공간 생물학: Nanostring 대 10x Genomics

생물학의 새로운 프런티어가 아직 남아 있다

In previous articles, we discussed the rise of Next-Generation-Sequencing (NGS) and its potential to revolutionize medicine. Biotechnology and medicine are getting more precise by the day thanks to cheaper tools for sequencing DNA, utilizing RNA, and synthesizing proteins. The makers of these tools were discussed in “Illumina vs Pacific Bioscience: 차세대 유전체 시퀀싱 회사를 선택하기”

그럼에도 불구하고 아직 부족한 데이터가 있습니다. NGS 시퀀서는 수천, 심지어 수백만 개의 세포 데이터를 동시에 집계합니다. 하지만 연구자들은 종종 단일 세포 하나씩, 나노미터 수준의 정밀도로 무슨 일이 일어나고 있는지 파악해야 합니다.

This is now becoming possible thanks to the emergence of a new field of science: spatial biology. => 이는 새로운 과학 분야인 공간 생물학의 등장 덕분에 이제 가능해지고 있습니다.

공간 생물학

Instead of looking at the “mix” of molecules in a sample, spatial biology can determine where in a tissue or a single cell a molecule of interest, like a specific sequence of RNA, is located. And this is either in 2D or 3D. => 샘플 내 분자들의 “혼합물”을 보는 대신, 공간 생물학은 조직이나 단일 세포 내에서 관심 있는 분자, 예를 들어 특정 RNA 서열이 어디에 위치하는지를 2D 또는 3D로 파악할 수 있습니다.

이는 연구자들에게 세포들이 서로 어떻게 상호작용하는지, 방어 메커니즘이 어떻게 활성화되는지, 세포가 바이러스와 접촉했을 때 어떻게 반응하는지 등을 알려줍니다.

또한 이 방법은 훨씬 더 민감한 데이터를 제공한다는 장점이 있습니다. 몇 개의 세포에서 일어나는 현상이 큰 샘플에 묻혀 사라질 수 있지만, 공간 생물학의 타깃 접근법은 국소 현상이나 희귀 세포 유형의 핵심 역할을 드러낼 수 있습니다.

You can read in more detail the unique advantages of spatial biology 이 Nanostring FAQ에서 자세히 확인하세요.

출처: Yahoo Finance

공간 생물학의 투자 잠재력

In the 2000s, genome sequencing initiated a revolution that is now turning into gene therapies, gene editing, mRNA vaccines, etc… in the 2020s. This turned the $16/share of Illumina at its 2000s IPO into $495/share in 2021 at its peak (and still $190-$220 since) => 2000년대에 유전체 시퀀싱은 현재 유전자 치료, 유전자 편집, mRNA 백신 등으로 이어지는 혁명을 시작했습니다. 이는 Illumina가 2000년대 IPO 당시 주당 $16이었지만 2021년 최고점에서는 주당 $495가 되었으며(현재는 $190‑$220 수준)이라는 변화를 가져왔습니다.

In 2020, Nature Methods가 공간 전사체학을 “올해의 방법”으로 선정.

It is possible that the first dedicated machines for spatial biology of our day will be seen as the early stage of another revolution that will fully take over by the late 2030s. It usually pays off to be early in new technology.

This is also a way for startups and innovators to outrun established competitors. It can be very hard to beat a $35B company like Illumina on its own turf like NGS. But the playing field is more equal for new techniques where the larger competitor holds no key patents, like spatial biology.

Some estimates put the Spatial biology total addressable market at $16B, as most of the genetic and molecular biology research is still done using older, less powerful technologies.

출처: Nanostring

Currently, the 2 leading companies in the segment are 10x Genomics (TXG ) and Nanostring. => 현재 이 분야의 선두 두 기업은 10x Genomics와 Nanostring입니다.

10x Genomics 기술

The company was founded in 2012, with among its founders Serge Saxonov, the director of R&D of the personalized genome testing company 23andMe. The company initially focused on single-cell gene expression before branching into spatial biology with Visium Spatial.

10x Genomic grew using a mix of R&D ($1B+ investing in R&D so far) and acquisitions. Notably, its Visium platform was obtained through the acquisition of Spatial Transcriptomics in 2018.

10x Genomics 인수 타임라인

This is also how 10x Genomics would acquire its Xenium platform through the acquisition of Readcoor and Cartana in 2020.

In 2020, it would also launch the Chromium platform, updated the year after to Chromium X.

Through the acquisition of Tetramer Shop in 2021, 10x Genomics would also launch BEAM in 2022.

Visium

Visium is among the leading technologies for tissue spatial biology. It is currently used by thousands of customers and is referred to in 440 publications. In Q3 2022, 10x Genomics sold more than 100 Visium machines. => Visium은 조직 공간 생물학 분야의 선도 기술 중 하나이며 현재 수천 명의 고객이 사용하고 440편의 논문에서 인용되었습니다. 2022년 3분기에 10x Genomics는 100대 이상의 Visium 장비를 판매했습니다.

Chromium

Chromium is focused on single-cell data, looking at the nanometer scale. 4,150 instruments have been sold and represent the bulk of 10x Genomics installed park of machines. => Chromium은 단일 세포 데이터를 다루며 나노미터 수준을 탐색합니다. 현재까지 4,150대가 판매되어 10x Genomics가 설치한 장비 중 대부분을 차지합니다.

Xenium

Xenium is a platform allowing for the simultaneous analysis of both RNA and proteins with complete and accurate spatial data. This is something really powerful for researchers, with thousands of different molecules looked at once. This is likely the direction 10x Genomics machines will take in the future for all analyses. => Xenium은 RNA와 단백질을 동시에 분석하고 정확한 공간 데이터를 제공하는 플랫폼입니다. 수천 가지 서로 다른 분자를 한 번에 살펴볼 수 있어 연구자들에게 매우 강력한 도구이며, 향후 10x Genomics 장비가 모든 분석에 활용할 가능성이 높습니다.

BEAM

BEAM (Barcode Enabled Antigen Mapping) is a new technology that would allow researchers to identify immune system components in detail. This could be very impactful in research on immunity, pathogens, and new diseases like Covid-19. => BEAM(Barcode Enabled Antigen Mapping)은 면역 체계 구성 요소를 상세히 식별할 수 있게 하는 새로운 기술로, 면역, 병원체 및 Covid-19와 같은 신종 질병 연구에 큰 영향을 미칠 수 있습니다.

(you can read the technical details in this document)

Software

10x Genomics offers a full set of software for analyzing the data produced by its equipment in 5 different categories and also offers cloud capability and custom designs. => 10x Genomics는 5가지 카테고리로 구성된 자사 장비에서 생성된 데이터를 분석하기 위한 전체 소프트웨어 세트를 제공하며 클라우드 기능 및 맞춤형 설계도 지원합니다.

Nanostring 기술 및 제품

Nanostring was launched in 2003 to leverage the digital molecular barcoding technology invented at the Seattle Institute for Systems Biology. => Nanostring은 2003년에 시애틀 시스템 생물학 연구소에서 발명된 디지털 분자 바코딩 기술을 활용하기 위해 설립되었습니다.

nCounter

By 2008, it had launched its first product, nCounter. => 2008년까지 첫 번째 제품인 nCounter를 출시했습니다.

This was great progress in transcriptomic (the study of mRNA). Previous and alternative methods were either slower or more complex. They also introduced a lot of errors and had lower-quality results. Nanostring summarized it simply: “Faster than NGS (Next Generation Sequencing), simpler than qPCR.

출처: Nanostring

GeoMx & CosMX

nCounter carried the company forward while it developed the next steps. In 2019, it launched the GeoMx DSP, followed by the CosMx SMI. => nCounter는 회사를 지속 성장시키며 다음 단계들을 개발했습니다. 2019년에는 GeoMx DSP를, 이어 CosMx SMI를 출시했습니다.

GeoMx is designed to study RNA expression in whole tissues and is also able to analyze 150+ proteins, more targets than 10x’s Xenium.

CosMx Single Molecular Imager (SMI) instead can look at a single cell and what happens inside for RNA and up to 64 protein targets, and possibly up to 120 in 2024.

Both brought a powerful and automatized process to spatial biology. Before that, less sensitive, more costly and more labor-intensive methods would have had to be used. In this segment, GEoMX is the market-leading spatial profiler.

They are also able to use FFPE tissue samples, the most commonly made tissue sample in medical research. This means that millions of preexisting samples archived by researchers worldwide can be analyzed again for new insights. This expertise is directly derived from Nanostring’s experience in that field through its nCounter legacy product.

So, Nanostring was instrumental to the explosion in scientific publications using spatial biology. No less than 7,117 publications mention Nanostring machines from various fields like research on cancer, Infectious disease (including Covid-19), immunology, agriculture, or neurology. => 따라서 Nanostring은 공간 생물학을 활용한 과학 논문 급증에 핵심적인 역할을 했습니다. 7,117편 이상의 논문이 Nanostring 장비를 언급하고 있으며, 암, 감염 질환(코로나19 포함), 면역학, 농업, 신경학 등 다양한 분야에서 활용되고 있습니다.

AtoMx

The company is also developing dedicated software to help researchers. It launched AtoMx, a SaaS solution (Software as a Service), in Q4 of 2022. This should help researchers analyze their data, share them with colleagues, and create large publicly or privately accessible databases of spatial biology research. => 이 회사는 연구자를 돕기 위한 전용 소프트웨어도 개발하고 있습니다. 2022년 4분기에 AtoMx라는 SaaS(Software as a Service) 솔루션을 출시했으며, 이를 통해 연구자들은 데이터를 분석하고 동료와 공유하며, 공간 생물학 연구를 위한 대규모 공개·비공개 데이터베이스를 구축할 수 있게 됩니다.

재무 및 가치 평가

10x Genomics

10x Genomics is by far the largest company of the 2 discussed in this article.  It has a total of 1,200 employees, and its market capitalization is standing at $5.7B. => 이 기사에서 다룬 두 기업 중 10x Genomics가 압도적으로 규모가 크며, 직원 수는 1,200명, 시가총액은 57억 달러에 달합니다.

Its revenues were $516M in the last quarter, up 9% year-to-year. 85% of its revenues are from consumables used by the previously sold machines.  Net income was $6M in Q4 2022, the first time it reached a positive net income since the company was IPOed in 2019.

Due to very large investments in R&D and capex (-$131M), the company has a negative free cash flow of -$165M. It has a cash cushion of $429M.  The company has a net debt of -$335M, better than the -$505M in 2021.

The company sales-to-price ratio is standing at 11, which is not cheap but expected for a company valued on its growth potential. Its valuation is even rather reasonable for a growth startup getting in the green for the first time. Some more dilution of existing shareholders is to be expected, as the company will need more cash in 1-2 years to accelerate growth and finance R&D + capex.

Overall, 10x Genomics is likely to become really profitable only once spatial genomics gets commonly used in most research labs instead of being the most advanced technology available, as it is today. Another step of growth can be expected in the future when spatial genomics starts to be used for medical diagnostics. => 10x Genomics는 현재 가장 진보된 기술로 남아 있는 상황에서, 공간 유전체학이 대부분의 연구실에서 일반적으로 사용되기 시작해야만 실질적인 수익성을 달성할 것으로 보입니다. 향후 의료 진단에 공간 유전체학이 활용되면 또 다른 성장 단계가 기대됩니다.

Nanostring

NanoString is smaller than 10x Genomics, with less than 800 employees. Its market cap is also 1/13^th of 10x Genomics at $413M. => NanoString은 10x Genomics보다 작으며 직원 수는 800명 미만, 시가총액은 10x Genomics의 1/13에 해당하는 4억 1,300만 달러입니다.

Its revenues were $34M in Q4 2022, for a net loss of $44M. In the last 4 quarters, revenues were $127Mm and net losses $115M.  Revenues were roughly split 50/50 between nCounter and Spatial biology items. 80%-85% of revenues are from service and consumables for the previously sold equipment.  Free cash flow was -$31M in Q4 2022 and was an accumulated -$239.9M in the last 2 years.  It also has a net debt of $114M.

Available cash has declined from $410M in Q1 2021 to just $197M in Q4 2022. The company will need to raise more money at the current burn rate in 12-18 months.

Nanostring’s price-to-sales ratio is relatively low at 3.1. It most likely reflects its recent losses, negative cash flow, and the impending need to raise more capital soon. The dramatic fall in stock price since 2021 might force a larger-than-planned dilution of existing shareholders.

Similarly to 10x Genomics, the path to profitability is through most research labs adopting spatial biology routinely in their workflow.

Nanostring 또는 10x Genomics?

Both companies have impressive technology, bringing revolutionary new understanding to RNA and proteomic analyses. There is little doubt spatial biology will soon become the favorite tool for researchers in oncology, neurology, and other fields where discrete and transient gene expression are the key to solving deadly diseases. => 두 기업 모두 인상적인 기술을 보유하고 있으며, RNA와 단백질 분석에 혁신적인 통찰을 제공하고 있습니다. 공간 생물학이 곧 종양학, 신경학 및 급성 유전자 발현이 중요한 분야에서 연구자들의 가장 선호하는 도구가 될 것이라는 점은 의심의 여지가 없습니다.

The two companies’ competitive situation seems to be shaped similarly to the early Illumina vs PacBio rivalry. If that analogy holds true, the smaller competitor might struggle to keep up and turn profitable, as it will have to match the R&D budget despite lower total revenues. The higher income also allows the larger competitor to acquire promising startups and integrate their technologies into their own machines.

From an investment point of view, 10x Genomics seems safer. It is starting to be profitable and has more employees, cash on hand, cash flow, and an R&D budget to keep moving forward.

It is nevertheless priced much higher than Nanostring on a price-to-sales ratio basis. So, Nanostring is likely to outperform in terms of returns on invested capital IF it manages to close the gap in total sales with 10x Genomics. If this condition is fulfilled, Nanostring can outperform its larger rival and compensate for incoming shareholders’ dilution.