Why Your DNA Is Still Uncharted Territory

Maybe it is time for another US gov funded “Manhattan Project”. There are already websites pooling genetic profiles of mRNA or proteins. A map of each chromosome with its nuclear location, a 3 dimensional layout would be invaluable. I wonder if the human nucleus is organized with crosstalk between chromosomes.

Perhaps we can introduce robot/technology automation into the mix to reduce the amount of physical labor in studying the genes? Consider a scattershot approach where many people have their gene sequenced and their health records detailed and then analyzed. That might jump start some significant studies?

I am not a geneticist, and I need some help. There are 20,000 of these genes, and we're complaining that still 5,400 are uninvestigated. Gee, 14,600 out of 20,000 sounds to me like great progress. This is especially so if the standard asks for being the focus of a research paper. Are we upset that the hard-to-extract genes are getting less attention? Sure, but that's the well-known "low-hanging fruit" phenomenon. Research grants are hard to get? I believe we already knew that.

Curiosity-driven research has brought us many of the great strides in biological sciences and genetics. But to show real-world results from research - (increasingly an emphasis at funding agencies) - requires vast amount of time, effort and money. Even those genes that have been studied for several decades have yielded few new therapeutics; eventually more will, but the time frame is uncertain. Another problem is the sheer number of understudied genes, not to mention non-coding DNA, small and large noncoding RNAs, and other dark matter of the genome. How does one justify studying one of these genes vs. the other 19,999? Critical for getting funded and published in the current environment is to have a project that has some level of familiarity to enough peer reviewers, without being too familiar, and enough tools (antibodies, knockouts etc) to be clearly feasible. Some NIH institutes have funding for "high-risk, high-reward" studies but even there those studies are tough sells. Ultimately resolving the problem will require committing funding to these vital explorations of the genome.

I think the comments to the effect of "you don't know how genetics research works" are really missing the point. This is a phenomenon that goes well beyond genetics research. In my own field, it is common for scientists to swarm around a topic that happens to be trendy at the time, often without citing the pioneers who studied it when it wasn't trendy, only to abandon it a few years later when some other topic becomes trendy. In effect, the problem is that scientists are using their freedom to decide what to study in a way that maximizes rather than minimizes duplication of effort. I've also found that it is very difficult to get funding for new ideas. The reason has less to do with risk than it has to do with grade inflation: new ideas create controversy, and since so many peer reviewers are in the habit of giving top grades to mediocre research, there is no way for a new idea to compensate if it gets one bad review. The history of science is full of great discoveries that weren't recognized until much later. Much of this can be explained by psychology, but when you add institutional pressures on top of that you have a recipe for stagnation. Not to mention you have evidence that we really aren't learning from history.

I work with plants, not humans, but it is much the same. For my MSc, I was able to clone four related genes of closely related species to a well-studied model plant species. The tools were there. It was relatively straight forward. For my PhD, I simply wanted to understand where important genes might be in the genome in a species that is not nearly as well studied, and the historical resources are a bit lacking. It took twice as long to discover general targets for regions of the genome to study in my PhD work compared to cloning actual genes in a well-studied species for my MSc. As for the outcomes of my PhD, people ask, and what genes are important? My response is- I don't know. I spent 4.5 years building the foundations so this could be studied. I can tell you where to look, but finding which genes will have to BUILD on my work. It is important, but not 'sexy'. If you don't have intriguing findings that can be published in high impact journals, you can't get that stellar research job, or the next grant, or tenure. Unless you're doing science that has a predictable rate of producing significant results, you're career is in jeopardy just as the article stated. Anyone who has spent a minimum of 10 years in school and likely has loans to pay cannot risk studying something with totally unknown outcomes. If results are 'this is not significant', it still may be important, but it will be difficult to publish and our current BUSINESS model of science funding won't pay for it

To understand the current dysfunction in genetic research and science more generally look first at the system of distorting rewards tied to opaque vetting, which in turn create an artificial system of journal impact factor. Researchers pile into a giant ponzi-like scheme hoping to endear themselves to a powerful academic elite. A simple illustration will reveal all that is wrong with academia. A trivial finding was recently published in Nature (default, but unproven index of real scientific merit for a paper) that was squeezed out of more than 30,000 subjects to show marginal increase in risk in schizophrenia associated with a single nucleotide polymorphism of a complement factor. This was stage managed by the journal, Broad Institute and a compliant media as a near revolutionary finding. Except its not. It reveals almost nothing about the fundamentals of the disease and previous findings show its not even specific. Yet researchers feel they need to be seen to identify with the finding in order to publish in a high impact factor journal (the only pathway to career success and not true scientific discovery). So the paper has more than 600 citations justifying impact factor status of the journal and reveals the hopes of researchers to bask in the Nature limelight. Now all this activity is for a likely dead-end but generates a blind pathway with a very long tail. So scientists are not necessarily chasing a lead on the disease process but status in the game of publishing.

Where are the thought process genes? When someone tells me I have the same ‘mannerisms’ as my dad, what gene causes that? What are the chances that some of my memories came from my parents and aren’t actually mine? As a baby if I did something ‘instinctively, was that from a gene? Just how much passes with DNA? Take the profit motive out of these studies. Fund it like NASA, with government money.

But for the number 1 reason why progress is not faster we only need to look at the number of comments this article has received. At the same time, a juicy Trump piece receives 30 times as many and 100 times as many recommends. We have to do a lot more to rekindle the interest into science that energized the country in the 60s, folks!!

We don't just happen to fail to fund basic or risky research, we intentionally deny ourselves the money to fund it with. Its a choice, it advantages the most powerful people, and it will not be easily undone. So, where's all this money go? Much of it to notorious tax cuts for the extremely rich. Some significant portion disappears into Caribbean basements, and another reasonable share to shell corporations intentionally designed by our legislators and financiers to make ownership impossible to detect. A lot goes to making our woefully inept military look threatening just virtue of the shadow it casts. And a decent amount goes to supporting churches and religious boneheads like Franklin Graham who then spend our money denying the value of science and playing politics from his a-political pulpit, convincing the great uninterested that science is the devil's workshop. Our former national enthusiasm for exploration and discovery, whether in space or an electron microscope, has been sapped, crushed for the the sake of malign ideology and personal financial gain. We could fund excellent research, risky, confirmatory, controversial, speculative. We have the resources. We just don't feel like it. Not to worry: other countries (having noticed the fun and success we used to have) are stepping into our beautifully designed void and taking up the slack. Too bad for us.

Yes, there are 20,000 genes. Paternity is commonly determined by matching 13 of them. As between any two potential fathers, that is generally pretty good, but if you did a population wide search, you'd find a lot of "fathers" who match those 13. Hundreds, possibly tens of thousands. Criminal ID is often made with fewer than 13, whatever they've got. That is why the database of all people ever in prison can give more than one "match" to a crime. Fortunately, most of them can be eliminated by other means. Still, it is not the absolute accuracy we so often assume. This is why there are attorneys who can specialize in debunking DNA evidence. It just isn't what it is cracked up to be. It will be, one day, if we get deeper into those 20,000 genes. There is a lot of work to do. What we have now is more promise of all that could be.

To quote a well-known writer Zat Rana--"At its core, in one way or another, what keeps life interesting is growth....This kind of growth can come in many ways, but the most substantial way is also the most counterintuitive — through adversity, discomfort, challenge, and ultimately, difficulty".

This article overlooks the elephant in the lab, which is that most of your DNA is not coding for proteins, therefore is not called a gene. Still, it's there, and we don't know what almost all of it does. This is the part that was called "junk DNA" years ago, until some of it was found to be as essential as the genes through its regulatory action. That still leaves most of the DNA with unknown function.

Too much human genetic research is misguided and malignly driven by corrupt crony capitalist corporate plutocrat oligarch welfare profits. Business is the antithesis of science and humble humane empathy. Basic research into human genetics also conflicts with the supernatural ignorant and stupid myths that are the root of all human faiths. Human hubris regarding genetic research is running well ahead of our educational legal moral political and socioeconomic ability to objectively and rationally weigh the costs and benefits. Swe " Frankenstein; or, The Modern Prometheus" by Mary Shelley; "Prometheus " Classical Greco-Roman myth and film

I'm someone who works on the role of genes in brain function and development. And the trends described in this article don't concern me because biology is undergoing a revolution right now that will likely solve this problem. Currently, with next generation sequencing and the ability to perform it at the single cell level, we will soon have a very clear picture of where every gene is "expressed" - the word we use when the genomic DNA sequence that makes up a gene is transcribed into RNA for the cell to use. Because of this new single cell data and the promise of spatial transcriptomics - think about having a spatial map of where every single gene is expressed in the body in each and every cell - we may gain a much clearer and more detailed understanding of what each of these genes does and where they do it. This will happen in the next decade, and will make it a lot easier for scientists to form hypotheses about genes that were not studied extensively before. This will make it more likely for scientists to choose and work with genes that were overlooked in the past. It's really hard to know where to start working on a gene if you don't have any idea what it does or where it works. But that's about to change.

The general message of the article is not entirely fair. Getting the best bang for the buck requires to expand knowledge by building on a logical framework. If I were to ask you what were more likely to succeed on D-Day: concentrating the attack on a few beaches and retake the continent from there or randomly drop the invasion forces in enemy occupied country, what would be your strategy?

I can't get past the 'sequencing gel' in the image at the top of the article. That is NOT a sequencing gel! I suspect Carl Zimmer didn't select it, but still--doesn't anyone who knows about science/molecular biology check these things prior to publication?

Fishing is not an activity appreciated by the standard senior scientist or academic.

I don't completely agree on the article. Yes, often research is done for survival, but projects quering the function of unknown genes are currently ongoing in cutting edge labs worldwide. Whole genome screening are getting better and better and tools to study genes' function are rapidly evolving. It is in our nature choosing what is more appealing to study rather than following the grants $. But in my experience, exceptional novel projects aimed at studying the unknown part of the genome are very well appreciated. A good number of scientists still choose to study the unknown! And I am one of those :D

A great number of the genes whose functions we know have much more powerful systems to really study their BIOLOGICAL functions (Yeast, flies, fish, frogs, mice for examples). Humans have been in fact a terrible system for studying biological function in the most direct way possible (get rid of gene, see what happens). Disease mutations, in addition to being disease related, have been the best surrogate for this approach and therefore have gotten the lions share of attention because the Nat Inst of HEALTH has decided that a gene's HUMAN function is a disease context is all that they care about because of shortsighted political influence. Current genome editing techologies (even my 8 year old has heard CRISPR on his favorite Disney show) lower this barrier significantly for human cell culture models, and the application of that tech on a large scale is really in its infancy. However these experiments cannot address the actual biological system, i.e. people, and never will.

I think they aren’t telling the truth because it would reveal many genes were spliced in by unethical population control experiments in the 70’s delivered via vaccines. This has already been proven by Kenya’s health Ministry and the WHO, the Kissinger cables show the CIA was conducting cytokene angonist experiments in Cairo that were found unethical by the HEW, and how else explain the doom and gloom of the “population bomb” against the inexplicable decline in sperm counts, which skew racially. I had to give saliva for a “real ID” in order to board an airplane. Obama’s science advisor used to advocate putting contraceptives in the water supply and requiring you to apply to the Federal Government to be deemed worthy to be dispensed a fertility antidote. It’s published in a textbook. Perhaps they actually did it, taking chimpanzee retroviruses.

This all comes down to how research is funded. Funding bodies rarely give money to scientists for research they deem is “speculative”, “hypothetical” or a “fishing expedition”. To survive, scientists have to do research that is low-risk, safe, and usually already half known. Hence the focus on known genes, to the detriment of our knowledge and understanding of the complete human genome.

I believe that we have achieved the $1,000 full genome sequencing. However you can not buy it. We need the data first, then we can try to figure it out.

Just another reason why government funded basic research is so important.

To understand why genes of unknown function are not studied one has to understand the way funding for scientific research works. Grants are awarded based on at least some preliminary information. One of the reasons is that those who make the decisions are too cautious and reluctant to fund risky projects that require a long time to produce results. They want to be sure that the money is not wasted as funding is quite limited for basic research. Good luck getting a grant approved to study a gene that cannot be shown it is “important”, i.e.: cancer, Alzheimer’s, autism, etc. No preliminary data, no grant. And no grant, no preliminary data. This is the “mystery” of the known unknown genes. Yeah, I'm a scientist!

I would strongly argue that this article reveals the lack of understanding the general population has concerning molecular biology in particular and modern scientific research in general. I unfortunately have space for only two very brief points. The author (and a lot of commenters) remarked that there is no such thing as an unimportant gene. Surely this is the view expressed by Stoeger et al. in their article (they use the phrase "the majority of protein-coding genes have biological relevance"). However, certain genes are extremely "relevant", genes whose proteins interact with dozens of partners, genes encoding proteins like P53, Calmodulin, RhoA and Rac1. C9Orf72, while potentially really important in FTD and ALS, simply does not compare to the complexity and variability of these other "popular" genes. Which leads me to the only other point I have space for here: it's just not as simple as "gene X does Y". There are splice variants that are still being discovered, different interactions and activities in different tissue types, and new posttranslational modifications affecting functions of already well-studied genes. Take for instance ATM, a gene cloned in the mid-90s and known to be part of DNA repair. It was discovered several years ago that it also functions as a reactive oxygen species sensor. We hardly know anything about the genes we know about now. Molecular biology is still new, and we're still learning. We can't adequately study all 20,000 genes at once.

I had a 35 year career in molecular biology and genetics and retired comfortably very young. Followed the typical trajectory and ended up a PI with a faculty position at a good university. I lasted six years of trying to get major research funding for what I felt was an interesting medical problem (millions of people affected with significant morbidity) with clear and unquestioned major genetic components. I was able to get small amounts of research funding from foundations with interest in the disease from foreign countries but nothing major from my home country. It was obvious to me that the most successful researchers (secured major grants) were often those who never did anything different through their training. It was a lesson in how the research world worked. I left my academic career, went into genetic diagnostics and set up my own company. Best decision I ever made!

Some folks have suggested that the genes that haven't been studied are less important and don't have an important function in the human body. Patent nonsense. Nature abhors inefficiency, a useless gene just expends unnecessary energy when it's duplicated whether via meiosis or mitosis. The example cited in the article should refute that notion. In an article last week in the NYT science section on elephant tusks, they're equivalent to our lateral incisors. The article then delved briefly into tooth development. Each tooth (neglect the left/right symmetry) has a different function and therefore a different shape. They all develop from the same primitive cell layers in the embryo. How does a molar know to assume its shape instead of a canine? It's when the genes are turned on or off. Similarly for every minor development and change from when the sperm and egg unite until birth, development and maturity, gradual decline and death. Just because we haven't figured out what a gene does in no way implies it does nothing. Ala absence of evidence isn't evidence of absence. Just think of the myriad of things biologists thought were unimportant until we developed more tools to analyze and evaluate them. Mother nature doesn't fool around, if something isn't necessary in biology it's expunged to conserve energy for the organism.

Gel electrophoresis was used to sequence DNA in the early 1980s. Huge advances have been made since then. Replace the photo with something that is used today!

Forget the "curing disease" approach, and just think up a clever "military angle" for your genetics research. The US military budget for 2019 is $886 billion, whereas the NIH budget is $39 billion. Any questions?

Fund Basic Research!!!

Half of those 20,000 genes are expressed in the brain. Yet, many of the top journals now (Nature, Science, Nature Neuroscience) are no longer interested in publishing manuscripts on gene function unless that gene is directly related to a disease. They are interested in circuits now and if we were ever successful in mapping out the brain, how would we come up with new treatments for epilepsy, depression, addiction? Oh yah... go back to the genes.

The NIH actually supports several programs to explore these "poorly annotated" genes with the aim of providing preliminary data and experimental resources. With these nuggets, scientists are better able to put together competitive applications and start new avenues of research. Background info for just two examples can be found here: https://commonfund.nih.gov/idg https://commonfund.nih.gov/KOMP2

The author misses the key problem in that it is virtually impossible to consider the effects of a single gene without assessing the impact of all the other genes. Given the state of today’s computing power and ignorance regarding most of the other genes, the differential equation with 20,000 variables is virtually impossible to fathom. However, the chipping away at the equation by exploring what the genes do is critical to the future because computing power is growing and the additive knowledge of each gene will eventually provide answers. If we fail to continue chipping away, our research will be largely curve fitting and anecdotal. The answers we eventually find may not be accurate, btw, because they’re being sought without the influence of the environment that adds a gazillion more variables.

Of course, should a researcher go looking at any of these genes she would be accused of genetic butterfly chasing, for spending research dollars on speculation. The consequence of the human genome project is that we would have sequence information on thousands of genes that did not provide a readily appreciated phenotype. We are like a person having a car, and next to it all the components of that car laid out. We understand the car and the components, but it will take some time to understand how they are all put together (and when changes are life-threatening or merely an annoyance. The fact that doing this research takes time shouldn't be used to imply, as the subtitle of the article does, that the delay is due to self-serving, cowardly, careerist scientists.

The incentives to make a small, publishable improvement to the edifice of knowledge is locked in throughout the research process in the United States. If you can add a brick, quickly and certainly, to that edifice, your time is well spent. If you are trying to get a better sense of what other parts of the structure might look like, be careful. Here are two problems: 1. Research with a testable hypothesis is almost exclusively favored over "natural history" research that tries to obtain an overview or to gather large amounts of data in the expectation that hypotheses will come to the researcher while struggling to make sense of these data. 2. Negative results generally are not publishable. Even a very clever hypothesis that receives no support from the data may not produce a publication. This creates two additional biases. First, researchers are pressured to tweak the tests until a positive result emerges; that result may be a statistical anomaly, un-replicable. Second, there is pressure to modify the hypothesis itself to fit the result, which is not in itself bad, but the negative results with the clever initial hypothesis might never find its way into the literature or into the body of knowledge. There needs to be more support for risky, exploratory work. In general, there needs to be more support for the part of science in which hypotheses are first developed through inferences from data. Researchers should be exploring more, disseminating more pure information.

This is another insightful article by Carl Zimmer that provides a window into the world of basic research and the problem of securing grant funding for research on these types of poorly characterized genes. As commenter Stephen noted earlier, reviewers on NIH grant study sections strongly favor applications with extensive preliminary data, and write off other types of proposals as "speculative". On the whole, it's not clear in the NIH granting system where the support for generating this type of preliminary data is supposed to come from (other institutional funds presumably), but it is prohibitively risky for most labs to invest the time and effort required to explore the biology of unstudied genes to a sufficient degree to obtain funding. This is despite the fact that the explosion of genomic technologies in recent years (e.g., single cell transcriptomics) has uncovered many new potentially interesting biological pathways that often involve these types of uncharacterized genes. The problem is, while generating lists of candidate genes for disease risk/biological processes is (relatively) easy, working out the biology for each gene can take years of research, with no guarantee of finding something interesting enough to obtain subsequent funding.

As a geneticist, I think there are some issues with this. For the vast majority of the history of genetics, genes across all organisms were discovered and studied because of the phenotypes associated with them—diseases in humans, slow growth in a microbe, developmental abnormalities in a mouse or fly, etc. This means that we know an awful lot about the genes that have a functional importance across a wide range of organisms, and modern tools allow us to apply our knowledge of model organisms to human biology much more rapidly. At the same time, our knowledge of the still-uncharacterized genes is not as much of a black box as this article makes it seem. We have lots of clues relating to function that can inform whether they deserve further attention: we know where in the body these genes are active, we know whether they are conserved with other organisms and thus likely to be important, and we know if they are associated with any disease. So we have studied in depth genes of known importance and we have strong tools to identify genes that might be important to study in the future. It’s undeniable that there are important genes of unknown function left to be characterized, but the approach to studying them cannot simply be to pick a random one and invest years of research and hundreds of thousands of dollars to study it. This is not how genetics is done: we (rightly!) study genes that we have reason to think might be important.

Not every gene among these 18,000 little or unexamined genes will turn out to have a major function, or a function that can be readily discerned. In fact, there are people who carry homozygous mutations in some genes that were expected to be important, living happily without any troubles. It could easily be that only one out of twenty among these 18,000 has a definable role in the organism or in human disease. So picking a bunch of of these randomly for in-depth analysis is a matter of diminishing returns, or a lottery that most likely ends your career as a researcher. The reason why the other 2,000 have hogged our attention is because most of these were identified through their important functions in the first place, either in model organisms such as yeast, fruit flies, nematode worms, frogs, and others, or because aberrant versions of them were strong drivers of human disease. Unbiased screens in model organisms and basic research into new connections with well-known gene pathways continues to be one of the most promising routes to fill the gaps.

Scientists in China may prove to be the intrepid explorers to first navigate these uncharted genetic waters simply because the Chinese state is more willing to invest public funds this way. Current US policy-makers, busy making America great again, seem headed in the opposite direction. Smart.

The loss of interest in original research is a tragic milestone on our national way to decline. Its also a symptom of the plague of "everything government does is a crime against democracy and the free market" and "Hey, I know, we should run our country (and our colleges) like a business!", twin abominations against our country and our people. The swarms of middle-management and administration lo9custs afflict American education at every level; the billions invested in fraudulent 'report cards' and 'holding schools responsible' has denigrated the once-mighty educational program that secured our former position as a world leader. To say nothing of the curse of standardized testing. One can hardly blame individual scientists safeguarding their professional futures. This is all about stupid and partisan ideas about education, and our idiotic refusal to improve.

It might have been helpful supplement the data science perspective with that of molecular geneticists. From the data science perspective, the allocation of resources might seem arbitrary, but from the biological perspective these genes might be more promising leads with good supporting evidence.

The parable of the drunk looking for his keys under a streetlamp comes to mind. “It’s the only place where I can see.”

Related to the article is the dire need to increase federal support for individual research projects. At the moment around 1 in 10 grant proposals that are submitted by individual researchers is funded. The decision to fund a project is dependent upon peer review. Reviewers, in general, will support projects that are the most likely to give a positive result. This means that the outcome of a proposal must be supported by huge amounts of data that the researcher generates prior to submitting their proposal for review. This requirement leads to a 'catch 22' situation. It is impossible to generate such data without the funds, yet supporting data are essential to convince reviewers to fund the research. Funded research therefore focuses on genes and proteins that have preexisting information that can be built upon. The result of a severely broken system is the funding of very conservative research projects that are low risk, lack innovation, and that lead to incremental advances at best. If federal funding for investigator initiated research is increased, and any expansion in research buildings is capped, then the number of projects that are funded by the National Institutes of Health can expand to accommodate high risk, high reward topics.