Science, Explained

DNA DAVE’s Straight Talk on Genetics, Medicine, and How Science Really Works

Grant Dollars, Publication and the Academic Scientist’s “bottom line

By DNA DAVE

It is important to understand what motivates academic scientists to understand how science works. This essay can be considered a hurriedly prepared opinion piece, intended to stimulate discussion; these are observations I have made after nearly 45 years as a practicing scientist, grant writer, author and journal editor. I am a molecular, stem cell, cancer biologist so the space is biological/biomedical science. If you are thinking about being a scientist, I hope that this stimulates you to think about what type of scientist you are. If you are not a budding scientist but curious about how the culture of science works and how scientific ideas evolve, I hope you will find this of some interest.

What motivates a scientist:

First, let’s exclude industry from this discussion. Scientists in industry are motivated by the same bottom line as any commercial enterprise. They work for a company, a profit margin must be maintained or the company shrinks and/or dies. Making products people need or want is the goal, identifying the market and selling to it are the means. Between marketing and sales are the scientists whose work is mandated by the current mission of the company, dictated by management. Here I discuss the academic scientist or basic researcher. Basic research provides the incubator for novel discoveries that cannot be made via a business model. It fills an important gap, that is, breakthrough knowledge, without which clinical research and biotech would be limited to solving problems with existing knowledge. A major cultural difference is that, in basic or academic research, the profit motivation is removed and salaries are not a measure of success. Success in basic research is measured somewhat differently from different vantage points. To the scientific community it is a “body of work”, generally measured by the quantity and quality of publications. To a University administrator, it is the number of grant dollars garnered. To the grant awarding agencies it is the impact of a scientists discoveries to their mission. Here we will focus on how the basic/academic scientist views success. I will argue that there are different motivations and definitions of success for different personalities, which I place into 3 basic categories: the artist, the ladder climber and the tinkerer.

The artist is one who is truly motivated by finding the true answer to an important question, rather than by any other measure of success. They may want to be at the top of their field, but the amount of grant dollars, size of laboratory, number of publications and in what journal those publications appear do not trump getting to the true bottom of a scientific problem that drives them. The artist is often found at a teaching University, where they can be more free to pursue riskier problems because: a) the goals of a University do not put as much weight on quantitative measures of success such as grant dollars; b) a University provides part of the scientists salary; c) a University allows access to PhD students whose salaries can be offset when they serve as teaching assistants. Altogether, the University scientist can stretch their grant dollars to get more research done on a smaller budget, in exchange for teaching and service to the University, allowing them to pursue types of questions that would not be possible to address in other environments. The main distraction from their quest for success (finding the truth) is wanting so badly to answer a question that they become blind to their own data and that of others, seduced by an idea to the point that their intuitions become self-evident truths. Their quest for success transforms into a quest for the appearance of success in the eyes of others. Thus, the truly successful artist is continually seeking out criticism and rigorously challenging their own hypotheses. Depending upon their dose of human altruism, the artist can either be a mentor extraordinaire, taking great joy in nurturing the creativity of their trainees and helping them find their most rewarding career path, or they can be overly judgmental of trainees who do not adhere to their vision of success. Regardless, what motivates the artist is a quest for objective truth through deep Socratic self-questioning and rigorously executed science. When you interact with the scientist/artist, do not confuse rigorous thinking with judgmentalism or condescension.

The ladder climber on the other hand, cares little about the specific question being addressed, but is more concerned with identifying a question that will garner the most grant dollars, high impact publications, invitations to speak at meetings and the general delusion of power, glory and being “famous”. I say delusion because I challenge you to find a single person in a crowd who knows or cares who won the last Nobel Prize, as opposed to the name of the sidekick’s pet dog on a popular Netflix series. But the ladder climber spends their time with people who worship them, and in this relatively small circle, being viewed by others as successful is more important to the ladder climber than solving any particular problem or even being correct, so long as they are perceived as being correct. The ladder climber is more often found in Medical Schools or Institutions where there are no distractions from the goal: building the largest and most well-funded empire possible and attracting great trainees that require little mentoring so that the ladder climber can attend every meeting and schmooze every journal editor and grants program officer. The ladder climber will follow every new trend, and as their empire grows they can catch new trends early enough to apply a substantial force and quickly claim to have been a pioneer in the new trend, while in fact they rarely initiate any innovation because their concern is not with the innovation itself. Their view of success has little to do with actual innovation. The main pitfall of the ladder climber is that success and truth often clash, and the ladder climber will be tempted to overlook the truth in favor of success. By the time the magnanimous claims that hooked the magazine editors have been de-bunked, the ladder climber is on to the next trend. This is not to say that the ladder climber’s contributions to science have no merit. Quite the contrary. Their laboratories can be fertile incubators for talented scientists of all types, particularly those who build off of the trend and expand it into new areas of research. They start Centers and Institutes and raise funds for cutting edge fields that trickle down to the artists and tinkerers, they raise public awareness of science and sometimes champion important causes. However, breakthrough knowledge rarely comes from the ladder climber because their vision of success is not compatible with creativity, risk taking and artistry needed for breakthroughs and rarely are these attributed nurtured in this environment. Moreover, the ladder climber is rarely a strong mentor, because their vision of success requires that they spend all their time on the ladder with the other ladder climbers.

Finally, there is the tinkerer. The tinkerer is interested in developing technologies to make things happen that were not possible before. Like the ladder climber, the tinkerer is not so interested in the specific question. But, the tinkerer’s vision of success can be either more like an artist or more like a ladder climber. The tinkerer may be genuinely motivated by the impact of a potential technology and, like the artist, the amount of grant dollars, size of laboratory, and number of publications may not trump the goal of developing some really innovative new way of doing things. Alternatively, the tinkerer may see technology development as a stepping stone to things that constitute success for the ladder climber. The tinkerer is a ladder climber when their perception of success is to be viewed by others as successful.

Note that what distinguishes these three types of scientists is their own perception of success. All three can collaborate very successfully and symbiotically, using each other’s vision of success to bolster their own. They clash when the ladder climber chooses to publish less than rigorous science that confuses the pursuit of truth, or when the artist or tinkerer upends the ladder climber’s next big hit for having overlooked a key caveat in pursuit of a magazine article. Also note that all three MUST garner grant dollars and publications to continue to be viable in any pursuit of success, which we discuss below. Finally, note that there is no relationship between salary and these three visions of success. A less successful scientist by these three visions can achieve a higher salary by pursuing administration or an M.D. degree or working in industry, starting a company and patenting inventions. This is not to say that you can’t make a very comfortable living doing science of all three types. And in some niches one can even do quite well. But salary cannot be the primary motivation because it is a distraction that is not compatible with the academic scientists vision of success. With these motivations in mind, let’s briefly review the process of generating revenue and work product in academic science: grant dollars and publications.

Obtaining Grant Dollars

Grants are obtained by identifying funding sources, funding missions and funding deadlines. Grant dollars are very hard to come by, so if the mission matches your question and the deadline provides sufficient time, a grant should be written. Thereafter, the goal is to convince a small panel of reviewers (usually 2-3 experts in the field) that you have an idea that shifts conceptual or technological paradigms (innovative), has a high probability of success (feasible), will drive the field beyond current roadblocks (significant) and will exert a sustained influence on the field (impact). Every aspect of the process of scientific inquiry must be thoroughly developed, including consideration of all reasonably possible outcomes of each experiment and how you will interpret and extend each possible outcome. The latter process is not unlike a game of chess, thinking 2-3 moves ahead what your opponent might do in response to each of your moves and how you will respond to each of their possible counter moves. The approach must have clear advantages over other obvious approaches, and it must be clear that all reasonably possible outcomes will provide important new knowledge that was never achievable before. If you cannot satisfy all of these criteria, then your grant is not ready. After an application is submitted, it is usually many months before you will hear about funding, and many more months before you can re-submit a revision of a rejected application, so planning well in advance and not prematurely submitting a grant that might score poorly and have a bigger uphill battle upon re-submission is very important. Most granting agencies fund from 2-10% of the grants they receive, so identifying the right agency and crafting an impeccable proposal is an essential part of a scientists job. With large funding agencies, there is often a second level of review by administrators, where grants that are on the cusp or just below the expected payline are discussed. If a grant is highly relevant to the mission, it can be funded over a grant with a higher scientific score. For these reasons, it is important for scientists to establish good working relationships with grant agency officials, sometimes called Program Officers. The artist will restrict this relationship to discussions about the mission of the program, making sure the proposal matches the mission and emphasizes those components of the application that are to be evaluated. The ladder climber will actively seek a more friendly “collegial” relationship with the Program Officers, known as “schmoozing”. Good Program Officers see through schmoozing but, still, when it comes time to put together committees for deciding new directions for funding, the ladder climbers will always be the on the committees, pushing their agendas so that more dollars move into the new trend that they have caught wind of and tooled up for. The Program Officers will be hearing from the ladder climbers and as a result will be obliged to appoint them. The artist will not push to be on these committees, because committees and top down programs that attempt to dictate what questions people should be asking are not interesting to the artist. But, if such a committee happens to fall right into their question of passion and they are asked to serve, they will do so and the Program Officer will be thankful for those committee members. The artist is motivated to focus on rigorously testing their hypothesis and will seek funding for their work when their current funding enters its final year. The ladder climber will seek out science that is likely to become a big direction for funding, reproduce some of the key findings in their laboratory, and then try to move the money in their direction. Again, both systems work, and successful scientists achieve their vision of success.

Publishing

After the data are in, and if the results are interpretable and provide novel insight, it is time to publish the data. Publication is the culmination of years of hard work, and is the tangible product of academic research. The writing itself can take months as holes in the logical flow of the work are identified and more experiments are performed. The data are pored over and the first and last authors will repeatedly discuss something call “spin”. Rarely is a manuscript written in the chronological order in which the experiments were performed. In order to communicate science, it must be abundantly clear to readers “why” each experiment was performed, what was concluded from each experiment, and how that led to the next question. This story must flow and must converge on one or a few highly related and well-supported conclusions. The spin, therefore, is the most seamless and significant story that can be woven from the set of data. As the spin emerges, it becomes clear what data to include and what data is not informative and what data are missing and must be collected. To the artist, the “spin” is the most substantiated and significant conclusion of the body of work. To the ladder climber, the “spin” is the most popular conclusion that will interest a magazine editor. The ladder climber and the editors attend a lot of the same scientific meetings, where it becomes clear what the other ladder climbers think is the most popular interpretation of emerging data. There then ensues a race to find data that support those interpretations because they will be most well-received, well read and well cited. As discussed, human beings are driven by their intuitions more than their rational thinking, and scientists, when all is said and done, are human beings. Thus, the artist, whose vision of success is unveiling truths not intuitions, will struggle to evade the temptation of intuition while the ladder climber will thrive on it. This works for the ladder climber quite well because popular interpretations take a long time to die even if the data show that they are, well, wrong. The ladder climber will publish conclusions that are not supported by their data because they measure success by how others perceive them and so they prioritize the conclusion over the truth. However, the artist is not immune to the temptation to overlook data that do not support their hypothesis or, when clashing with the popular view, of slipping into a burning desire to disprove a popular interpretation, in either situation compromising the objectivity of how they present their work to the public. Fortunately, science itself is disinterested and impervious to human intuition, so the truth shall eventually prevail, however delayed by these frailties of human nature.

An important question early on in publishing is authorship: who should be an author and in what order should those authors’ names be listed. Many believe that to deserve authorship at all, a person should have made a contribution that goes beyond what could be contributed by anyone with general expertise. In this view, technicians, staff in University facilities and those who were paid for a service should not receive authorship, nor should those who simply provided reagents or materials that were already published elsewhere. Those who make intellectual contributions (even facility staff), help with innovations, or provide essential reagents that have not been published should have authorship. By convention, the intellectual driver of the work and/or the person who put the most work into a project and usually the principle writer of the manuscript takes first author, while the head of the lab (known as the Principle Investigator or PI) in which the majority of the work takes place takes last author. It is customary for the PI to be tagged along solely as the person who paid for the work, whether or not the PI made any intellectual or written contribution. Usually, however, the PI is promoting the work in their oral presentations at meetings and seminar invitations and provides at least some serious critical evaluation of the manuscript describing the work prior to its submission for publication. Usually, but not always. Beyond the standard conventions, there are much greyer areas in publication authorship. Some believe it is best to be generous with authorship because it helps everyone’s career to be acknowledged for contributions however small, while others believe that authorship for minor contributions diminishes the value of authorship. For example, individuals are often unwilling to provide reagents (even published reagents) unless they are promised authorship, and one is then faced with the decision of including them as author for shipping a reagent or having a much more difficult road. Of course if this reagent is something that requires expertise to produce and must be produced from scratch every time, then collaboration and co-authorship is appropriate. But often reagents are made in a virtually limitless fashion and require very little effort to share. It is a huge, wasteful, and often prohibitive duplication of effort to produce a reagent that is already been produced and, while journals stipulate that authors must agree to distribute reagents freely after publication, journals have little motivation or power to uphold these stipulations. The simplest thing is to take the reagent and add the provider as author. From the perception of success then, the ladder climber is tempted to pad their publication list simply by providing reagents while the artist by contrast is motivated to share new reagents with other people to enlist their help in getting to the truth. Both enjoy a low cost/benefit collaboration. Another grey area principle of authorship that is less often discussed is whether every author should be responsible for every conclusion in the manuscript. Science is becoming increasingly collaborative, making it impossible for every author to understand every experiment. However, the bar is raised significantly when an author does not even read the paper and/or was simply included as author for stature to increase the chances of publication. Many journals now require each author’s contribution to the article to be stated clearly on the first or last page of the paper. But, of course this is all done on an honor system.

Authorship discussions are common, because it is often difficult to discern who made the most important contribution to the manuscript. It is generally perceived that the first author made the largest contribution, the second author the second largest, and so on. The last author is the principle investigator of the laboratory that made the largest contribution, and the second to last author the head of the lab that made the second most important contribution, etc. In the majority of cases, reasonable people can agree on such things beforehand, and the first author with their PI/mentor assumes responsibility for writing and submitting the manuscript. In some cases, authorship order may be completely clear before a body of work begins, for example if the work will constitute a PhD student’s doctoral thesis or part of a post-doctoral scientists developing direction of research. Other times, particularly if the parties have a collegial or collaborative history, the parties agree to work thinks out as they unfold. This requires strong leadership to identify critical junctions when the authorship discussion should be re-visited. Disputes happen, but if communication lines remain open and PIs stay on top of it, authors generally find a way to agree. For example, a student may concede a close call by saying: “I’m OK with being second author if first author does the lion’s share of the writing.” Moreover, it is increasingly common to see 2 or 3 or even more authors be listed as “equal contributors” to a manuscript, allowing them to claim the manuscript as a “first author” contribution in their CV. What is most important in these matters is that the young scientists, working hard to get their careers started, remain the priority. This is a top responsibility of the PI as a mentor. Unfortunately, there are PIs who do not take this responsibility seriously and ignore the warning signs until it is too late, leading to a very difficult and painful dispute where peoples’ expectations are unnecessarily thwarted, and even those who actively refuse to accept their responsibility, and either dictate first authorship without discussion or tell the disputing parties to work it out amongst themselves. Given the focus of the artist on the integrity and quality of the science, it is natural that they would be more likely to take a strong role in these matters, while the ladder climber has no success-driven motivation to do so. However, this is an area where individual personalities may dominate PI behavior. Young scientists considering a laboratory for their PhD or post-doc work should make a point of discussing with current and former members of the lab how issues of authorship are handled, or this most important mark of their productivity could become compromised.

During the publication process the authors must also make decisions about what data to withold. This is a slippery slope that requires careful mentoring to navigate. There are often a few loose ends here and there that do not support the overall spin of the manuscript. It is legitimate to withhold (ignore) an experiment if the controls failed or if certain important controls are currently impossible to obtain, because one cannot properly interpret the experiment. It will be up to the student or post-doc and their mentor to decide whether an outlier result is ignorable or must be repeated until it is interpretable. By contrast, it is not appropriate to ignore an experiment with a clear interpretable result that contradicts the spin of the manuscript. This can happen innocently, when the artist and tinkerer are so caught up with the excitement of the spin and simply can’t believe the contradictory result, or egregiously, when the ladder-climber wishes to have the work withheld because it could compromise publication in a high impact factor journal. Such results might also be withheld from the mentor by the graduate student or post-doc without the mentor’s knowledge, so responsibility is not always easy to assign, and public knowledge of the contradictory results may never emerge. However, the true to form artist would never ignore such a result; a well-designed experiment never lies and there is nothing worse than someone else reporting results that contradict your work, when you had those results in your hand. To the artist who is on their game, interpretable results are screaming at you to come up with a better hypothesis. For the ladder-climber, the risk is small because by the time someone discovers that the interpretation was wrong, they are two or three rungs higher on the ladder and will have dozens of other trendy reports to dilute any past mistakes. For the tinkerer, it may be the method or technology that is more important than the conclusion, but the concept is the same: if the tinkerer is an artist, then the spin is in how truly powerful the technology is, and any well executed experiments that point to fatal flaws in the technology should not be ignored.

Once the spin is clear and the manuscript is nearly finished, it is time to choose which journal to submit the work to. Impact factor (IF) is often discussed. The question arises as to whether particular journals are “a reach” or “a slam dunk”. Do the authors want to invest the time it takes to convince a high IF journal that the work is worth publishing in their journal, or do they need to publish the work rapidly to avoid a “scoop” (someone else publishing the findings first). As with grants, this involves a discussion of the mission of each journal and the “fit” of the manuscript to that mission. This may involve phone calls or other correspondences with the editors of specific journals, which introduces another opportunity for inter-personal lobbying, or “schmoozing”: the specialty of the ladder climber. The high IF journals Science, Cell and Nature, as well as their various “spin-off” journals they have created to corner every possible scientific market, hire full-time “professional editors” to handle the manuscripts. These are individuals who often have a PhD, but have left research for a career in scientific journalism. Their job is to increase the IF of their journal. Their motivation is to find material that can be easily sensationalized to maintain the visibility of their journal, and will garner as many citations as possible. These individuals hold a tremendous amount of power to the ladder-climber, as they will ultimately make the decision as to whether a paper is accepted for publication in their prestigious journal, and that is more important to the ladder climber than the science itself. The ladder-climber feels obliged to befriend or “schmooze” journal editors, and their discussions generally revolve around how to “spin” the novelty and impact of the findings to broaden the readership. The artist and tinkerer are also hopeful that their work will merit publication in such journals and be broadly interesting, but are not willing to compromise the science by over-extending the conclusions or compromising their scientific principles to sensationalize the work. Their discussions with the editors will focus on the science, while the editors will try to convince them to focus on ways to emphasize novelty and impact. The ladder climber will continuously resubmit their work to the same editor for well over a year from the time of submission until acceptance. The artist and tinkerer are more likely to send to another journal in order to move on to the next important question in their field. The ladder climber is much more likely to grovel to the editor and fear rejection, while the artist will move on to other journals.

The next IF tier of journals are the society journals and a handful of independent journals that have some budget for staff, but for which the decisions to publish submitted articles are made mainly by scientists working as editors pro-bono. The motivation of scientist/editors in working so hard for these journals can be varied: they may truly want to give back and in academia some degree of service to the community is expected both as a rule and as a criteria for academic performance in their University, or they may enjoy the prestige of being associated with a strong journal or in some cases may enjoy the power to decide whether papers get published. These journals still have strong reputations, but place a much stronger emphasis on the quality of the science than the novelty and impact, so long as the manuscript has something significant to present that will be of interest to the readers of their journal. These journals move more quickly, particularly since editors are scientists working pro bono who do not have the patience to entertain any particular manuscript for longer than necessary. The process in the best of cases already takes 5 months from submission to acceptance, allowing a month for assignment of reviewers, reviews to be completed and an editorial decision made, followed by a 3 month period to respond to the reviews if invited, and another month for the second review and final decision. With the high IF magazines there can be myriad layers of review, from 3-4 weeks of pre-review to determine if a paper is worthy of sending out for review, to 3-5 rounds of review followed in some cases by cross-reviews where reviewers check each other’s reviews. In the majority of cases, these full-time professional editors are incapable of making their own decisions. They will continually go back to reviewers unrealistically expecting 3 scientists with different expertise to agree that a paper is ready for publication in their journal. The high IF magazine editor’s letters to authors will be generic and vague, frequently placing all the responsibility on one or more reviewers, even though the decision is their responsibility alone. With the second tier IF journals for which scientists make the editorial decisions, there are typically two rounds of review (in some cases only one) and if reviewers are not in agreement, the scientific editor makes a call. It rarely pays to argue with a scientific editor who is not motivated by more than an obligation to serve the scientific community. Moreover, the scientific editor, despite their many other professional obligations, will typically write a decision letter that states precise reasons for their decision and if the authors are invited to re-submit a revised manuscript, the scientific editor will explain which specific aspects of the reviews the authors must address. The scientific editor knows that reviewers ask for experiments that are really just discussion points or follow up questions of interest to the reviewer, recognizes the salient points raised by reviewers, does not waste time trying to please everyone, and is not afraid to make a decision. Thus, for the artist, moving to a second tier journal is not a terrible compromise because scientific rigor will be upheld, the truth will be revealed, good science in good journals gets read, and, importantly, whether a professional magazine editor sees their work as exciting is truly irrelevant to its scientific merit. For the artist, if a magazine editor happens to appreciate their work, and if a set of reviewers make it easy for the magazine editor to be satisfied, then great, champagne will be had. But, if the process gets bogged down in indecision, the artist moves on because their vision of success is solving the next scientific problem, while the ladder climber keeps re-submitting because their vision of success prioritizes authorship in high IF magazines.

Well, I hope you have enjoyed this little piece of prose as much as I have enjoyed writing it. Over the years I have had many animated discussions over the meaning of success in science, usually measured in some way by grant dollars and publications. I have tried to cover those various arguments without advocating for one vision over another, but rather taking a strong stance against actions taken under the auspices of any of our three visions of success that impinge upon, deprive, or belittle the right of another to pursue their vision of success. Certainly I feel strongly that there is no single correct way to judge professional success in science. Unless, of course, it is the universal vision of success that supersedes all others, that true success in life must be measured in inner happiness, as a life of joy is without question, a life of success!

What Is CRISPR-Cas9 and What are its Potential Applications?

CRISPR-Cas9 is a powerful gene-editing technology that allows scientists to modify DNA with remarkable precision. The system is derived from a natural defense mechanism used by bacteria to protect themselves against viruses. Yes, bacteria also suffer from viral infections.

CRISPR (clustered regularly interspaced short palindromic repeats) refers to distinctive DNA sequences that bacteria use as a molecular “memory” of past viral infections. When a virus infects a bacterium, fragments of the virus’s DNA are stored in the bacterium’s CRISPR region. If the same virus attacks again, the bacterium can recognize it and destroy it.

Cas9 is the enzyme that does the cutting. Guided to a particular DNA sequence by a short RNA molecule (encoded by those DNA fragments stored in the CRISPR), Cas9 acts like molecular scissors, slicing DNA at a specific, predetermined sequence. Together, CRISPR and Cas9 form a programmable system that can identify and cut DNA with extraordinary accuracy.

This bacterial immune strategy is conceptually similar to our own adaptive immune system, which “remembers” past infections and mounts a rapid response when the same pathogen reappears. The difference is that our immune system uses proteins called antibodies to recognize protein structures unique to invaders, while Cas9 is using information encoded in DNA.

How Scientists Use CRISPR

Researchers have repurposed this natural system to edit genes in living cells. The process begins by designing a guide RNA (gRNA) that matches a specific DNA sequence of interest. The gRNA directs the Cas9 enzyme to that precise location in the genome, where Cas9 makes a cut in the DNA.

Once the DNA is cut, the cell’s own repair machinery takes over. Scientists can harness these repair pathways to disable a gene (loss of function), change its function (gain of function) or repair a faulty genetic code (restore function).

Prior to CRISPR-Cas9, making these changes was difficult, slow, or impossible.

Beyond CRISPR-Cas9

Cas9 is not the only CRISPR-associated enzyme. Other enzymes, such as Cas12 and Cas13, have been discovered and adapted for research and therapeutic use. This is important because CRISPR-Cas9 has restrictions on where it can cut, rendering some genes more difficult to edit than others. These other enzymes differ in the repertoire of sequences they are able to target or how they cut. Scientists are also modifying CRISPR enzymes in the laboratory to optimize or combine the functions of natural enzymes. These efforts are rapidly expanding the CRISPR toolbox beyond traditional DNA editing activities to make them better suited for certain applications.

More recent developments—including base editing and prime editing— go beyond CRISPR-Cas9, to make precise DNA edits without cutting both strands of DNA, reducing some risks associated with CRISPR-Cas9.

Medical Applications

CRISPR has opened new possibilities for treating genetic disease. In principle—and increasingly in practice—it can be used to correct the underlying mutations responsible for genetic disorders. CRISPR is also being explored in cancer therapy to disrupt genes that drive cancer growth or to engineer our own immune cells to better recognize and attack tumors.

Applications Beyond Medicine

While the hype, hope and fear surrounding CRISPRs impact on human health, human genetics and human nature has taken center stage, the more immediate and potentially equally impactful applications of CRISPR lie outside of human health. In agriculture, gene editing can produce crops that are more resilient to disease, pests, and environmental stress, or that offer improved nutritional value.

In biotechnology and environmental science, CRISPR enables rapid engineering of microbes for applications such as biofuel production, pharmaceutical manufacturing and environmental cleanup such as toxic waste and plastics.

These applications deserve more of the public’s attention. Perhaps this author will do them justice in a future article, but for now, this article focuses on medical applications.

Challenges and Ethical Considerations

Despite its enormous promise, the medical applications of CRISPR is not without risks. A major technical concern is off-target editing, where unintended DNA sequences are altered. Continued improvements in guide design and editing chemistry have reduced this risk, but careful validation remains essential.

CRISPR also raises profound ethical and societal questions. While somatic gene editing (editing non-reproductive cells to treat disease) is broadly supported, editing human embryos or reproductive cells raises serious concerns about safety, consent, and long-term consequences (see the case study below).

These ethical boundaries are now a central part of the global conversation surrounding gene-editing technologies.

Significant Real Applications of CRISPR to Human Disease

CRISPR has moved rapidly from a laboratory tool to real-world medical applications. Below are some of the most important—and carefully distinguished—examples.

1. Human Embryo Editing (2018 – What Not to Do)

In 2018, Chinese scientist He Jiankui announced the birth of twin girls whose embryos had been genetically edited using CRISPR to alter the CCR5 gene. The justification for this alteration was to change these children’s CCR5 genes to a form that renders humans resistant to HIV infection. Unfortunately, the edits that were made were not correct and disrupted the genes, producing unprecedented alterations, rather than changing the genes to a version that normally exists in HIV-resistant, healthy, humans.

An important distinction is that this experiment involved germline editing, meaning the changes were made when the embryo was a single cell and are thereby present in all cells in the body, including the germline (sperm and eggs), and could be inherited by future generations. The work was widely condemned as unethical and premature. He Jiankui was sentenced in China on Dec. 30, 2019, to three years in prison for illegal medical practices related to his embryo gene-editing experiment. The case remains a cautionary example of unethical human gene editing.

These two twins remain the only confirmed cases of genetically engineered humans (as opposed to the more common situation of humans that have received genetically engineered cells). Because the edits were germline, any effects could persist lifelong and be passed on to future generations—underscoring why the experiment is widely viewed as unethical and scientifically irresponsible. The health status of the two CRISPR-edited children cannot be verified due to steps that China has taken to protect the family’s privacy. Thus, no credible public data exist on the long-term outcomes of this procedure.

2. Sickle Cell Disease: First Widely Approved CRISPR Therapies

CRISPR has achieved clear clinical success in treating sickle cell disease and related blood disorders. There is a good reason why sickle cell disease was the first disease to tackle with a new gene therapy tool. Blood disorders are more amenable to gene therapy approaches because they do not require the technology to be delivered to the many cells that make up a body tissue. Rather, the blood-forming hematopoietic stem cells—the cells that give rise to all the cell types of the blood—are single cells that can be removed, manipulated and replaced relatively easily. This is called “ex vivo” gene therapy as it can be done outside of the body. Sickle cell disease, more specifically, is a good candidate for gene therapy because it is caused by a mistake in one single letter in the genetic code of one single gene. Genetic diseases that involve more than one gene present additional challenges for any gene editing technology.

In ex vivo therapies, doctors:

remove a patient’s own blood-forming stem cells,
edit them outside the body using CRISPR,
and transplant the corrected cells back into the patient.

The accuracy of CRISPR technology made this therapy possible, and it has now allowed many patients—mostly teens and young adults—to become free of severe pain crises and repeated blood transfusions. These therapies were approved by the U.S. Food and Drug Administration in late 2023 and represent the first large-scale, durable medical success of CRISPR in humans.

3. Personalized In-Vivo Editing in an Infant (2025 – CPS1 Deficiency)

In 2025, physicians reported a landmark case involving an infant born with CPS1 deficiency, a rare and often fatal metabolic disorder.

Similar to sickle cell therapies, this treatment did not involve embryo editing and did not affect the germline, so will not affect future generations. However, CPS1 affects the liver, so, unlike blood disorders, the CRISPR editing machinery must be delivered to the tissue in the human body, or “in vivo”.

To do this, doctors used a custom base-editing therapy delivered intravenously, designed to reach the liver and correct the disease-causing mutation in liver cells inside the patient’s body. This represented the first successful use of in-vivo CRISPR editing tailored to a single patient’s genetic disease. This example sets the stage for treatments of virtually any genetic disease caused by relatively simple mistakes (“mutations”) in the genetic code at one single gene.

Some media outlets inaccurately (and irresponsibly in this author’s opinion) described this as the “first genetically engineered baby.” In reality, it was a form of somatic gene therapy, conceptually closer to conventional gene therapies used to treat diseases for decades. The baby was not genetically engineered, rather, a fraction of the baby’s liver cells were genetically engineered. This distinction is extremely important, as is evidenced by the grave consequences of actually editing a human embryo and bringing that embryo to full term, as described above.

4. Other Emerging Health-Related CRISPR Applications

Additional CRISPR-based therapies are currently in clinical trials for:

inherited blindness,
certain liver disorders,
muscular dystrophies,
and immune system diseases.

While most of these treatments remain experimental, they demonstrate that CRISPR is transitioning from a research breakthrough to a therapeutic platform.

A Key Distinction

CRISPR today is primarily being used to treat disease, not to design humans.
Somatic gene editing aims to help patients without altering future generations. Germline editing, by contrast, remains ethically unresolved and largely shunned.

Importantly, engineering embryos to design humans is detectable by comparing a child’s DNA to that of the parents. Thus, concrete legal actions against it could be made enforceable. Indeed, more than 35 countries have enacted laws banning human reproductive cloning. The United States is not one of those countries, although 13 U.S. states have such laws.

Understanding this distinction is essential for separating real medical progress from speculative or misleading narratives. Responsible science reporting is key to helping the public navigate these issues.