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Video transcript :

I studied genomes and I love the work I

do everyone in this room has a genome it's your DNA it's what makes you

tick it's what took you from a single fertilized egg into a human being it's a

blue print if you will some people call it a

recipe now you got your genome from your mom and

dad they got theirs from their mom and dad and so on back pretty much for all

of time on this planet my colleague Ed green has shown

that if you're of European or Asian descent you probably have some

that if you're of European or Asian descent you probably have some

percentage of neander DNA from a when Neanderthal mom or pop

way way back when some of us may be more than

others I had the incredible privilege of being

part of the effort to sequence the first human

genome the Human Genome Project it was an international

collaboration of research organizations medical centers and universities like

mine and late in the game at the 11th Hour a private company joined the race

salera so that set up a challenge the winner would hold the

humanity I joined the public project with my Merry band of computer geeks at

UC Santa Cruz so

that the human genome the first human genome would be

public a genome is three billion bases of A's C's T's and G's the chemical

letters of DNA it took sequencing machines all

around the world from 20 major sequencing centers months to churn out

the pieces of DNA from our first genome those pieces came out in random

order creating an amazing jigsaw puzzle of hundreds of thousands of pieces of

DNA and there was no computer program and certainly no human being

ready to solve that jigsaw puzzle enter a

remarkable graduate student from UC Santa Cruz Jim Kent

Jim stepped up at that moment and spent four months writing code so furiously he

had to ice his wrists he wrote tens of thousands of

lines of code to solve this first and fundamental jigsaw

puzzle meanwhile

speed back and forth between these medical

centers those a c's T's and G's I'm thinking about a child let's

call him Robin who at age six two years ago had a

cancer of the lining of his brain the doctors treated it with radiation

therapy and chemotherapy and it went away but now it's come

back working with the doctor we were able to try to match that genome to the

other genomes in our database now we don't have that many genomes really in

the larger scheme of things so it would be surprising to get a close match but

we did find that there were a group of genomes that actually were cancer

genomes from a different organ some of them from

adults but they were a better molecular match for this particular child's cancer

genome and in fact my colleague Josh Stewart is doing a study comprehensive

study he's actually leading it with a number of international collaborators to

look at how frequently this happens how frequently is it that cancer that comes

from one tissue actually at the moleculas.

genomes from a different organ some of them from

adults but they were a better molecular match for this particular child's cancer

genome and in fact my colleague Josh Stewart is doing a study comprehensive

study he's actually leading it with a number of international collaborators to

look at how frequently this happens how frequently is it that cancer that comes

from one tissue actually at the molecular level looks more like cancer

that comes from another tissue this has profound implications for treatment and

the answer is that it might happen one in five

cases so it's incredibly important now that we be able to compare cancers at

the molecular level now in Robin's case this suggested

a new therapy at a time when his doctor was totally out of

options and this weighs particularly heavy on me because just three days ago

I found out that Robin had had a response to this new therapy but only a

partial response so we don't know maybe

there's a little girl in Paris or a little boy in

Berlin who has a cancer genoma

we just became the first species to read its own genetic

recipe we're still understanding the implications of

that we went on to build a browser of information so that the world could

better understand the architecture of the human

genome thousands of research archers all around the world have contributed to

this UC see Santa Cruz genome browser now it gets a million page hits a

day it's been cited in more than 20,000 scientific

papers it really is the Nexus of a continuing radical collaboration to

understand the human genome everyone in the scientific world

who uses genomics or who wants to apply genomics

in medicine for example wants to use this

resource in fact things are so dramatically

different now that we are sequencing many

individual genomes the first human genome cost $300

million now you can sequence a human genome for just about a thousand

bucks my colleague Yan Ashley once remarked that if the automobile had

progressed industry had progressed at the same rate a Ferrari would cost about

40 cents today it's a very disruptive exciting

the

we're creating an open source platform that will allow DNA sequence to

be shared at light speed immediately from point to point on the internet so

that patients who have so little time can get the information they need

immediately you can help you can ask your medical center to

share data you can opt in

we really at this point need to do it imagine if under the umbrella of the

Global Alliance for genomics and health medical centers all over the world felt

comfortable enough to share their data imagine if this was happening for

all diseases from A to Z Alzheimer's asthma

autism we could get a new perspective on medicine we could get more precise

we could invent new therapies we could imply new

therapies so you can make a difference genome sharing is Humanity's next

radical collaboration thank

you turn around and look at

the

Article: The Future of Gene-Editing Treatments for Rare Diseases

be shared at light speed immediately from point to point on the internet so

that patients who have so little time can get the information they need

immediately you can help you can ask your medical center to

share data you can opt in

we really at this point need to do it imagine if under the umbrella of the

Global Alliance for genomics and health medical centers all over the world felt

comfortable enough to share their data imagine if this was happening for

all diseases from A to Z Alzheimer's asthma

autism we could get a new perspective on medicine we could get more precise

we could invent new therapies we could imply new

therapies so you can make a difference genome sharing is Humanity's next

radical collaboration thank

you turn around and look at

the another relevant article:The Future of Gene-Editing Treatments for Rare Diseases

Angelman syndrome is a rare genetic disorder caused by a mutation on chromosome 15, which hinders the production of a protein crucial for brain function. As a result, people living with Angelman syndrome experience severe developmental and intellectual disabilities.

For more than a decade, February 15 has been designated as International Angelman Syndrome Day, a significant date as February is Rare Disease Month, and the day symbolizes chromosome 15. Angelman syndrome affects approximately one in 15,000 individuals in the United Statesor about 500,000 globallyand like most rare diseases, there is currently no cure. Among the 10,000 known rare diseases, there are fewer than 900 FDA-approved treatments.

But researchers are hopeful that cures for Angelman syndrome and other rare diseases, such as the neurodevelopmental disorder known as H1-4 syndrome, are within reach. Yong-Hui Jiang, MD, PhD, professor and chief of medical genetics, and Jiangbing Zhou, PhD, Nixdorff-German Professor of Neurosurgery, are among researchers at Yale School of Medicine dedicated to the development of new gene-editing treatments that aim to correct genetic alterations underlying rare neurogenetic disorders. Jiang is also the director of the Yale National Organization for Rare Disorders (NORD) Center of Excellence.

We spoke to Jiang and Zhou about exciting new rare disease research and therapies on the horizon.

What drew you to rare disease research?

Jiang: As a clinical geneticist, working with rare diseases is part of my job. As a researcher, it was my choice to focus on rare diseases. The patients I see while working in the clinic motivate me to understand their conditions from the scientific perspective and figure out how to help them.

For most genetic diseases, there are almost no treatments that specifically target the genetic defects. With the application of new genome technology in clinics, we are successfully identifying the genetic cause of these diseases and diagnosing them, but we are often not able to actually offer the next step of treatment or intervention. A better understanding of how to develop treatments that target the genetic defect is our ultimate goal.

Zhou: I'm a biomedical engineer who mainly works on developing non-viral, gene-based therapies. I've been working in this area for over 16 years. I think gene therapy could be widely used for a lot of major diseases in the future. But at this stage, I feel that gene therapy is particularly suitable for rare diseases such as Angelman syndrome, because they often have a very defined genetic cause.

This is one of the reasons I have focused on rare diseases over the past few years. I've been collaborating with Dr. Jiang, who sees patients with genetic disorders every day. It's a benefit for scientists like me to work with physicians or physician-scientists such as Dr. Jiang because they see the great clinical need for new treatments.

What do you wish more people knew about rare diseases?

Jiang: There are a few aspects. One is that we want people to know that although rare diseases are rare individually, we estimate that there are about 10,000 rare diseases in total. So altogether, they actually are not rare. Almost one in 10 Americans is affected by a rare disease.

Second, although we know of 10,000 rare diseases, we only understand the cause of about half of them. For the other 5,000, we don't even have names. As geneticists, we do a lot of rare disease research because almost 80% of rare diseases are genetic. But not every rare disease is geneticthat is also a common misperception.

The third is that there is a great unmet clinical need for families contending with a rare disease. But rare disease researchers have very limited resources. Almost 10,000 diseases are in need of research to better understand how to treat them, but not every disease gets resources from the government or any other sort of funding source. This can be very frustrating for a lot of families who have spent years trying to find a diagnosis, but in the end find very little information or help because there is so little knowledge.

How has Yale been a global leader in rare disease research?

Jiang: Yale has been one of the leading institutions for rare disease research for almost half a century. Our history started with Leon Rosenberg, MD, who was the founding chair of the department of human genetics back in 1972, and he led the first clinical genetics division at Yale New Haven Hospital. During his tenure at Yale, he was a pioneer in the rare disease field, particularly for what we call metabolic diseases, such as methylmalonic acidemia and homocystinuria.

Following Leon Rosenberg, Richard Lifton, MD, PhD, another former chair of the department of genetics, and many other faculty and clinicians at Yale also dedicated their research to rare diseases. Yale investigators have discovered genetic bases for several hundred rare genetic diseases. Those efforts helped lead to the creation of the Centers for Mendelian Genomics, supported by the National Institutes of Health (NIH), as well as the creation of the Yale Center for Genome Analysis.

In 2023, Yale joined the NORD Rare Disease Centers of Excellence network. What work has the center accomplished since its launch?

Jiang: We've accomplished quite a bit, mostly in patient care. For example, we organize a rare disease event every year to promote public awareness of these diseasesespecially rare genetic diseasesand educate attendees on how to recognize them. The event brings together leading experts and patient advocates who lead lectures and roundtables on new insights and ways to support the rare disease community. We were also awarded NIH Undiagnosed Diseases Network (UDN) Phase III funding to join UDN as a new Diagnostic Center of Excellence.

You recently received an NIH grant to support the development of a novel CRISPR-based gene-editing technology and delivery platform called STEP. How might this technology revolutionize the treatment of rare diseases?

Jiang: The majority of rare diseases are genetic. Over the last 20 yearsdue to a new generation of genome technology in clinics, such as an exome sequencing method that was pioneered at Yalewe have diagnosed genetic rare diseases much more rapidly. However, the challenge is the treatment or intervention; almost 95% of rare genetic diseases have no available treatment options.

For all genetic diseases, the best treatment would be to correct the genetic mistake, which could potentially slow down or stop the disease progression and offer a cure. CRISPR-mediated genome editing technology [which is designed to modify an individual's DNA] offers promise and hope. Two-thirds of all rare genetic diseases affect the brain, which is the most challenging organ for gene therapy.

That's where we step in. We hope that the STEP platform can eventually apply to rare genetic diseases that affect the brain. We're currently focusing on neurodevelopmental disorders like Angelman and H1-4 syndrome because of our expertise. But this technology could also eventually be helpful for many brain disorders, including neurodegenerative conditions such as Alzheimer's or Parkinson's disease. It will have very broad applications.

Zhou: STEP technology is a non-viral, chemical-based delivery system developed here at Yale. I have not seen anyone else working on this type of delivery system. It's unique in that it uses chemicals instead of other vectors such as viral vectors or nanoparticlesthe two most commonly used vectors in the fieldto deliver genome editors to the brain.

It seems that the STEP technology works well for many neurogenetic diseases. We have applied the delivery system to a few diseases, including Angelman syndrome and H1-4 syndrome, and our findings have been very exciting. We have been working together with the NIH to translate this technology to clinical use. Hopefully, we can achieve that in the next few years.

What other research are you most excited about?

Zhou: We have an array of new technologies under development or under evaluation for correcting genes through either gene correction or epigenetic regulation. This will allow us to potentially treat many rare genetic diseases. Dr. Jiang and I are working on ways to treat Rett syndrome, ALS, and Alzheimer's disease, among others. The advances in our technologies open the door to study many genetic, neurodevelopmental, and neurodegenerative diseases.

How do you foresee the treatment of rare diseases evolving in the future?

Jiang: Our goal is to be able to treat or cure every rare genetic disease. The FDA approved CRISPR genome editing treatment for sickle cell therapy in 2023which is quite impressive since CRISPR technology is relatively new. So I have a lot of hope that our work will move fast over the next decade because of the success of the sickle cell program. But we do expect challenges. For instance, many of the critical steps required to navigate CRISPR technology from the bench to the clinic are new to the FDA, the NIH, the research community, and pharmaceutical companies.

However, we remain optimistic that society will address these issues accordingly. We hope that we will be able to deliver therapy for a few dozen of these diseases over the next five years in the clinic.

Zhou: I think that with advances in gene-editing technology, it will now be possible to treat many rare diseases, even through a one-time administration. Along with FDA regulation, there will be challenges in how to engineer our system for efficiency, specificity, and delivery. But we have seen a lot of progress in the field, and we are definitely optimistic about the treatment options that will be available in the next decade.

What gaps in this field most urgently need to be addressed?

Jiang: CRISPR editing aims to correct the genetic mistakeoften there is only one mistake in the entire genome. But the technology itself may cause what we call off-target events [in which the technology edits DNA at sites other than the intended target] that might cause harm in an individual's genome. The question is first, how can we maximize the safety of our technology from the design perspective? And second, how do we assess off-target events in the clinical sense?

Another major gap is in resources. From beginning to end, the development of each biological drug requires tens of millions of dollars. And then, we have 5,000 rare genetic diseases now that are eligible for CRISPR gene-editing technology. But because the individual diseases are rare overall, pharmaceutical companies may not be interested in investing due to financial reasons.

Is there anything else you would like to add?

Jiang: We have our Rare Disease Day celebration scheduled for February 21 on Yale School of Medicine's campus. It will include families dealing with rare diseases, physicians from Yale School of Medicine and Yale New Haven Hospital who treat patients, and rare disease researchers from across campus. Rare diseases can affect any organ system. We want to raise awareness across the academic hospital community because we hope that other specialties will take interest in investing more in rare diseases in terms of clinical care and research.

Zhou: We're lucky to have support from the NIH for our work on Angelman syndrome. It's an exciting time, but hopefully there will be support and investments from other sources so that we can continue these programs and help families. Over the last couple of years, we have been supported by multiple philanthropy efforts that have helped offset some of these limitations.