Charlotte Hu | Vox

What if colon cancer screening didn’t involve poop?

2024-07-29T10:02:41-04:00

A microscopic image of colorectal carcinoma.

The current methods for colon cancer screening have an unavoidable “ick” factor: Either get a long scope inserted up your rectum, or collect a sample of your own poop, pack it up, and ship it off to a lab.

But with colon cancer rates rising, especially in adults under 50, spotting irregularities before they become dangerous is more urgent than ever. Enter a third, more palatable option: a blood test designed to screen for cancer, known in clinical terms as a liquid biopsy.

In March, biotech firm Guardant Health reported in the New England Journal of Medicine (NEJM) that its Shield blood test successfully detected cancer in 83 percent of patients whose colon cancer had already been confirmed by a colonoscopy, which is the gold standard for colon cancer screening. After submitting its data to the US Food and Drug Administration earlier this year, the company received approval in late July for the new test.

Freenome, another company developing colon cancer blood tests, announced the preliminary results from their own clinical trial in early April, revealing that their test identified cancer in 79 percent of confirmed cases.

The results come with qualifications, however. An American Gastroenterological Association expert panel published studies in the journals Gastroenterology and Clinical Gastroenterology and Hepatology in March concluding that the new tests are not as sensitive as existing screening techniques, like colonoscopies and specialized stool tests, especially in detecting precancerous lesions. (Sensitivity refers to a test’s ability to correctly detect positive cases of an illness.)

Colonoscopies detect cancers and precancer lesions at the highest sensitivity level, but they also cost the most. While other stool tests are comparatively less sensitive than colonoscopies, they perform similarly to Guardant and Freenome’s blood tests and are also much cheaper.

For now, the current blood tests are less cost-effective than colonoscopies and fecal tests because they aren’t accurate enough at the early stages of disease, which is when detection is more valuable for treatment. A study published last year in JAMA, which measured the cost of different treatment against the years of life gained by patients who use them, reached similar conclusions: These blood tests need to either be cheaper or more accurate if it’s to replace the traditional screening process.

“The biggest difference is that these blood tests aren’t very good at finding precancerous lesions,” said Zainab Aziz, a medical student at Columbia University and the first author on the JAMA paper. “That’s how screening really helps with cancer incidence.”

Without better sensitivity, two of the blood tests furthest along in development lack a strong clinical and cost advantage over the screening methods already available.

“If you substituted a blood test for one of the currently recommended tests, the outcomes would be worse than they are today,” said David Lieberman, a professor of medicine at Oregon Health and Science University and an author on the Gastroenterology paper. There would be more cancers and more deaths than if the patients were electing to have one of the recommended tests.

Still, the blood tests have achieved a new level of accuracy in the recent trials, outperforming their predecessors and clearing the standard set by the federal government for Medicare coverage. Now Guardant’s test has the FDA’s signoff. They hold the potential to make cancer screening much easier for patients.

“A blood test is very attractive for many reasons … A lot of people really don’t like stool tests. They’re messy,” said Chin Hur, a physician specializing in gastroenterology at Columbia University Irving Medical Center, and the senior author on the JAMA paper. “And a colonoscopy is a big deal — it feels like surgery.”

Effective blood tests could significantly expand the number of patients who get screened amid a worrying uptick in cases, but experts stress that they need to be cheaper and more accurate to make a significant difference in improving the outlook for colon cancer patients.

What are liquid biopsies?

To patients, liquid biopsies look no different from a normal blood test they would get at a doctor’s office to check out cholesterol, vitamin levels, or the makeup of their blood. In their case, liquid biopsies look for specific biological molecules that are left behind by cancer cells or that can otherwise indicate their presence in the body.

In a liquid biopsy, a patient’s blood sample is sent to a lab, where it is analyzed for biomarkers such as proteins, DNA, RNA, and other molecules that can be measured and correlated with possible disease. (Similar tests are being developed for urine and saliva.) Different biomarkers can be mixed and matched to create a signature for a specific cancer.

Screening, though, is a new use of this technology — Guardant and other companies like it started out by using these blood tests not as a way to initially detect and diagnose new cancers, but to track genetic changes in a known tumor in order to match them to targeted cancer treatments, a function known as companion diagnostics.

Guardant’s first liquid biopsy, Guardant 360 CDx, received FDA approval in 2020 as a companion diagnostic for several cancer therapies with specific targets. The test uses a patient’s blood sample to detect mutations in any of the 55 common tumor genes that would make the person a good candidate for particular medications.

For example, patients with advanced or metastatic lung cancer who test positive for the EGFR exon 20 insertion mutation would be eligible for a specialized therapy called amivantamab. Specialization can make a difference in treatment success: In a 2016 review article in Annals of Translational Medicine, researchers found that cancer drugs used in tandem with a companion diagnostic had treatment response rates ranging from 41 percent to 80 percent. For cancer drugs used without a companion diagnostic, the range was 7 percent to 45 percent. (The response rate is the percent of patients who saw their tumor either shrink or disappear after treatment.)

Ultimately, Guardant wants to build blood-based diagnostic tests that can detect multiple cancers early in their development. The race is on for such a breakthrough: Academic researchers and other biotech companies like Grail are working on similar concepts.

Guardant’s new Shield test uses DNA shed by tumors, called circulating tumor DNA (ctDNA), to identify the presence of cancer. Since 1977, researchers have known that cancer patients have such cell-free DNA (which includes ctDNA) in their blood, but at the time, genetic sequencing tools were far too slow and too expensive to be used in patients, and were mostly reserved for preclinical research. By the 2000s, sequencing technology had become advanced enough to prove that these pieces of DNA had the same characteristic mutations as the tumor they originated from. Early-generation blood tests could use those biomarkers to assist doctors in selecting treatments, estimating a patient’s prognosis, and identifying residual disease or risk of relapse.

One of the limitations of the early tests, however, was that ctDNA levels tend to be low in early-stage cancers, and its concentration can be highly variable. That limited their value compared to other screening techniques; even if some of the latter tools are more laborious and expensive up front, they have a greater payoff because they can catch the cancer at an early point when it can be more effectively treated.

The US Preventive Services Task Force, an independent, volunteer panel of national experts in prevention and evidence-based medicine, recommends that healthy adults between 45 and 75 elect one of seven screening methods at regular intervals to reduce the risk of colorectal cancer. The Task Force lists out the pros and cons of each test, but ultimately leaves it up to the physician and patient to discuss which test is best for them.

The fecal immunochemical (FIT) test, a stool test for detecting human hemoglobin, costs about $24 with insurance and is recommended annually for all healthy adults between the ages of 45 and 75. Hemoglobin is a protein found in blood, and blood in stool may be a sign of colorectal cancer since “blood vessels in larger colorectal polyps or cancers are often fragile and easily damaged by the passage of stool,” according to the American Cancer Society.

Guardant recommends its new Shield tests for healthy adults between age 45 and 75 every three years, with an expected price tag of $895 per test, according to the Associated Press. That makes it more expensive than Cologuard, a stool-based DNA detection test for colon cancer that is recommended every 1 to 3 years with an out-of-pocket price range between $500 and $600. On the high end of the spectrum is a colonoscopy, which is recommended every 10 years starting at age 45 and has an average cost of around $2,750. The US Preventive Services Task Force also recommends that abnormal results from the more noninvasive tests should be followed up with a colonoscopy.

“When you look at cost-effectiveness, all of those tests are cost-effective when analyzed with their ability to reduce colon cancer mortality incidence,” Lieberman said. But because blood tests are currently less sensitive than the alternatives, they’re still too expensive to be as cost-effective on a dollar-by-dollar basis. “For a blood test to be equally cost-effective, our modeling suggests that it would probably have to be less than $100. That’s going to be a heavy lift because the development process for these tests was very expensive.”

There is also the risk of false positive tests driving unnecessary use of health care services. It could also cost patients extra medical bills associated with follow-up appointments that turn out to be unnecessary, not to mention the psychological distress that comes with thinking you have cancer. If a large number of patients who don’t actually have cancer receive a false positive test, “those patients are going to go on and get colonoscopies and that drives up the cost and potentially the risk of the program,” Lieberman noted. In their NEJM study, Guardant’s Shield test had a false positive rate of around 10 percent. FIT, by contrast, has a false positive rate of around 5 percent.

Although follow-up colonoscopies when done correctly can be lifesaving when cancer is present, studies have found that unnecessary colonoscopies can expose patients to high out-of-pocket costs from anesthesia and other related services as well as potential clinical harms like bleeding and GI tract perforation. UnitedHealthcare, one of the nation’s largest insurers, recently restricted its coverage of colonoscopies in response to what they say is overutilization of these procedures. The company then modified the policy after protests from patients and physician organizations, instead asking patients and physicians to provide “advanced notification” if, for example, they were scheduling a follow-up colonoscopy after receiving a positive result from a non-invasive stool or blood test.

How screening tests measure up

Colonoscopies remain the primary form of colon cancer screening in the US. They are effective because they function both as a diagnostic and as an early form of treatment. The scope’s camera can clearly see polyps, or an out-of-place protrusion of cells, which can then be snipped off. Most polyps are harmless. But a type of polyp called an adenoma can potentially turn into cancer. Regular colonoscopies decrease colon cancer deaths between 29 to 68 percent, according to various studies.

In many countries including the US, UK, Australia, and India, there are preventive, government-overseen population-based cancer screening programs that look for early signs of common age- or gender-related diseases to improve health outcomes and decrease disease burden on the community. Most countries with such programs for colorectal cancer utilize stool tests performed yearly or every other year. Such tests look for DNA, blood, or proteins that can indicate the presence of a tumor. If a test comes back positive, the patient is supposed to follow up with a colonoscopy.

The FDA reviews new laboratory-developed tests and approves them if they’re safe and effective. The Centers for Medicare and Medicaid Services has a parallel but separate process for coverage of these tests, evaluating not only their quality and safety but also whether they are clinically necessary and cost-effective.

CMS has set a minimal sensitivity criteria for approving a new cancer blood test. Although Epi proColon was the first FDA-approved blood-based screening test for colon cancer, CMS declined to cover it. The test performed inconsistently during clinical trials, with an average sensitivity of 69 percent. (In medical tests, sensitivity is a test’s ability to accurately detect a positive case, while specificity is the ability to accurately detect a negative case.) In a decision memo in 2021, CMS stated that a blood test needs to surpass a sensitivity of 74 percent in order for it to be covered, using the current fecal and stool tests as benchmarks. It also needs a specificity of 90 percent.

From the NEJM data, Guardant’s Shield blood test had an 87.5 percent sensitivity for stage 1, 2, or 3 colorectal cancer, which passes the CMS threshold. But it has only a 13.2 percent sensitivity for advanced precancerous lesions. The fecal immunochemical test can detect these advanced precancerous adenomas with a sensitivity rate of around 20 to 30 percent. Cologuard, which combines FIT with stool DNA detection, has a 42 percent sensitivity for adenomas. Colonoscopies can detect adenomas larger than 6 millimeters with a 75 to 93 percent sensitivity. (Small polyps or outgrowths are usually harmless, and 6 millimeters is the standard lower limit for identifying advanced adenomas that are likely to grow into cancer.)

Detecting and cutting off such advanced adenomas is key to preventing colorectal cancer from developing. “If you can only detect cancer and you can’t detect pre-cancer, then it’s not going to be as effective,” Hur said.

Colon cancer forms on the interior surface, or lumen, of the colon “tube,” Hur explained. “As the stool is created, it sloughs off cancer cells or blood. If you’re trying to look for some type of cancer cell, circulating tumor cells, or DNA from a cell, stool is much better [than blood]. In order for it to be picked up by blood, it has to go into the bloodstream. Early cancer hasn’t invaded through the wall of the colon.”

Early detection matters because the more time a cancerous cluster of cells has to grow and spread, the harder it is to treat and cure. The five-year survival rates for colorectal cancer plummet drastically as it progresses past stage 3, falling from roughly 70 percent in stage 3 to 12 percent in stage 4. According to the American Cancer Society, stage 3 is when the colon cancer has spread to nearby lymph nodes, but not to other parts of the body. Stage 4 is when it is metastatic, and has spread to other tissues and organs in the body.

According to Lieberman, CMS didn’t set any minimum sensitivity rate at which new blood tests need to find advanced precancerous adenomas in order to approve them for coverage. In an email statement to Vox, a CMS spokesperson said that while they acknowledge the utility and potential clinical benefit of screening for advanced adenomas, there is limited available evidence on the accuracy of blood-based tests to detect advanced adenomas. The agency noted the sensitivity of fecal tests for advanced adenoma is also fairly low. For now, to maximize early pre-cancer detection, colonoscopies remain the best option for patients.

Can blood tests get better for early cancer detection?

Experts believe that blood tests will become more accurate as science advances. But how much they can be improved will dictate their long-term value to medicine.

Some of that depends on the kind of cancer doctors are looking to find. Unsurprisingly, for liquid tumors that affect the blood, bone marrow, or lymphatic system, an early-detection liquid biopsy “totally makes sense,” Hur said. “The tumor is in the bloodstream.” But it’s unclear whether or not a liquid biopsy will ever be sensitively attuned enough that it will be able to consistently detect an adenoma inside a person’s colon.

There could be a scenario where scientists can identify a more specific immune response to a growing polyp that can be targeted with a blood test. But that carries a risk of more false positives, since a wide range of conditions, including something as innocuous as a cold, could trigger a similar immune response. Inflammation is our immune system’s response to trauma or the presence of a pathogen such as a virus, bacteria, or toxin. Scientists have known since the 19th century that cancer can cause an inflammatory response that sends specialized immune cells into disarray. Elevated white blood cells are a telltale sign of all kinds of infection, but they can also be a sign of leukemia.

Despite the hype, experts caution that additional research is needed to improve liquid biopsies. If scientists can learn more about the biology and genomics of tumors, they could identify more specific biomarkers or a combination of biomarkers that could make these tests more accurate and therefore more valuable.

Lieberman acknowledged that scientists are becoming more sophisticated in how they analyze the genomes of cancer cells, which means they could identify more genes that are present in patients at higher risk of colon cancer, and that can be detected before the cancer starts to develop.

“This is still a ripe new area for development,” he said. “I think this first [Guardant] study is exciting in the sense that we can detect cell-free DNA in patients with colon cancer at an early enough stage that it can make a difference for those individuals.”

Blood will tell?

In the long run, blood might not always be the most revealing substance circulating through the human body when it comes to finding early markers of disease. The accuracy of blood tests will likely vary based on the type of cancer and the organs in which they’re located. For cancers in which blood tests are less effective, the goal is still to develop less invasive diagnostics, but the mechanism might be different.

Urine is also being investigated for its potential to detect circulating tumor DNA in urological and non-urological cancers. It has already shown promising sensitivity rates for non-small cell lung cancer and breast cancer in clinical trials. In an April study in JAMA, a urine test that scans for 18 genes showed a 95 percent sensitivity in patients with more aggressive prostate cancer. In January, a urine-based test using bioengineered bacteria was able to detect colorectal adenomas in mice.

Despite the limited utility of the current tests, the pursuit of better liquid biopsies is unlikely to slow down because they continue to hold enormous theoretical potential. For cancers with no established screening tests at all — like pancreatic cancer, which has an average five-year survival rate of 13 percent — a viable blood test with clinically significant sensitivity for early signs of disease would be a game-changer.

Earlier in April, a new study presented at the American Association for Cancer Research’s annual meeting found that an exosome-based blood test combined with another protein as an added biomarker identified stage 1 and stage 2 pancreatic cancer with 97 percent accuracy. Cells use tiny vesicles called exosomes to communicate with one another, and they’re commonly shed by both cancer cells and healthy cells. Researchers developed a signature associated with pancreatic cancer based on eight microRNAs “uniquely found in exosomes shed from pancreatic cancer” and five cell-free DNA markers found in the blood of patients with pancreatic cancer, according to AACR.

An advantage of these noninvasive blood and stool tests is that they’re a relatively cheap way to get a lot of people screened. However, much of the value of these tests is lost if patients who receive an abnormal result don’t follow up with a colonoscopy to confirm whether or not they have cancer.

“The Achilles’ heel of noninvasive testing is that many patients don’t follow up and get the colonoscopy after they get a positive stool test,” Lieberman said.

A 2023 study in JAMA found that only 56 percent of patients followed up with a colonoscopy after receiving a positive stool-based test. “We don’t really know yet what it will be like with a positive blood test,” he said.

Even with the limitations, there are upsides to having a blood test as another screening option. Prepping the bowels in the lead-up to a colonoscopy is unpleasant and inconvenient, requiring a special preparation for days before the procedure. And too often, people avoid them altogether — the US adherence rate for colorectal cancer screening guidelines is around 65 percent. With the recommended age for colorectal cancer screening recently dropping from 50 to 45, there may be more demand for a less invasive test.

Fast and easy blood tests, along with proper education on the importance of screening for colorectal cancer, could also be beneficial in regard to achieving health equity. Colon cancer deaths, estimated by the American Cancer Society to reach 53,010 in 2024, are highest in Black patients, and screening rates are lower compared to white patients.

“There’s an expression in colon cancer screening: The best colon cancer screening test is the one that gets done,” Hur said. “There’s potential to do good. … People want this … They don’t want to do the scope test. But people just need to know what they’re getting.”

Update, July 29, 10:00 am ET: This story was originally published on June 4 and has been updated to include the recent FDA approval of Guardant Health’s Shield blood test.

The one huge obstacle standing in the way of progress on gene-editing medicine

2024-05-09T11:52:03-04:00

There’s a significant impediment to maximizing CRISPR’s potential for developing novel therapies: the lack of diversity in genetics research. | Paige Vickers/Vox; Getty Images

Medicine has entered a new era in which scientists have the tools to change human genetics directly, creating the potential to treat or even permanently cure diseases by editing a few strands of troublesome DNA. And CRISPR, the gene-editing technology whose creators won the Nobel Prize for Chemistry in 2020, is the face of this new normal.

CRISPR’s novel harnessing of bacterial proteins to target disease-carrying genes has reshaped medical research over the past decade. While gene-editing itself has been around for more than 30 years, scientists can use CRISPR to edit genomes faster, cheaper, and more precisely than they could with previous gene-editing methods.

As a result, investigators have gained far more control over where a gene gets inserted and when it gets turned on. That in turn has opened the door to a new class of better gene therapies — treatments that modify or replace people’s genes to stop a disease.

Last December, the US Food and Drug Administration approved the first-ever CRISPR-based therapy, designed to treat sickle cell disease. In February, the treatment, called Casgevy, gained approval from the European Commission as well. It joins the dozen or so pre-CRISPR gene therapies that are already available to patients. In early May, the first patients began to receive treatment

But there’s a significant impediment to maximizing CRISPR’s potential for developing novel therapies: the lack of diversity in genetics research.

For decades, gene therapy has been defined by both its enormous therapeutic potential, and by the limitations imposed by our imprecise knowledge of human genetics. Even as gene-editing methods, including CRISPR, have become more sophisticated over the years, the data in the genetic databases and biobanks that scientists use to find and develop new treatments are still riddled with biases that could exclude communities of color from enjoying the full benefits of innovations like CRISPR. Unless that gap is closed, CRISPR’s promise won’t be fully fulfilled.

Gaps in research

Developing effective gene therapies depends on growing our knowledge of the human genome. Data on genes and their correlation with disease have already changed the way cancer researchers think about how to design drugs, and which patients to match with which drug.

Scientists have long known that certain genetic mutations that disrupt regular cell functions can cause cancer to develop, and they have tailored drugs to neutralize those mutations. Genetic sequencing technology has sped that progress, allowing researchers to analyze the genetics of tumor samples from cancer patients after they’ve participated in clinical trials to understand why some individuals respond better than others to a drug.

In a clinical trial of the colorectal cancer drug cetuximab, investigators found retrospectively that tumors with a mutation in the KRAS gene (which helps govern cell growth) did not respond to treatment. As a result, clinicians are now asked to confirm that patients do not have the mutation in the KRAS gene before they prescribe that particular drug. New drugs have been developed to target those mutations in the KRAS gene.

It’s a step-by-step process from the discovery of these disease-related genes to the crafting of drugs that neutralize them. With CRISPR now available to them, many researchers believe that they can speed this process up.

The technology is based on — and named after — a unique feature in the bacterial immune system that the organism uses to defend itself against viruses. CRISPR is found naturally in bacteria: It’s short for Clustered Regularly Interspaced Short Palindromic Repeats, and it functions like a mugshot database for bacteria, containing snippets of genetic code from foreign viruses that have tried to invade in the past.

When new infections occur, the bacteria deploys RNA segments that scan for viral DNA that matches the mugshots. Special proteins are then dispatched to chop the virus up and neutralize it.

To develop CRISPR into a biotech platform, this protein-RNA complex was adapted from bacteria and inserted into human and animal cells, where it proved similarly effective at searching for and snipping strands of DNA.

Using CRISPR in humans requires a few adjustments. Scientists have to teach the system to search through human DNA, which means that it will need a different “mugshot database” than what the bacteria originally needed. Critical to harnessing this natural process is artificial RNA, known as a guide RNA. These guide RNAs are designed to match genes found in humans. In theory, these guide RNAs search for and find a specific DNA sequence associated with a specific disease. The special protein attached to the guide RNA then acts like molecular scissors to cut the problematic gene.

CRISPR’s therapeutic potential was evident in the breakthrough sickle cell treatment approved by the FDA late last year. What made sickle cell such an attractive target is not just that it affects around 20 million people or more worldwide, but that it is caused by a mutation in a single gene, which makes it simpler to study than a disease caused by multiple mutations. Sickle cell is one of the most common disorders worldwide that is caused by a mutation in a single gene. It was also the first to be characterized at a genetic level, making it a promising candidate for gene therapy.

In sickle cell disease, a genetic mutation distorts the shape of a person’s hemoglobin, which is the protein that helps red blood cells carry and deliver oxygen from the lungs to tissues throughout the body. For people with sickle cell disease, their red blood cells look like “sickles” instead of the normal discs. As a result, they can get caught in blood vessels, blocking blood flow and causing issues like pain, strokes, infections, and death.

Since the 1990s, clinicians have observed that sickle cell patients with higher levels of fetal hemoglobin tend to live longer. A series of genome-wide association studies from 2008 pointed to the BCL11A gene as a possible target for therapeutics. These association studies establish the relationships between specific genes and diseases, identifying candidates for CRISPR gene editing.

Casgevy’s new CRISPR-derived treatment targets a gene called BCL11A. Inactivating this gene stops the mutated form of hemoglobin from being made and increases the production of normal non-sickled fetal hemoglobin, which people usually stop making after birth.

Out of the 45 patients who have received Casgevy since the start of the trials, 28 of the 29 eligible patients who have stayed on long enough to have their results analyzed reported that they have been free of severe pain crises. Once the treatment moves out of clinical settings, its exact effects can vary. And if the underlying data set doesn’t reflect the diversity of the patient population, the gene therapies derived from them might not work the same for every person.

The nuances of genetics

Sickle cell disease as the first benefactor of CRISPR therapy makes sense because it’s a relatively simple disorder that has been studied for a long time. The genetic mutation causing it was found in 1956. But ironically, the same population that could benefit most from Casgvey may miss out on the full benefits of future breakthrough treatments.

Scientists developing CRISPR treatments depend on what’s known as a reference genome, which is meant to be a composite representation of a “normal” human genome that can be used to identify genes of interest to target for treating a disease.

However, most of the available reference genomes are representative of white Europeans. That’s a problem because not everybody’s DNA is identical: Recent sequencing of African genomes shows that they have 10 percent more DNA than the standard reference genome available to researchers. Researchers have theorized that this is because most modern humans came out of Africa. As populations diverged and reconcentrated, genetic bottlenecks happened, which resulted in a loss of genetic variation compared to the original population.

Most genome-wide association studies are also biased in the same way: They have a lot of data from white people and not a lot from people of color.

So while those studies can help identify genes of importance that could lead to effective treatments for the population whose genes make up the majority of the reference data — i.e., white people — the same treatments may not work as well for other nonwhite populations.

“Broadly, there’s been an issue with human genetics research — there’s been a major under-representation of people of African ancestry, both in the US and elsewhere,” said Sarah Tishkoff, professor of genetics and biology at the University of Pennsylvania. “Without including these diverse populations, we’re missing out on that knowledge that could perhaps result in better therapeutics or better diagnostics.”

Even in the case of the notorious breast cancer gene BRCA1, where a single gene mutation can have a serious clinical impact and is associated with an increased risk of developing cancer, underlying mutations within the gene “tend to differ in people of different ancestries,” Tishkoff said.

These differences, whether large or small, can matter. Although the vast majority of human genomes are the same, a small fraction of the letters making up our genes can differ from person to person and from population to population, with potentially significant medical implications. Sometimes during sequencing, genetic variations of “unknown significance” appear. These variants could be clinically important, but because of the lack of diversity in previous research populations, no one has studied them closely enough to understand their impact.

“If all the research is being done in people of predominantly European ancestry, you’re only going to find those variants,” Tishkoff said.

Those limitations affect scientists up and down the developmental pipeline. For researchers using CRISPR technology in preclinical work, the lack of diversity in the genome databases can make it harder to identify the possible negative effect of such genetic variation on the treatments they’re developing.

Sean Misek, a postdoctoral researcher at the Broad Institute of MIT and Harvard, started developing a project with the goal of investigating the differences in the genetic patterns of tumors from patients of European descent compared to patients of African descent. CRISPR has become a versatile tool. Not only can it be used for treatments, but it can also be used for diagnostics and basic research. He and his colleagues intended to use CRISPR to screen for those differences because it can evaluate the effects of multiple genes at once, as opposed to the traditional method of testing one gene at a time.

“We know individuals of different ancestry groups have different overall clinical responses to cancer treatments,” Misek said. “Individuals of recent African descent, for example, have worse outcomes than individuals of European descent, which is a problem that we were interested in trying to understand more.”

What they encountered instead was a roadblock.

When Misek’s team tried to design CRISPR guides, they found that their guides matched the genomes in the cells of people with European and East Asian ancestry, whose samples made up most of the reference genome, but not on cells from people of South Asian or African ancestry, who are far less represented in databases. In combination with other data biases in cancer research, the guide RNA mismatch has made it more difficult to investigate the tumor biology of non-European patients.

Genetic variations across ancestry groups not only affect whether CRISPR technology works at all, but they can also lead to unforeseen side effects when the tool makes cuts in places outside of the intended genetic target. Such side effects of “off-target” gene edits could theoretically include cancer.

“A big part of developing CRISPR therapy is trying to figure out if there are off-targets. Where? And if they exist, do they matter?” said Daniel Bauer, an attending physician at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.

To better predict potential off-target edits, Bauer collaborated with Luca Pinello, associate professor at Massachusetts General Hospital and Harvard Medical School, who had helped develop a tool called CRISPRme that makes projections based on personal and population-level variations in genetics. To test it, they examined the guide RNA being used for sickle cell disease treatment, and found an off-target edit almost exclusively present in cells donated by a patient of African ancestry.

It is currently unclear if this off-target edit detected by the CRISPRme tool has any negative consequences. When the FDA approved the sickle-cell therapy in December 2023, regulators required a post-marketing study to look into off-target effects. Any off-target edits affecting a person’s blood should be easily detected in the blood cells, and drawing blood is easier to do than collecting cells from an internal organ, for example.

The genetic variant where the off-target effect occurred can be found in approximately every 1 in 10 people with African ancestry. “The fact that we actually were able to find a donor who carried this variant was kind of luck,” Bauer said. “If the cells we were using were only of European ancestry, it would’ve been even harder to find.”

“Most of these [off-target] effects probably won’t cause any problems,” he said. “But I think we also have these great technologies, so that’s part of our responsibility to look as carefully as we can.”

To CRISPR or not to CRISPR

These issues recur again and again as investigators hunt for novel treatments. Katalin Susztak, professor of medicine and genetics at the University of Pennsylvania, thinks one promising candidate for a future CRISPR therapy is a standout gene for kidney disease: APOL1.

Researchers identified the gene when they looked into kidney disease risk in African Americans. While genome-wide association studies turned up thousands of distinct genes increasing risk for people of European ancestry, in African Americans, this single gene was responsible for “3 to 5 times higher risk of kidney disease in patients,” said Susztak.

The APOL1 variant is common among African Americans because it protects people from developing African sleeping sickness, which is spread by the Tsetse fly present across much of the continent. This is similar to the story of the sickle cell mutation, which can protect people from malaria.

“The variant is maybe only 5,000 years old, so this variant has not arisen in Europe, Asia, or anywhere else. Just in West Africa,” Susztak said. “But because of the slave trades, West Africans were brought to the United States, so millions of people in the United States have this variant.”

The variant also predisposes people to develop cardiovascular disease, high blood pressure, and COVID-related disease, “which maybe explains why there was an increased incidence of deaths in African Americans during COVID than in Europeans,” Susztak said. “APOL1 is potentially a very interesting target [for CRISPR] because the disease association is strong.”

A CRISPR treatment for kidney disease is currently being investigated, but using the tool comes with complications. Cutting the APOL1 gene would set off an immune response, Susztak noted, so they will have to somehow prevent undesirable side effects, or find a related, but editable gene, like they did with sickle cell.

An alternative RNA-based strategy utilizing CRISPR is also in the works. DNA needs to be transcribed into a messenger RNA sequence first before it can be turned into proteins. Instead of permanently altering the genome, RNA editing alters the sequence of RNAs, which can then change what proteins are produced. The effects are less permanent, however, lasting for a few months instead of forever — which can be advantageous for treating temporary medical conditions.

And it may turn out that gene therapy is simply not the right approach to the problem. Sometimes, a more conventional approach still works best. Susztak said that a small molecule drug developed by Vertex — which works similarly to most drugs except special classes like gene therapies or biologics — to inhibit the function of the APOL1 protein has enjoyed positive results in early clinical trials.

An outlook on the future of CRISPR

Even with these limitations, more CRISPR treatments are coming down the pike.

As of early last year, more than 200 people have been treated with experimental CRISPR therapies for cancers, blood disorders, infections, and more. In the developmental pipeline is a CRISPR-based therapeutic from Intellia Therapeutics that treats transthyretin amyloidosis, a rare condition affecting the function of the heart tissues and nerves. The drug has performed well in early trials and is now recruiting participants for a Phase III study. Another CRISPR drug from Intellia for hereditary angioedema, a condition that causes severe swelling throughout the body, is slated to enter Phase III later this year.

As the CRISPR boom continues, some research groups are slowly improving the diversity of their genetic sources.

The All of Us program from the National Institutes of Health, which aims to find the biological, environmental, and lifestyle factors that contribute to health, has analyzed 245,000 genomes to date, over 40 percent of which came from participants who were not of European ancestry. They found new genetic markers for diabetes that have never been identified before.

Then there’s the Human Pangenome project, which aims to create a reference genome that captures more global diversity. The first draft of its proposal was released last May. Another project called the PAGE study, funded by the National Human Genome Research Institute and the National Institute on Minority Health and Health Disparities, is working to include more ancestrally diverse populations in genome-wide association studies.

But at the current pace, experts predict that it will take years to reach parity in our genetic databases. And the scientific community must also build trust with the communities it’s trying to help. The US has a murky history with medical ethics, especially around race. Take the Tuskegee experiment that charted the progression of syphilis in Black American men while hiding the true purpose of the study from the participants and withholding their ability to seek treatment when it became available, or the controversy over Henrietta Lacks’ cervical cells, which were taken and used in research without her consent. Those are just two prominent historical abuses that have eroded trust between minority communities and the country’s medical system, Tishkoff said. That history has made it more difficult to collect samples from marginalized communities and add them to these critical data sets.

Where the research is being done, where the clinical trials are being held, as well as who’s doing the research, can all have an impact on which patients participate. The Human Genetics & Genomics Workforce Survey Report published by the American Society of Human Genetics in 2022 found that 67 percent of the genomic workforce identified as white. Add in the financial burden of developing new treatments when using a reference genome, or a pre-made biobank from past efforts to collect and organize a large volume of biological samples, saves time and costs. In the race to bring CRISPR treatments to market, those shortcuts offered valuable efficiency to drug makers.

What this means is that the “first-generation” of CRISPR therapeutics might therefore be blunter instruments than they might otherwise be. However, if improvements can be made to make sure the source genomes reflect a wider range of people, Pinello believes that later generations of CRISPR will be more personalized and therefore more effective for more people.

Finding the genes and making drugs that work is, of course, momentous — but ultimately, that’s only half the battle. The other worry physicians like Susztak have is whether patients will be able to afford and access these innovative treatments.

There is still an overwhelming racial disparity in clinical trial enrollment. Studies have found that people of color are more likely to suffer from chronic illness and underuse medications like insulin compared to their white counterparts. Gene therapies easily rack up price tags in the millions, and insurance companies, including the Centers for Medicare and Medicaid Services, are still trying to figure out how to pay for them.

“Because it’s the pharmaceutical industry, if they don’t turn around profit, if they cannot test the drug, or if people are unwilling to take it, then this inequity is going to be worsened,” said Susztak. “We are essentially going to be creating something that makes things worse even though we are trying to help.”