Genome Reading and Editing Tools for All
In 2006, the cover of Scientific American was "Know Your DNA" and the inside story was "Genomes for All." Today, we are closer to that goal than ever. Making it affordable for everyone to understand and change their DNA will fundamentally alter how we manage diseases, how we conduct clinical research, and even how we select a mate.
A frequent line of questions on the topic of making genome reading affordable is: Do we need to read the whole genome in order to accurately predict disease risk?
Since 2006, we have driven the cost of reading a human genome down from $3 billion to $600. To aid interpretation and research to produce new diagnostics and therapeutics, my research team at Harvard initiated the Personal Genome Project and later, Openhumans.org. This has demonstrated international informed consent for human genomes, and diverse environmental and trait data can be distributed freely. This is done with no strings attached in a manner analogous to Wikipedia. Cell lines from that project are similarly freely available for experiments on synthetic biology, gene therapy and human developmental biology. DNA from those cells have been chosen by the US National Institute of Standards and Technology and the Food and Drug Administration to be the key federal standards for the human genome.
A frequent line of questions on the topic of making genome reading affordable is: Do we need to read the whole genome in order to accurately predict disease risk? Can we just do most commonly varying parts of the genome, which constitute only a tiny fraction of a percent? Or just the most important parts encoding the proteins or 'exome,' which constitute about one percent of the genome? The commonly varying parts of the genome are poor predictors of serious genetic diseases and the exomes don't detect DNA rearrangements which often wipe out gene function when they occur in non-coding regions within genes. Since the cost of the exome is not one percent of the whole genome cost, but nearly identical ($600), missing an impactful category of mutants is really not worth it. So the answer is yes, we should read the whole genome to glean comprehensively meaningful information.
In parallel to the reading revolution, we have dropped the price of DNA synthesis by a similar million-fold and made genome editing tools close to free.
WRITING
In parallel to the reading revolution, we have dropped the price of DNA synthesis by a similar million-fold and made genome editing tools like CRISPR, TALE and MAGE close to free by distributing them through the non-profit Addgene.org. Gene therapies are already curing blindness in children and cancer in adults, and hopefully soon infectious diseases and hemoglobin diseases like sickle cell anemia. Nevertheless, gene therapies are (so far) the most expensive class of drugs in history (about $1 million dollars per dose).
This is in large part because the costs of proving safety and efficacy in a randomized clinical trial are high and that cost is spread out only over the people that benefit (aka the denominator). Striking growth is evident in such expensive hyper-personalized therapies ever since the "Orphan Drug Act of 1983." For the most common disease, aging (which kills 90 percent of people in wealthy regions of the world), the denominator is maximal and the cost of the drugs should be low as genetic interventions to combat aging become available in the next ten years. But what can we do about rarer diseases with cheap access to genome reading and editing tools? Try to prevent them in the first place.
A huge fraction of these births is preventable if unaffected carriers of such diseases do not mate.
ARITHMETIC
While the cost of reading has plummeted, the value of knowing your genome is higher than ever. About 5 percent of births result in extreme medical trauma over a person's lifetime due to rare genetic diseases. Even without gene therapy, these cost the family and society more than a million dollars in drugs, diagnostics and instruments, extra general care, loss of income for the affected individual and other family members, plus pain and anxiety of the "medical odyssey" often via dozens of mystified physicians. A huge fraction of these births is preventable if unaffected carriers of such diseases do not mate.
The non-profit genetic screening organization, Dor Yeshorim (established in 1983), has shown that this is feasible by testing for Tay–Sachs disease, Familial dysautonomia, Cystic fibrosis, Canavan disease, Glycogen storage disease (type 1), Fanconi anemia (type C), Bloom syndrome, Niemann–Pick disease, Mucolipidosis type IV. This is often done at the pre-marital, matchmaking phase, which can reduce the frequency of natural or induced abortions. Such matchmaking can be done in such a way that no one knows the carrier status of any individual in the system. In addition to those nine tests, many additional diseases can be picked up by whole genome sequencing. No person can know in advance that they are exempt from these risks.
Furthermore, concerns about rare "false positives" is far less at the stage of matchmaking than at the stage of prenatal testing, since the latter could involve termination of a healthy fetus, while the former just means that you restrict your dating to 90 percent of the population. In order to scale this up from 13 million Ashkenazim and Sephardim to billions in diverse cultures, we will likely see new computer security, encryption, blockchain and matchmaking tools.
Once the diseases are eradicated from our population, the interventions can be said to impact not only the current population, but all subsequent generations.
THE FUTURE
As reading and writing become exponentially more affordable and reliable, we can tackle equitable distribution, but there remain issues of education and security. Society, broadly (insurers, health care providers, governments) should be able to see a roughly 12-fold return on their investment of $1800 per person ($600 each for raw data, interpretation and incentivizing the participant) by saving $1 million per diseased child per 20 families. Everyone will have free access to their genome information and software to guide their choices in precision medicines, mates and participation in biomedical research studies.
In terms of writing and editing, if delivery efficiency and accuracy keep improving, then pill or aerosol formulations of gene therapies -- even non-prescription, veterinary or home-made versions -- are not inconceivable. Preventions tends to be more affordable and more humane than cures. If gene therapies provide prevention of diseases of aging, cancer and cognitive decline, they might be considered "enhancement," but not necessarily more remarkable than past preventative strategies, like vaccines against HPV-cancer, smallpox and polio. Whether we're overcoming an internal genetic flaw or an external infectious disease, the purpose is the same: to minimize human suffering. Once the diseases are eradicated from our population, the interventions can be said to impact not only the current population, but all subsequent generations. This reminds us that we need to listen carefully, educate each other and proactively imagine and deflect likely, and even unlikely, unintended consequences, including stigmatization of the last few unprotected individuals.
If you look back on the last century of scientific achievements, you might notice that most of the scientists we celebrate are overwhelmingly white, while scientists of color take a backseat. Since the Nobel Prize was introduced in 1901, for example, no black scientists have landed this prestigious award.
The work of black women scientists has gone unrecognized in particular. Their work uncredited and often stolen, black women have nevertheless contributed to some of the most important advancements of the last 100 years, from the polio vaccine to GPS.
Here are five black women who have changed science forever.
Dr. May Edward Chinn
Dr. May Edward Chinn practicing medicine in Harlem
George B. Davis, PhD.
Chinn was born to poor parents in New York City just before the start of the 20th century. Although she showed great promise as a pianist, playing with the legendary musician Paul Robeson throughout the 1920s, she decided to study medicine instead. Chinn, like other black doctors of the time, were barred from studying or practicing in New York hospitals. So Chinn formed a private practice and made house calls, sometimes operating in patients’ living rooms, using an ironing board as a makeshift operating table.
Chinn worked among the city’s poor, and in doing this, started to notice her patients had late-stage cancers that often had gone undetected or untreated for years. To learn more about cancer and its prevention, Chinn begged information off white doctors who were willing to share with her, and even accompanied her patients to other clinic appointments in the city, claiming to be the family physician. Chinn took this information and integrated it into her own practice, creating guidelines for early cancer detection that were revolutionary at the time—for instance, checking patient health histories, checking family histories, performing routine pap smears, and screening patients for cancer even before they showed symptoms. For years, Chinn was the only black female doctor working in Harlem, and she continued to work closely with the poor and advocate for early cancer screenings until she retired at age 81.
Alice Ball
Pictorial Press Ltd/Alamy
Alice Ball was a chemist best known for her groundbreaking work on the development of the “Ball Method,” the first successful treatment for those suffering from leprosy during the early 20th century.
In 1916, while she was an undergraduate student at the University of Hawaii, Ball studied the effects of Chaulmoogra oil in treating leprosy. This oil was a well-established therapy in Asian countries, but it had such a foul taste and led to such unpleasant side effects that many patients refused to take it.
So Ball developed a method to isolate and extract the active compounds from Chaulmoogra oil to create an injectable medicine. This marked a significant breakthrough in leprosy treatment and became the standard of care for several decades afterward.
Unfortunately, Ball died before she could publish her results, and credit for this discovery was given to another scientist. One of her colleagues, however, was able to properly credit her in a publication in 1922.
Henrietta Lacks
onathan Newton/The Washington Post/Getty
The person who arguably contributed the most to scientific research in the last century, surprisingly, wasn’t even a scientist. Henrietta Lacks was a tobacco farmer and mother of five children who lived in Maryland during the 1940s. In 1951, Lacks visited Johns Hopkins Hospital where doctors found a cancerous tumor on her cervix. Before treating the tumor, the doctor who examined Lacks clipped two small samples of tissue from Lacks’ cervix without her knowledge or consent—something unthinkable today thanks to informed consent practices, but commonplace back then.
As Lacks underwent treatment for her cancer, her tissue samples made their way to the desk of George Otto Gey, a cancer researcher at Johns Hopkins. He noticed that unlike the other cell cultures that came into his lab, Lacks’ cells grew and multiplied instead of dying out. Lacks’ cells were “immortal,” meaning that because of a genetic defect, they were able to reproduce indefinitely as long as certain conditions were kept stable inside the lab.
Gey started shipping Lacks’ cells to other researchers across the globe, and scientists were thrilled to have an unlimited amount of sturdy human cells with which to experiment. Long after Lacks died of cervical cancer in 1951, her cells continued to multiply and scientists continued to use them to develop cancer treatments, to learn more about HIV/AIDS, to pioneer fertility treatments like in vitro fertilization, and to develop the polio vaccine. To this day, Lacks’ cells have saved an estimated 10 million lives, and her family is beginning to get the compensation and recognition that Henrietta deserved.
Dr. Gladys West
Andre West
Gladys West was a mathematician who helped invent something nearly everyone uses today. West started her career in the 1950s at the Naval Surface Warfare Center Dahlgren Division in Virginia, and took data from satellites to create a mathematical model of the Earth’s shape and gravitational field. This important work would lay the groundwork for the technology that would later become the Global Positioning System, or GPS. West’s work was not widely recognized until she was honored by the US Air Force in 2018.
Dr. Kizzmekia "Kizzy" Corbett
TIME Magazine
At just 35 years old, immunologist Kizzmekia “Kizzy” Corbett has already made history. A viral immunologist by training, Corbett studied coronaviruses at the National Institutes of Health (NIH) and researched possible vaccines for coronaviruses such as SARS (Severe Acute Respiratory Syndrome) and MERS (Middle East Respiratory Syndrome).
At the start of the COVID pandemic, Corbett and her team at the NIH partnered with pharmaceutical giant Moderna to develop an mRNA-based vaccine against the virus. Corbett’s previous work with mRNA and coronaviruses was vital in developing the vaccine, which became one of the first to be authorized for emergency use in the United States. The vaccine, along with others, is responsible for saving an estimated 14 million lives.On today’s episode of Making Sense of Science, I’m honored to be joined by Dr. Paul Song, a physician, oncologist, progressive activist and biotech chief medical officer. Through his company, NKGen Biotech, Dr. Song is leveraging the power of patients’ own immune systems by supercharging the body’s natural killer cells to make new treatments for Alzheimer’s and cancer.
Whereas other treatments for Alzheimer’s focus directly on reducing the build-up of proteins in the brain such as amyloid and tau in patients will mild cognitive impairment, NKGen is seeking to help patients that much of the rest of the medical community has written off as hopeless cases, those with late stage Alzheimer’s. And in small studies, NKGen has shown remarkable results, even improvement in the symptoms of people with these very progressed forms of Alzheimer’s, above and beyond slowing down the disease.
In the realm of cancer, Dr. Song is similarly setting his sights on another group of patients for whom treatment options are few and far between: people with solid tumors. Whereas some gradual progress has been made in treating blood cancers such as certain leukemias in past few decades, solid tumors have been even more of a challenge. But Dr. Song’s approach of using natural killer cells to treat solid tumors is promising. You may have heard of CAR-T, which uses genetic engineering to introduce cells into the body that have a particular function to help treat a disease. NKGen focuses on other means to enhance the 40 plus receptors of natural killer cells, making them more receptive and sensitive to picking out cancer cells.
Paul Y. Song, MD is currently CEO and Vice Chairman of NKGen Biotech. Dr. Song’s last clinical role was Asst. Professor at the Samuel Oschin Cancer Center at Cedars Sinai Medical Center.
Dr. Song served as the very first visiting fellow on healthcare policy in the California Department of Insurance in 2013. He is currently on the advisory board of the Pritzker School of Molecular Engineering at the University of Chicago and a board member of Mercy Corps, The Center for Health and Democracy, and Gideon’s Promise.
Dr. Song graduated with honors from the University of Chicago and received his MD from George Washington University. He completed his residency in radiation oncology at the University of Chicago where he served as Chief Resident and did a brachytherapy fellowship at the Institute Gustave Roussy in Villejuif, France. He was also awarded an ASTRO research fellowship in 1995 for his research in radiation inducible gene therapy.
With Dr. Song’s leadership, NKGen Biotech’s work on natural killer cells represents cutting-edge science leading to key findings and important pieces of the puzzle for treating two of humanity’s most intractable diseases.
Show links
- Paul Song LinkedIn
- NKGen Biotech on Twitter - @NKGenBiotech
- NKGen Website: https://nkgenbiotech.com/
- NKGen appoints Paul Song
- Patient Story: https://pix11.com/news/local-news/long-island/promising-new-treatment-for-advanced-alzheimers-patients/
- FDA Clearance: https://nkgenbiotech.com/nkgen-biotech-receives-ind-clearance-from-fda-for-snk02-allogeneic-natural-killer-cell-therapy-for-solid-tumors/Q3 earnings data: https://www.nasdaq.com/press-release/nkgen-biotech-inc.-reports-third-quarter-2023-financial-results-and-business