CRISPER-Cas9 (a gene editing technology, which I will talk about in more details in the next book summary. I am working on it!) and “gene drive” (technology to rapidly alter genes of entire population of plants and animals) raised the urgency of discussing the ethics of gene editing — it is no longer a hypothetical debate, but a critical discussion that can potentially change the course of human history

Research v.s. Clinical use or Pathology v.s. Normalcy?

Where should we draw the line of gene editing? Should we allow gene editing only for research purposes rather than clinical use? Should we only allow gene editing technology to cure diseases versus enhancing human features? But do we have a unified definition of “disease” and “enhancement”? Most people would agree that editing cancer-causing gene in babies can be justified because it alleviates great human suffering; Most people would also feel uncomfortable about editing the height, IQ and skin color of babies because those are clearly in the territory of “enhancement”. Giving “God’s hand” to people with access to those technology challenges our (at least most Western societies’) fundamental belief that “all human beings are created equal” However, for every case that has a clear line between disease and enhancement, there are 10 more cases that are ambiguous. For example, the gene PCSK9 can lower risk of heart disease by regulation level of low-density lipoprotein; the gene CCR5 provides lifelong resistance to HIV, APOE and lowering risk of Alzheimer’s. Is it morally ok to edit these two genes? The answer is not so obvious anymore because we can’t clearly distinguish between disease and enhancements in these cases.

Somatic v.s. Germline?

Even if we solved the above dilemma and managed to draw a clear, non-controversial line between disease and enhancement, the next question is: should we allow both somatic gene editing (genetic changes that impact only the individuals receiving them) and germline editing (genetic changes that can be passed to future generations)? Most people (myself included) feel extremely uncomfortable with the later for many reasons:

a) Any permanent changes will be extremely hard to remove in the future;

b) We do not yet fully understand the consequences of gene editing — what if genes are interlinked and that editing one gene could cause a chain effect in our body? changing the force of nature and the course of evolution without fully understanding the mechanism can be disastrous;

c) Who are we to determine the fate of future human beings? do we have any right to change their genomes?

That being said, if we can eradicate malaria and save millions of lives in the developing world by changing the genome of mosquitoes permanently (we have the potential technology for this today), and that we can work out the potential long-term effect on the ecosystem of this change (scientists are still working on it), is it ethically right to ban it? If we can help parents avoid having kids with a horrible (and somewhat inevitable) genetic disease (and hence avoid lifelong suffering) such as cystic fibrosis, Huntington disease, etc, do we not have a moral duty to do it?

State regulation v.s. individual choices?

Should the state mandate interventions related to genetic issues? Today, our gene testing technology can identify cases of cystic fibrosis in embryos, should the state mandate interventions given there’s no cure and that the disease causes great suffering for the individuals and families? Most people (myself included)’s initial reaction is — absolutely no! This is a matter of individual choice and parents should have the right to give birth to children with cystic fibrosis given that they are fully aware of the implications. The state is obligated to provide all relevant information and strong guidance, but not a step beyond strong guidance. However, if we push this argument further, we shouldn’t mandate individuals to wear seat-belt either (not wearing seat belt risks your own life but does not have an obvious impact on others) — yet most of us have absolutely no problem with the “seat-belt” law. Should there be a “seat-belt” law for genetics? And if so, where does the line draw?